Treatment Results With Dasatinib Or Nilotinib In Third Line Therapy Of Chronic Myeloid Leukemia After Failure Of Two Tyrosine Kinase Inhibitors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5189-5189
Author(s):  
Beatriz F Ribeiro ◽  
Eliana C M Miranda ◽  
Marcia T Delamain ◽  
Gislaine Borba Oliveira ◽  
Maria Helena Almeida ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Molecular Responses ◽  
The Third ◽  
Line Therapy ◽  
Third Line Therapy ◽  
Third Line ◽  
Tki Discontinuation

Abstract Chronic myeloid leukemia (CML) patients with imatinib failure are usually treated with second generation tyrosine kinase inhibitors (TKI). In case of dasatinib or nilotinib intolerance or resistance patients with HLA matched donor are submitted to allogeneic hematopoietic stem cell transplantation (HSCT) or switch treatment to a different TKI. Aims to evaluate complete hematological response (CHR), cytogenetic and molecular responses, overall, progression free and event free survival (OS, FPS and EFS) in CML patients in third line therapy that previously used 2 TKI. BCR-ABL mutations was also evaluated in this population Patients and methods between July 2008 and August 2012 26 CML patients were evaluated: 10 patients (pts) treated with dasatinib (38,5%) and 16 with nilotinib (61,5%) in third line therapy. OS, PFS and EFS were calculated with Kaplan-Meier method and Log-Rank was used for comparison, from the date of the third TKI start. The events for PFS were progression to accelerated phase (AP) or blast crisis (BC) and death. For EFS, were considered loss of CHR, loss of complete cytogenetic response (CCR), TKI discontinuation for failure or intolerance, progression or death. Patients were censored in HSCT date or TKI discontinuation for cytogenetic and molecular responses evaluation, but not for OS. Mutational analysis was done with Sanger sequencing. Results 13 male (50%) and 13 female patients with median age 54 years (22-75) and median follow-up of 32 months were analyzed (1-59). Previous response to imatinib: only one patient has achieved CCR. Status before third TKI start: 19 (73%) less than partial cytogenetic response (PCyR); 2 (7,7%) PCyR; 4 (15,5%) CCR;and 1 (3,8%) clonal evolution. 8/18 (42%) patients presented the following mutations: F317L (2), E255V (1), Y253H (1), M351T (1), M244V (1) e F359V (2). The median time of the third TKI treatment was 171 days (15-1140). Responses to third line TKI: CHR 17/19 (89%) in CP; 3/3 AF; 0/4 BC; CCR: 3/19 in CP (2 pts at 3 months and one in the 12º month); 1/3 AP; 0/4 BC; MMR: 4/19 in CP; 1/3 AP; 0/4 in BC. Nine lost CHR (45%) (8 in CP and one in AP). At 3 months, 1/21 pts (4.5%) achieved MMR; 2/13 (15%) at 6 months, while at 12 months 1/11 (9%) had MMR. At 3 months 11/21 had a BCR-ABL/ABL(IS) >10% and at 6 months 10/13 >1%. Three patients progressed to advanced phases (11,5%) ; 6 (23%) died (4 due to LMC, 1 acute myocardial infarction and 1 from graft vs host disease after HSCT; one lost follow-up. Third line treatment was discontinued in 12 (46%) pts: 6 for resistance, 2 death; 2 intolerance and resistance; 1 intolerance and one loss of follow-up. OS, PFS and EFS were 69%, 68% e 30% respectively(figure 1). OS was inferior in AP and BC in comparison with CP (0% vs 50% vs 90% - p< 0,0001)(figure 2). In summary responses may be obtained with dasatinib or nilotinib after 2 TKI failure, but they are not durable in advanced phases. Besides the results, that is an alternative for disease stabilization until the identification of a suitable donor or for patients with no performance status for HSCT. Disclosures: No relevant conflicts of interest to declare.

