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

Imatinib Resistance Mutation Analysis Pattern In Chronic Myeloid Leukemia (CML) Patients on Imatinib In Indian Population.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4491-4491 ◽  
Author(s):  
Mukul Goyal ◽  
K.C. Lakshmaiah ◽  
K.Govind Babu ◽  
Amit Rauthan ◽  
Linu Abraham Jacob ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Indian Population ◽  
Kinase Inhibitors ◽  
Resistance Mutation ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Second Line ◽  
Imatinib Resistance ◽  
Loss Of Response

Abstract Abstract 4491 Background- Imatinib has revolutionized the treatment of CML. Still there are hurdles with the drug, as, with the passage of time patients are either not responding or showing loss of response. The nonresponsiveness has been proved to be due to genetic mutations which may be primary or acquired. Still less is known about the pattern of mutations especially in asian countries. So there is a need to identify the pattern of mutations, so that second line tyrosine kinase inhibitors’ response may be studied with respect to these mutations and new drugs can be designed concentrating on the most common mutations. In an attempt to identify a pattern of mutation in asian population we carried out an analysis at our centre. Methods- The patients who were on imatinib at Kidwai memorial institute of oncology, underwent testing for hematological response(HR) every month, cytogenetic response (CyR) every 6 month and molecular response(MR) every year. Patients who did not achieve either hematologic or cytogenetic or molecular milestones or had loss of response underwent imatinib resistance mutation analysis(IRMA). We analyzed a total of 102 patients. The IRMA was done at Oncquest Laboratories Ltd.,New Delhi, India. The method used at the laboratory is a combination of RTPCR and double pass sequencing. The sequence results were analyzed using BLAST software from NCBI and GRAPH ANALYSIS software from applied biosystems. Results- Between Jan. 2007 to May 2010, a total of 102 patients were analysed for imatinib resistance. Out of these 102 patients, 5(4.9 %) patients presented in blast crisis, 7(6.86%) in accelerated phase and 90(88.23%) in chronic phase. Male to female ratio was 1.7:1. 95 patients had achieved complete hematological response(CHR) at the end of 3 mths but 7 patients did not achieve CHR at 3 mths. So these were the candidates of IRMA. 2 patient had loss of HR. 42 patients did not achieve cytogenetic milestones. 28 patients had loss of cytogenetic response. 15 patients did not achieve major molecular response. and 8 had loss of molecular response. So these 102 patients were candidates for IRMA. Analysis revealed: No mutation - 74 patients. F 359 I – 3 patients, T 315 I(Thr to Ile) – 4 patients, M 351 T (Met to Thr) – 5 patients, M 244 V (Met to Val) – 2patients, H 395 R – 1 patients, Y 253 H – 2 patients, 355 G(GLU to GLY) – 1 patient, 250 E (GLY to GLU)- 1 patient, G250 E (GLY to GLY) - 1patient, F 359 C (Phe to Cys) – 1 patient, F 311 L(Phe to Leu) – 1 patient, Y 253 F(Tyr to Phe) – 1 patient, E 275 K (Glu to Lys) – 2 patients, V 253 F – 2 patients and F317L- 1 patient. Conclusions- Most of the patients (74/102 patients) did not show any mutations. Most common mutation seen was M 351 T in 5 patients. T 315 I mutation was seen in 4 patients and all these patients had a loss of response. All these mutations should be studied with respect to response to second line tyrosine kinase inhibitors particularly in asian Indian population. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Front-Line Therapy With Second-Generation Tyrosine Kinase Inhibitors in Patients With Early Chronic Phase Chronic Myeloid Leukemia: What Is the Optimal Response?

2011 ◽  
Vol 29 (32) ◽  
pp. 4260-4265 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Jianqin Shan ◽  
Alfonso Quintás-Cardama ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Front Line ◽  
Line Therapy

