The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 655-663 ◽  
Author(s):  
Christine Schuster ◽  
Karin Forster ◽  
Henning Dierks ◽  
Annika Elsässer ◽  
Gerhard Behre ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Granulocytic Differentiation ◽  
Abl Kinase ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor ◽  
Macrophage Adhesion

The clinical progression of chronic myeloid leukemia (CML) from chronic phase to blast crisis is characterized by the increasing failure of myeloid precursors to differentiate into mature granulocytes. This study was undertaken to investigate the influence of Bcr-Abl and of the small molecule Abl tyrosine–kinase inhibitor imatinib mesylate on granulocyte colony-stimulating factor (G-CSF)–induced neutrophilic differentiation. We show that differentiation of 32Dcl3 cells into mature granulocytes is accompanied by the increased expression of the antigens macrophage adhesion molecule–1 (Mac-1) and Gr-1, of the G-CSF receptor (G-CSFR), of myeloid transcription factors (CCAAT/enhancer-binding protein–α [C/EBPα], C/EBPε, and PU.1), and of the cyclin-dependent kinase inhibitor p27Kip1. In 32Dcl3 cells transfected with thebcr-abl gene (32DBcr-Abl), G-CSF did not trigger either granulocytic differentiation or the up-regulation of C/EBPα, C/EBPε, and the G-CSFR. This could be correlated to a defect in c-Myc down-regulation. In contrast, the up-regulation of PU.1 and p27Kip1 by G-CSF was not affected by Bcr-Abl. Importantly, incubation of 32DBcr-Ablwtcells with the kinase inhibitor imatinib mesylate prior to G-CSF stimulation completely neutralized the effects of Bcr-Abl on granulocytic differentiation and on C/EBPα and C/EBPε expression. Taken together, the results suggest that the Bcr-Abl kinase induces a reversible block of the granulocytic differentiation program in myeloid cells by disturbing regulation of hematopoietic transcription factors such as C/EBPα and C/EBPε.

Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4611-4614 ◽  
Author(s):  
Amie S. Corbin ◽  
Paul La Rosée ◽  
Eric P. Stoffregen ◽  
Brian J. Druker ◽  
Michael W. Deininger
Keyword(s):  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Abl Kinase ◽  
Cellular Assays ◽  
Kinase Domain Mutations

Abstract Imatinib mesylate is a selective Bcr-Abl kinase inhibitor, effective in the treatment of chronic myelogenous leukemia. Most patients in chronic phase maintain durable responses; however, many in blast crisis fail to respond, or relapse quickly. Kinase domain mutations are the most commonly identified mechanism associated with relapse. Many of these mutations decrease the sensitivity of the Abl kinase to imatinib, thus accounting for resistance to imatinib. The role of other mutations in the emergence of resistance has not been established. Using biochemical and cellular assays, we analyzed the sensitivity of several mutants (Met244Val, Phe311Leu, Phe317Leu, Glu355Gly, Phe359Val, Val379Ile, Leu387Met, and His396Pro/Arg) to imatinib mesylate to better understand their role in mediating resistance.While some Abl mutations lead to imatinib resistance, many others are significantly, and some fully, inhibited. This study highlights the need for biochemical and biologic characterization, before a resistant phenotype can be ascribed to a mutant.

scholarly journals A common phosphotyrosine signature for the Bcr-Abl kinase

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4888-4897 ◽  
Author(s):  
Valerie L. Goss ◽  
Kimberly A. Lee ◽  
Albrecht Moritz ◽  
Julie Nardone ◽  
Erik J. Spek ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitor ◽  
Imatinib Treatment ◽  
Treatment Comparison ◽  
Abl Kinase ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor ◽  
Disease Stages ◽  
Insight Into ◽  
Fusion Type

