Evolution of definitions of response, progression-free survival and event-free survival in front-line studies of chronic myeloid leukemia

Abstract Abstract 1691 Dasatinib and nilotinib have been founded to be effective and well-tolerated in patients who develop resistance or intolerance to imatinib. Not enough data are currently available to recommend one over the other as the preferred second-line therapy based on efficacy data. Therefore we planned a multicenter retrospective study to analyze the efficacy and safety of dasatinib and nilotinib in patients with imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. In this Korean multicenter study, 126 patients imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase were treated with dasatinib (n=76) or nilotinib (n=50) The purpose of this study was to compare rates of cytogenetic and molecular response rate, event-free survival (EFS), progression-free survival (PFS) and overall survival (OS), and toxicities of nilotinib and dasatinib treatment of imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. PFS was defined as the time from the start of treatment to the earliest date of any of following event: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), progression to accelerated phase (AP) or blastic phase (BP), discontinuation due to treatment failure as assessed by the clinician, and death from any cause on therapy. Event was defined by any one of the following: loss of CHR, loss of MCyR, progression to AP or BP, discontinuation due to treatment failure as assessed by the clinician, treatment discontinuation due to toxicity, and death from any cause on therapy. For dasatinib and nilotinib group, median ages (51 years old vs. 53), median durations of CML (23.7 months vs. 19.8 ) before receiving dasatinib or nilotinib and duration of prior imatinib treatment (21.7 months vs 17.7) were comparable. Nilotinib group had a higher proportion of intermediate and high sokal scores at the time of diagnosis than dasatinib group (41.5 vs 29.3% (high), 41.5% vs 32.5%(intermediate), 17.1% vs 37.9(low), p= 0.04). After median follow-up durations of 20.2 months of dasatinib group and 25.3 months of nilotinib group, the rates of major molecular response were 50.0% for dasatinib group and 59.6% for nilotinib group (p=NS) and the rates of MCyR (complete and partial cytogenetic response) were 78.4% for dasatinib group and 74.5% for nilotinib group (p=NS). The estimated EFS at 24 months was 67% and 48% in dasatinib and nilotinib group, respectively. (p<0.05). The estimated PFS at 24 months was 85% and 56% in dasatinib and nilotinib group, respectively. (p<0.05) Overall survival rates were comparable in both treatment groups (24-months OS; dasatinib 91%, nilotinib 94%; p=0.65). Both were generally well tolerated. Hematologic toxicities were more frequent among patients receiving dasatinib. 10 patients (13%) had pleural effusion in dasatinib; 9 events were grade 1 or 2. Elevated liver enzyme were more frequent among patients receiving dasatinib. In conclusion, In this study population, nilotinib and dasatinib showed similar cytogenetic and molecular response rates and survival. Toxicity profiles of two drugs were different and both drugs showed tolerable toxicities. In terms of event-free survival and progression-free survival, dasatinib was superior to nilotinib, but caution is warranted in interpretation because baseline characteristics including hematologic and cytogenetic response at the time of start with dasatinib and nilotinib and sokal scores at the time of diagnosis were different. Disclosures: No relevant conflicts of interest to declare.

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5 Year Experience in Chronic Phase-Chronic Myeloid Leukemia Treated with Imatinib Copy Drugs in a Peruvian Hospital

Blood ◽

10.1182/blood.v118.21.4449.4449 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4449-4449

Author(s):

Aimee Torres ◽

Juan Ramon Navarro ◽

Jose Untama ◽

Mariela Moreno ◽

Sergio Murillo

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Median Time ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Event Free Survival ◽

