Two-Year Consolidation By Nilotinib Is Associated with Successful Treatment Free Remission in Chronic Myeloid Leukemia with MR4.5: Subgroup Analysis from STAT2 Trial in Japan

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1889-1889 ◽  
Author(s):  
Naoto Takahashi ◽  
Chiaki Nakaseko ◽  
Kaichi Nishiwaki ◽  
Hisashi Wakita
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Subgroup Analysis ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Second Generation ◽  
Second Line ◽  
First Line ◽  
Prior Therapy ◽  
Line Therapy ◽  
Treatment Free Remission

Abstract Background Nilotinib (NIL) is a second-generation tyrosine kinase inhibitor (TKI) that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). Superior rates of deeper molecular responses (DMR) were achieved with NIL vs. imatinib (IM) in patients newly diagnosed with CML in chronic phase (CML-CP) in the ENESTnd trial. In addition, the ENESTcmr study demonstrated that switching to NIL after a minimum of 2 years on IM led to increased rates of DMR vs. remaining on IM. Switching to NIL treatment for 2 years safely led to MR4,5 (BCR-ABLIS…0.0032%) in 47.5% of patients with major molecular response (MMR) on long-term IM therapy in our STAT1 trial. Recently, treatment free remission (TFR) was proposed as one of the goals in CML treatment. Indeed, prospective trials suggest that IM therapy may be safely and successfully discontinued in 40% of CML patients with MR4.5. STAT2 is the first study to evaluate the efficacy of two-year consolidation by NIL for successful TFR in patients with CML-CP who had achieved MR4.5. Before enrolling in STAT2, some patients were treated by not only IM but also NIL because of MMR but no MR4.5 after IM therapy, and some patients changed over from STAT1 to STAT2. Here, we present the results of the subgroup analysis from STAT2 based on the prior treatments at the time of entry into the study. Methods In the STAT2 trial, patients who achieved MR4.5 on IM front line therapy (subgroup 1; SG1) or NIL second line therapy after IM therapy (subgroup 2; SG2) were eligible and NIL was given twice daily at the dose of 600 mg/day for 2 years in consolidation phase. The primary endpoint of STAT2 was the proportion of patients with successful TFR, defined as no confirmed loss of MR4.5 (2 consecutive IS RQ-PCR tests), within the first 12 months of TFR phase. Thirty-five institutions in STAT study group participated. The study was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was signed by all patients according to institutional guidelines. The study was approved by all institutional review boards and registered with UMIN-CTR (000005904). Results Between July 2011 and December 2012, 96 patients were enrolled in STAT2. Among 96 patients, 50 patients were treated by IM first line only as prior therapy (SG1). On the other hand, 40 patients were treated by IM first line and NIL second line including 21 patients who changed over from STAT1 to STAT2 because they achieved MR4.5 (SG2). Six patients were excluded in this analysis because second generation TKIs were taken as a first line therapy. Among patients treated by NIL for 2 years in this study, 40/50 (80%; 95% CI, 68.4%-88.7%) in SG1 and 33/40 (82.5%; 95% CI, 69.6%-91.5%) in SG2 entered the TFR phase, respectively. The median age was 54.5 years in SG1 and 56.0 years in SG2. The ratio of men to women was 26:14 in SG1 and 18:15 in SG2. The total duration of TKI treatment was 110 months for the SG1 with a median of 86 months of IM, and 24 months of NIL, and 93 months in SG2 with a median of 62 months of IM, and 31 months of NIL,, respectively. All patients achieved MR4.5 at the time of entry into the study and the median time to MR4.5 was 47 months in SG1 and 60 months in SG2.The proportion of patients who maintained TFR at 12 months after stopping NIL was similar across the 2 subgroups: 25/40 (62.5%; 95% CI, 48.3%-77.3%) in SG1, and 23/33 (69.7%; 95% CI, 54.0%-82.5%) in SG2. The Kaplan-Meier (KM) analysis of TFR survival showed that in the 2 subgroups, the majority of events occurred within the first 6 months after stopping NIL (Figure 1). There were no significant differences between these 2 subgroups. Conclusion After two-year consolidation by NIL of CML-CP patients who achieved MR4.5, the TFR rate was 67.9% (90%CI: 58.2% to 76.6%) at 12 months in the STAT2 trial. In the present analysis looking at the prior TKI exposure, the TFR rate was similar in patients treated with IM first line only or who switched from IM to NIL before entering the study, despite the fact that the treatment duration of switched patients was slightly shorter. These findings suggest that two-year consolidation by NIL is associated with successful TFR in CML with MR4.5 that was achieved with IM alone or after switching to NIL. Figure Kaplan-Meiercurve of TFR survival in the 2 subgroups based onthe prior treatmentsbefore two-year consolidation by NIL, IM first line only as prior therapy (subgroup1) and IM first line and NIL second line (subgroup2). Figure. Kaplan-Meiercurve of TFR survival in the 2 subgroups based onthe prior treatmentsbefore two-year consolidation by NIL, IM first line only as prior therapy (subgroup1) and IM first line and NIL second line (subgroup2). Disclosures Takahashi: PFIZER: Honoraria, Research Funding; BMS: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding. Nakaseko:BMS: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; NOVARTIS: Honoraria. Nishiwaki:Novartis PHARMA: Research Funding.