Abstract The Bcr-Abl fusion kinase drives oncogenesis in chronic myeloid leukemia (CML). CML patients are currently treated with the Abl tyrosine kinase inhibitor imatinib, which is effective in early stages of the disease. However, resistance to imatinib arises in later disease stages primarily because of a Bcr-Abl mutation. To gain deeper insight into Bcr-Abl signaling pathways, we generated phosphotyrosine profiles for 6 cell lines that represent 3 Bcr-Abl fusion types by using immunoaffinity purification of tyrosine phosphopeptides followed by tandem mass spectrometry. We identified 188 nonredundant tyrosine-phosphorylated sites, 77 of which are novel. By comparing the profiles, we found a number of phosphotyrosine sites common to the 6 cell lines regardless of cellular background and fusion type, several of which are decreased by imatinib treatment. Comparison of this Bcr-Abl signature with the profile of cells expressing an alternative imatinib-sensitive fusion kinase, FIP1L1-PDGFRα, revealed that these kinases signal through different pathways. This phosphoproteomic study of the Bcr-Abl fusion kinase highlights novel disease markers and potential drug-responsive biomarkers and adds novel insight into the oncogenic signals driven by the Bcr-Abl kinase.

Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3540-3546 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Francis Giles ◽  
Norbert Gattermann ◽  
Kapil Bhalla ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor ◽  
Philadelphia Chromosome Positive

Abstract Nilotinib, an orally bioavailable, selective Bcr-Abl tyrosine kinase inhibitor, is 30-fold more potent than imatinib in pre-clinical models, and overcomes most imatinib resistant BCR-ABL mutations. In this phase 2 open-label study, 400 mg nilotinib was administered orally twice daily to 280 patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) after imatinib failure or intolerance. Patients had at least 6 months of follow-up and were evaluated for hematologic and cytogenetic responses, as well as for safety and overall survival. At 6 months, the rate of major cytogenetic response (Ph ≤ 35%) was 48%: complete (Ph = 0%) in 31%, and partial (Ph = 1%-35%) in 16%. The estimated survival at 12 months was 95%. Nilotinib was effective in patients harboring BCR-ABL mutations associated with imatinib resistance (except T315I), and also in patients with a resistance mechanism independent of BCR-ABL mutations. Adverse events were mostly mild to moderate, and there was minimal cross-intolerance with imatinib. Grades 3 to 4 neutropenia and thrombocytopenia were observed in 29% of patients; pleural or pericardial effusions were observed in 1% (none were severe). In summary, nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance. This clinical trial is registered at http://clinicaltrials.gov as ID no. NCT00109707.

scholarly journals Dasatinib-Induced Colitis with Rectal Sparing in a Patient with Chronic Myeloid Leukemia (Chronic Phase) on Dasatinib as an Upfront Therapy: Case Report

2021 ◽  
Vol 14 (3) ◽  
pp. 1441-1446
Author(s):  
Zakaria Maat ◽  
Kamran Mushtaq ◽  
Mohamed A. Yassin
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Prior Therapy ◽  
Abl Tyrosine Kinase ◽  
Upfront Therapy ◽  
Abl Tyrosine Kinase Inhibitor

Dasatinib is a BCR-ABL tyrosine kinase inhibitor which was approved in 2006 for the treatment of adults diagnosed with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) and accelerated (myeloid or lymphoid blast) phase and CML with resistance or intolerance to prior therapy including imatinib and in adults with Ph+ acute lymphoblastic leukemia. Common adverse reactions (>15%) in patients diagnosed with CP-CML include myelosuppression, fluid retention, and diarrhea. We report a 34-year-old Filipino female patient who received dasatinib as upfront therapy for the treatment of CP-CML who experienced chronic diarrhea for 2 months, which progressed to colitis.

Efficacy and Safety of Radotinib in Chronic Phase Chronic Myeloid Leukemia Patients with Resistance or Intolerance to BCR-ABL Tyrosine Kinase Inhibitors: Radotinib Phase 2 Clinical Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 695-695 ◽  
Author(s):  
Sung-Hyun Kim ◽  
Hari Menon ◽  
Saengsuree Jootar ◽  
Tapan Saikia ◽  
Jae-Yong Kwak ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Abl Tyrosine Kinase ◽  
Phase 2 Clinical Trial ◽  
Abl Tyrosine Kinase Inhibitor

