Early Prediction of Stable MR4.5 By Achievement of 2.8 Log Reduction in BCR-ABL1 qPCR Levels at 6 Months in Patients with Chronic Myeloid Leukemia Treated with Frontline Imatinib

Abstract Introduction Tyrosine kinase inhibitor (TKI) therapy has dramatically improved the prognosis of CML, with life expectancy now approaching that of the general population. TKIs are, however, associated with impaired quality of life, toxicity and financial burden to the patient and economy. Treatment free remission (TFR) is achievable in approximately half of patients who attain a sustained deep molecular response (DMR), however, it is not yet fully elucidated how best to predict candidates for successful TFR attempt. It is even harder to predict which patients will achieve a sustained DMR for 2 years or longer, which is a pre-requisite for TKI discontinuation. If it were possible to identify the patients who will not achieve a sustained DMR with Imatinib, a TKI switch could be considered earlier in order to make them a candidate for TFR attempt. Aims We aimed to identify disease characteristics and molecular responses that can predict future achievement of Stable MR4.5 (defined as a reduction in BCR/ABL1 transcripts of 4.5 logs or deeper on repeated testing for 2 consecutive years) with frontline Imatinib. Patients and Methods We collected data on pre-TKI variables (baseline disease characteristics), post-TKI variables (molecular response at various timepoints) and outcomes in patients commencing frontline Imatinib in our institution from 1999 to 2014 (n=593). Statistical analysis was performed using EZR software. Univariate analysis was performed by cumulative incidence method considering competing events and Gray test. Cut-offs for continuous variables were determined by recursive partitioning (rpart). Multivariable analysis was performed using Fine-Gray model. Results With 8.9 years of median follow-up duration, the overall survival was 96.9% at 8 years. The median time to MR4.5 was 8.8 years. The rate of MR4.5 was 39.7% at 5 years and 48.3% at 8 years. The rate of Stable MR4.5 was 25.6% at 8 years. In the subset of patients achieving MR4.5, over 80% subsequently achieved Stable MR4.5 (82.4% at 8 years) (Fig. 1). The median time from achievement of first MR4.5 to Stable MR4.5 was 3.5 years. Univariate analyses of baseline variables (age, gender, disease phase, additional cytogenetic abnormalities and baseline blood counts) were performed, using rpart method to determine cut-offs for blood counts as follows: white cell count (WBC) ≥218x109/L, blast percentage ≥4%, hemoglobin (Hb) ≥88.5g/L and platelets ≥176x109/L. The only statistically significant pre-TKI variables on these analyses were WBC, blast percentage, Hb and platelet count. Univariate analyses of the following post-TKI variables were also performed: molecular response at 3, 6 and 12 months, time to complete cytogenetic response, major molecular response and MR4.5.Early molecular responses of ≥1 log reduction in transcripts at 3 months, ≥2 logs at 6 months and ≥3 logs at 12 months were tested. The following cut-offs for molecular response, as determined by rpart method, were also tested: ≥2.2 log reduction at 3 months, ≥2.8 logs at 6 months and ≥3 logs at 12 months.Univariate analysis showed statistical significance (p<0.0001) for all the post-TKI variables tested. Multivariable analyses of baseline blood counts and molecular response at 3 and 6 months were performed. The only variable that remained statistically significant was molecular response at 6 months using a cut-off of ≥2.8 log reduction in transcripts (HR 3.1, p<0.001) (Table 1). 44.4% of patients achieved ≥2.8 log reduction in transcripts at 6 months, with a rate of Stable MR4.5 at 8 years of 65.8%, compared to 17.2% for those with <2.8 log reduction at 6 months (Fig. 2). Conclusions In patients who achieved MR4.5, over 80% subsequently achieved Stable MR4.5, making them eligible for TKI discontinuation. In multivariable analysis, molecular response at 6 months was the only predictor for subsequent achievement of Stable MR4.5. Based on this data, a patient at high-risk of failing to attain Stable MR4.5 with Imatinib therapy can be identified if they fail to achieve a 2.8 log reduction or deeper within 6 months of Imatinib therapy. If a patient interested in TFR has a molecular response at 6 months of less than a 2.8 log reduction, then a switch in therapy to a second generation TKI may be considered. The optimal 6 month response to predict future Stable MR4.5 remains unclear, but our data suggest that a cut-off in transcripts of ≥ 2.8 log reduction may be a better predictor of future Stable MR4.5. Disclosures Lipton: ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Paladin: Consultancy.

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Long Term Adherence to Imatinib Therapy Is the Critical Factor for Achieving Molecular Responses in Chronic Myeloid Leukemia Patients.