Efficacy of Tyrosine Kinase Inhibitors (TKIs) as Third Line Therapy In Patients with Chronic Myeloid Leukaemia In Chronic Phase Who Have Failed Two Prior TKIs

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2274-2274
Author(s):  
Amr R Ibrahim ◽  
Marco Bua ◽  
Jamshid S Khorshad ◽  
Dragana Milojkovic ◽  
Lina Eliasson ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Cytogenetic Response ◽  
Second Line ◽  
Second Line Therapy ◽  
The Third ◽  
Line Therapy ◽  
History Of ◽  
Third Line Therapy ◽  
Third Line

Abstract Abstract 2274 Patients with CML in chronic phase who have failed imatinib therapy are commonly treated with dasatinib or nilotinib, but a significant proportion fail to respond or relapse in which case they are often treated with the other tyrosine kinase inhibitor (TKI) that they had not yet received. We report here the largest series of CML patients in CP treated with a third line TKI after failing both imatinib and another TKI. We enrolled 26 patients. The median age was 64 years and 54% were male. 20 patients had received dasatinib and 6 nilotinib as second line therapy. All patients were still in first CP at the moment of commencing third line therapy, and none was harboring a T315I mutation. Failure to second line therapy was defined as no CHR at 3 months, no major cytogenetic response (MCyR) at 12 months or loss of a hematological or cytogenetic response. Patients who were unable to continue therapy on account of toxicity were also considered as having failed therapy. The median follow up for the surviving patients after starting third line therapy was 21.5 months (range, 6 – 46.5 months). The 2.5 years (30 months) cumulative incidences of MCyR, CCyR and MMR were 48.2%, 32.4%, 21.1% respectively. Multivariate analysis showed that the achievement of at least MiCyR (<95% Ph-positive) on imatinib (RR=5.6, p=0.03) or on second line therapy (RR=11.8, p=0.006) were the only independent predictors for the achievement of CCyR. When combining both variables we found that patients who had achieved MiCyR on one of the two prior therapies had a significantly better OS and higher probability of achieving cytogenetic response on third line therapy, i.e. the 30 month probability of OS and CCyR were 72.7% vs 20.4% (p=0.03) and of 71.4% vs 0% (p=0.0005) respectively (Figure). During follow up 9 (34.6%) patients died. The probability of OS at 30 months was 46.7%. The achievement of a cytogenetic response on second line and age younger than 64 (possibly reflecting eligibility for transplantation) were the only independent predictors for OS (RR=6.5, p=0.02 and RR=0.13, p= 0.02). Seventeen patients (65%) were classified as intolerant to previous therapies (imatinib or second line TKI). Intolerant patients had a probability of responding to the third line therapy similar to those of the resistant patients, but when this cohort was subdivided according to the type of intolerance we found that 11 patients who had hematologic toxicity with either therapy had a probability of CCyR at 30 months lower than that of the remaining 15 patients (11.1% vs 47.5 %, p=0.03), while the 8 patients with non-hematologic intolerance to the imatinib or to the second line had a probability of 30-month CCyR greater than that of the remaining 18 patients (87.5% vs 5.6%, p<0.001). At 3 months 26 patients remained on follow up, of whom 9 patients had achieved at least MiCyR. These 9 patients had better 30-month probabilities of CCyR and OS than the patients who had failed to achieve MiCyR, namely 88.9% vs 13.3% (p<0.0001), and 87.5% vs. 35.0% (p=0.1). When we excluded the only patient who died of non-leukemia related causes while in CCyR, the probabilities of OS was 100% vs 35.0% (p=0.04) Which patients should be offered third line TKI therapy? Patients who achieved cytogenetic response on first or second line therapy and patients with a history of non-hematologic intolerance to the prior TKI benefited from a third TKI. Patients with primary cytogenetic resistance to two TKIs or with a history of hematologic intolerance should receive an allogeneic stem cell transplant when possible. For patients in this situation who lack a transplant option we would recommend only a short course (3 months) of the third line therapy to identify responders. Non-responders should be offered experimental studies. Disclosures: Marin: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding.

scholarly journals Efficacy of tyrosine kinase inhibitors (TKIs) as third-line therapy in patients with chronic myeloid leukemia in chronic phase who have failed 2 prior lines of TKI therapy

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5497-5500 ◽  
Author(s):  
Amr R. Ibrahim ◽  
Christos Paliompeis ◽  
Marco Bua ◽  
Dragana Milojkovic ◽  
Richard Szydlo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Second Line ◽  
Line Therapy ◽  
Third Line Therapy ◽  
Third Line

Abstract We analyzed a cohort of 26 patients with chronic myeloid leukemia who had failed imatinib and a second tyrosine kinase inhibitor but were still in first chronic phase and identified prognostic factors for response and outcomes. The achievement of a prior cytogenetic response on imatinib or on second-line therapy were the only independent predictors for the achievement of complete cytogenetic responses on third-line therapy. Younger age and the achievement of a cytogenetic response on second line were the only independent predictors for overall survival (OS). At 3 months, the 9 patients who had achieved a cytogenetic response had better 30-month probabilities of complete cytogenetic responses and OS than the patients who had failed to do so. Factors measurable before starting treatment with third line therapy and cytogenetic responses at 3 months can accurately predict subsequent outcome and thus guide clinical decisions.

