Nilotinib: A Review of its Use in Chronic Myelogenous Leukemia

2010 ◽  
Vol 2 ◽  
pp. CMT.S24
Author(s):  
Ting-Wei Lu ◽  
Ronan Swords ◽  
Francis J. Giles ◽  
Kevin Kelly
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Standard Of Care ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Large Randomized Control Trial ◽  
Prior Therapy ◽  
Frontline Treatment ◽  
Favourable Safety Profile

Chronic myeloid leukemia (CML) is characterized by the reciprocal chromosomal translocation, t(9;22), forming the BCR-ABL oncogene known as the Philadelphia chromosome. The development of imatinib, a small-molecule kinase inhibitor targeted against BCR-ABL, has revolutionized the management of CML and significantly improved the prognosis and outcome and until very recently was the standard of care in patients presenting with newly diagnosed CML. Nilotinib (Tasigna®) is an orally administered kinase inhibitor made by the Novartis Pharmaceuticals Corporation that was rationally designed to bind to the ABL kinase domain of BCR-ABL resulting in enhanced BCR-ABL inhibition. It is well tolerated and has a favourable safety profile. Nilotinib has been shown to be effective in patients who have failed prior therapy with imatinib. Recently a large randomized control trial comparing imatinib and nilotinib has demonstrated that niloitinb is superior to imatinib in the frontline treatment of CML. This review summarizes the preclinical and clinical data supporting the use of nilotinib in the frontline and secondline treatment of CML.

Dasatinib (BMS354825), a dual Src-Abl inhibitor, is active in Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML) following treatment failure with imatinib mesylate and AMN107

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6530-6530 ◽  
Author(s):  
Z. Estrov ◽  
S. O’Brien ◽  
F. Giles ◽  
G. Garcia-Manero ◽  
G. Borthakur ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Therapy Response ◽  
Myelogenous Leukemia ◽  
Prior Therapy ◽  
Abl Kinase ◽  
Resistant Disease ◽  
Daily Dose

6530 Background: Dasatinib is a dual Src-Abl kinase inhibitor which is 300 fold more potent than imatinib and 20-fold more potent than AMN107 (a selective potent Bcr-Abl kinase inhibitor). Dasatinib also inhibits Src which may overcome CML resistance. Methods: Study Aims: To report the experience with dasatinib in patients who develop CML failure post AMN107. Patients and Methods: All patients on the ongoing dasatinib studies at our institution were reviewed for prior therapy/response to AMN107 and outcome on imatinib. Results: 16 patients with Ph+CML following treatment failure with AMN107 received dasatinib. All patients had previously shown hematologic resistance to imatinib. AMN107 failure was due to hematologic resistance in all 16 pts. Median age was 60 years (range 22 to 76 years); median follow-up on dasatinib is 3 months (range <1 to 9 months). CML phase was chronic in 2, accelerated in 6, blastic in 6, and second chronic/accelerated in 2. Abl mutations were found in 7/16 patients before dasatinib therapy: G250E+F359L, G250E, Y253F, Y253H, H396R (1 patient each), T315I (2 patients). All patients received dasatinib 70 mg orally BID (n = 10), 140 mg single daily dose (n = 5), or 120 mg orally BID (n = 1). Responses were observed in 5 of 7 patients with mutations including 4/4 with P loop mutations and 1/2 with other mutations; the 2 patients with T315I had resistant disease. Conclusions: Dasatinib is active in patients with CML resistant to both imatinib and AMN107. [Table: see text] [Table: see text]

Dasatanib (D) in patients (pts) with chronic myelogenous leukemia (CML) in lymphoid blast crisis (LB-CML) or Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ALL) who are imatinib (IM)-resistant (IM-R) or intolerant (IM-I): The CA180015 ‘START-L’ study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6528-6528 ◽  
Author(s):  
S. Coutre ◽  
G. Martinelli ◽  
H. Dombret ◽  
A. Hochhaus ◽  
R. Larson ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Poor Response ◽  
Myelogenous Leukemia ◽  
Cell Transplant ◽  
Open Label ◽  
Prior Therapy ◽  
Hematologic Response