Abstract Abstract 695 Background Radotinib is a novel, selective Bcr-Abl tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm, South Korea. Radotinib showed a good efficacy and safety profile to chronic myeloid leukemia (CML) in preclinical and phase 1 clinical studies. To investigate the clinical efficacy and safety of radotinib 400 mg twice daily, data from CML patients treated during phase 2 clinical trial are reported. Methods Philadelphia chromosome (Ph+)-positive chronic phase CML (CP-CML) patients who failed or were intolerable to TKIs (imatinib and/or dasatinib and/or nilotinib) were enrolled between July 2009 and November 2011. Patients were treated with radotinib 400 mg twice daily for 12 cycles (1 cycle=4 weeks). The primary end point was an achievement of major cytogenetic response (MCyR, Ph+£35%) by 12 months. Safety parameters were also analyzed. Results A total of 77 CP CML patients (18 years of age or over) were enrolled from 12 sites in Korea, India, and Thailand. This analysis includes data from last enrolled patient who received at least 3 months of radotinib therapy. The median age of patients was 47 (range; 24–76) years, and 65 (84.4%) were imatinib-resistant and 12 (15.6%) were imatinib-intolerant. Four patients also had intolerance to dasatinib. With a median follow-up of 10.6 months, treatment with radotinib is ongoing in 46 patients (59.7%) and 31 patients (40.3%) discontinued the treatment including two deaths (2.6%). However, there were no CML-related deaths. Median duration of radotinib exposure was 296 (8–798) days. Overall MCyR rate was 63.6%, including 35 patients (45.4%) complete cytogenetic response and 14 patients (18.2%) partial cytogenetic response. The median time to MCyR was 2.8 months (85 days) and the median duration of MCyR was 315 (range; 5–726) days. Of patients achieving complete cytogenetic response, 37% (13/35) achieved major molecular response. Within follow-up durations, 44 patients (57.1%) required dose interruption and 41 patients (53.3%) had dose reduction. Most common grade 3/4 hematologic and laboratory adverse events (AEs) were thrombocytopenia (27.3%), neutropenia (10.4%), anemia (6.5%), and hyperbilirubinemia (31.2%). Common non-hematologic AEs were rash (29.8%), fatigue (14.3%), nausea/vomiting (14.3%), headache (13.0%), and pruritus (11.7%). The majority of AEs were easily manageable with temporal dose interruption and/or reductions. In all patients with CP-CML treated with second-line radotinib, estimated progression-free survival and overall survival rate at 12months was 84.9% (95% CI, 72.7–92.0%) and 97.4% (95% CI, 89.9–99.3% ), respectively. Conclusion Radotinib phase 2 trial confirmed the efficacy and safety of radotinib 400 mg twice daily in patients with CP-CML after failure to TKIs. Most of the AEs occurred in the early treatment period, were tolerable, and were easily controlled by dose interruption or reduction. Disclosures: Off Label Use: Radotinib, new BCR/ABL tyrosine kinase inhibitor, treatment for CML. Lee:IL-YANG Pharm.: Employment. Park:IL-YANG Pharm.: Employment. Woo:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Lee:IL-YANG Pharm.: Employment. Cho:IL-YANG Pharm.: Employment. Shin:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Serial changes in bone marrow cellularity, reticulin fibrosis and microvessel density in patients with chronic myeloid leukemia (CML) in chronic phase treated with imatinib

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6596-6596
Author(s):  
N. M. Lokeshwar ◽  
L. Kumar ◽  
M. Vijayaraghavan ◽  
R. Dawar ◽  
A. Sharma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Imatinib Mesylate ◽  
Microvessel Density ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Minor Response ◽  
Bone Marrow Cellularity ◽  
Abl Tyrosine Kinase ◽  
Marrow Cellularity

