scholarly journals The Canadian Tyrosine Kinase Inhibitor Discontinuation Trial with Imatinib Discontinuation As a First Attempt and with Dasatinib Discontinuation As a Second Attempt of Treatment-Free Remission: Results of 4 Years of Follow-up

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1644-1644
Author(s):  
Dennis Dong Hwan Kim ◽  
Isabelle Bence-Bruckler ◽  
Lambert Busque ◽  
Donna L. Forrest ◽  
Lynn Savoie ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Total Duration ◽  
Transcript Level ◽  
Molecular Response ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
Treatment Free Remission ◽  
Reduced Risk

Introduction: The Canadian trial entitled "Treatment Free Remission Accomplished By Dasatinib" (BMS CA180543, NCT#02268370) is ongoing since Jan 2015, and has completed accrual of 131 patients. The study was designed to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation following imatinib (IM) treatment. The preliminary results (ASH 2018) indicate: 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4; 3) The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months [7.9-39.5%]). Herein, we report the 4-year follow-up results with updated TFR2 after second TFR attempt following DA discontinuation. Methods and materials: This prospective clinical trial has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. Molecular relapse is defined as an increase in BCR-ABL transcript level above MR4.0 on 2 consecutive occasions, or an increase in BCR-ABL transcript level above MR3.0 on a single occasion. 100mg daily of DA is started if molecular relapse is confirmed and is discontinued 12 months after achieving MR4 following a 2nd TFR attempt. Results: As of Jun 25, 2019, 58 (44.3%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 59.1% [50.1-67.0%] and 56.8% [47.8-64.8%] at 6 and 12 months, respectively. TFR using loss of MMR as an event was 69.8% at 6/12 months. Of the 58 patients who lost response, 53 patients (91.4%) lost response within 6 months after IM discontinuation: 7 (10.1%) lost response within 2 months, 20 (34.5%) within 3 months, 14 (24.1%) within 4 months, 9 (15.5%) within 5 months, and 3 (5.2%) within 5-6 months. Beyond 6 months, 5 patients (15.5%) lost response within 7, 8, 10, 20, 21 months, respectively. Only two patients experienced late relapse occuring 15 months after IM discontinuation. 54 patients started DA, of whom 49 patients (90.7%) achieved MR4.5 on DA. Median time to MMR, MR4 and MR4.5 was 0.94, 1.95, and 2.48, respectively. The incidence of MMR, MR4 and MR4.5 at 3 months was 99.0% (86.3-99.0%), 91.5% (78.4-96.7%), and 76.6% (60.9-86.0%), respectively. 32/49 patients receiving DA attained MR4.5, and discontinued DA for a 2nd TFR attempt (TFR2). 25/32 (78.1%) of these patients lost molecular response at a median of 3.67 months after DA discontinuation. The estimated TFR2 after DA discontinuation was 18.5% at 6 months [6.8-34.7%], TFR2 using loss of MMR as a definition of molecular relapse was 20.4% [7.6-37.4%], while TFR2 using two consecutive losses of MR4 was 25.4% [9.4%-45.2%]. Two patients continued to attain deep molecular response at MR4.2 and undetectable level (equivalent to MR5.5) beyond 18 months after DA discontinuation. At last follow-up of Jun 25, 2019, 30 patients are still being monitored on trial on IM discontinuation (n=20), DA rechallenge (n=4) or DA discontinuation phases (n=6). With a median follow-up duration of 36 months, risk factor analyses were performed using Cox's proportional hazard regression model suggesting a strong correlation of mRFS with total duration of IM treatment prior to IM discontinuation (p<0.001, HR 0.864), MR4 duration (p<0.001, HR 0.867), but not with time to achieve MR4 (p=0.216). When patients attained MR4 or deeper for longer than 10.59 years, their mRFS was 91.8% [71.1-97.9%] at 12 months. The group who attained MR4 duration of 6.93 years or longer had 40.3% reduced risk of mRFS (HR 0.597 [0.449-0.794], p<0.001] compared to those with MR4 duration less than 6.93 years. The group who attained 10.59 years of MR4 duration or longer had a 65.5% reduced risk of mRFS (HR 0.345 [0.171-0.699], p=0.003] compared to those with MR4 duration less than 10.59 years. Conclusion: The 4-year follow-up results suggests that DA rechallenge after failing a first IM discontinuation attempt for TFR was safe, feasible and well tolerated. It was effective in most cases rapidly regained at least MR4. Based on the two cases who successfully discontinued DA more than 18 months after DA consolidation following achievement of deep molecular response, second generation TKI therapy after imatinib discontinuation failure is a feasible option. Further follow-up is strongly warranted in order to reach a clear conclusion on this issue. Disclosures Busque: ExCellThera: Patents & Royalties; Paladin: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Savoie:Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Keating:Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees. Delage:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Liew:Novartis: Consultancy, Honoraria. Leber:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Treatment-Free Remission Accomplished By Dasatinib (TRAD): Preliminary Results of the Pan-Canadian Tyrosine Kinase Inhibitor Discontinuation Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1922-1922 ◽  
Author(s):  
Dennis Dong Hwan Kim ◽  
Isabelle Bence-Bruckler ◽  
Donna L. Forrest ◽  
Mary Lynn Savoie ◽  
Stephen Couban ◽  
...  