Blood ◽

10.1182/blood.v114.22.3290.3290 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3290-3290 ◽

Cited By ~ 6

Author(s):

Alex Bazeos ◽

Jamshid Khorashad ◽

François-Xavier Mahon ◽

Lina L Eliasson ◽

Dragana Milojkovic ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Independent Predictor ◽

Chronic Phase ◽

Imatinib Therapy ◽

Adherence Rate ◽

Molecular Response ◽

Molecular Responses ◽

Adherence To Therapy

Abstract Abstract 3290 Poster Board III-1 There is a great variability in the degree of molecular responses achieved by chronic myeloid leukemia (CML) patients treated with imatinib. These different levels of molecular response could reflect different degrees of adherence to therapy. We measured the adherence to imatinib therapy in 87 consecutive CML chronic phase patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment (range 25–104) and therefore all them were in complete cytogenetic response. Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS) and were related to levels of molecular response. MEMS consist of an electronic device fitted in the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of TKD mutations and the following prognostic factors measured at diagnosis: hOCT1 transcripts level, polymorphism 1236C>T in ABCB1, Sokal risk group, hemoglobin, leukocytes , BCR-ABL1 transcript type and BCR1-ABL1 ratio and demographic data. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate. The median adherence rate was 97.6% (range 22.6–103.8%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). We found a strong association between adherence rate (≤90% or >90%) and the 6-year probability of major molecular response (MMR) (28.4% vs 94.5%, p<0.0001) and complete molecular response (CMR) (0% vs 43.8%, p=0.002) (Fig 1). Multivariate analysis identified adherence (RR=11.7, p=0.001) and expression of the molecular transporter hOCT1, (RR=1.79, p=0.038) as the only independent predictors for MMR. Adherence was the sole independent predictor for CMR. No molecular responses were observed when the adherence was ≤20% (p=0.0001). In patients whose imatinib dose had been increased (n=32) the adherence was poor (median 86.4%). Adherence was the only independent predictor for failure to achieve a 3-log transcript reduction (RR=17.66, p=0.006) in this subgroup of patients. Patients with CML vary greatly in their response, as demonstrated originally by Sokal et al. in 1984, and the same variation is seen in patients treated with imatinib in the modern era. The basis for this variation is unknown but it has been attributed to the intrinsic biological heterogeneity of the leukemia. In contrast we show here that adherence to therapy is the major factor determining the degree of response that a CML patient treated with imatinib will achieve. Disclosures: Mahon: Novartis: Consultancy, Research Funding. Apperley:Novartis: Consultancy, Honoraria. Rezvani:Novartis: Consultancy, Honoraria, Research Funding. Marin:Novartis: Consultancy, Research Funding.

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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 ◽

10.1182/blood.v126.23.1578.1578 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1578-1578 ◽

Cited By ~ 1

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.

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Safety and Efficacy of Dasatinib Treatment Change for Patients Previosly Treated with Imatinib with Late Warning Response. Results from the Phase II, Open, Multicenter Dasapost Study

Blood ◽

10.1182/blood.v128.22.5450.5450 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5450-5450 ◽

Cited By ~ 1

Author(s):

Valentín García-Gutierrez ◽

Felipe Casado ◽

Fermín Sánchez-Guijo ◽

Rosa M. Ayala ◽

Concepcion Boque ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Median Time ◽

