γδ T Cells Number, CD200, and Flt3 Expression Is Associated with Higher Progression Free Survival in Patients with Chronic Myeloid Leukemia

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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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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PCN79 IMPACT OF NON-ADHERENCE TO IMATINIB ON PROGRESSION-FREE SURVIVAL AS 1ST TREATMENT FOR CHRONIC MYELOID LEUKEMIA IN BRAZIL: TWO YEARS FOLLOW UP

Value in Health ◽

10.1016/j.jval.2011.02.934 ◽

2011 ◽

Vol 14 (3) ◽

pp. A168-A169

Author(s):

V.A.M. Funke ◽

A. Moellmann-Coelho ◽

E. Asano ◽

M.E. Nita ◽

B.M. Donato ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Progression Free Survival ◽

Free Survival

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Frequent Inactivating Mutations of TET2 and CBL Are Associated with Acquired Uniparental Disomy in Atypical Chronic Myeloid Leukemia and Related Disorders.

Blood ◽

10.1182/blood.v114.22.3258.3258 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3258-3258

Author(s):

Thomas Ernst ◽

Andrew Chase ◽

Claire Hidalgo-Curtis ◽

Katerina Zoi ◽

Christine Zoi ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Myeloproliferative Neoplasms ◽

Hypereosinophilic Syndrome ◽

Uniparental Disomy ◽

Progression Free Survival ◽

Driver Mutations ◽

Free Survival ◽

Inactivating Mutations

Abstract Abstract 3258 Poster Board III-1 Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) such as atypical BCR-ABL negative chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML) combine dysplastic morphology with features of a CML-like myeloproliferative disorder. The underlying pathomechanism of these related disorders is poorly understood. Recent evidence has shown that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. In this study we sought to investigate if aUPD characterizes MDS/MPN of unknown molecular etiology, and whether it could be used as a tool to help identify novel driver mutations. Genome wide high resolution SNP 6.0 array analysis was performed on total leukocyte DNA from 148 patients with aCML (n=54), CMML (n=69), and unclassified MDS/MPN (n=25). All patients were negative for BCR-ABL, JAK2 V617F, FIP1L1-PDGFRA and cytogenetic indicators of other tyrosine kinase fusion genes. Homozygous copy neutral SNP calls >20 Mb, considered indicative of aUPD, were seen in 39 (26%) patients. In total, 15 different chromosomes were involved with the most common recurrent abnormalities being seen at 4q (n=7), 7q (n=12), and 11q (n=8). Sequencing of candidate genes in the minimally affected regions excluded the involvement of tyrosine kinases and several other genes. Following the identification of TET2 at 4q24 as a putative novel tumor suppressor gene of unknown function in patients with classic MPN and MDS we identified homozygous TET2 variants in 6 cases with 4q aUPD. Analysis of 210 additional patients revealed TET2 variants in aCML (16/53; 30%), CMML (28/70; 40%), unclassified MDS/MPN (5/17, 29%), hypereosinophilic syndrome (4/30; 13%) but none in blast crisis CML (n=40). In total, 70 TET2 variants were identified that were spread throughout the coding region. Of these, 35 were likely causative changes predicted to result in premature chain termination (nonsense, n=18; deletion, n=10; insertion, n=7) and 35 were missense substitutions that have not been reported as SNPs. 20 missense mutations (57%) clustered in two conserved regions. TET2 mutations were not associated with a change of overall or progression-free survival compared to mutation negative cases. Mutations in CBL, encoding a key regulator of tyrosine kinase signaling, were identified in 5 cases with 11q aUPD and analysis of 574 additional MPN and MDS/MPN patients revealed a total of 27 CBL variants in 26 patients with aCML (12/152; 8%), CMML (10/78; 13%), myelofibrosis (n=3/53; 6%) or hypereosinophilic syndrome (n=1/96; 1%). Most variants were missense substitutions in exons 8 or 9 (encoding the linker/RING domain) that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells that overexpressed FLT3. Patients with CBL mutations had a shorter overall survival and progression-free survival compared to mutation negative cases (OS: 33 months vs. 39 months; PFS: 22 months vs 32 months) but the differences were not significant. We conclude that aUPD is common in atypical CML and related disorders and that inactivating mutations of TET2 and CBL are associated with aUPD at 4q and 11q, respectively. Disclosures: Hochhaus: Novartis: Honoraria; BMS: Honoraria.

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Restrospective Multicenter Study Evaluating Efficacy and Safety of Dasatinib and Nilotinib in Patients with Imatinib-Resistant or –intolerant Chronic Myeloid Leukemia in Chronic Phase: Korean CML Working Party

Blood ◽

10.1182/blood.v120.21.1691.1691 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1691-1691

Author(s):

Jeong-Ok Lee ◽

Inho Kim ◽

Joo-Seop Chung ◽

Yeo-Kyeoung Kim ◽

Ho-Young Yhim ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Molecular Response ◽

Efficacy And Safety ◽

Event Free Survival ◽

Free Survival ◽

Imatinib Resistant

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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A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia

Blood ◽

10.1182/blood-2012-02-410688 ◽

2012 ◽

Vol 120 (19) ◽

pp. 3898-3905 ◽

Cited By ~ 110

Author(s):