Keyword(s):  
Tyrosine Kinase Inhibitor ◽  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Total Duration ◽  
Transcript Level ◽  
Molecular Response ◽  
Advisory Committees ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Abstract Introduction: Multiple studies have shown that tyrosine kinase inhibitor (TKI), usually imatinib (IM), can be successfully discontinued in chronic myeloid leukemia (CML) patients, achieving a 40-50% treatment free remission (TFR) rate. However, the remaining 60% of patients require reintroduction of TKI therapy. We have designed this study to answer the question if a second generation TKI, i.e. dasatinib, should be used after failing the first attempt of TKI discontinuation with IM. This prospective study attempts to evaluate whether the use of dasatinib after failure of a 1st attempt of TKI discontinuation with IM could improve TFR rate after a 2nd attempt of TKI discontinuation. Methods and materials: This is a prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) including all major CML centers across Canada (n=12). The primary objective is to determine the proportion of patients who remain in molecular remission (defined as maintaining ≥MR4.0) after dasatinib discontinuation following achieving ≥MR4.5. The present study has 3 phases: 1) IM discontinuation phase, 2) dasatinib rechallenge phase, 3) dasatinib discontinuation phase. A total of 135 patients is planned to be enrolled over 18-24 months. Key inclusion criteria include: 1) CML in chronic phase (CP), 2) total duration of IM therapy of minimum of 3 years, 3) total duration of MR4.5 or deeper response over 2 years with 2 consecutive confirmed MR4.5 or deeper response at the central lab with 3 months interval. Key exclusion criteria include prior allogeneic stem cell transplant or prior accelerated or blastic phase CML. Molecular recurrence was defined as an increase in BCR-ABL transcript level above MR4.0, on at least two consecutive occasions, or a single increase in BCR-ABL transcript level above MR3.0. Dasatinib is started at a dose of 100mg daily once molecular recurrence is confirmed. Results: The study was launched on March 2015. As of June 22 2016, 110 patients were entered into screening phase of whom 16 patients were not qualified due to 1) fluctuating transcripts (n=8) or 2) consent withdrawal (n=8). Two patients withdrew consent after losing their molecular response following IM discontinuation before starting dasatinib. Finally 75 patients were enrolled into IM discontinuation phase with 17 additional patients on screening in awaiting enrollment (Figure A). Of 67 patients evaluable for molecular relapse, 21 patients (31.3%) lost molecular response defined as loss of major molecular response (MMR; n=18) and loss of MR4 on 2 consecutive tests (n=3). The 6-month relapse free survival (RFS) rate was estimated as 58.0% (42.1-71.0%), while TFR rate using loss of MMR as an event was 64.7% (48.7-76.7%) at 6 months (Figure B) Of 21 patients who lost molecular response, 20 patients underwent dasatinib rechallenge phase, 14 of which were treated with dasatinib for at least 1 month and evaluated at least once with monthly BCR-ABL transcript monitoring (Figure C). Twelve patients achieved MMR at a median time of 56 days. The median time to achieve MR4.5 was 84 days. The incidence of MMR and MR4.5 at 3 months was 100% each (Figure D). Cox's proportional hazard regression model suggested strong correlation of RFS with total duration of IM therapy prior to IM discontinuation (p=0.001), duration of MR4 maintenance (p=0.004) or MR4.5 maintenance (p=0.006) prior to IM discontinuation, but not with time to achieve MR4 (p=0.289) or MR4.5 (p=0.330). Recursive partitioning method also defined the best cutoff for those variables: The group treated with IM for over 8.9 years (n=35) had RFS rate 81.1% vs 21.0% in those treated for less than 8.9 years (n=32; p<0.001, HR 0.125). The group who maintained MR4 for more than 7.7 years (n=29) had RFS rate 82.3% vs 36.3% in others (n=37; p=0.001, HR 0.192), while those who maintained MR4.5 for more than 7.9 years (n=21) had RFS rate 89.5% vs 39.2% in others (n=44; p=0.003, HR 