Phase Ii ◽

Research Funding ◽

Progression Free Survival ◽

Molecular Response ◽

Treatment Change ◽

Molecular Responses ◽

Warning Response

Abstract Background: Current European LeukemiaNet (ELN) recommendations (ELN 2013) endorse closely monitoring, due to risk of failure, for patients with so called late warning response (patients with complete cytogenetic response without major molecular response after 12 months of treatment). In this situation, for patients initially treated with imatinib, previous studies have shown a benefit of treatment change to nilotinib in terms of the achievement of deeper molecular responses. However, the role of treatment change to dasatinib in this group of patients have not been evaluated. DASAPOST is the first clinical trial evaluating efficacy and safety of dasatinib in patients with late warning responses. Methods: We are presenting results of the 18 patients enrolled in the phase II, open, multicenter DASAPOST study (NCT01802450). Main inclusion criteria were patients previously treated with imatinib with late suboptimal response by ELN2009 (CCyR without MMR after 18 months of treatment). The primary end point was rate of MMR by 6 moths after treatment change to dasatinib. Secondary end points were rate of MMR by 12 months, rate of deep molecular responses, progression free survival and safety of treatment change. Results were expressed as the proportion of patients who achieved molecular responses in the intention-to-treat (ITT) population, considering as failure if the evaluation was not performed in a specific time point. All BCR-ABL/ABL (IS) measurements were centralized in an EUTOS laboratory. Results: From April 2013 to May 2015, 18 patients were enrolled in 12 Spanish centers. Median age was 59 years (39-77). The ratio of men to women was 13/5, and the risk groups according to Sokal Score were 48%, 30% and 22% for low, intermediate and high risk, respectively. Median time from diagnosis to treatment change to dasatinib was 2.6 years (1.6-23) and median time while on imatinib to achieve CCyR 1.4 years (0.2-12). Median exposure to imatinib was 2.4 years (1.6-14). Seventy-two percent of the patients achieved MMR by 6 months (primary endpoint). Rates of MMR and deeper molecular responses at different time points are shown in table 1. Of interest 9/18 patients (50%) achieved MR4 by 12 months. Treatment change to dasatinib was safe, with only 3 study discontinuations (16%), due to adverse events (AE) and 4 serious AE (congestive heart failure, acute gastroenteritis, pyelonephritis and pancreatitis (only congestive heart failure was related to dasatinib). Most commonly reported (>5%) drug-related AEs are shown in table 1. Conclusions: Our study shows, for the first time, that in patients treated with imatinib and with late warning responses, switching to Dasatinib induced MMR in 2 out every 3 patients, and MR4 in half of the patients by 6 months, with a good safety profile. Table 1 Most commonly reported (>5%) drug-related AEs Table 1. Most commonly reported (>5%) drug-related AEs Table Table. Disclosures García-Gutierrez: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Casado:Ariad: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Sánchez-Guijo:Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers-Squib: Consultancy, Honoraria. Martinez-Lopez:BMS: Research Funding. Steegmann:Ariad: Honoraria, Other: Research funding for the Spanish CML Group; Pfizer: Honoraria, Other: Research funding for the Spanish CML Group; BMS: Honoraria, Other: Research funding for the Spanish CML Group; Novartis: Honoraria, Other: Research funding for the Spanish CML Group.

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Kinetics of Regulatory T Cells Predict the Recurrence of CML after Stopping Imatinib in Japanese CML Patiens

Blood ◽

10.1182/blood.v128.22.4240.4240 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4240-4240

Author(s):

Yuki Fujioka ◽

Hiroyoshi Nishikawa ◽

Naoto Takahashi

Keyword(s):

T Cells ◽

T Cell ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Research Funding ◽

Imatinib Therapy ◽

Molecular Response ◽

Molecular Responses ◽

Treg Population ◽

Kinetics Of

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Second Attempt to Discontinue TKI in CML Patients Who Have Sustained CMR for over 2 Years Is Rarely Successful Even with the Use of Second Generation TKIs

Blood ◽

10.1182/blood.v128.22.1887.1887 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1887-1887 ◽

Cited By ~ 5

Author(s):

Eri Matsuki ◽

Masatoshi Sakurai ◽

Daiki Karigane ◽

Hidenori Kasahara ◽

Taku Kikuchi ◽

...

Keyword(s):

Median Time ◽

Median Duration ◽

Research Funding ◽

Second Generation ◽

Treatment Discontinuation ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Initial Report ◽

