First- and second-line treatment strategies for chronic phase CML using tyrosine kinase inhibitors – present status discussed at ASH 2009

2010 β—½  
Vol 3 (3) β—½  
pp. 129-131
Author(s):  
T. Kühr
Keyword(s):  
Tyrosine Kinase β—½  
Tyrosine Kinase Inhibitors β—½  
Present Status β—½  
Kinase Inhibitors β—½  
Treatment Strategies β—½  
Chronic Phase β—½  
Line Treatment β—½  
Second Line

The Time to Cytogenetic Response Determines Survival in CML Patients (Pts) Receiving Second-Line Tyrosine Kinase Inhibitors, and Allows Early Identification of Pts Destined To Fail Therapy.

Blood β—½  
2007 β—½  
Vol 110 (11) β—½  
pp. 1931-1931
Author(s):  
Constantine S. Tam β—½  
Hagop Kantarjian β—½  
Gautam Borthakur β—½  
William Wierda β—½  
Farhad Ravandi β—½  
...  
Keyword(s):  
Tyrosine Kinase β—½  
Tyrosine Kinase Inhibitors β—½  
Early Identification β—½  
Kinase Inhibitors β—½  
Chronic Phase β—½  
Cytogenetic Response β—½  
Cumulative Probability β—½  
P Value β—½  
Second Line β—½  
Term Survival

Abstract Background: Novel Tyrosine Kinase Inhibitors (TKIs) are used in the treatment of CML pts who fail imatinib. However, more than half of chronic phase (CP) pts will not achieve complete cytogenetic response (CCyR), and the criteria for when to consider alternate therapy among such pts are not well defined. Methods: We analyzed the pattern of cytogenetic response in 113 pts with CML in CP receiving nilotinib (n=43, 38%) or dasatinib (n=70, 62%) after imatinib failure in order to determine which milestones are important for long-term survival, and to develop a predictive model for the early identification of poor-risk pts. Pts (n=26, 23%) with clonal evolution with no other criteria for accelerated phase were included in the analysis. The previous best response to imatinib was CCyR in 24%, major cytogenetic response (MCyR, 1–35% Ph+) in 20%, minor cytogenetic response (mCyR, 36–95% Ph+) in 15%, complete hematological response (CHR) in 39%, and no response (NR) in 3%. Results: Median follow-up was 27 months. The cumulative probability of CCyR was 35%, 42% and 48% after 3, 6 and 12 months of 2nd TKI therapy. The achievement of MCyR or better by 12 months (12MMCyR) was an important milestone in determining future survival: 1-year survival from the 12 month landmark was 97% for the pts who achieved 12MMCyR, compared with 84% for those who did not (p=0.01). In contrast, no protection was conferred by lesser responses, with comparable survival for pts in mCyR, CHR and NR (86%, 83% and 88% respectively, p=0.78). The one year risk of progression to accelerated or blast phase, loss of hematologic response or death was 3% for pts in 12MMCyR, and 17% for those in mCyR or CHR (p=0.003). Early cytogenetic response was predictive of eventual 12MMCyR, with pts not achieving any degree of cytogenetic response by 3 to 6 months being unlikely to reach MCyR or better by 12 months (Table). Significant (p<0.05) univariate associations of 12MMyCR included age, time from diagnosis, more than one previous therapy, previous cytogenetic response to imatinib, low hemoglobin, high white cell count, blood blast percentage and platelet count; of these, only previous cytogenetic response to imatinib (p<0.001) and hemoglobin (p=0.003) remained independent in a multivariate analysis. If the three month response was added to the multivariate model, it emerged as the only significant factor suggesting that early response is the most important determinant of 12MMCyR. Conclusion: Achieving 12MMCyR was associated with superior survival and decreased risk of disease progression in pts receiving second-line TKI therapy. Since pts not achieving any degree of cytogenetic response by 3 to 6 months are unlikely (<10%) to reach 12MMCyR, this milestone may be a reasonable indication for considering alternative therapy. Assessment Response 12MMCyR(%) P-Value Three Months Minor CyR 10/15 (67%) <0.001 Three Months No CyR 3/42 (7%) Six Months Minor CyR 8/16 (50%) <0.001 Six Months No CyR 1/38 (3)

scholarly journals Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors

10.3390/jcm9051542 β—½  
2020 β—½  
Vol 9 (5) β—½  
pp. 1542
Author(s):  
Jee Hyun Kong β—½  
Elliott F. Winton β—½  
Leonard T. Heffner β—½  
Manila Gaddh β—½  
Brittany Hill β—½  
...  
Keyword(s):  
Chronic Myeloid Leukemia β—½  
Tyrosine Kinase β—½  
Tyrosine Kinase Inhibitors β—½  
Myeloid Leukemia β—½  
Kinase Inhibitors β—½  
Chronic Phase β—½  
Molecular Response β—½  
Line Treatment β—½  
First Line β—½  
Blastic Phase

We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4–190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >3 TKIs (3 TKIs, n = 33; 4 TKIs, n = 17; 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6; myeloid blastic phase, n = 4; lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1–53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.