0.141). Conclusion: Preliminary results of this Canadian TKI discontinuation trial show a RFS rate of 58-65% after IM discontinuation in CP-CML patients who attained MR4.5 for over 2 years, similar to other TKI discontinuation studies. Dasatinib can be safely administered in CML patients who lost molecular response after IM discontinuation with 100% of MMR rate at 3 months. Prolonged duration of IM treatment, or duration of MR4/MR4.5 maintenance with IM therapy could predict the chance of TFR success, but not time to achievement of MR4/MR4.5. Disclosures Bence-Bruckler: Lundbeck: Membership on an entity's Board of Directors or advisory committees. Savoie:Amgen: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy; Lundbeck: Consultancy. Busque:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Delage:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Laneuville:BMS: 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; Paladin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Liew:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Xenocostas:Janssen Inc.: Research Funding. Kamel-Reid:BMS: Research Funding. Leber:BMS Canada: Honoraria, Research Funding, Speakers Bureau; Celgene: 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 Second Attempt of TKI Discontinuation with Dasatinib for Treatment-Free Remission after Failing First Attempt with Imatinib: Treatment-Free Remission Accomplished By Dasatinib (TRAD) Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 787-787 ◽  
Author(s):  
Dennis Dong Hwan Kim ◽  
Lambert Busque ◽  
Donna L. Forrest ◽  
Lynn Savoie ◽  
Isabelle Bence-Bruckler ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Null Hypothesis ◽  
Research Funding ◽  
Transcript Level ◽  
Molecular Response ◽  
Advisory Committees ◽  
Log Reduction ◽  
Relapse Pattern ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Abstract Introduction: A Canadian tyrosine kinase inhibitor (TKI) discontinuation trial is ongoing to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation after imatinib (IM) treatment. The preliminary result indicate : 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4. We report here the preliminary analysis of the TFR rate at 6 months after DA discontinuation for the second TFR attempt. Methods and materials: This prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. Molecular relapse is defined as an increase in BCR-ABL transcript level < MR4.0 on 2 consecutive occasions, or a single increase in BCR-ABL transcript level < MR3.0. 100mg daily of DA is started if molecular relapse is confirmed and is discontinued 12 months after achieving > MR4 for a 2nd TFR attempt. The null hypothesis was a TFR2 rate of 17.5% while the alternative hypothesis was a TFR2 rate of 35.0% and the study was designed to reject our null hypothesis if > 28% of patients remain in TFR after DA discontinuation. Results: As of Jun 15, 2018, 53 (40.4%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 58.0% at 12 months (95% CI, 42.1-71.0%). Of the 53 patients who lost response, 51 patients received DA. The incidence of MMR, MR4 and MR4.5 at 3 months was 97.7%, 89.9%, and 84.6%, respectively. 25/ 51 patients receiving DA attained MR4.5 for 12 months or longer and discontinued it for a 2nd TFR attempt (TFR2). 21/25 (84.0%) of these patients lost molecular response at a median of 3.7 months after DA discontinuation. The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months (95% CI [7.9-39.5%], Fig 1A). Thus we cannot reject our null hypothesis based on this result. For risk factor analysis for maintaining TFR2, the variables analysed included Sokal risk score, IM duration, MR4/MR4.5 duration, monthly doubling time after IM discontinuation, time to molecular relapse after IM discontinuation, molecular relapse pattern after IM discontinuation (MMR loss vs MR4 loss), and BCR-ABL1 qPCR value prior to DA discontinuation. 