Study Enrollment ◽

Tki Discontinuation

Abstract Background: Tyrosine kinase inhibitor (TKI) remains to be the mainstay of treatment for patients with chronic myelogenous leukemia (CML). Second generation TKIs have been shown to successfully treat patients who are resistant or intolerant to imatinib, as well as induce faster and deeper molecular response when used as first line therapy. Since the initial report of the French STIM study (Mahon FX, et al. Lancet Oncol 2010; 11: 1029-35) that showed successful discontinuation of imatinib therapy in approximately 50% of patients who have sustained complete molecular response (CMR), several groups have confirmed that a subset of patients can discontinue TKI for a long period. While factors associated with successful discontinuation are not yet well defined, it also remains an open question whether patients who have failed the initial attempt of discontinuation will have to remain on life-long treatment with TKIs. Patients and Methods: Patients who have been treated at Keio University Hospital for CML, who had been in confirmed stable CMR for over 2 years at the time of study enrollment, and who had no history of accelerated phase/ blastic phase while on treatment with TKI, were eligible to enroll in the study. Patients were monitored monthly for the first 6 months after discontinuation, every 2 months until 12 months, and every 2 to 3 months thereafter. Treatment with a TKI was initiated if the peripheral blood quantitative PCR (TMA method) value exceeded 100 copies. Once the patient was restarted on TKI therapy, and regained sustained CMR for over 2 years, they were allowed to reenter the study and discontinue treatment, upon patients' choice. Results: Sixty-seven patients have been enrolled in the study, of which 53 patients who have been observed for over 2 years since first TKI (imatinib 48; dasatinib 1; nilotinib 4) discontinuation were analyzed. The median age of the patients was 54 (range 28-83) years. Thirty-seven (69.8%) patients were male. In terms of baseline characteristics, 18 (34.0%) had been treated with interferon prior to TKI use, and 41 (77.4%) were CMV positive. The Sokal risk score was low in 34 (64.2%), intermediate in 11 (20.8%) and high in 4 (7.5%) patients. Among the 53 patients, 45 (84.9%) were checked for the existence of BIM deletion, among which 7 (13.2%) patients were positive. The median time on TKI treatment was 98 (range 32-147) months and the median duration of CMR was 38 (range 24-106) months. The median follow-up of the patients at the time of this analysis since study enrollment was 61 (range 26-66) months. Treatment was restarted in 28 (45%) patients (imatinib 7; dasatinib 20; nilotinib 1). While this occurred within the first 6 months of treatment discontinuation in most patients, 6 patients were started on treatment beyond 12 months of drug-free survival (DFS) (at month 14, 20, 23, 36, 36, and 52, respectively). Five patients presented with a fluctuating copy number early after TKI discontinuation, whereas 1 patient only became positive for bcr-abl after 30 months of treatment discontinuation. The estimated 24-months DFS was 52.8% (95% confidence interval (CI) 39.5-65.8%) (Fig 1). All patients have restored CMR at least at one occasion after recommencing TKIs. No single factor was significantly associated with success of discontinuation. Among the patients who had sustained CMR for over 24 months after re-initiation of TKI, 10 patients elected to challenge discontinuation of TKI for the second time. All patients were on dasatinib at the time of discontinuation. The median age of these patients was 58.5 (range 31-75) years. The median time on TKI prior to second discontinuation was 33 (range 26-45) months and the median duration of CMR after treatment re-initiation was 26.5 (range 25-44) months. All but one patient were restarted on treatment at the time of the analysis (median observation 26 (range 13-35) months), leading to a DFS of 20% (95% CI 5.0-54.1%) at 12 and 24 months (Fig 1). Conclusion: Long-term observation of the outcome of TKI discontinuation in CML patients who had sustained CMR for over 2 years showed cases of late relapses as well as small chance of success on the second attempt of TKI discontinuation even with the use of second generation TKIs. While the result of first discontinuation was similar to previous reports, attempt of second discontinuation was less successful compared to the French group, despite changing the drug of use from imatinib to dasatinib. Figure 1 Figure 1. Disclosures Matsuki: Nippon Shinyaku: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Sakurai:Celgene: Honoraria. Karigane:Celgene: Honoraria. Kikuchi:Celgene: Honoraria; Takeda Pharmaceutical Company: Honoraria; Kyowa Hakko Kirin: Honoraria. Yokoyama:BMS: Research Funding. Okamoto:Eisai Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Teijin Pharma Limited: Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.

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Predictive Factors For An Achievement Of 6-Month Early Molecular Response In New CP CML Patients Treated With Imatinib

Blood ◽

10.1182/blood.v122.21.5160.5160 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5160-5160

Author(s):

Sung-Eun Lee ◽

Soo Young Choi ◽

Soo-Hyun Kim ◽

Yun Jeong Oh ◽

Jin-Eok Park ◽

...

Keyword(s):