Second-line treatment of non-small-cell lung cancer: chemotherapy or tyrosine kinase inhibitors?

10.1586/era.11.120 β—½  
2011 β—½  
Vol 11 (10) β—½  
pp. 1587-1597 β—½  
Author(s):  
Antonio Passaro β—½  
Enrico Cortesi β—½  
Filippo de Marinis
Keyword(s):  
Lung Cancer β—½  
Tyrosine Kinase β—½  
Small Cell Lung Cancer β—½  
Tyrosine Kinase Inhibitors β—½  
Cancer Chemotherapy β—½  
Kinase Inhibitors β—½  
Small Cell β—½  
Line Treatment β—½  
Second Line β—½  
Small Cell Lung

MMR and CMR in Chronic Phase Chronic Myeloid Leukemia Patients: Role of Sokal Score and Different Tyrosine Kinase Inhibitors On Time of Their Obtention, Maintenance and Failure-Free Survival

Blood β—½  
2012 β—½  
Vol 120 (21) β—½  
pp. 4437-4437
Author(s):  
Mauricette Michallet β—½  
Hélène Labussière-Wallet β—½  
Mohamad Sobh β—½  
Stéphane Morisset β—½  
Madeleine Etienne β—½  
...  
Keyword(s):  
Tyrosine Kinase β—½  
Tyrosine Kinase Inhibitors β—½  
Median Time β—½  
Kinase Inhibitors β—½  
Chronic Phase β—½  
Molecular Response β—½  
Second Line β—½  
Free Survival β—½  
Sokal Score β—½  
Hasford Score

Abstract Abstract 4437 In order to describe the different treatments and factors involved in the first major molecular response (MMR) occurence in chronic phase CML, its maintenance, and its conversion to complete molecular response (CMR), we analyzed 211 CML patients [124 males and 87 females; median age: 50 years (17–81)] in first chronic phase who received tyrosine-kinase inhibitors (TKI) followed at our institution between 2001 and 2011. Among 196 patients evaluated for Sokal score, 79 (40%) were low, 82 (42%) were intermediate and 35 (18%) were high. According to hasford score (153 evaluated), 46% were low, 46% intermediate and 8% were high. First MMR was obtained in: 61% of patients after first line treatment [Imatinib, n=102; Imatinib+Peg-interferon, n=11; Dasatinib, n=10; Nilotinib, n=6]; 26% after second line [Imatinib, n=32; Dasatinib, n=11; Nilotinib, n=12] and 13% beyond second line [Imatinib, n=14; Dasatinib, n=7; Nilotinib, n=6]. The median time of MMR obtention was 15 months (2.5–94) after Imatinib, 6.4 months (3–24) after Imatinib+Peg-interferon, and it was significantly shorter after both Dasatinib [HR=2.6 (1.7–3.9), p<0.001] and Nilotinib [HR=3 (1.8–5), p<0.001] with 6 months (3–23) and 5 months (3–56) respectively no matter the treatment line number was. Sokal score was an independent significant factor that impacted MMR obtention delay, with a median time of 9 months (2.5–98) for low score, 13 months (3–78) for intermediate [HR=0.7 (0.5–0.9), p=0.03] and 12 months (3–94) for high score [HR=0.7 (0.5–1.02), p=0.05]. Patients who converted to CMR were: 50 (34%) under Imatinib after a median time of 25 months (3–97); 7 (64%) under Imatinib+Peg-interferon after a median time of 8 months (3–15); 10 (42%) under Nilotinib after 25 months (13–32) and the only significant faster treatment was Dasatinib [n=13 (46%)] after a median time of 11 months (3–52) [HR=2.1 (1.1–4.2), p=0.02]; according to Sokal score, low (n=41, 52%) and intermediate (n=27, 33%), while patients with high score (n=11, 31%) were significantly slower [HR=0.53 (0.25–1), p<0.001]. The current rate of CMR at 5 years was not statistically different between the treatments [Imatinib (36%), Imatinib+Peg-interferon (40%), Nilotinib (43%), Dasatinib (56.5%)] nor according to sokal score [Low (49%), intermediate (43%) and high (40%)]. Treatment was discontinued in 42 patients who had 5 years failure-free survival of 56% (43–73) while patients under Dasatinib, Imatinib+Peg-interferon, Imatinib, and Nilotinib had 70.5% (50–99), 79% (56–100), 84% (77–91) and 93% (84–100) respectively. In Conclusion, second generation TKI used at 1st, 2nd line or beyond, showed an independent significant faster time to MMR, as well as patients with low sokal score. Conversion to CMR was significantly faster only in Dasatinib patients and slower in patients with intermediate and high sokalscore. Treatment discontinuation did not have a benefit in terms of FFS while patients on TKI therapy seem to have better result. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors

Oncology Reviews β—½  
2011 β—½  
Vol 3 (1) β—½  
pp. 59
Author(s):  
Michael G. Martin β—½  
John F. DiPersio β—½  
Geoffrey L. Uy
Keyword(s):  
Tyrosine Kinase β—½  
Tyrosine Kinase Inhibitors β—½  
Chronic Myelogenous Leukemia β—½  
Kinase Inhibitors β—½  
Chronic Phase β—½  
Myelogenous Leukemia β—½  
Second Line β—½  
Durable Response β—½  
Duration Of Response β—½  
Selection Of

Tyrosine kinase inhibitors (TKIs) are the mainstay for treatment of chronic myelogenous leukemia (CML). Imatinib was the first TKI approved for use in CML, but resistance to this therapy has emerged as a significant issue, and second-line options are often necessary. Increased-dose imatinib may elicit responses in some patients, but clinical evidence suggests only a minority experience sustained benefit. The second-generation TKIs, dasatinib and nilotinib, have demonstrated efficacy in patients resistant or intolerant to imatinib. Changes in therapy, with the aim of inducing durable response, should occur promptly after imatinib failure is identified as all agents are more effective in chronic phase disease than in later stages. Selection of second-line agents should be driven by efficacy and safety: dasatinib may be more effective in patients with P-loop or F359C mutations; nilotinib may be more effective in those with F317L mutations.

scholarly journals Which Tyrosine Kinase Inhibitors Should Be Selected as the First-Line Treatment for Chronic Myelogenous Leukemia in Chronic Phase?

Cancers β—½  
2021 β—½  
Vol 13 (20) β—½  
pp. 5116
Author(s):  
Takaaki Ono
Keyword(s):  
Tyrosine Kinase β—½  
Tyrosine Kinase Inhibitors β—½  
Chronic Myelogenous Leukemia β—½  
Kinase Inhibitors β—½  
Chronic Phase β—½  
Treatment Goal β—½  
Myelogenous Leukemia β—½  
Line Treatment β—½  
First Line β—½  
First Line Treatment

With the use of tyrosine kinase inhibitors (TKIs), chronic myelogenous leukemia in chronic phase (CML-CP) has been transformed into a non-fatal chronic disease. Hence, β€œtreatment-free remission (TFR)” has become a possible treatment goal of patients with CML-CP. Currently, four types of TKIs (imatinib, nilotinib, dasatinib, and bosutinib) are used as the first-line treatment for newly diagnosed CML-CP. However, the second-generation TKI (2GTKI), the treatment response of which is faster and deeper than that of imatinib, is not always recommended as the first-line treatment for CML-CP. Factors involved in TKI selection in the first-line treatment of CML-CP include not only patients’ medical background, but also patients’ choice regarding the desired treatment goal (survival or TFR?). Therefore, it is important that clinicians select an appropriate TKI to successfully achieve the desired treatment goal for each patient, while minimizing the development of adverse events. This review compares the pros and cons of using imatinib and 2GTKI for TKI selection as the first-line treatment for CML-CP, mainly considering treatment outcomes, medical history (i.e., desire for pregnancy, aging factor, and comorbidity), and cost. The optimal use of 2GTKIs is also discussed.

scholarly journals P-241 First- and second-line treatment with tyrosine kinase inhibitors after chemoembolization in intermediate-stage hepatocellular carcinoma patients

Annals of Oncology β—½  
2020 β—½  
Vol 31 β—½  
pp. S168-S169
Author(s):  
E. Manthopoulou β—½  
E. Michalopoulou β—½  
D. Dimitroulopoulos β—½  
D. Kypreos β—½  
D. Katsinelos β—½  
...  
Keyword(s):  
Hepatocellular Carcinoma β—½  
Tyrosine Kinase β—½  
Tyrosine Kinase Inhibitors β—½  
Kinase Inhibitors β—½  
Intermediate Stage β—½  
Line Treatment β—½  
Second Line

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 β—½  
Vol 7 (2) β—½  
pp. 205-211
Author(s):  
Kaynat Fatima β—½  
Syed Tasleem Raza β—½  
Ale Eba β—½  
Sanchita Srivastava β—½  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia β—½  
Tyrosine Kinase β—½  
Protein Kinases β—½  
Tyrosine Kinase Inhibitors β—½  
Myeloid Leukemia β—½  
Kinase Inhibitors β—½  
Line Treatment β—½  
First Line β—½  
First Line Treatment

The function of protein kinases is to transfer a Ξ³-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

scholarly journals Antiangiogenic tyrosine kinase inhibitors and immunotherapy as first-line treatment for metastatic renal cell carcinoma: is there an increased risk of hypothyroidism?

2021 β—½  
Vol 13 β—½  
pp. 175628722110297
Author(s):  
Giandomenico Roviello β—½  
Sebastiano Buti β—½  
Carlo Cattrini β—½  
Alessia Mennitto β—½  
Carlo Messina β—½  
...  
Keyword(s):  
Renal Cell Carcinoma β—½  
Tyrosine Kinase β—½  
Cell Carcinoma β—½  
Tyrosine Kinase Inhibitors β—½  
Renal Cell β—½  
Kinase Inhibitors β—½  
Line Treatment β—½  
First Line β—½  
Increased Risk β—½  
First Line Treatment
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