1) Time to molecular relapse after IM discontinuation correlates with TFR2 (p<0.001, HR 0.485, 95% CI [0.302-0.778]), which implies that 1 additional month of TFR duration after IM discontinuation decreases the risk of molecular relapse after DA discontinuation by 51.5%. The 6 month TFR2 rate was 8.9% (median 2.79 mo) in the group who relapsed within 3 months of TFR1 (n=14) and 30.0% (median 4.25%) in the group who relapsed within 3-6 months of TFR1 (n=10). The one patient who relapsed beyond 6 months of TFR1 did not lose molecular response after DA discontinuation. Thus patients who lost molecular response within 3 months of IM discontinuation have a faster loss of response after DA discontinuation (median 2.8 mo) compared to those who lost response after 3 mo (median 4.3 mo; P=0.018; Fig 3A) 2) Molecular relapse pattern after IM discontinuation correlates with TFR2. The group who had loss of MMR after IM discontinuation lost molecular response faster after DA discontinuation (n=19; median 3.0 months) compared to those with two consecutive losses of MR4(n=6; 6.43 months; p=0.0435, HR 2.991; Fig 3B). 3) The group with 5.5 log reduction or deeper in BCR-ABL1 qPCR transcripts prior to DA discontinuation (n=19) showed a TFR2 rate of 28.7% at 6 months (median TFR2 duration of 4.04 months) versus 0% in the group with qPCR transcript level between 4.5 and 5.4 log reduction (n=6, median TFR2 duration of 2.89 months; p=0.017; Fig 3C). We did not identify any other risk factor for molecular relapse after DA discontinuation . The expansion kinetics of the leukemic clone after DA discontinuation is similar to that after IM discontinuation. Conclusion: These preliminary results suggest that rechallenge with DA after failing a first IM discontinuation attempt for TFR is well tolerated and effective as most cases rapidly regained at least MR4. However, more strict criteria should be considered for TFR2 attempt, including achievement of a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the 2nd TKI discontinuation attempt, and a MR4 duration of more than 12 months. Disclosures Kim: Pfizer: Consultancy; Paladin: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Bence-Bruckler:Lundbeck: Membership on an entity's Board of Directors or advisory committees. Delage:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Liew: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. Laneuville:BMS: 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; Paladin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Treatment Free Remission in Patients with Chronic Phase CML: A Single Center Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3612-3612
Author(s):  
Quinto J Gesiotto ◽  
Akriti G Jain ◽  
Somedeb Ball ◽  
Lisa Nodzon ◽  
Amanda Rodriguez ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Univariate Analysis ◽  
Chronic Phase ◽  
Published Data ◽  
Molecular Response ◽  
Advisory Committees ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Abstract Introduction: Treatment-free remission (TFR) is an emerging treatment goal in chronic phase chronic myeloid leukemia (CP-CML). The NCCN guidelines suggest patients must meet the following criteria in order to be eligible for an attempt at TKI discontinuation: use of a TKI for at least 3 years with no history of TKI resistance who have maintained a deep molecular response (MR4 - BCR-ABL IS ≤0.01%) for at least 2 years. The aim of this study was to identify predictors of long-term TFR in CP-CML patients who discontinue TKI therapy at our institution. Methods: We retrospectively identified all CP-CML patients who had discontinued TKIs after meeting TKI discontinuation criteria at Moffitt Cancer Center. Patient charts were reviewed to collect data on demographics, disease characteristics, and outcomes. TFR was calculated from date of TKI discontinuation to date of molecular recurrence (defined as loss of MMR (BCR-ABL IS ≥0.1%) or date of last follow up). Statistical analysis was performed utilizing Kaplan-Meier curves and log rank (Mantel-Cox) test. Results: A total of 102 patients met TKI discontinuation criteria and stopped treatment to attempt TFR. The median age at diagnosis was 53.5 years (19-83 years). The median age at TKI discontinuation was 61 years (28-92 years). Fifty (49.5%) patients were male. Four patients (3.9%) had previously received interferon α. At a median follow up of 29 months, the TFR rate was 56.8%, with molecular recurrence occurring in 44 patients. 