Switch to nilotinib versus continued imatinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with detectable BCR-ABL after 2 or more years on imatinib: ENESTcmr 12-month (mo) follow-up.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6505-6505
Author(s):  
Jeffrey Howard Lipton ◽  
Timothy P. Hughes ◽  
Brian Leber ◽  
Carmino De Souza ◽  
Pedro E Dorlhiac-Llacer ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Molecular Responses ◽  
Log Reduction ◽  
To Receive ◽  
Tki Discontinuation ◽  
Minimal Evidence

6505^ Background: Nilotinib induced significantly faster and deeper molecular responses vs imatinib in the ENESTnd trial. Achieving these deeper molecular responses may increase patient eligibility for future TKI discontinuation studies. Methods: CML-CP pts (N = 207) who achieved a complete cytogenetic response but were still BCR-ABL positive by RQ-PCR after ≥ 24 mo on imatinib were randomized 1:1 to receive nilotinib 400 mg BID (n = 104) or to continue their imatinib dose (400 or 600 mg QD [n = 103]). The primary endpoint was confirmed CMR (undetectable BCR-ABL by RQ-PCR with a sample sensitivity of ≥ 4.5 logs in 2 consecutive samples). Other endpoints included molecular responses (MMR ≤ 0.1%IS, MR4 ≤ 0.01%IS, and MR4.5 ≤ 0.0032%IS) and BCR-ABL ratio over time. Results: Rate of confirmed CMR was higher in the nilotinib arm vs imatinib by 12 mo (12.5% vs 5.8%) (Table). Rate of CMR (undetectable BCR-ABL in at least 1 sample) by 12 mo was significantly higher on nilotinib vs imatinib (23.1% vs 10.7%; P = .02). Rates of MMR, MR4, MR4.5, and CMR were also superior in pts switched to nilotinib, and these pts had significantly shorter times to achieve these responses. Imatinib-treated pts had minimal evidence of improvement in molecular response vs a median 0.5-log reduction in BCR-ABL by 12 mo for the nilotinib cohort. With 12-mo follow-up, 84% of pts remained on nilotinib and 96% on imatinib. The nilotinib safety profile was consistent with prior studies. Both drugs were well tolerated. Conclusions: Twice as many pts achieved deeper molecular responses after switching to nilotinib vs staying on imatinib. [Table: see text]

Is There a Clinical Benefit for Less Than a Complete Cytogenetic Response (CCyR) for Patients (Pts) with Chornic Myeloid Leukemia (CML) Receiving Tyrosine Kinase Inhibitors (TKI) as Second or Third Line Therapy?

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1241-1241
Author(s):  
Jorge E. Cortes ◽  
Alfonso Quintas-Cardama ◽  
Elias Jabbour ◽  
Elizabeth Burton ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Survival Probability ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Survival Advantage ◽  
Probability Of Survival ◽  
Best Response ◽  
Third Line Therapy ◽  
Third Line