Free Survival ◽

Hasford Score

Abstract Abstract 4449 BACKGROUND AND OBJECTIVES: In our Hospital patients with Chronic Myeloid Leukemia (CML) in chronic phase (CP) were treated with imatinib (Glivec) 400 mg qd from june 2001 to june 2006. Since july 2006, only imatinib copy drugs (brand names: Zeite, Imatec, Imatib, Millatus and Celonib, all of Indian origin) are being used to treat this disease at the Rebagliati Hospital in Lima Peru. We present here the efficacy, security, event-free survival, progression free survival, overall survival of patients treated with imatinib copy drugs. METHODS Retrospective and descriptive analysis of CP-CML patients treated only with imatinib since july 2006. They all initiated the treatment with 400 mg qd. Five year experience is presented here. RESULTS We analyzed data from 51 patients (pts) with CP-CML. Median age at diagnosis was 45.1 years (15–90), 49% female and 51% male, all patients were Chromosome Philadelphia positive. Low, Intermediate and High Hasford Score were 32%, 48% and 20%, respectively. Median time from diagnosis to start of imatinib was 7.6 months (0–123). Five patients (9.8%) began treatment more than six months after diagnosis. All patients had at least a 3 month cytogenetic monitoring. Thirty five (68.6%) and 39 patients (76.4%) achieved Complete Cytogenetic Response (CCyR) and Mayor Cytogenetic Response (MCyR), respectively. Median time to CCyR was 7.6 months and 71.4% of these patients achieved it during the first six months of treatment. CCyR and MCyR were 38% and 67% at 3 months, 57% and 70% at 6 months, 63% and 83% at 12 monhts, 78% and 91% at 18 months, respectively. Quantitative RT-PCR was performed in 22 patients with CCyR and 18 pts (81.8%) had Mayor Molecular Response (MMR) in five years of follow up. Four pts (7.8%) progressed to Blastic Phase and all of them had Low Hasford Risk at diagnosis. Eight pts (15.6%) changed to 2nd line treatment. Two pts (3.9%) abandoned treatment. Only 1 pt (1.9%) had both anemias 3–4. Eighteen pts (35.2%) had neutropenia-3, 8 pts (15.6%) had neutropenia-4, 7 pts (13.7%) had thrombocytopenia-3 and 4 pts (7.8%) had thrombocytopenia-4. Neutropenias 3–4 were managed with filgrastim, as treatment and as prophylaxis. At 5 years, Event Free Survival (EFS), Progression Free Survival (PFS) and Overall Survival (OS) were 82%, 89% and 91%, respectively (Figure 1, 2 and 3). CONCLUSIONS In our hospital, CP-CML patients treated with imatinib copy drugs obtained important cytogenetic and molecular responses with prolonged EFS, PFS and OS and an acceptable safety profile. Hasford Score was not a good prognosis predictor. Treatment with Imatinib copy drugs has proven to be an acceptable treatment in CML patients in our hospital. Disclosures: Torres: Bristol Myers Squibb: Speakers Bureau.

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Epidemiologic study on survival of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia patients with BCR-ABL T315I mutation

Blood ◽

10.1182/blood-2009-04-219410 ◽

2009 ◽

Vol 114 (26) ◽

pp. 5271-5278 ◽

Cited By ~ 80

Author(s):

Franck E. Nicolini ◽

Michael J. Mauro ◽

Giovanni Martinelli ◽

Dong-Wook Kim ◽

Simona Soverini ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Mutation Detection ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Epidemiologic Study ◽

Progression Free Survival ◽

Free Survival ◽

T315i Mutation

Abstract The BCR–ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP), or blastic-phase (BP) and Philadelphia chromosome—positive (Ph)+ acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation detection was 54 years; 57% cases were men. Median time between TKI treatment initiation and T315I mutation detection was 29.2, 15.4, 5.8, and 9.1 months, respectively, for CP, AP, BP, and Ph+ ALL patients. After T315I mutation detection, second-generation TKIs were used in 56% of cases, hydroxyurea in 39%, imatinib in 35%, cytarabine in 26%, MK-0457 in 11%, stem cell transplantation in 17%, and interferon-α in 6% of cases. Median overall survival from T315I mutation detection was 22.4, 28.4, 4.0, and 4.9 months, and median progression-free survival was 11.5, 22.2, 1.8, and 2.5 months, respectively, for CP, AP, BP, and Ph+ ALL patients. These results confirm that survival of patients harboring a T315I mutation is dependent on disease phase at the time of mutation detection.

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Current event-free survival after sequential tyrosine kinase inhibitor therapy for chronic myeloid leukemia

Cancer ◽

10.1002/cncr.25604 ◽

2010 ◽

Vol 117 (2) ◽

pp. 327-335 ◽

Cited By ~ 17

Author(s):

Aref Al-Kali ◽

Hagop Kantarjian ◽

Jianqin Shan ◽

Roland Bassett ◽

Alfonso Quintás-Cardama ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Inhibitor Therapy ◽

Event Free Survival ◽

Current Event ◽

Free Survival ◽

Tyrosine Kinase Inhibitor Therapy

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Age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival

Leukemia Research ◽

10.1016/j.leukres.2014.06.020 ◽

2014 ◽

Vol 38 (10) ◽

pp. 1173-1176 ◽

Cited By ~ 17

Author(s):

Massimo Breccia ◽

Luigiana Luciano ◽

Roberto Latagliata ◽

Fausto Castagnetti ◽

Dario Ferrero ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Elderly Patients ◽

Initial Dose ◽

Myeloid Leukemia ◽

Event Free Survival ◽

Free Survival

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Prediction of Response to Imatinib by Prospective Quantitation of BCR-ABL Transcript in Late Chronic Phase Chronic Myeloid Leukemia PatientsBy GIMEMA Working Party on CML.