93 patients had a follow up of at least 6 months. Of the 44 patients with molecular recurrence, 37 (84%) recurred within 6 months and 41 (93%) within 12 months of TKI cessation. The rate of TFR at 12 months and 24 months was 58% (95% CI: 48-68%) and 53% (95% CI: 43-64%), respectively [Figure 1]. Baseline characteristics along with univariate analysis of the 102 patients included in the study are shown in Table 1. Age, BMI at discontinuation, gender, Sokol risk index, last TKI prior to discontinuation, lines of therapy, or duration on TKI prior to discontinuation did not significantly affect rates of TFR. Patients with sustained MR4.5 (BCR-ABL IS &lt;0.0032%) for 2 years prior to discontinuation showed a trend toward higher probability of TFR at 12 months compared to those in MR4 (62% vs 49%; p=0.055). Median time to regain MMR after restarting treatment in patients with molecular recurrence was 90 days (range 28-443 days). 32 patients (31%) developed TKI withdrawal syndrome with symptoms including headache, arthralgia, myalgia and fatigue. Conclusions: At our center, 102 CP-CML patients qualified for TKI cessation. The rate of TFR at 12 months was 58% which is consistent with published data from numerous TKI discontinuation clinical trials. We were unable to identify any factors that were predictive of successful TFR, however those patients with a deeper molecular response (MR 4.5) at the time of TKI cessation trended towards higher rates of TFR at 12 months, suggesting that the depth of response is important for achieving prolonged TFR. Identifying methods to further deepen molecular response in CP-CML patients may ultimately lead to higher rates of TFR in the future. Figure 1 Figure 1. Disclosures Nodzon: Takeda: Consultancy. Komrokji: Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Incyte: Speakers Bureau; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Padron: Blueprint: Honoraria; Incyte: Research Funding; Stemline: Honoraria; Taiho: Honoraria; Kura: Research Funding; BMS: Research Funding. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; PharmaEssentia: Honoraria. Lancet: Jazz: Consultancy; Astellas: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; MEI, Sunesis: Research Funding. 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.

scholarly journals Second Imatinib Discontinuation Outcomes in Patients Regaining Durable Deep Molecular Response in the Korean Imatinib Discontinuation Study; KID Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 51-52
Author(s):  
Sung-Eun Lee ◽  
Joon Seong Park ◽  
Young Rok Do ◽  
Sung-Hyun Kim ◽  
Dae Young Zang ◽  
...  
Keyword(s):  
Prospective Study ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Close Monitoring ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
Multicenter Prospective Study

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: 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.

Outcome of Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) with Relapse After Tyrosine Kinase Inhibitor (TKI) Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1518-1518
Author(s):  
Hun Ju Lee ◽  
Susan O'Brien ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Advisory Committees ◽  
Cns Relapse ◽  
Complete Hematologic Response

Abstract Abstract 1518 Background: Treatment with TKIs has greatly improved the outcome of patients with Ph+ ALL. However, many patients treated with TKI-based therapy eventually have a relapse. The response to salvage therapy and long-term outcomes of these patients are unknown. Aims: Describe the outcomes of patients with Ph+ ALL with resistance to or relapse after frontline TKI-based chemotherapy. Methods: We analyzed the outcome of patients who were treated in clinical trials at our institution between February 2001 and July 2008 with TKI-based chemotherapy for newly diagnosed Ph+ ALL who had refractory or relapsed disease. Results: One hundred thirteen patients were treated with frontline hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone (HCVAD) plus imatinib (HCVAD+I; n=54) or HCVAD plus dasatinib (HCVAD+D; n=59). Of these, 35 (31%) experienced primary resistance (n=1) or relapse (n=34). The median age was 51 years [range (r): 20–85]; 12 patients (34%) were older than 60 years. Median follow-up was 21.1 mo (r: 4.2–56.7). Median white blood cell and platelet counts at diagnosis were 14.4 × 109/L (r: 1.2–292.9) and 48 × 109/L (r: 4–425), respectively. White blood cell count was >30 × 109/L in 13 patients (37%). Median peripheral and bone marrow blast percentages were 53% (r: 0–97%) and 80% (r: 1–98%), respectively. Twenty-two patients (63%) had received HCVAD+I and 13 (37%) HCVAD+D. Twenty-three patients (66%) had experienced first complete remission (CR1) with 1 cycle of induction. Median CR1 duration was 12 mo (r: 1.9–42). Four patients underwent allogeneic stem cell transplantation (ASCT) in CR1. ABL kinase domain mutations were investigated in 28 patients (80%) at relapse; 16 (57%) had mutations, including 5 (14%) with T315I (all had received HCVAD+D). Upon relapse, 31 patients received first salvage therapy (S1), 24 with chemotherapy [HCVAD+D, n=8; HCVAD+I, n=3; HCVAD+nilotinib (N), n=1; HCVAD+asparaginase (Asp), n=1; methotrexate, vincristine, Asp, and dexamethasone (MOAD), n=2; others, n=9]; 6 with a TKI only (I, n=2; D, n=1; N, n=1; others, n=2); and 1 with ASCT. Three patients were unfit for treatment. Median cycles of S1 were 2 (r: 1–8). Thirteen patients (42%) had second complete remission (CR2) (HCVAD+D, n=6; HCVAD+I, n=2; HCVAD+N, n=1; HCVAD+Asp, n=1; others, n=3). Median time to CR2 was 1.5 mo (r: 0.7–8.8). Five patients underwent ASCT in CR2. Median CR2 duration was 7.3 mo (r: 1.4–36.2). Complete cytogenetic response was seen in 11 patients (35%); major molecular response (BCR-ABL/ABL ratio <0.05%) in 9 (29%); and complete molecular response in 7 (22%); and complete hematologic response in 15 (48%). Times to complete cytogenetic response and complete molecular response were 1.3 mo (r: 0.7–10.6) and 3 mo (r: 1.5–8.7), respectively. Seven patients had second relapse. Fifteen patients (7 relapse, 8 refractory) received second salvage therapy (S2) with systemic chemotherapy (MOAD, n=2; phase I/single-agent TKI, n=8; others, n=5); 1 patient had solitary central nervous system (CNS) relapse treated with intrathecal cytarabine and methotrexate. CR3 was obtained in 1 patient, the patient with sole CNS relapse. Median disease-free survival (DFS) and overall survival (OS) after S1 were 6.5 mo (r: 0.5–45) and 7.3 mo (r: 1.4–36.2), respectively. At last follow-up, 2 patients (6%) were alive and 33 had died, 11 (33%) of infectious complications, 5 (15%) of organ failure, 3 (9%) of bleeding complications, 2 (6%) of graft-versus-host disease complications, 2 (6%) of CNS relapse, and 10 (30%) of other or unknown causes. Median OS after S2 was 2.1 mo (r: 1.4–2.6). In univariate analysis, age >60 years was associated with worse OS after S1 [4.2 vs. 12.7 mo; 95% confidence interval (CI) 1.8 to 6.7 vs. 7.5 to 17.9 (P=0.006)]. Complete hematologic response was associated with improved OS after S1 [15.4 vs. 4.3 mo; 95% CI 9.1 to 21.8 vs. 2.5 to 6.0 (P<0.001)]. Major molecular response was associated with improved OS after S1 [18.1 vs. 5.7 mo; 95% CI 9.3 to 26.8 vs. 3.6 to 7.8 (P=0.003)]. Choice of prior TKI (HCVAD+I vs. HCVAD+D) did not significantly influence CR and OS after relapse. Conclusion: Patients with refractory or relapsed Ph+ ALL after TKI-based therapy have poor outcome, particularly those who are older or have persistent BCR/ABL transcripts. New agents are needed to improve the outcome in this population. Disclosures: Kantarjian: BMS: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:Chemgenex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Switching to Nilotinib Is Associated with Continued Deeper Molecular Responses in CML-CP Patients with Minimal Residual Disease After ≥ 2 Years On Imatinib: Enestcmr 2-Year Follow-up Results

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 694-694 ◽  
Author(s):  
Timothy P. Hughes ◽  
Jeffrey H. Lipton ◽  
Nelson Spector ◽  
Brian Leber ◽  
Ricardo Pasquini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Molecular Response ◽  
Advisory Committees ◽  
Molecular Responses ◽  