Abstract Abstract 1241 Background: Achieving a CCyR is the minimum acceptable response for pts with CML. This is based on the association of CCyR with prolonged survival. Thus, for a newly diagnosed patient with CML in CP not achieving a CCyR should be considered failure. With Interferon the rate of CCyR was low, but with imatinib >80% of pts achieve a CCyR, and with dasatinib or niloitnib as frontline therapy the rate may be >90%. However, for pts with resistance to frontline therapy only approximately 50% of pts achieve CCyR, and this rate is even lower with third line therapy. Thus, most pts receiving 2nd or 3rd line tyrosine kinase inhibitors (TKI) either do not respond or achieve responses that are less than a CCyR. The value of achieving a CCyR in this setting is undisputed; however, it is unclear whether lesser responses may also confer a survival advantage to pts treated in the 2nd and 3rd line setting compared to not responding at all. Aim: To investigate the clinical significance of achieving a response less than CCyR in pts with CML in CP treated with TKI. Methods: We analyzed the records of all pts with CML in CP receiving therapy with second generation TKI bosutinib, dasatinib, or niloitnib in prospective clinical trials. The cytogenetic response was recorded by standard criteria based on cytogenetic analysis in 20 metaphases. Survival was measured from the time of start of treatment with 2nd or 3rd TKI to last follow-up or death from any cause at any time. To account for time to achieve response, calculations for survival were done with a landmark analysis at 6 months. Results: A total of 161 pts were treated with 2nd generation TKI bosutinib (n=51), dasatinib (n=64), or niloitnib (n=46) after imatinib failure and are evaluable for response. There were no significant differences between the pts treated with the 3 agents and thus their characteristics and outcome are presented together for the overall population. Their median age was 56 yrs (range, 21–92 yrs), median PS 0 (range, 0–2), and median time from diagnosis to treatment 70 months (4 – 70). The reason for imatinib failure was resistance in 127 (79%), intolerance in 29 (18%), and unknown in 5 (3%). The response to 2nd TKI is presented in Table 1. After a median follow up of 42 months, 105 (65%) of pts have been taken off study, most frequently because of resistance or progression (32%). The median survival has not been reached, and the 2-year probability of survival for all pts is 89%. Table 1 shows the survival probability for pts according to their best response to therapy. Pts who achieved CCyR had a superior survival probability (98% at 2 years). Pts with best response partial cytogenetic response (PCyR), minor cytogenetic response (mCyR) or CHR, no cytogenetic response had similar survival probabilities (84-88%), all of them significantly better than those with no response (43%). Another 18 pts were treated with bosutinib (n=9), dasatinib (n=4) or niloiotnib (n=5) after failure to 2 prior TKI. Their median age was 58 years (range, 22–79) and median time form diagnosis 69 months (12- 239). After a median follow-up of 30 months 13 (72%) have discontinued therapy. The median survival is 56 months. The response to 3rd TKI and survival by best response to TKI is presented on table 1. The survival probability is significantly worse for pts not responding to therapy, but there is no significant difference in the 2-year probability of survival for pts achieving CCyR, PCyR or CHR only. Conclusions: Achievement of CCyR is unquestionably the optimal goal of therapy as it is associated with a survival advantage. However, in a salvage setting, pts achieving partial or minor cytogenetic responses, and perhaps those achieving a CHR, may also have a survival advantage over those not responding at all to therapy. Thus, when evaluating new therapies in pts with CML that are heavily pre-treated and who are much less likely to achieve CCyR, agents that induce at least these lesser responses should be considered of potential benefit to pts. Disclosures: Cortes: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Pfizer: Consultancy. Quintas-Cardama:Novartis: Consultancy; BMS: Consultancy. O'Brien:Novartis: Research Funding; BMS: Research Funding. Verstovsek:INCYTE: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Kantarjian:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding.

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.

scholarly journals Efficacy and safety of nilotinib as third-line therapy in an elderly patient with CML

2015 ◽  
Vol 6 (2S) ◽  
pp. 15-18
Author(s):  
Giovanni Caocci ◽  
Sandra Atzeni ◽  
Giorgio La Nasa
Keyword(s):  
Pleural Effusion ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Day Treatment ◽  
Skin Toxicity ◽  
Drug Dose ◽  
Molecular Response ◽  
Line Therapy ◽  
Third Line Therapy ◽  
Third Line

This case report describes a 74 year old male patient with low Sokal risk chronic myeloid leukemia (CML). Treatment was started four years ago with imatinib, 400 mg/day. The patient achieved complete hematologic response but, after 3 months of treatment, developed grade 3 skin toxicity. Imatinib was stopped and the patient was started on dasatinib, achieving complete cytogenetic and molecular response. Two months later, physical examination revealed bilateral gynecomastia. After 2 years of treatment the patient presented with pleural effusion and the drug dose was reduced but, following relapse of CML, therapy was switched to nilotinib, 800 mg/day. Treatment with nilotinib is currently ongoing and is well tolerated by the patient who is again in complete molecular response, with no signs of pleural effusion. Considering the growing availability of new and more potent tyrosine kinase inhibitors (TKI) it is important for the clinician to be aware of the possible inhibitory effects of these molecules against other members of the tyrosine kinase family. Safety of TKI in frail and elderly patients with CML is a fundamental goal. The results achieved in our patient show that nilotinib is safe and effective even when used as third line therapy.