Purpose The response definitions proposed by the European LeukemiaNet (ELN) are defined on the basis of imatinib front-line therapy. It is unknown whether these definitions apply to patients treated with second-generation tyrosine kinase inhibitors (TKIs). Patients and Methods One hundred sixty-seven patients with newly diagnosed chronic myelogenous leukemia (CML) in chronic phase were treated with second-generation TKIs in phase II trials (nilotinib, 81; dasatinib, 86). Median follow-up was 33 months. Event-free survival (EFS) was measured from the start of treatment to the date of loss of complete hematologic response, loss of complete or major cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, progression to accelerated or blastic phases, or death at any time. Results Overall, 155 patients (93%) achieved complete cytogenetic response (CCyR), including 146 (87%) with major molecular response (MMR; complete in 46 patients [28%]). According to the ELN definitions, the rates of suboptimal response were 0%, 2%, 1%, and 12% at 3, 6, 12, and 18 months of therapy, respectively. There was no difference in EFS and CCyR duration between patients who achieved CCyR with and without MMR across all the landmark times of 3, 6, 12, and 18 months. Conclusion The use of second-generation TKIs as initial therapy in CML induces high rates of CCyR at early time points. The ELN definitions of response proposed for imatinib therapy are not applicable in this setting. We propose that achievement of CCyR and partial cytogenetic response at 3 months should be considered optimal and suboptimal responses, respectively. The achievement of MMR offered no advantage over CCyR in defining long-term outcome in patients with newly diagnosed CML treated with second-generation TKIs.

Sokal and Hasford Scores Are Able To Predict Cytogenetic Response and Survival in CML Patients Who Failed Prior Therapy and Are Receiving Salvage Therapy with Imatinib or Other Tyrosine Kinase Inhibitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2157-2157
Author(s):  
Constantine S. Tam ◽  
Hagop M. Kantarjian ◽  
Jenny Shan ◽  
William G. Wierda ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Salvage Therapy ◽  
Kinase Inhibitors ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Risk Groups ◽  
Cytogenetic Response ◽  
Intermediate Risk ◽  
Clinical Value

Abstract Sokal and Hasford scores have been used to estimate the survival of CML patients following alkylator-based or interferon-based therapy, and may also predict the outcome of patients receiving first-line imatinib. These scores were designed for patient characteristics at the time of diagnosis and they have been assumed to have no clinical value at other times during the course of the disease (eg. second-line or subsequent therapy). We seek to determine the applicability of the Sokal and Hasford scores in predicting outcomes in patients receiving second or subsequent-line therapy with imatinib and other novel tyrosine kinase inhibitors (TKI). This analysis is based on 379 CML patients in chronic phase (90%) or accelerated phase as defined by cytogenetic clonal evolution (10%), who were enrolled on clinical trials of imatinib following interferon failure (n=294), or nilotinib or dasatinib following imatinib failure (n=85). Significance of relationship between Sokal and Hasford risk categories and response were tested using the Chi-Square test, and differences in survival assessed using the log-rank method. P-values are summarised below: Imatinib following Interferon Failure Nilotinib/Dasatinib Following Imatinib Failure Sokal Hasford Sokal Hasford *comparison between low and intermediate risk groups only Low Risk 219 (74%) 176 (60%) 39 (46%) 45 (53%) Intermediate Risk 65 (22%) 111 (38%) 34 (40%) 38 (45%) High Risk 10 (3%) 6 (2%) 12 (14%) 2 (2%) Any Cytogenetic Response p<0.001 p<0.001 p=0.01 p=NS Major Cytogenetic Response p<0.001 p<0.001 p=0.002 p=0.04* Complete Cytogenetic Response p<0.001 p<0.001 p=0.005 p=0.07* Survival p<0.0001 p<0.0001 Insuff Events Insuff Events Among patients receiving imatinib following failure of interferon therapy, both Sokal and Hasford scores were highly predictive of cytogenetic response and overall survival. Due to the low number of deaths (n=5) on the nilotinib and dasatinib trials, the effect of Sokal and Hasford scores on predicting survival could not be assessed but they remain predictive of cytogenetic response. We conclude that the Sokal and Hasford scores calculated at the time of therapy failure are useful predictors of subsequent response to salvage therapy with imatinib and other TKIs.

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 ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4437-4437
Author(s):  
Mauricette Michallet ◽  
Hélène Labussière-Wallet ◽  
Mohamad Sobh ◽  
Stéphane Morisset ◽  
Madeleine Etienne ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Median Time ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Second Line ◽  
Free Survival ◽  
Sokal Score ◽  
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 Management of Chronic Myeloid Leukemia Patients Resistant to Tyrosine Kinase Inhibitors Treatment

2015 ◽  
Vol 10s3 ◽  
pp. BMI.S22431 ◽  
Author(s):  
Agnieszka Wieczorek ◽  
Lutz Uharek
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dramatic Improvement ◽  
Term Survival

Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with a characteristic chromosomal translocation called the Philadelphia chromosome. This oncogene is generated by the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus (ABL) genes and encodes a novel fusion gene translating into a protein with constitutive tyrosine kinase activity. The discovery and introduction of tyrosine kinase inhibitors (TKIs) irreversibly changed the landscape of CML treatment, leading to dramatic improvement in long-term survival rates. The majority of patients with CML in the chronic phase have a life expectancy comparable with that of healthy age-matched individuals. Although an enormous therapeutic improvement has been accomplished, there are still some unresolved issues in the treatment of patients with CML. One of the most important problems is based on the fact that TKIs can efficiently target proliferating mature cells but do not eradicate leukemic stem cells, allowing persistence of the malignant clone. Owing to the resistance mechanisms arising during the course of the disease, treatment with most of the approved BCR-ABL1 TKIs may become ineffective in a proportion of patients. This article highlights the different molecular mechanisms of acquired resistance being developed during treatment with TKIs as well as the pharmacological strategies to overcome it. Moreover, it gives an overview of novel drugs and therapies that are aiming in overcoming drug resistance, loss of response, and kinase domain mutations.

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

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

A Phase II Study of Oral Panobinostat (LBH589) for Chronic Phase Chronic Myeloid Leukemia (CML) with Resistance to ≥2 BCR-ABL Tyrosine Kinase Inhibitors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4254-4254 ◽  
Author(s):  
Andrey Zaritskey ◽  
Giuliana Alimena ◽  
Lech Konopka ◽  
Jila Shamsazar ◽  
Priscille M. Bourquelot ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Phase Ii ◽  
Kinase Inhibitors ◽  
Phase Ii Study ◽  
Chronic Phase ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Abl Tyrosine Kinase ◽  
Stage 1

Abstract Background: Panobinostat (LBH589) is a novel, high potent pan-deacetylase inhibitor, which acetylates HSP90 and promotes degradation of its client proteins, such as BCR-ABL. It induces degradation of wild-type, as well as BCR-ABL with the T315i and E255K mutations in BaF3 cells. Based on this encouraging data, we initiated a Phase II trial to investigate the efficacy and safety of oral panobinostat in patients (pts) with chronic phase (CP) CML who had received at least 2 prior BCR-ABL tyrosine kinase inhibitors (TKI). Methods: This was a single arm, 3-stage, open-label, multicenter, Phase II study. The primary objective was to estimate the proportion of pts attaining major cytogenetic response (MCyR). Complete hematologic response (CHR) was one secondary objective. All patients received panobinostat orally 20 mg/day on a thrice weekly, consecutive weekly schedule. If ≥3 confirmed MCyRs were observed among 25 pts in Stage 1, Stage 2 was planned to be opened with a total of 32 pts. Dose reduction to 10 and 5 mg/day for toxicity and re-escalation to 20 mg/day was allowed. Dose escalation beyond 20 mg/day for poor response was not foreseen. Results: 29 pts were enrolled in Stage 1 between February and November 2007. Median age was 56 years (yrs) (range 31–75). Time since diagnosis of CML was ≥5 yrs in 69% and &lt;2 yrs in 3%. All pts met the study criteria for TKI resistance. Best cytogenetic response to any prior TKIs was evaluable in 26 pts: MCyR in 7 pts, minor in 6 pts, and no response in 13 pts. Median time since last treatment of any kind, including hydroxyurea, was 20 days (range 0–224). Median duration of panobinostat treatment was 26 days (1–334). No MCyR was observed, and therefore, Stage 2 of the study was not opened. However, one CHR, accompanied by the eradication of the BCR-ABL T315i mutated clone, occurred in Cycle 2 (Week 6). This pt remained on panobinostat without progression until Cycle 12 (Week 48). Overall, non-hematological AEs were similar to the safety profile of 20 mg/day panobinostat reported before.1 Gastrointestinal AEs were reported by 10 pts (nausea; all Gr 1–2, but 1 Gr 3), diarrhea in 7 pts, and vomiting in 5 pts. Fatigue was reported in 8 pts and asthenia in 3 pts. An atrial fibrillation (Gr 2) in 1 pt and a QTcF prolongation &gt;500 ms (Gr 3) in another pt required study drug discontinuation. 5 serious AEs were reported as possibly related to study drug: pulmonary embolism and the QTcF prolongation (see above) in 1 pt, and sepsis, followed by multiple organ failure with fatal outcome in a second pt. SAEs considered as non-related to study drug included: 1 case each of DVT, lung infection, pericardial effusion, pleural effusion, and cardiac failure. To date, 452 post baseline ECGs were assessed: minimal QTcF prolongations (30–60 ms) were seen in 4 and &gt;60 ms in 1 pt. Gr 3/4 hematologic lab abnormalities were: anemia and neutropenia in 4 pts each and thrombocytopenia in 3 pts. Nonhematologic lab abnormalities were: Gr 4 hypokalemia (1), Gr 3 hyponatremia (1), hyperkalemia (1), and hypermagnesemia (2). Conclusions: No MCyR but 1 CHR with eradication of the T315i mutation were observed in 29 TKI-resistant CP CML pts, treated orally with 20 mg/day panobinostat, thrice weekly. Since the number of MCyRs required by the protocol was not seen, Stage 2 of the study was not opened. Safety/tolerability were comparable to what was reported for the same dose/schedule in other panobinostat studies, and no new safety findings were identified. The explanation that no more CRs were seen might be 2-fold: a dosing issue considering encouraging responses reported with oral, thrice weekly ≥40 mg/day single-agent panobinostat in pts with refractory Hodgkin’s disease and AML1 and quite early hematologic progression in many pts, not allowing for longer exposure to panobinostat in this more resistant population.