Predictive Factors ◽

Prognostic Significance ◽

Molecular Response ◽

Molecular Responses ◽

Log Reduction ◽

Qrt Pcr ◽

Level Data ◽

Daily Dose ◽

Univariate Analyses ◽

Transcript Type

Abstract Background Recent studies have demonstrated that early molecular response (EMR) is predictive for long-term outcomes. However, the value of EMR has not been fully defined. Recently, European Leukemia Net (ELN) recommended that BCR-ABL1 ≤ 10%, and/or Ph+ <35% at 6 months of treatment was an optimal response. The aim of this study was to identify predictive factors for an achievement of 6-month EMR (BCR-ABL1 ≤ 1%) and to evaluate prognostic implications of 6-month EMR. Methods CP CML patients who were newly diagnosed and receiving 400mg IM once daily with no prior treatment were eligible for this study. Molecular responses were monitored using qRT-PCR assay with 3 month intervals, and then 6 month intervals after achieving major molecular response (MMR). All qRT-PCR tests were performed in a single laboratory (Cancer Research Institute, The Catholic University of Korea, Seoul, Korea). Pharmacokinetics data of IM, drug adherence, and dose intensity as well as baseline biological characteristics were included as variables affecting the achievement of 6-month EMR. Results A total of 102 patients (including 61 men and 41 women) were enrolled. One patient changed IM treatment to second-generation TKI due to less than complete hematologic response before 3 months. At the time between 3 and 6 months, 9 patient were discontinued permanently from IM treatment due to progression (n = 1), ELN failure (n = 3), and intolerance (n = 5). Ninety-two patients’ molecular responses were analyzed at 6 months. Day 29 trough IM level data were available from 99 patients and trough IM level data on the end of cycle 6 were available from 84 patients. Univariate analyses revealed that age of ≥ 40 years (P = 0.061), male sex (P = 0.042), b3a2 transcript type (P = 0.008), intermediate (P = 0.007) and high Sokal risk (P = 0.013), increased leukocyte count (P = 0.018), increased blast percentage (0.028), large splenic size (P = 0.020), and mean daily dose by 6 months of <350 mg/day (P = 0.004) were potential predictive factors for no achievement of 6-month EMR. Increased log reduction of BCR-ABL1 from baseline to 3 months (P <0.001) was associated with achievement of 6-month EMR. After adjusting for factors affecting relapse on univariate analyses, multivariate analyses showed that b2a2 transcript type (RR of 9.35, P = 0.013), increased log reduction of BCR-ABL1 from baseline to 3 months (RR of 9.58, P = 0.001), and mean daily dose by 6 months of ≥350 mg/day (RR of 13.10, P = 0.019) were independent factors for a achieving of 6-month EMR. In addition, patients with high Sokal risk had a lower 6-month EMR, compared with those with low Sokal risk (RR of 0.02, P= 0.035). In the current study, patients with BCR-ABL1 ≤1% at 6 months had a better MMR rates at 12 months (63% vs 10%, P<0.001), 3-year CI of CCyR (100% vs 76.1%, P<0.001) and MMR (100% vs 66.4%, P<0.001), EFS (78.9% vs 30.6%, P<0.001), and FFS (97.2% vs 68.7%, P<0.001). Patients with BCR-ABL1 >1% at 6 months showed a trend for lower 3-year PFS, compared with those who achieved ≤1% (100% vs 94.1%, P = 0.063). Conclusions In this study, we re-confirmed the prognostic significance of 6-month EMR and found that b2a2 transcript type, early decline of BCR-ABL1 transcript, mean daily dose by 6 months (≥350 mg/day), and Sokal risk were associated of the achievement of 6-month EMR. These predictive factors for 6-month EMR should be considered in the clinical decision of changing therapy at this time point. Further clinical investigations in a larger patient population with longer follow-up are needed. Disclosures: No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood-2018-99-114656 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 787-787 ◽

Cited By ~ 6

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.

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Prognostication of Molecular Relapses after Dasatinib or Nilotinib Discontinuation in Chronic Myeloid Leukemia (CML): A FI-LMC STOP 2G-TKI Study Update

Blood ◽

10.1182/blood-2019-124408 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 30-30 ◽

Cited By ~ 6

Author(s):

Delphine Rea ◽

Franck E Nicolini ◽

Michel Tulliez ◽

Philippe Rousselot ◽

Martine Gardembas ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Blast Crisis ◽