Blood ◽

10.1182/blood.v104.11.4672.4672 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4672-4672

Author(s):

Giovanni Martinelli ◽

Gianantonio Rosti ◽

Fabrizio Pane ◽

Marilina Amabile ◽

Simona Bassi ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Working Party ◽

Progression Free Survival ◽

Prediction Of Response ◽

Free Survival ◽

Blood Samples

Abstract Imatinib mesylate (STI571), a specific Bcr-Abl inhibitor, has shown a potent antileukemic activity in clinical studies of chronic myeloid leukemia (CML) patients. Early prediction of response to imatinib cannot be anticipated. We used a standardized quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR) for bcr-abl transcripts on 191 out of 200 late-chronic phase CML patients enrolled in a phase II clinical trial with imatinib 400 mg/day. Bone marrow samples were collected before treatment, after 3, 6 and 12 months or at the end of study treatment (12 months) while peripheral blood samples were obtained after 2, 3, 6, 10, 14, 20 and 52 weeks of therapy. The amount of Bcr-Abl transcript was expressed as the ratio of Bcr-Abl to β2-microglobulin (β2M). We show that, following initiation of imatinib, the early Bcr-Abl level trends in both bone marrow and peripheral blood samples made it possible to predict the subsequent cytogenetic outcome after 6 and 12 months of treatment, and that these early trends were also predictive of progression-free survival.

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Event-Free Survival According to Age in Patients with Chronic Myeloid Leukemia Receiving Imatinib Frontline: The Younger, the Later, the Worse?

Blood ◽

10.1182/blood.v126.23.4038.4038 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4038-4038 ◽

Cited By ~ 1

Author(s):

Roberto Latagliata ◽

Massimo Breccia ◽

Ida Carmosino ◽

Federico Vozella ◽

Federico De Angelis ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Real Life ◽

Age At Diagnosis ◽

Molecular Response ◽

Event Free Survival ◽

Secondary Resistance ◽

Free Survival

Abstract Differences in baseline features and follow-up among patients with chronic myeloid leukemia (CML) according to age at diagnosis have been recently reported in cohorts from clinical controlled trials (Castagnetti F et al, 2015). To evaluate this issue in a real-life setting, we revised 207 consecutive CML patients treated at our Institution with imatinib frontline from 6/2002 to 6/2013, dividing them in young adults (>20 <45 years) (YA), middle-aged adults (≥45 <65 years) (MA) and elderly (≥65 years) (EL). The main features at baseline of the whole cohort and of the 3 age groups are reported in the Table. Table.ALLYAMAELpN° of patients207617274M/F108/8930/3140/3238/360.752Median WBC (x 109/l)IQR66.1 (32.7 - 119.0)109.8 (65.9 - 148.0)59.5 (31.3 - 126.6)40.1 (26.5 - 81.4)<0.001Median Hb (g/dl)(IQR)12.5 (11.0 - 13.5)11.7 (9.8 - 12.7)12.7 (11.0 - 14.2)12.8 (11.3 - 13.7)0.002Median PLT (x 109/l)IQR414 (275 - 616)445 (291 - 597)378 (262 - 546)457 (271 - 732)0.287Spleen enlargement (>5cm) N° (%)17 (8.3)11 (18.3)4 (5.6)2 (2.7)0.003Sokal score (N°)Low/Int/High89/93/2047/9/338/27/54/57/12<0.001Comorbidities ≥ 2, N° (%)77 (37.2)5 (8.1)26 (36.1)46 (62.1)<0.001 The rates of complete cytogenetic response (CCyR) were similar (86.4% in YA, 95.5% in MA and 91.0% in EL, p=0.227) while the rate of major molecular response was higher in the MA group (89.7% vs 63.8% in YA and 75.8% in EL, p=0.001). The number of events (permanent discontinuation due to toxicity, primary or secondary resistance, any death for CML related or unrelated causes) was lower in the MA group [8 (11.1%) vs 21 (34.4%) in YA and 28 (37.8%) in EL, p=0.001]: no difference was observed in the rate of evolution to blastic phase [3 (4.9%) in YA, 1 (1.4%) in MA and 2 (2.7%) in EL, p=0.478]. The number of deaths was higher in the EL group [12 (16.2%) vs 2 (3.2%) in YA and 0 in MA, p<0.001]: it is worth of note, however, that 11/12 deaths in the EL group were not related to CML progression. The 4-year event-free survival (EFS) for the whole cohort was 73.5% (95%CI 67.0 - 80.0): the 4-year EFS in the MA group [92.0% (95%CI 85.1 - 98.9)] was significantly higher than in YA group [67.3% (95%CI 55.1 - 79.5)] and in EL group [61.1% (95%CI 49.5 - 73.7)] (p=0.001). The 4-year overall survival (OS) for the whole cohort was 94.4% (95%CI 90.9 - 97.9): the 4-year OS in the EL group [72.4.% (95%CI 56.9 - 87.9)] was significantly lower than in YA group [96.3% (95%CI 91.2 - 100)] and in MA group (100%) (p<0.001). In conclusion, age at diagnosis influences significantly the course of CML patients treated with imatinib: the MA group has the best follow-up with an excellent OS and EFS, while the relatively lower OS and EFS in the EL group are clearly related to the incidence of unrelated deaths like in the general aged population. A possible explanation of the counterintuitive worse course of YA group is the delayed diagnosis in these patients (higher WBC counts, lower Hb levels, higher rate of spleen enlargement > 5 cm) compared to aged patients, who have often concomitant diseases and make routinely blood analyses: however, a more aggressive biology of CML in YA could not be excluded and warrants further investigations. Disclosures No relevant conflicts of interest to declare.