scholarly journals Treatment Interruption and Regimen Change in Firstgeneration versus Second-generation Tyrosine Kinase Inhibitors used as First-line Therapy for Chronic Myeloid Leukemia

10.36469/9899 ◽  
2015 ◽  
Vol 2 (2) ◽  
pp. 181-191
Author(s):  
Melea A. Ward ◽  
Gang Fang ◽  
Gang Fang ◽  
Kristy L. Richards ◽  
Christine M. Walko
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Treatment Interruption ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Treatment Interruptions ◽  
Regimen Change

Background: Research has shown that treatment interruptions are associated with worse failure-free survival in chronic myeloid leukemia (CML); however they are commonly used in clinical trials to manage adverse events. Objectives: This study assessed the comparative rates of treatment interruption and regimen change between patients initiating first-line therapy with a first-generation tyrosine kinase inhibitor (1GTKI) imatinib versus second-generation TKI (2GTKI), dasatinib or nilotinib, for the treatment of CML in clinical practice. Methods: This was a retrospective cohort study using the Humana Research Database. Patients with CML who were between the ages of 18 and 89 and newly initiated 1GTKI or 2GTKI therapy between June 1, 2010 and December 31, 2011 were included. Treatment interruption and regimen change were compared using multivariable Cox proportional hazard regression models. Treatment interruption was defined as a gap in any TKI pharmacy claim that was longer than an allowable refill gap plus days’ supply from the previous TKI medication claim. Regimen change was defined as 1) a prescription claim for a different TKI therapy, or 2) increase in dose for the same medication. Results: 368 patients met the inclusion criteria: 1GTKI n=237, 2GTKI n=131. Patients initiating therapy with a 2GTKI had a 48% higher risk of treatment interruption versus patients initiating therapy with a 1GTKI (hazard ratio=1.48, 95% confidence interval 1.08-2.02). The time to treatment interruption was significantly longer in patients initiating therapy with a 1GTKI. Approximately 19% of patients had a regimen change, but there were no differences in rates of regimen changes between the two generations. Conclusions: In this study from a large single health plan population, treatment interruptions were more common among patients initiating therapy with a 2GTKI, yet regimen change rates did not vary by generation of TKI. Future research should assess reasons for treatment interruption and investigate these associations in other populations.

Comparasion Between Nilotinib and Dasatinib as Second-Line Therapy for Patients with Chronic Myeloid Leukemia: A Single Center Retrospective Study.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3440-3440
Author(s):  
Clarisse Lobo ◽  
Carla Boquimpani ◽  
Tania Silva Madeira ◽  
Patricia Wendling ◽  
Claudia Maximo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Randomized Clinical Trials ◽  
Molecular Response ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Third Line Therapy ◽  
Third Line