Molecular Response ◽

Advisory Committees ◽

History Of ◽

Time To Relapse ◽

Tki Discontinuation

Background : Providing achievement and sustainability of deep molecular responses (DMR), patients (pts) taking tyrosine kinase inhibitors (TKI) against CML may discontinue therapy. The STOP 2G-TKI observational study showed that dasatinib and nilotinib could be safely stopped and prior suboptimal response or resistance to imatinib was an adverse prognostic factor for treatment-free remission (TFR). We present updated results with a specific focus on the risk of relapse using post-baseline information during follow-up. Methods : Adult CML pts treated with dasatinib or nilotinib without a history of allogeneic stem cell transplantation (ASCT) or progression to advanced phase stopped TKI provided that: (1) BCR-ABL transcripts were of the major type, (2) total TKI treatment duration was ≥36 months, (3) uMR4.5 had been achieved and maintained for ≥24 months (undetectable BCR-ABL with ≥32000 copies of ABL). Relapse was defined by loss of major molecular response (MMR: BCR-ABL IS >0.1%) on a single occasion and triggered TKI reintroduction. The primary objective was TFR at 12 months. After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 6-12 months, every 3 months during the 2nd year and then every 3-6 months. Data as of July 1, 2019 are reported in 104 pts (median follow-up 55 months (range: 6-70)). Results: Median age at inclusion was 56 years (range: 21-82) and 65.4% of pts were female. Sokal risk score was low in 49%, intermediate in 31%, high in 16% and unknown in 4%. 2G-TKIs were given after imatinib intolerance in 47% of pts, suboptimal response or resistance to imatinib in 22%, lack of DMR on imatinib in 3% and as 1st line treatment in 28%. Median duration of TKI, 2G-TKI and uMR4.5 was 74 months (range: 36-163), 49 months (range: 19-112) and 31 months (range: 24-72), respectively. Overall, 43 pts (41%) lost MMR within a median time of 5 months (range: 1-59). Overall 60-month TFR was 56% (95% CI, 45.8-66.3) but TFR probabilities increased up to 64% (95% CI: 53.3-74.8), 76.7% (95% CI, 65.9-87.5), 86.2% (95% CI; 76.3-96.2), and 92.1% (95% CI: 83.4-100) for pts still in MMR at 3, 6, 12 and 18 months, respectively (Figure 1). Prior suboptimal response or resistance to TKI was confirmed as the strongest adverse baseline prognostic factor with a 60-month TFR rate of 29.8% (95% CI; 10.8-48.7) (median TFR 12 months) versus 63.6% (95% CI; 52.1-75.2) (median not reached) in pts without such history (logrank p=0.0012). This was explained by significantly higher risk of early relapses (within 6 months but not later) in pts with prior suboptimal response or resistance to TKI (cumulative incidence of relapses by 6 months 47.8% (95% CI; 31.2-73.2) versus 20.9 (95% CI; 13.7-32) in other pts (p=0.00879)). Landmark analyses at specific time points were performed to study the prognostic value of molecular responses categories after TKI discontinuation. All pts in MMR but not deeper at 3 months relapsed by month 9 (median time to relapse 4 months) while pts in ≥MR4 (BCR-ABL IS ≤0.01%) had 12- and 60-months probabilities of 86.8% (95% CI; 79.1-94.4) and 74.9% (95% CI: 64-85.7), respectively (logrank p<10-4). All pts but 1 in MMR but not deeper at 6 months relapsed (median time to relapse 12 months) while pts in ≥MR4 had 12- and 60-months probabilities of 95% (95% CI; 89.6-100) and 87.5% (95% CI: 78.7-96.2), respectively (logrank p<10-4). Forty three pts restarted treatment including 1 who lost MR4.5 but not MMR and 42 who lost MMR. When treatment was reintroduced, 42 pts were in CHR and all regained MMR after a median time of 3 months (range: 1-11). The remaining pt lost MMR but not CHR 5 month after 1st line nilotinib cessation and was found in sudden myeloid blast crisis at the month 6 TKI reintroduction visit. No BCR-ABL mutation was found but an inversion of chromosome 3 at karyotyping analysis. The pt underwent ASCT after chemotherapy + ponatinib and is alive in remission 29 months later. Conclusion: 2G-TKI may be successfully stopped in CML pts with long-lasting MR4.5. Those without a history of suboptimal response or resistance have greatest chances of success. Sudden blast crisis is rare but unpredictable. Post-TKI discontinuation estimates of TFR change overtime. Together with that of molecular response type at specific time points, they represent important dynamic prognostic measures of outcome. They may also help individualizing molecular monitoring programs after TKI cessation. Disclosures Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Etienne:Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Guerci:INCYTE: Consultancy, Honoraria. Legros:Pfizer: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria, Research Funding. Coiteux:Pfizer: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mahon:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.

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Early Molecular Response and Female Sex Strongly Predict Achievement of Stable Undetectable BCR-ABL1, a Criterion for Imatinib Discontinuation in Patients with CML

Blood ◽

10.1182/blood.v120.21.165.165 ◽

2012 ◽

Vol 120 (21) ◽

pp. 165-165 ◽

Cited By ~ 4

Author(s):

Susan Branford ◽

David Ross ◽

Jodi Prime ◽

Chani Field ◽

Haley Altamura ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Cumulative Incidence ◽