Causes of Death for Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Treated with Imatinib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4279-4279
Author(s):  
Andrea Renata Dean ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Mary Beth Rios ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Causes Of Death ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Cardiac Complications ◽  
Time Of Death ◽  
Lost To Follow Up

Abstract Abstract 4279 Background Imatinib is the current standard initial therapy for patients with CML in CP. Over 80% of patients achieve a complete cytogenetic remission (CCyR), and the projected overall survival at 7 years is 89%. This survival probability is significantly better than the historical pre-imatinib era (approximately 50% at 5 years). Understanding the causes of death among patients treated with imatinib is needed to further improve the long-term results. Aim To determine cause of death in patients treated with imatinib as initial therapy for CP Philadelphia-chromosome positive CML. Methods We reviewed the records of all patients with CML in CP treated with imatinib (standard or high-dose) as initial therapy since 2000. Results A total of 281 patients were treated. The overall rate of major cytogenetic response (MCyR) was 94% and CCyR 89%. At 6 years the projected event-free survival was 83% and overall survival 91%. After a median follow-up of 5.6 years, 29 (10%) patients have died. The median age at diagnosis was 56 years (range, 20 to 84 years) and at the time of death 60 years (23 to 91 years). The median time from start of therapy to death was 3.9 years (6 months to 8 years). Initial imatinib dose was 400mg for 13 patients (out of 281, 26% treated at that dose) and 800mg for 16 patients (out of 281, 74% treated at 800mg). All patients had achieved a complete hematological response. Among those that eventually died, 24 (82%) pts achieved a MCyR with imatinib: 19 (65%) achieved CCyR and 5 (17%) partial cytogenetic response (PCyR). Two patients achieved a minor cytogenetic response and 2 had no cytogenetic response; one patient was lost to follow up soon after starting treatment. Causes of death included the following: CML (8), transplant-related complications (4), cardiac complications (3), cerebral vascular accident (2), motor vehicle accident (2), acute myeloid leukemia (1), suicide (1), sudden cardiac death (1), metastatic melanoma (1), metastatic renal cell carcinoma (1), and bowel obstruction (1). Four patients were lost to follow up and cause of death could not be determined. All eight patients that died from CML had lost their hematological response to imatinib; 7 transformed to blast phase. Three of these patients received treatment with second generation tyrosine kinase inhibitors and one achieved a transient MCyR. The four patients that died from transplant-related complications ranged in age from 20 to 48 years at diagnosis. Patients underwent transplant (2 in CP, 2 in 2nd CP) after failing treatment with imatinib and other therapies. Three patients where in CCyR at time of death and 1 had unknown cytogenetic response. Among the other 17 pts, 9 (53%) were in CCyR at the time of death. The 3 patients that died from cardiac complications had past medical histories of heart disease and all were in CP at time of death: 2 with CCyR and 1 with PCyR. These patients died from congestive heart failure, myocardial ischemia, or arrthymia, respectively. The 2 patients that died from cerebral vascular accidents had prior histories of stroke. Both patients were in CP: 1 in CCyR and 1 with PCyR. The 2 patients who died of car accidents were in CP at the time of death: 1 in CCyR and 1 with PCyR. The patients that died of acute myeloid leukemia, suicide, sudden cardiac death, metastatic renal cell carcinoma and bowel obstruction were all in CCyR prior to death. The patient who died from metastatic melanoma had unknown cytogenetics prior to death. Among the patients that died for reasons other than CML or transplant-related complications, all except three were treated with imatinib only. Two of the 4 patients lost to follow up underwent bone marrow transplants at other facilities and status at time of death is unknown. The other 2 patients lost to follow up discontinued imatinib due to side effects long before their death. Discussion The survival probability of CML CP patients treated with imatinib is excellent. Less than half of the deaths are related to CML or stem cell transplant. These deaths might be preventable if 2nd generation tyrosine kinase inhibitors are more effective as initial therapy. Other deaths result from co-morbidities, with no deaths attributed to the treatment with imatinib. Close monitoring of patients with predisposing factors for these events could improve their long-term outcome. Disclosures: Rios: BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau. Jabbour:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Cortes:Novartis: Research Funding.