Abstract Abstract 3440 Nilotinib and dasatinib are second-generation tyrosine kinase inhibitors (TKI) used in patients with chronic myeloid leukemia (CML) resistant or intolerant to imatinib. There are no randomized clinical trials comparing these drugs in this context. The aim of this study was to compare, retrospectively, the hematological, cytogenetic and molecular response in patients submitted to these second-generation TKI at Hemorio, a public brazilian institution. A total of 114 patients were analyzed, 63 received nilotinib and 51 dasatinib as second-line therapy (55.3% and 44.7%, respectively). The following variables were equally distributed between these two groups (nilotinib vs. dasatinib, respectively): male sex (54% vs. 60.8%, p=0.46), median age at diagnosis (46 vs. 45 years, p=0.76), median time in months using imatinib before the switch (45.2 vs. 44.1, p=0.96), resistance to imatinib (98.4% vs. 98%, p=0.88), presence of the mutation T315I (3.2% vs. 3.9%, p=0.09), patients in chronic phase before the switch (85.7% vs. 86.3%, p=0.93). Use of another second generation TKI, as a third-line therapy, was necessary in 30 out of the 114 patients analyzed (26.1%) because of lack of response. This modification was slightly more frequent in the group initially submitted to nilotinib (31.7% vs. 19.6%, p=0.21). Patients who used a third-line therapy were excluded from response and survival analyzes. Response rates after the second-generation TKI were similar between these two groups (nilotinib vs. dasatinib): complete hematological response until three months (77.8% vs. 87.3%, p=0.24), complete cytogenetic response until six months (21.6% vs. 22.2%, p=0.95) and 12 months (32.4% vs. 33.3%, p=0.94) and major molecular response reached before 12 months (32.7% vs. 21.6%, p=0.25). Two-year overall survival (OS) and progression free-survival (PFS) were similar between these two groups (nilotinib vs. dasatinib, respectively): 92.2% vs. 87.8% (p=0.38) for OS and 87.8% vs. 83.7% (p=0.14) for PFS. Although not statistically significant, two-year OS was inferior in the group of patients who needed a third-line therapy (70.5% vs. 95.6%, p=0.70). Our results suggest that the response and survival rates are similar between nilotinib and dasatinib as second-line therapy for patients with imatinib resistant or intolerant CML. Also, they suggest an inferior prognosis for patients who need a third-line therapy. In this way, the choice between these two TKI for second-line therapy should be guided by the clinical characteristics and the mutation status of the patient. Disclosures: Lobo: NOVARTIS: Research Funding.

Frequency of Complete Molecular Response In Chronic Myeloid Leukemia Patients In Real Life Practice.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1227-1227
Author(s):  
Matthieu Decamp ◽  
Dina Istasi ◽  
Atchroue Johnsonansah ◽  
Oumedaly Reman ◽  
Xavier Levaltier ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Response ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Line Therapy ◽  
Ifn Treatment ◽  
Complete Molecular Response

Abstract Abstract 1227 Introduction: Scarce data are available on the frequency of complete molecular response (CMR) in chronic myeloid leukemia (CML) patients. The European Leukemia Net defined CMR lately as an undetectable transcript quantified by Real Time PCR and/or nested PCR in two consecutive blood samples of adequate quality, using strict sensitivity criteria (sensitivity > 10 4). CMR is the best response that we can achieve in CML patients. Generally it is obtained after hematopoietic stem cell transplantation (HSCT) but since the administration of tyrosine kinase inhibitors (TKI), the number of patients seen with CMR is continuously increasing. The aim of this study is to assess the frequency of CMR in CML patients, and study their characteristics. Methods: A retrospective study was conducted to collect epidemiological, clinical, therapeutic and laboratory data of CML patients followed in hospitals of the region of Basse Normandie in France. All CML patients who had been followed up, between 1999 and 2010, by molecular monitoring for their Bcr-Abl transcript level were included. Clinical and biological responses were defined according to the ELN 2009 recommendations. Results: 199 patients were included in this study, 154 were diagnosed during the study period. Median age at diagnosis was 54 years and 46% were females. 61.3% were diagnosed in the chronic phase while the accelerated and the blast crisis phase accounted for 10.5% and 0.02%. Among these patients, 2 had the p190 BCR-ABL transcript and 2 the p230 transcript type. 169 were still followed at the end of this study and the median follow up duration was 6,4 years. Out of these 199 patients 12 died and 18 were lost out of sight. Imatinb (IM) alone or Imatinib-based combined therapies in clinical trials, was administrated as a first line treatment in 51,2% of patients. Interferon (INF) alone or in association with other chemotherapy was the frontline therapy in 37,7%; 52% of them started IFN treatment before 2000 and 73% switched to IM. At the time of analysis 26.6% of patients achieved a complete molecular response and 39.7% obtained a major molecular response (MMR) as defined by the international scale; this figure is to be tempered by the fact that the follow up duration was less than 18 months for 9,5% of patients. CMR was obtained in 11 patients following HSCT. With IM as a first line therapy, 11 patients achieved CMR or had an undetectable transcript after a median duration of 43.3 months and lasted for 13.3 months. When IM was given as a second line therapy, 17 obtained a CMR or had an undetectable transcript, in this case the median time calculated starting from the second line treatment administration was 37,3 months and in half of them, it persisted for 28 months. Among these patients, two discontinued therapy and currently they are still on CMR, 24 and 18 months after IM arrest. There was no significant difference in the median CMR achievement duration between the first and second line IM therapy groups. CMR following IFN treatment had been observed in 8 patients, 7 of them stopped IFN and have been in CMR for more than 5 years since its discontinuation. Finally five patients achieved a CMR after administration of second generation TKI. Altogether, a total of 63 patients were followed up for undetectable BCR-ABL transcript. In 53, the transcript remained undetectable; whereas 10 had lost that level of molecular response; 7 of them had regressed to a MMR though they were under IM therapy; 2 lost the MMR, one of them after IM arrest and one progressed to acute leukemia. Conclusion: A significant proportion of patients is in CMR or at least had no detectable transcript. In case of TKI therapy, the response is obtained after continuous administration (median duration was 36 months) and is durable in most cases. In this study, few patients in CMR have discontinued treatment but maintained their CMR response. Unfortunately one stopped the treatment and relapsed rapidly. The maintenance of this level of response appears to be dependent on continued suppression of the Bcr-Abl clone by TKI. Disclosures: No relevant conflicts of interest to declare.