Research Funding ◽

Univariate Analysis ◽

Imatinib Therapy ◽

Cumulative Probability ◽

Molecular Response ◽

Advisory Committees ◽

Significant Difference

Abstract Abstract 165 Introduction. The opportunity to discontinue kinase inhibitor therapy while maintaining a deep remission is desirable for many CML patients. Despite good responses to imatinib for most patients, treatment related side effects remain problematic and can affect quality of life. Studies have demonstrated that a proportion of carefully selected patients can sustain response after imatinib discontinuation. The first requirement for successful discontinuation is likely to be stable deep molecular response based on a sensitive RQ-PCR assay. The criteria for patient selection in the French Stop Imatinib (STIM) and Australian CML8 (TWISTER) imatinib discontinuation trials included stable undetectable BCR-ABL1 transcripts for at least 24 months with a PCR sensitivity of 5 and 4.5 log, respectively. The probability of continued remission after discontinuation for imatinib treated patients without prior interferon-α therapy was approximately 33%. It is not known how many imatinib treated patients will eventually meet these PCR criteria for a discontinuation trial. Aims. We aimed to determine 1) the cumulative probability of achieving the PCR criteria for imatinib discontinuation as defined in the CML8 study, and 2) factors that predicted its achievement. Method. The molecular response of 415 de-novo CML patients in chronic phase enrolled in consecutive clinical trials of imatinib since July 2000 was examined. The assigned daily imatinib dose was 400 mg for 90 patients, 600 mg for 202 patients and 800 mg for 123 patients. Molecular data were included until imatinib cessation or last follow-up. The minimum time since commencing imatinib was 30 months and the median time on imatinib was 45 months, range 3 to 136. The CML8 PCR criteria for imatinib discontinuation were confirmed undetectable BCR-ABL1 transcripts at a sensitivity of 4.5 log that remained undetectable on all PCR tests for at least 24 months while on imatinib therapy. In the current analysis the CML8 PCR discontinuation criteria are defined as ‘stable UMR4.5'. Results. At 8 years of imatinib therapy the cumulative incidence of stable UMR4.5 was 43%, Figure A. Patients were divided into groups according to the time to a confirmed major molecular response (MMR): by 3, 6, 12 or 18 months. There was a significant difference in stable UMR4.5, P<.001, Figure B. The cumulative incidence of stable UMR4.5 was more than 60% for all patients who achieved MMR by 12 months and only 16% for patients with MMR between 12 and 18 months. The time to a confirmed MMR influenced the time to reach a stable UMR4.5 after achieving MMR. Considering only patients who achieved stable UMR4.5, patients achieving MMR by 3 months took a further 39 months (median) to achieve stable UMR4.5. For those with MMR by 6 months and 12 months, the median month to a stable UMR4.5 was 50 and 76 months after MMR, P<.001. This suggests slower dynamics of BCR-ABL1 decline with delayed time to MMR. 52 patients achieved MMR after 18 months and none achieved a stable UMR4.5 by 8 years: median time to MMR was 27 months, range 21–87. Factors at the time of commencing imatinib (baseline) were examined for their association with stable UMR4.5; Sokal risk, age, sex, assigned imatinib dose and baseline BCR-ABL1 value, as well as the 3 month BCR-ABL1 value. Quantitative factors were categorized into groups, with cut-offs set at the median for age and quartiles for the baseline BCR-ABL1 value. By univariate analysis the only baseline factor that predicted for higher cumulative incidence of stable UMR4.5 at 8 years was female versus male, 68% versus 30%, P<.001, Figure C. During imatinib therapy females had significantly lower median BCR-ABL1 values at every assessment up to 42 months. The 3 month BCR-ABL1 value also predicted stable UMR4.5, P<.001, Figure D. Baseline and 3 month factors were entered into a multivariate analysis. The 3 month BCR-ABL1 value and sex were independent predictors of stable UMR4.5, P=.004 and P=.005, respectively. Conclusion. The time to achieve an MMR, sex and the 3 month BCR-ABL1 value predicted stable undetectable BCR-ABL1 while on imatinib. Lower BCR-ABL1 values and higher rates of stable UMR4.5 in females could be related to better drug adherence or biological differences. Further studies are indicated. Early MMR led to early achievement of the discontinuation criteria. The findings justify the focus on early achievement of MMR as a strategy to maximize recruitment to discontinuation studies. Disclosures: Branford: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid: Consultancy. Ross:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Yeung:Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hughes:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding.

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Around 70% of Japanese CML Patients Could Stop Imatinib According to a-STIM Criteria: The JALSG-STIM213 Study

Blood ◽

10.1182/blood.v126.23.4035.4035 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4035-4035 ◽

Cited By ~ 3

Author(s):

Naoto Takahashi ◽

Tetsuzo Tauchi ◽

Kunio Kitamura ◽

Koichi Miyamura ◽

Yoshio Saburi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Pharmaceutical Research ◽