6596 Background: Imatinib Mesylate, a BCR-ABL tyrosine kinase inhibitor produces sustained complete hematological response (CHR) in CML patients in chronic phase. There is a paucity of information on the effects of imatinib on the bone marrow (BM) morphology and angiogenesis. We evaluated the sequential changes in these parameters in 22 CML chronic phase patients treated with first line imatinib (400 mg) and compared with 10 controls (non-hematological malignancies). Methods: Trephine BM biopsies were evaluated by means of morphology, morphometry, Gomori’s stain and CD 34 staining. Reticulin fibrosis was graded from grade 1 to grade 4. Microvessel density (MVD) was calculated by counting the microvessels in hot spots (400 ×). Final value was mean of 10 fields. Total vascular area (TVA) was calculated by image analysis and expressed as percentage of the total area. Results: 22 patients were included in the study. Median age was 34 years (range 20–58 years). All patients attained a CHR at a median of 18 days. Major cytogenetic response was seen in 64%, minor response in 27% and no response in 9% of patients. Baseline BM cellularity was increased in all patents as compared to controls. The median cellularity at 6 months and 1 year was decreased to 60% and 50% respectively. The median grade of reticulin fibrosis at baseline was grade 3 as compared to controls (median grade 1). There was a significant decrease in reticulin fibrosis at 6 months and 1 year (median-grade 1, p=0.04). The median MVD at baseline was 8.25 (range 6–26) and was increased as compared to controls (median MVD-3.6). There was a significant decrease in MVD at 6 months and 1 year (median MVD-4.0, p=0.04). Similarly the TVA decreased from 6.2% at baseline to 4.3% at 1 year. These changes correlated with the cytogenetic responses. Two patients who had disease progression during therapy showed reversal in the bone marrow changes. Conclusions: Imatinib Mesylate produces significant effects on bone marrow morphometry and angiogenesis in patients with CML in chronic phase. There is a consistent decrease in bone marrow cellularity, reticulin fibrosis and microvessel density during therapy. No significant financial relationships to disclose.

Nilotinib is associated with minimal cross intolerance to imatinib in patients with imatinib-intolerant chronic myelogenous leukemia (CML) in chronic phase (CP)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7039-7039
Author(s):  
E. Jabbour ◽  
P. le Coutre ◽  
M. Baccarani ◽  
K. Bhalla ◽  
G. J. Ossenkoppele ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Open Label ◽  
Abl Tyrosine Kinase ◽  
Imatinib Resistant ◽  
Secondary Endpoints ◽  
Abl Tyrosine Kinase Inhibitor ◽  
Grade 3

7039 Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib and is an important therapeutic option for patients (pts) who have either imatinib-resistant or -intolerant CML disease. Results of a subset of pts with Ph+ CML-CP who received nilotinib for imatinib-intolerance are reported Methods: Pts were part of a phase II open-label study evaluating the safety and efficacy of nilotinib in imatinib-resistant or -intolerant CML-CP. Imatinib intolerance was defined as no MCyR and discontinuation of imatinib due to Grade 3/4 AEs or persistent (> 1 mo) or recurrent Grade 2 AE (recurred > 3 times) despite optimal supportive care. The proportion of pts achieving MCyR was the primary endpoint, and safety and toxicity were secondary endpoints. Planned starting dose was nilotinib 400mg BID. Results: Of the 316 pts with CML-CP enrolled, 95 (30%) pts had imatinib-intolerance for either non-hematologic and/or hematolgic AEs. Some pts had more then one AE satisfying the criteria for intolerance. The frequency of intolerant symptoms for imatinib and nilotinib is shown in the table below. Only 2/80 (3%) pts with non-hematologic imatinib-intolerance experienced a recurrence of similar symptoms during nilotinib therapy. 33 patients entered the study due to hematologic intolerance (neutropenia, thrombocytopenia) and only 7/33 (21%) developed similar problems. In 86 pts with intolerance and at least 6 mos of follow up, 55% of these patients achieved MCyR, similar to that previously reported for imatinib-resistant patients. Conclusions: These are the first reported results evaluating cross intolerance symptoms to TKIs. The results demonstrate that nilotinib is effective in imatinib-intolerant CML-CP and has a very low rate of cross- intolerance, further supporting the excellent tolerability of nilotinib No significant financial relationships to disclose. [Table: see text]

Evolution of bosutinib (BOS) toxicity in patients (pts) with Ph+ leukemia after resistance/intolerance to prior therapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7099-7099
Author(s):  
Carlo Gambacorti-Passerini ◽  
Tim H. Brummendorf ◽  
Jorge E. Cortes ◽  
Jeffrey H. Lipton ◽  
Dong-Wook Kim ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Blast Phase ◽  
Prior Therapy ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor ◽  
Grade 3 ◽  
Clinical Trial Information ◽  
Common Teaes