The Difference ◽  
Minimal Residual

Abstract Abstract 694 Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up. Methods: Patients with Ph+ CML-CP who had achieved complete cytogenetic responses but still had persistent BCR-ABL positivity by real-time quantitative polymerase chain reaction (RQ-PCR) after ≥ 2 years on imatinib were eligible. Patients (n = 207) were randomized to switch to nilotinib 400 mg twice daily (BID; n = 104) or to continue on the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103). Rates of MMR, MR4 (BCR-ABL ≤ 0.01% according to the International Scale [IS], corresponding to a 4-log reduction), MR4.5 (BCR-ABL ≤ 0.0032%IS, corresponding to 4.5-log reduction), and undetectable BCR-ABL via RQ-PCR with ≥ 4.5-log sensitivity were measured. Results: Among all randomized patients (intent-to-treat population), significantly more patients treated with nilotinib continued to achieve undetectable BCR-ABL by 24 mo (32.7% on nilotinib vs 16.5% on imatinib; P =.005; Table).The difference between the arms in achievement of this endpoint increased between 1 and 2 years (from 12.4% to 16.2%). The median time to MR4.5 and undetectable BCR-ABL was also significantly faster on nilotinib than on imatinib (P = .005 and .003, respectively). Cumulative rates of MR4.5 and undetectable BCR-ABL continued to be higher with nilotinib in patients without those responses at baseline, and the difference between arms appeared to increase over time. The safety profiles for nilotinib and imatinib were consistent with prior studies. By 24 mo, no patients in either arm progressed to accelerated phase/blast crisis. No patients on nilotinib died since the 12-mo analysis; 1 patient on imatinib died from metastatic prostate cancer in follow-up after discontinuation from the study. Conclusions: Switching to nilotinib led to significantly faster, deeper molecular responses in patients with minimal residual disease on long-term imatinib therapy. Since the 12-mo analysis, rates of deep molecular response (MR4.5 and undetectable BCR-ABL) have remained significantly higher in patients who did not have the response at baseline and were switched to nilotinib (vs those remaining on imatinib). In fact, the difference in favor of nilotinib increased between 1 and 2 years. These results suggest that switching to the more potent, selective tyrosine kinase inhibitor nilotinib is beneficial in patients with minimal residual disease after long-term imatinib therapy. Achievement of these deeper molecular responses (MR4.5 and undetectable BCR-ABL) after switching to nilotinib may enable a greater proportion of CML-CP patients to be eligible for future discontinuation studies. Cumulative rates of confirmed undetectable BCR-ABL by 24 mo will be presented as the confirmation assessments for several responders were not available at the time of this analysis. Disclosures: Hughes: Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding. Lipton:Novartis: Consultancy, Research Funding, Speakers Bureau. Spector:Novarits: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy. Leber:Novartis: Advisory Board Other, Honoraria, Speakers Bureau. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Purkayastha:Novartis Pharmaceuticals Corp: Employment. Collins:Novartis Pharmaceuticals Corp: Employment. Szczudlo:Novartis Pharmaceuticals Corp: Employment. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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 The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2552-2552
Author(s):  
Franck E. Nicolini ◽  
Vincent Alcazer ◽  
Stephanie Dulucq ◽  
Sandrine Hayette ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Median Dose ◽  
First Line ◽  
Advisory Committees ◽  
French Group ◽  
Treatment Free Remission ◽  
The Impact