Imatinib Therapy ◽

Molecular Response ◽

Imatinib Treatment ◽

Advisory Committees ◽

Molecular Responses ◽

Chugai Pharmaceutical ◽

Significant Difference

Abstract Introduction: Imatinib have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to significant improvement in clinical outcome and survival rates. Recently, treatment free remission (TFR) is one of the goals in CML treatment, and some prospective trials suggest that imatinib therapy may be safely discontinued in CML patients with deep and sustained molecular responses (Mahon Lancet Oncol 2010, Ross Blood 2013, Rousselot JCO 2014). The purpose of this study was to confirm TFR in Japanese CML patients and to define prognostic biomarkers of successful TFR after stopping imatinib. Methods: Japanese CML patients on imatinib treatment in confirmed deeper molecular response (DMR) for at least two year (>4 log reduction on imatinib therapy for >24 months confirmed by four consecutive PCR tests) and under imatinib treatment for at least 3 years were eligible. Patients treated with other tyrosine kinase inhibitors or who received stem cell transplantations were excluded. MR4.5 was confirmed at the beginning of this study using Ipsogen BCR-ABL1 M-BCR IS-PCR kit in a central laboratory (Sysmex, Kobe, Japan). Primary endpoint was the major molecular remission (MMR) rate at 12 months after stopping imatinib. Molecular recurrence of CML was defined as loss of MMR according to A-STIM criteria (Rousselot JCO 2014). Results: From November 2013 to March 2014, 77 CML patients in chronic phase from 26 institutions were enrolled in this study. Nine were excluded (consent withdrawal n=1, not eligible n=8). Of the eligible 68 patients, 38.2% were female. Median age was 55.0 years (range, 23 to 84), and 13.2% and 16.2 % were high-risk according to EUTOS and Sokal Scores. Thirteen patients were treated with interferon prior to imatinib therapy. Median duration of imatinib treatment was 8 years (range, 3-12 years). The duration of imatinib treatment was less than 5 years in 12%, 5-8 years in 34% and > 8 years in 54% of pts. Time to MMR was 11.5 months (25%-75%, 7.5-22.7 months) and time to DMR (not detected by PCR) was 30.6 months (25%-75%, 17.6-59.9 months). Among the 68 patients, 46 patients (67.6%, 95%CI: [56.5% to 78.8%]) remained without molecular recurrence the first 12 months according to A-STIM criteria, defined as loss of MMR. Moreover, 43 patients (63.2%, 95%CI: [51.8% to 74.7%]) remained without molecular recurrence the first 12 months according to STIM criteria, defined as two consecutive loss of MR4.5 with 1 log increase. On the other hand, 22 patients who lost MMR were treated again with imatinib and all patients achieved MMR within 6 months. Time to 2nd MMR was 40 days. Although there was a trend for a better TFR rate for patients treated longer with Imatinib (Figure 1), no significant difference could be observed for molecular relapse within 12 months according to clinical characteristics including age, sex, Sokal risk score, prior IFN, and time to MMR/DMR (Table 1). Ten patients (15%) showed "withdrawal syndrome" which is transitory musculoskeletal pain within several weeks after imatinib discontinuation, and all patients except one recovered without any treatments. Conclusion: According to the A-STIM criteria, around 70% of patients with deep and sustained molecular responses could safely stop imatinib. TFR in this prospective Japanese clinical study was higher than previously reported, probably because there were much more patients who treated with imatinib for longer duration than previous studies. We will report prognostic factors in the exploratory research of JALSG-STIM213 study including T/NK-cell profiling in peripheral blood, BIM deletion polymorphism, and ABCG2 421C/A polymorphism at this ASH meeting. Table 1. Table 1. Figure 1. Figure 1. Disclosures Takahashi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Astellas: Speakers Bureau; Masis: Consultancy; Sysmex: Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Hatta:CHUGAI PHARMACEUTICAL CO. LTD: Honoraria; Kyowa Hakko Kirin CO., Ltd, Japan: Honoraria; Celgene K.K.: Honoraria. Usuki:Fuji Film RI Pharma: Other: personal fees; Fujimoto Pharmaceutical: Research Funding; Otsuka Pharmaceutical: Research Funding; Eisai: Research Funding; Shionogi: Other: personal fees; MSD: Other: personal fees, Research Funding; Nippon Shinyaku: Other: personal fees, Research Funding; Astellas: Research Funding; Chugai Pharmaceutical: Other: personal fees; Takeda Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Other: personal fees, Research Funding; SymBio Pharmaceutical: Other: personal fees, Research Funding; Sanofi: Other: personal fees, Research Funding; Novartis: Other: personal fees, Research Funding; Boehringer Ingelheim: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Sumitomo Dainippon Pharma: Other: personal fees, Research Funding; Taiho Pharmaceutical: Other: personal fees, Research Funding; Shire: Research Funding; GlaxoSmithKline: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other. Kobayashi:Gilead Sciences: Research Funding. Naoe:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties; Pfizer Inc.: Research Funding; Toyama Chemical CO., LTD.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Celgene K.K.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Patents & Royalties, Research Funding.

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