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.

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.

Determinants of Choice of Front-Line Tyrosine Kinase Inhibitor for Chronic Phase CML: A Study from the "Registro Italiano LMC & Campus CML"

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Mario Tiribelli ◽  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Isabella Capodanno ◽  
Maria Cristina Miggiano ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Multivariable Analysis ◽  
Chronic Phase ◽  
Front Line ◽  
Line Therapy ◽  
Concomitant Medications

Introduction : therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice. Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib. Results: median age at diagnosis was 59.9 years [interquartile range (IQR) 47.1 - 71.7], with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively. Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start. As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged <45 (69.1%) while imatinib was used in 76.9% of patients over 65 (p<0.001). There was a predominance of imatinib use across all Sokal (51.1% in low, 61.3% in intermediate and 51.4% in high) and ELTS (50.3% in low, 60.4% in intermediate and 66.5%) risk categories. We observed a prevalent use of 2G-TKIs in patients presenting with higher WBC counts (55.1% if WBC >100,000/mm3 vs 38.2% if WBC <100,000/mm3; p<0.001), lower Hb (53.8% if Hb <10 g/dl vs 41.9 if Hb >10 g/dl; p=0.001) and bigger spleen (65.1% if spleen >5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p<0.001). There was a decreasing use of 2G-TKIs with higher number of concomitant drugs: 64.4% for 0, 47.7% for 1-2, 27.0% for 3-5 and 13.6% for >5 drugs, respectively (p<0.001). Concordantly, there was a significant higher use of imatinib in patients with hypertension (69.8%), diabetes (70.0%), COPD (73.7%), previous neoplasms (73.0%), AMI (86.3%) or stroke (97.2%) history (p<0.001 for all conditions). Lastly, we observed a wider use of imatinib (61.1%) in patients diagnosed in years 2018-19, compared to those of the period 2012-17 (53.7%; p=0.01). In multivariable analysis, factors correlated with imatinib use were age > 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications. Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib. Figure Disclosures Breccia: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.

scholarly journals Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

2015 ◽  
Vol 4 (2S) ◽  
pp. 17-20
Author(s):  
Mario Annunziata
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Chronic Myeloid Leukemia Patient ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Cutaneous Rash

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

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)

scholarly journals Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5058-5063 ◽  
Author(s):  
Carmen Fava ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Susan O'Brien ◽  
Nitin Jain ◽  
...  
Keyword(s):  
Survival Rate ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Blast Phase ◽  
Complete Hematologic Response

Abstract Second-generation tyrosine kinase inhibitors are effective in Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). Occasionally, patients with Ph+ ALL, or accelerated phase (AP) or blast phase (BP) CML achieve a major cytogenetic response (MCyR) but not a complete hematologic response (CHR). We analyzed 126 patients with CML in AP or BP, or with Ph+ ALL treated with dasatinib or nilotinib after imatinib failure. Twenty patients received sequential treatment with both dasatinib and nilotinib for a total of 146 instances. CHR and MCyR rates were 54% and 37%, respectively in AP, 17% and 39% in BP, and 33% and 50% in Ph+ ALL. Failure to achieve a CHR at the time of achievement of a MCyR was associated with an inferior outcome, similar to that of patients without a MCyR (2-year survival rate, 37% and 35%, respectively). In contrast, patients with MCyR and concomitant CHR had a 77% 2-year survival rate. Twelve of 29 patients with MCyR without concomitant CHR later achieved a CHR; the 2-year survival rate for these patients was 55% compared with 22% for those who never achieved a CHR. These results suggest that achievement of a MCyR without concomitant CHR is associated with poor outcome.

A Phase I Study of INNO-406 in Patients with Advanced Philadelphia (Ph+) Chromosome-Positive Leukemias Who Are Resistant or Intolerant to Imatinib and Second Generation Tyrosine Kinase Inhibitors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 469-469 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge Cortes ◽  
Philipp le Coutre ◽  
Arnon Nagler ◽  
Javier Pinilla ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitors ◽  
Phase Ii ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Complete Cytogenetic Response ◽  
Lyn Kinase ◽  
Ph Chromosome

Abstract Background: INNO-406 is an orally available, dual Abl/Lyn kinase inhibitor that is up to 55-times more potent than imatinib in Bcr-Abl expressing cell lines. Numerous Bcr-Abl mutant proteins are sensitive to INNO-406 in vitro, including the F317L mutant. Unlike other second generation tyrosine kinase inhibitors (TKIs), INNO-406 demonstrates specific Lyn kinase activity with no or limited activity against other Src-family member kinases. Methods: In this phase I dose finding study, patients (pts) with imatinib-resistant or -intolerant Philadelphia (Ph+) chromosome-positive leukemias were eligible for treatment with INNO-406 orally at doses ranging from 30 mg once daily (qd) through 480 mg twice daily (bid). Results: INNO-406 was administered to 41 pts (23M, 18F); median age 61 yrs (range, 20–76). Median duration of CML was 6 yrs (range, 0.1–23); median time on imatinib was 0.8 yrs (range, 0.1–6.5). Pts had CML in chronic phase (CP, n=21), accelerated phase (AP, n=7), or blast phase (BP, n=6), or Ph+ ALL (n=7). Previous treatment included nilotinib (n=9), dasatinib (n=13), and dasatinib/nilotinib (n=10). Pts have been treated with INNO-406 for a median of 42 days (range, 7–240+). Common mutations on study entry included Y253H (n=4), F311L (n=3), F317L (n=2), and T315I (n=2). Currently, 14 pts remain on study; 22 pts discontinued due to disease progression, 4 pts discontinued to pursue other treatment options, and 1 pt discontinued due to toxicity. Hematologic and cytogenetic responses have been reported. 2 of 7 CP pts who had failed only imatinib demonstrated a complete cytogenetic response, including 1 major molecular response. An additional pt had a minor cytogenetic response after 4 weeks of therapy before going off study to pursue an alternate treatment option. Among pts in CP who had failed more than one TKI, a complete cytogenetic response was reported in 1 pt who was intolerant to both imatinib (lung/skin toxicity) and dasatinib (pleural effusion). All 7 AP pts on study had failed multiple TKIs. In this population, 2 pts experienced complete hematologic responses. Additionally, in 1 pt, a reversion of the Y253H mutation was demonstrated, and 1 pt has experienced a disappearance of the F317L mutation. Related adverse events include reversible grade 2/3 elevation in the activity of transaminases. A DLT was reported in 1 pt in the 480 mg bid cohort (intrahepatic cholestasis and renal failure secondary to tumor lysis syndrome). Conclusions: INNO-406 is well tolerated in pts with clinical activity demonstrated across a range of dosing. Responses occur even in the setting of a heavily pretreated population thus making INNO-406 a viable option for CML therapy. The recommended phase II dose is anticipated to be 240 mg bid. Pivotal phase II studies are planned for late 2007.

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