Abstract Aims: The absolute number of chronic phase CML patients (pts) reaching the treatment-free remission (TFR) criteria has been substantially increased by the use of second-generation TKI (TKI2), initiated since diagnosis, comparing to Imatinib first-line. However, the relative rate of unsuccessful TFR (i. e. pts loosing their MMR after TKI2 cessation) still remains around 50% at 2 years and beyond, whatever the TKI2 was. The aim of this study is to analyse the rate of successful TFR in pts receiving Nilotinib (Nilo) or Dasatinib (Dasa) first-line obtaining the appropriate criteria. Methods: Observational retrospective study in 3 reference centers of the French group of CML lead between 2010 and 2021. Eligible pts were CP CML pts initiating either Nilo 300 mg BID or Dasa 100 mg daily since diagnosis, until cessation for sustained MR4.5 (i.e. ≥2 years on ≥4 datapoints). Data were retrospectively collected according to the national regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2009, 2013 and 2020 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) for TFR. In this regard, the TKI2 was resumed in case of 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. All patients were harbouring major BCR-ABL1 transcripts. The primary endpoint was the survival without loss of MMR after TKI2 cessation. The secondary endpoints were the kinetics of MMR loss, and the identification of factors influencing MMR loss. Results: Seventy-two pts were reported (47 Nilo, 25 Dasa) with 57% females with a median age at diagnosis of 48 (36.75-61.25) years. The median follow-up since diagnosis was 9.26 (3.75-13.75) years (8.8 for Nilo and 9.47 for Dasa p=ns) and after TKI2 cessation 3.94 (0.7-8.8) years (3.92 for Nilo and 3.90 for Dasa p=ns). Sokal scores were 42% Low, 41% Intermediate, 17% High in Nilo and 39% L, 25% I and 35% H in Dasa pts (p=ns). ELTS scores were 50% L, 22% I, 9.5% H (18.5% Uk) in Nilo and 46.5% L, 28.5% I and 3.5% H (21.5% Uk) in Dasa pts (p=0.95). Five (9%) pts harboured ACA at diagnosis in the Nilo group and 2 (7%) in the Dasa group (p=1.00). The median time from TKI2 initiation to sustained MR4.5 was 19 (3.12-36) months in the Nilo group and 16 (6.3-39) months in the Dasa group (p=0.644). The duration of sustained MR4.5 until cessation was 3.04 (1.5-9.3) years for Nilo and 2.65 (1.11-7.95) for Dasa (p=0.96). The median dosing of Nilo was 600 (300-800) mg daily and 80 (20-100) mg at TKI2 cessation. None of these patients switched to another TKI during the follow-up. TKI2 cessation occurred after 60.5 (43-74.5) months in the Nilo group and 68 (39-90) months in the Dasa group (p=0.581). Thirty-seven pts out of 47 (79%) were BCR-ABL1 undetectable at Nilo cessation 18/25 (72%) at Dasa cessation (p=0.60). At M3 after discontinuation, 58% of pts remained undetectable after Nilo cessation and 30.4% after Dasa cessation (p=0.05).The median survival of pts without loss of MMR was not reached in the Nilo group, and was 14 (4.73-NR) months in the Dasa group, (p=0.042) as analysed by the KM method (Figure 1.). Two patients died (1 Nilo, 1 Dasa) from competing events (solid tumours) after unsuccessful TFR. Twenty-eight pts (14 Dasa, 14 Nilo) restarted their TKI2 after MMR loss and all regained ≥ MMR after 3 months of Dasa at a median dose of 75 (40-100) mg daily and all except one (who regained MMR at M12) after resumption of Nilo at a median dose of 350 (300-600) mg daily. Univariate analysis identified pts with H+I Sokal (as compared to low) as an unfavourable factor for successful TKI2 cessation [HR=0.35 (0.15-0.83), p=0.017] and type of TKI2 (Nilo as reference vs Dasa) was discriminant [HR=2.1 (1.01-4.35), p=0.047]. Multivariate analysis identified the type of TKI2 as a significant factor impacting on TFR outcome [HR 2.11 (0.97-4.55], p=0.05]. Conclusions: As it is likely that no prospective head-to-head comparison will be performed in this setting, on this limited series of pts, we conclude that the outcome of TFR seems to be different according to the TKI2 used since diagnosis, suggesting the impact of distinct biological variables modified by the type of TKI2 on the long run (such as immunological system, BM micro-environment, others) on TFR outcome. Figure 1 Figure 1. Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; 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; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Rea: Novartis: Consultancy, 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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