Jerald P. Radich ◽

Kenneth J. Kopecky ◽

Frederick R. Appelbaum ◽

Suzanne Kamel-Reid ◽

Wendy Stock ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Remission Rate ◽

Chronic Phase ◽

Progression Free Survival ◽

Hematologic Toxicity ◽

Molecular Response ◽

Newly Diagnosed ◽

Free Survival

Abstract Tyrosine kinase inhibitor therapy with imatinib (IM), dasatinib (DAS), or nilotinib is very effective in chronic-phase chronic myeloid leukemia. Two hundred fifty-three patients with newly diagnosed chronic-phase chronic myeloid leukemia were randomized to IM 400 mg/day or DAS 100 mg/day. The proportion of patients achieving a complete cytogenetic remission rate was superior with DAS (84% vs 69%), as was the 12-month molecular response by the proportions of patients achieving > 3-log, > 4-log, and > 4.5-log reduction in BCR-ABL transcript levels. Overall and progression-free survival was similar in the 2 arms. Among patients who achieved hematologic CR, 3-year relapse-free survival was 91% with DAS and 88% with IM 400 mg. Grade 3 and 4 toxicities were most commonly hematologic, including thrombocytopenia in 18% and 8% of DAS and IM patients, respectively. DAS induced more complete cytogenetic response and deeper molecular responses after 12 months, compared with IM 400 mg, and with a median follow-up of 3.0 years there have been very few deaths, relapses, or progressions in the 2 arms. In summary, DAS compared with IM appeared to have more short-term cytogenetic and molecular response, more hematologic toxicity, and similar overall survival. This trial is registered at www.clinicaltrials.gov as NCT00070499.

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

Leukemia & Lymphoma ◽

10.3109/10428194.2011.653786 ◽

2012 ◽

Vol 53 (7) ◽

pp. 1273-1281

Author(s):

George Ansstas ◽

Ravi Vij

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Progression Free Survival ◽

Event Free Survival ◽

Front Line ◽

Free Survival

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Determinants of Overall and Progression-Free Survival of Nigerian Patients with Philadelphia-Positive Chronic Myeloid Leukemia

Advances in Hematology ◽

10.1155/2015/908708 ◽

2015 ◽

Vol 2015 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Anthony A. Oyekunle ◽

Rahman A. Bolarinwa ◽

Adesola T. Oyelese ◽

Lateef Salawu ◽

Muheez A. Durosinmi

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Progression Free Survival ◽

Long Term Effects ◽

Free Survival ◽

First Line Therapy ◽

Kaplan Meier ◽

Blastic Phase

Objective. The tyrosine kinase inhibitors have markedly changed the disease course for patients with Ph+and/orBCR-ABL1+chronic myeloid leukemia (CML). This study was embarked upon to assess the long-term effects of imatinib therapy on survival in adult Nigerian patients with CML.Methods. All adult patients on imatinib (400–600 mg) seen from July 2003 to December 2010 were assessed. Male/female distribution was 171/101, with a median age of 38 (range, 20–75) years. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier techniques.Results. Of all the 272 patients, 205 were in chronic phase, 54 in accelerated phase, and five in blastic phase, at commencement of imatinib. As at December 2010, 222 were alive. OS at 1 and 5 years was 94% and 63%, while PFS was 89% and 54%, respectively. Similarly, amongst the 205 patients in chronic phase, OS at 1 and 5 years was 97% and 68%, while PFS was 92% and 57%.Conclusion. Imatinib’s place as first-line therapy in the treatment of CML has further been reinforced in our patients, with improved survival and reduced morbidity, comparable with outcomes in other populations.

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European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor

Blood ◽

10.1182/blood-2008-06-162388 ◽

2008 ◽

Vol 112 (12) ◽

pp. 4437-4444 ◽

Cited By ~ 230

Author(s):

David Marin ◽

Dragana Milojkovic ◽

Eduardo Olavarria ◽

Jamshid S. Khorashad ◽

Hugues de Lavallade ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Predictive Value ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Progression Free Survival ◽

Initial Response ◽

Cytogenetic Response ◽

Single Institution ◽

Free Survival ◽

Eventual Outcome

Abstract The majority of patients with chronic myeloid leukemia in chronic phase gain substantial benefit from imatinib but some fail to respond or lose their initial response. In 2006, the European LeukemiaNet published recommendations designed to help identify patients responding poorly to imatinib. Patients were evaluated at 3, 6, 12, and 18 months and some were classified as “failure” or “suboptimal responders.” We analyzed outcomes for 224 patients with chronic myeloid leukemia in chronic phase treated in a single institution to validate these recommendations. Patients were followed for a median of 46.1 months. At each time point, patients classified as “failure” showed significantly worse survival, progression-free survival, and cytogenetic response than other patients; for example, based on the assessment at 12 months, the 5-year survival was 87.1% versus 95.1% (P = .02), progression-free survival 76.% versus 90% (P = .002), and complete cytogenetic response rate 26.7% versus 94.1% (P < .001). Similarly, the criteria for “suboptimal response” at 6 and 12 months identified patients destined to fare badly, although criteria at 18 months were less useful. The predictive value of some other individual criteria varied. In general, the LeukemiaNet criteria have useful predictive value, but a case could now be made for combining the categories “failure” and “suboptimal response.”

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