Efficacy of Tyrosine Kinase Inhibitors in Third Line Therapy in Chronic Phase Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4051-4051 ◽  
Author(s):  
Elza Lomaia ◽  
Andrey Zaritskey ◽  
Vasily Shuvaev ◽  
Irina Martynkevich ◽  
Mikhail Fominykh ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Line Therapy ◽  
Third Line

Abstract Introduction. Overall survival (OS) of patients in chronic phase (CP) chronic myeloid leukemia (CML) dramatically increased in the era of tyrosine kinase inhibitors (TKI). Meanwhile nearly half of patients discontinue 1-st line Imatinib due to resistance or intolerance. Half of them subsequently failure treatment with second line TKI. It seems that 20-25% of CP CML patients need 3-d line therapy (TKI-3l). There are a few reports regarding durable outcome of TKI-3l. Materials and Methods. In our retrospective study 53 patients (20 male, 33 female) with CML CP treated either by Nilotinib 400 mg BID (n=18), Dasatinib 100 mg QD (n=33) or Bosutinib 500 mg QD (n=5) as TKI-3l were included. The median age at the time of diagnosis was 46 years (23-88 years). The main reason for previous TKIs discontinuation was resistance: 48/53 (91%) had failure of one and 42/53 (79%) patients had failure of both previous TKIs treatment. Median CML duration before TKI-3l was 55 months (2-314 months). Before TKI-3l mutation analysis was performed in 35 patients: 18 mutations were revealed in 16 (46%) patients including T315I mutation in 3 cases. At the moment of 3-d line TKIs therapy initiation, all patients were in CP and 43/53 (81%) had at least complete hematologic response (CHR), 8/53 (15%) patients had major cytogenetic response (MCyR) including 1 patient with complete cytogenetic response (CCyR). Results. At the time of analysis, the median duration of TKI-3l therapy was 21 months (1-67 months). No additional patients achieved CHR, but during observational time CHR was maintained nearly in all 40/43 (93%) patients with CHR at baseline. New cases of MCyR and CCyR were observed in 15/45(33%) and 11/52(21%) of patients, respectively. Median time to MCyR and CCyR was 3.4 (3-8) and 5.2 (3-13) months, respectively. Median duration of MCyR and CCyR was 9.3 (1-43) months and 4.5 (3-6) months, respectively. Patients with resistant mutations did not obtain any cytogenetic response. TKI-3l treatment was discontinued in 21 patients. Intolerance was the reason of treatment discontinuation in 5/53(10%) cases. Progression to accelerated or blastic phases during therapy or after discontinuation occurred in 8/53 (15%) patients. Median time to progression was 14.7 months (1-46 months). There were 13 deaths in overall group of 53 patients. Two-year OS in TKI-3l was 67%. All patients with MCyR were alive and preserved CP phase. Concluson: Our results showed that 20% of patients might obtain at least CCyR and benefit with TKIs as third line. Therefore, after two TKI lines patients, who are not eligible for allogeneic transplantation and without resistant mutations should be treated with one more line of TKI therapy. Disclosures Lomaia: Novartis: Consultancy. Zaritskey:University of Heidelberg: Research Funding; Novartis: Consultancy.

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