7099 Background: BOS is an oral dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of Ph+ CML following resistance/intolerance to prior therapy. Prior reports from this phase I/II trial indicated the BOS safety profile was primarily characterized by myelosuppression, gastrointestinal events, and rash. The current analysis compares the incidence of toxicity in Year 1 (Y1) for pts on treatment ≤1 y and within Y1 and Year 2 (Y2) for pts on treatment for >1 y. Methods: BOS 500 mg/d was evaluated in 3 cohorts: chronic phase (CP) CML after imatinib only (CP 2L cohort; n = 286); CP CML after imatinib + dasatinib and/or nilotinib (CP 3L cohort; n = 119); and accelerated/blast phase CML or ALL after prior TKI therapy (ADV cohort; n = 164). Results: The most common treatment-emergent adverse events (TEAEs) in each cohort occurred more frequently within Y1 than Y2 (Table). The incidence for grade 3/4 events followed a similar pattern. AEs were the most common reason for BOS discontinuation in Y1 (CP 2L, 53%; CP 3L, 32%; ADV, 41%). Of the pts whose primary reason for discontinuing BOS was an AE during the first 2 y, most did so during Y1 (CP 2L, n = 51/60 [85%]; CP 3L, n = 22/24 [92%]; ADV, n = 24/25 [96%]); the most common reasons during Y1 were thrombocytopenia (12%; 9%; 4%), increased ALT (6%; 4%; 2%), neutropenia (3%; 6%; 0%), diarrhea (4%; 3%; 0%), and vomiting (3%; 4%; 1%). Serious AEs were more common among pts who discontinued BOS ≤1 y versus on treatment >1 y in the CP 3L and ADV cohorts, but similar in the CP 2L cohort (Table). Conclusions: Discontinuation due to AEs was observed primarily in Y1. For pts on BOS for >1 y, the incidence of common TEAEs decreased substantially after Y1, suggesting BOS tolerability improves after long-term exposure. Clinical trial information: NCT00261846. [Table: see text]

Update on lower-dose dasatinib 50 mg daily as frontline therapy in newly diagnosed chronic phase chronic myeloid leukemia (CML-CP).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7052-7052
Author(s):  
Kiran Naqvi ◽  
Elias Jabbour ◽  
Jeffrey A Skinner ◽  
Kristin N Anderson ◽  
Musa Yilmaz ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Treatment Interruption ◽  
Molecular Response ◽  
Abl Tyrosine Kinase ◽  
Cumulative Response ◽  
Abl Tyrosine Kinase Inhibitor ◽  
Dose Reductions

7052 Background: Dasatinib, a potent BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. Notable side effects include pleural effusions and myelosuppression. We previously reported dasatinib 50 mg daily to be active and better tolerated than the approved 100 mg daily dose (CANCER. 2018 Jul 1;124(13):2740-2747). We present an update on the efficacy and toxicity profile of lower dose dasatinib 50 mg orally daily in patients with early CML-CP. Methods: All patients presenting to our institution in early CML-CP were eligible to participate. Prior TKI therapy for up to 1 month was allowed. Responses were assessed according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122.872:884). Results: From March 2016 to March 2018, 81 patients have been enrolled. Median age is 47 years (20-84). Patients categorized by Sokal risk are: low 53; intermediate 22 and high 6. Median follow-up is 18 months (9-31). Cumulative response rates over time are shown below: At 3 months, 96% patients achieved early molecular response ( BCR-ABL PCR ≤10%). Median time to CCyR was 4.6 months, MMR 6.0 months, MR4.0 11.4 months and MR4.5 12.2 months. Eighteen patients had treatment interruption: pleural effusion 4 (possibly related 3, unrelated 1 due to pneumonia); gastrointestinal bleed 2; thrombocytopenia 3; transaminitis 2; renal dysfunction 1; asthma exacerbation 1; pneumonitis 1; lower extremity edema 1; myalgias 1, and pregnancy 2. Four patients had dose reductions: pleural effusion 3; myalgias 1. Four patients had dasatinib dose increased to 100mg: lack of CCyR at 6 months, 3; lack of MMR at 12 months, 1. Four patients are off study: no response 2, pneumonitis 1, and insurance 1. None of the patients have transformed or died. Conclusions: These updated results continue to support dasatinib 50 mg daily as an effective and safe dose for early CML-CP. Clinical trial information: NCT02689440. [Table: see text]

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