Efficacy Of Dasatinib Therapy In Patients With Imatinib-Resistant Or -Intolerant Chronic Myeloid Leukemia From Physician’s and Patient’s Perspective: “Real World” Data

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5185-5185
Author(s):  
Tatyana I Ionova ◽  
Tatyana P Nikitina ◽  
Taras A Gritsenko ◽  
Valentina L Ivanova ◽  
Galina B Kuchma ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Real World ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Base Line ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Patient Reported ◽  
Dasatinib Treatment

Abstract There is limited published data about the efficacy and safety of the second-line therapy with dasatinib in patients in chronic phase chronic myeloid leukemia (CML-CP) in a “real world” patients setting outside clinical trials. In addition, comprehensive evaluation of benefits and risks of the treatment is worthwhile to better define treatment outcomes in this patients’ population. We aimed to study clinical and patient-reported outcomes as well as safety of dasatinib treatment in a “real world” setting within the context of its approved indication through the analysis of prospectively collected data in patients with imatinib resistance or intolerance receiving dasatinib as the second-line therapy. 75 CML-CP patients resistant or -intolerant to imatinib were enrolled in the prospective, multicenter, non-interventional study (mean age 51.3 years old, SD 15.4; range 22–83 years; male/female – 37/38). The median of disease duration was 5.0 years (0.75–17 years). 63 patients had resistance to imatinib; 12 patients were intolerant to imatinib; the median duration of imatinib treatment 40 months (3–121 months). All the patients received dasatinib as the second-line therapy (100 mg daily). Median follow-up was 12 months. For quality of life (QoL) and symptom assessment patients filled out the SF-36 and Comprehensive Symptom Profile in Chronic Myeloid Leukemia Patients (CSP Leuk-CML), respectively, at base-line, in 1, 3, 6 months after treatment start and every 6 months thereafter. Comparison of QoL and symptom scores was conducted using t-test. QoL scores were analyzed using t-test, adjusting for sociodemographic and disease status. Mean symptom severity and percentage of patients with moderate-to-severe (ratings ³ 5) symptoms was evaluated. After 12 months of treatment 83% patients achieved or maintained complete hematologic response and 35 % – complete cytogenetic response. The twenty four-month progression free survival rate was 93% (95% CI; 84–97%). Four cases of pleural effusion events were registered: they were easily managed in 3 cases; one patient died at 1 month after treatment start due to accompanied infection complication. No severe hematological adverse effects were observed except two cases of grade III-IV neutropenia. Two patients were resistant to dasatinib. Two patients died of disease progression at 6 months of follow-up. At 12 months of dasatinib treatment QoL parameters were stable for 5 out of 8 scales; vitality, social functioning and mental health significantly improved as compared with base-line (p< 0.01). At 24 months of dasatinib treatment improvement of physical functioning, vitality, social functioning and mental health as compared with base-line was registered (p< 0.01); no worsening was observed for other QoL scales. Before treatment 75% of patients experienced at least one moderate-to-severe symptom; more than 40% had more than 7 moderate-to-severe symptoms. The majority of patients (96%) experienced fatigue; half of them suffered from moderate-to-severe fatigue. While treatment the number of patients with moderate-to-severe symptoms decreased. After 12 months of therapy only 25% of patients experienced moderate-to-severe fatigue. Before treatment 36% of patients exhibited critical or severe QoL impairment. Remarkably, in the subgroup of patients (44%) with critical or severe QoL impairment at base-line dramatic QoL improvement was observed: QoL index increased 3.4 fold (p<0.01). Thus, our study on “real world” patient data confirms that dasatinib as second-line therapy in CML-CP patients is effective both in terms of clinical outcomes and patient-reported outcomes, as well as exhibits good tolerability. Comprehensive evaluation of the outcomes of the second-line treatment of CML-CP allows to assess the benefits and risks of therapy both from physician’s and patient’s perspective. Disclosures: Ionova: BMS: Research Funding. Nikitina:BMS: Research Funding. Gritsenko:BMS: Research Funding. Ivanova:BMS: Research Funding. Kuchma:BMS: Research Funding. Shnaider:BMS: Research Funding. Sannikova:BMS: Research Funding. Fedorenko:BMS: Research Funding. Kurbatova:BMS: Research Funding.