Outcome of Patients with CML Treated with Dasatinib or Nilotinib after Failure of Second Prior TKIs

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2294-2294
Author(s):  
Antonella Russo Rossi ◽  
Massimo Breccia ◽  
Fausto Castagnetti ◽  
Luigiana Luciano ◽  
Antonella Gozzini ◽  
...  
Keyword(s):  
Median Time ◽  
Conflicts Of Interest ◽  
Cell Uptake ◽  
Second Line ◽  
The Third ◽  
Line Therapy ◽  
Third Line ◽  
New Mutations

Abstract Abstract 2294 Background. The TKIs Nilotinib and Dasatinib offer additional therapeutic options for patients with CML who are resistant or intolerant to Imatinib. These agents, active against the majority of Imatinib resistant BCR-ABL mutated clones, have a different pattern of kinase target selectivity, pharmacokinetics parameters, cell uptake, efflux properties and adverse events profiles. Preliminary results suggest that some patients may respond to a second TKI used as third line therapy, but little is known about the long term benefit of such an approach.Aim of this collaborative Italian study was to verify the response (rate and duration) and the clinical outcome in patients with CML treated with a third TKI after sequential failure of the previous ones. Methods. We evaluated 66 patients with CML, resistant/intolerant to Imatinib and treated with Dasatinib or Nilotinib, then switched to a third- line TKI after treatment failure. Of these, 29 patients were treated with dasatinib after imatinib/nilotinib failure and 37 with nilotinib after imatinib/dasatinib failure. Patients were monitored with complete blood counts, cytogenetic analysis, bone marrow aspiration RT-PCR and mutational analysis. Results. A total of 66 patients (median age 63 years, range, 33–85 years) were treated with sequential TKIs; 40 (61%) patients had received interferon-a before starting Imatinib; 26 (39%) patients received imatinib as first line therapy. The median time on imatinib therapy was 47.5 months (range 4–101 months). At the start of nilotinib as second line, 27/29 (93%) patients were in CP, 1 (3.5%) in AP, and 1 (3.5%) in BP. 9 patients (31%) had developed mutations before starting treatment. The median time on second line TKI was 8 months (range 2–36 months). In the resistant patients 4 new mutations were identified (F359V in two patients, T315I, Y253H+F359V). At the start of dasatinib as second line, 33/37 (89.2%) patients were in CP, 4 (10.8%) in AP. 7 patients (18.9%) had developed mutations before starting treatment. The median time on second line TKI was 14 months (range 4–59 months).In the resistant patients 5 new mutations were identified (F137L in three pts, M318T, M244V+F317L). At the start of the third TKI, 60/66 (90.9%) patients were in CP, 5 (7.6%) in AP, and 1 (1.5%) in BP. Of these, 7 patients (18.9%) on dasatinib and 7 (24.1%) on nilotinib had mutations before starting treatment. The best response to the third line treatment with TKI was 10 (15.2%) MMR, 10 (15.2%) CCyR, 8 PcyR (12.1%), 5 (7.5%) mCyR, 24 (36.4%) CHR and 9 (13.6%) No Response (NR). In the dasatinib group, 9 (31%) patients discontinued treatment because of toxicity versus 17 (45.9%) patients in the nilotinib group.Two new mutations (F317L, E255V) emerged with dasatinib as third line therapy.After a median follow up of 13 months (range 2–37 months) 50 patients (48 CP, 2 AP) are continuing therapy (33 on nilotinib, 17 on dasatinib).Since the start of the third TKI, 61 patients (92.4%) are still alive for a median overall survival of 110 months (range 15–300) (52 CP, 7 AP, 2 NA); the 5 deaths (7.6%) were caused by disease progression and spread of the gene mutation T315I. Discussion. In our study, about one third of patients derived benefit from the use of three sequential TKIs; patients with better, longer response (28.7%) to third TKI were the same patients with a better response to the Imatinib and 2TKIs therapy. All these patients had taken interferon therapy before the Imatinib. In this subset of patients (good responders: CCyR and MMR) 5 patients developed mutations that were sensitive to the sequential treatment.The lack of a durable cytogenetic remission could be explained by the emergence of new kinase domain mutations as patients are exposed to sequential TKI; a change of therapy resulted in an adequate response. In our series, patients with poor prognosis showed mutations not sensitive to the TKIs treatment. Conclusions. Although allogeneic SCT is the treatment of choice in all patients failing 2 TKIs who are suitable candidates for this approach, alternative strategies are required for ineligible patients. The use of a third TKI after failure of two previous TKIs induces response in some patients. Longer follow up of a larger series of patients is needed to determine the long term impact of the response. Disclosures: No relevant conflicts of interest to declare.

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.

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