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Initial Molecular Response at 3 Months May Predict Both Response and Event-Free Survival at 24 Months in Imatinib-Resistant or -Intolerant Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase Treated With Nilotinib

Journal of Clinical Oncology ◽

10.1200/jco.2011.40.5217 ◽

2012 ◽

Vol 30 (35) ◽

pp. 4323-4329 ◽

Cited By ~ 65

Author(s):

Susan Branford ◽

Dong-Wook Kim ◽

Simona Soverini ◽

Ariful Haque ◽

Yaping Shou ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Cumulative Incidence ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Molecular Response ◽

Close Monitoring ◽

Event Free Survival ◽

Free Survival ◽

Transcript Levels ◽

Imatinib Resistant

Purpose The association between initial molecular response and longer-term outcomes with nilotinib was examined. Patients and Methods Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237). Results BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of > 1% to ≤ 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of > 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of > 0.1% to ≤ 1%, > 1% to ≤ 10%, and > 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR–ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of ≤ 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of > 1% to ≤ 10% and 48% for patients with BCR-ABL1 (IS) of > 10%. Conclusion Patients with BCR-ABL1 (IS) of > 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of ≤ 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response.

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EVI-1 oncogene expression predicts survival in chronic-phase CML patients resistant to imatinib treated with second-generation tyrosine kinase inhibitors

Blood ◽

10.1182/blood-2010-01-264234 ◽

2010 ◽

Vol 116 (26) ◽

pp. 6014-6017 ◽

Cited By ~ 20

Author(s):

Mustafa Daghistani ◽

David Marin ◽

Jamshid Sorouri Khorashad ◽

Lihui Wang ◽

Philippa C. May ◽

...

Keyword(s):

Overall Survival ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Second Generation ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Progression Free Survival ◽

Event Free Survival ◽

Free Survival

Abstract Activation of the EVI-1 oncogene has been reported in acute myeloid leukemia, chronic myeloid leukemia (CML) in blast crisis, and less commonly, in chronic-phase CML patients. We screened an unselected cohort of 75 chronic-phase CML patients who had failed imatinib for expression of EVI-1 and sought a correlation with subsequent outcome on the second-generation tyrosine kinase inhibitors dasatinib (n = 61) or nilotinib (n = 14). The 8 patients (10.7%) who expressed EVI-1 transcripts detectable by real-time polymerase chain reaction had significantly lower event-free survival, progression-free survival, and overall survival than patients with undetectable transcript. The predictive value of EVI-1 expression was validated in an independent cohort. In a multivariate analysis, EVI-1 expression status and the best cytogenetic response obtained on imatinib were the only independent predictors for overall survival, progression-free survival, and event-free survival. Our data suggest that screening for EVI-1 expression at the time of imatinib failure may predict for response to second-line TKI therapy and consequently aid clinical management.

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