scholarly journals Physicians' Attitude Towards Selection of Second Line Therapy with Nilotinib and Dasatinib in Chronic Myeloid Leukemia Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5939-5939
Author(s):  
Fabio Efficace ◽  
Gianantonio Rosti ◽  
Francesco Cottone ◽  
Laura Cannella ◽  
Marco Vignetti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Treatment Schedule ◽  
Line Treatment ◽  
Second Line ◽  
Personality Profile ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Selection Of

Abstract Background: One of the main challenges in the treatment of chronic myeloid leukemia (CML) is the selection of second line therapy. While Nilotinib (NILO) and dasatinib (DASA) are available for use as second line treatment for several years, few evidence-based data is available on how physicians make decisions on the use of one drug over another. Aim: We performed a pilot study to describe which factors physicians consider most relevant when deciding therapy with either NILO or DASA in patients who previously failed or were intolerant to Imatinib (IMA) therapy. Patients and methods: Analyses are based on a sample 67 CML patients, recruited as part of a larger international study, who switched from IMA therapy to either NILO (N=36; 53.7%) or DASA (N=31; 46.3%). Patients had to be in second line treatment for at least three months to be eligible for this analysis. Also, in all participating centers, NILO and DASA should have been equally available for use. There were 15 physicians involved in the management of these patients and they were asked to complete an ad-hoc questionnaire investigating reasons based on which they made the decision to either use one drug over another. All questions were phrased as follows: "To what extent have the following issues been determinant to make a decision on which agent (NILO or DASA) to use for this patient?" All answers were rated on a four point likert-scale (ie, not at all, a little, quite a bit and very much). Items investigated were: 1) accessibility of the drug in the hospital; 2) cost of drug; 3) patients' comorbidities; 4) patients' age; 5) patients' personality profile; 6) discussion with patients about Pro and Cons; 7) different treatment schedule of drugs; 8) type of mutation during IMA therapy. Physician characteristics were also collected and analyzed. Other treatment-related variables were investigated such as main reason for changing of TKI (IMA intolerance or resistance), high grade adverse events (AEs) experienced during IMA treatment, or previous duration of IMA therapy. Results: Physicians' experience in treating CML patients was on average 14 years (range 4-32). Patient median age at the time of treatment switch was 47 and 55 years in the NILO and DASA group, respectively. Median time of duration of IMA therapy, before receiving second line therapy, was 1.4 years and 3.3 years for those who switched respectively to NILO or DASA. No differences existed between groups with regard to reasons for switching from IMA therapy (intolerance or resistance) or AEs reported with previous IMA therapy. The top issue considered as most relevant when making the decision was previous discussion with patients on advantages and disadvantages of drugs, being reported as "quite a bit" and "very much" important in 73% of evaluations. Cost of the drug was not considered relevant at all, in the selection of which drug to use, in 97% of the 69 evaluations considered. Also, type of mutation during IMA therapy was considered as of negligible relevance for the decision, but it should not be overlooked that mutations were detected in few patients. Patient's comorbidity or personality profile was quoted as a 'quite a bit' or 'very much' relevant reason for the selection of 2nd line TKI, respectively in 43% or 48% of all questionnaires. Low relevance was assigned to patient age and different treatment schedule: 'not at all' or 'a little' relevance was reported respectively in 64% and 70% of all questionnaires. The analysis of physician-reported grading distribution according to the type of second line treatment did not show any significant difference (no reason lead to a preferential selection of one drug), see table 1. Conclusions: No differences were detectablein selected factors, driving the decision to switch either to NILO or DASA when physicians consider switching from first line IMA therapy. Also, type of TKI selection does not seems to be guided by only one factor. Further research is needed to elucidate on potential reasons underlying clinical decision making in 2nd TKI selection. Disclosures Efficace: Seattle Genetics: Consultancy; TEVA: Consultancy, Research Funding; Lundbeck: Research Funding; Bristol Myers Squibb: Consultancy. Rosti:Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau. Breccia:Celgene: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau.

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