6528 Background: Dasatinib (D) (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Preliminary data from a phase I study suggest high efficacy of D in IM pretreated pts. Methods: START L is an open label phase II study of D in IM-R or IM-I pts with LB-CML and Ph+ALL conducted at 42 centers worldwide. D was given orally, 70 mg twice a day (bid), with escalation to 100 mg bid for poor response or reductions to 50 mg and 40 mg bid for toxicity. Pts had weekly blood counts and monthly bone marrow exams, including cytogenetics. The primary endpoint was confirmed (sustained for at least 4 weeks) major hematologic response (MaHR) rates. Results: From January to June 2005, 101 pts were accrued. Data are available on the first 78 treated pts (42 LB-CML, 36 Ph+ALL). Of the 42 LB-CML pts, 37 were IM-R, 52% were male with median (med) age of 47 years. Prior therapy included IM >600 mg/day in 52% and stem-cell transplant (SCT) in 33% of pts. Med baseline platelet (plt) count was 32.5/nl, med BM blasts were 82%, Bcr-Abl mutations were seen in 48%, and extramedullary disease (EMD) was seen in 29% of pts. The D dose was reduced in 14%, temporarily interrupted in 33%, and escalated in 26% of pts. At 6-months, the MaHR rate was 31% including 26% complete hematologic response (CHR), the MCyR rate was 50%, and 17% of pts remained on study. Of the 36 Ph+ALL pts, 34 were IM-R, 64% were male with med age 46 years. Prior therapy included IM> 600 mg/day in 47% and SCT in 42% of pts. Baseline plt count was 53.5/nl, med BM blasts were 69%, Bcr-Abl mutations were seen in 47% and EMD was seen in 31% of pts. The D dose was reduced in 28%, temporarily interrupted in 39%, and escalated in 47% of the pts. At 6-months, the MaHR rate was 42% including 31% CHR, the MCyR rate was 58%, and 33% pts remained on study. Among all 78 pts, grade 3–4 thrombocytopenia and neutropenia was seen in 82% and 76% of pts, respectively. The most frequent D-related non-hematologic toxicities were diarrhea (30%), nausea (23%), fatigue (19%), rash (17%) and pleural effusion (13%). Conclusions: D is active in IM pretreated LB-CML and Ph+ALL pts. Data on all 101 pts will be presented at the meeting. [Table: see text]

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 Frequent and extensive deletion during the 9,22 translocation in CML

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1123-1128 ◽  
Author(s):  
DW Popenoe ◽  
K Schaefer-Rego ◽  
JG Mears ◽  
A Bank ◽  
D Leibowitz
Keyword(s):  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Protein Product ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Related Protein ◽  
Limited Region ◽  
Cellular Oncogenes ◽  
The Individual ◽  
Rna Transcript

Abstract Chromosomal translocation is one mechanism by which cellular oncogenes may be activated during tumorigenesis. The translocation of the abl oncogene to the Philadelphia chromosome in chronic myelogenous leukemia (CML) results in a new RNA transcript that fuses sequence from chromosome 22 to sequence from the abl oncogene. This RNA presumably codes for a new abl-related protein product found in CML, the activity of which is different from the normal abl protein. The molecular structure of the translocation varies from patient to patient, and the individual variation in RNA transcript and protein product remains to be defined. This report describes the frequent occurrence of chromosomal deletion within the 9q+ chromosome during these translocations. The location of the deletions suggests that some mechanism maintains the chromosomal breakpoint on the Philadelphia chromosome within a limited region. These deletions complicate the interpretation of Southern blots as a means of detecting the translocation.

scholarly journals Molecular Approaches to Sarcoma Therapy

Sarcoma ◽  
2002 ◽  
Vol 6 (1) ◽  
pp. 27-42 ◽  
Author(s):  
R. J. Olsen ◽  
S. R. Tarantolo ◽  
S. H. Hinrichs
Keyword(s):  
Kinase Inhibitor ◽  
Clinical Success ◽  
Philadelphia Chromosome ◽  
Gene Mutations ◽  
Soft Tissue Sarcomas ◽  
Chimeric Protein ◽  
Chromosomal Translocation ◽  
Cellular Transformation ◽  
Molecular Approaches ◽  
Apoptotic Pathways

Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed.

Mutations within BCR-ABL1 295–312 Define a Novel Region Associated with Poor Prognosis in Patients with Chronic Myelogenous Leukemia (CML) Resistant to Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1936-1936
Author(s):  
Alfonso Quintás-Cardama ◽  
Don L. Gibbons ◽  
Hagop Kantarjian ◽  
Moshe Talpaz ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Amino Acid ◽  
Catalytic Domain ◽  
Kinase Inhibitor ◽  
Direct Sequencing ◽  
Amino Acid Position ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Low Frequencies

Abstract ABL kinase domain (AKD) mutations are found in 20%–40% of pts with CML who fail therapy with the tyrosine kinase inhibitor (TKI) imatinib. Except for T315I, resistance conferred by most mutations can be overcome by the 2nd generation TKI dasatinib. In pts failing TKI therapy with no detectable AKD mutations by conventional direct sequencing (DS) of the AKD, other mechanisms of resistance (e.g., BCR-ABL1 amplification, SRC overexpression) have been proposed. However, these mechanisms occur at low frequencies in vivo. To ascertain whether imatinib-resistant pts may harbor mutations not detected by standard DS, we evaluated 61 pts with CML after imatinib failure by DNA expansion of specific clones (DESC) followed by DNA sequencing of at least 10 clones. At this point and prior to start of dasatinib therapy, 26 pts were in CP, 14 in AP, and 21 in BP. A total of 118 distinct AKD mutations at 112 amino acid positions were detected (77 previously unreported) in 58/61 (95%) pts. As previously reported, most mutants mapped to 4 AKD regions: P-loop (16%), catalytic domain (17%), 315–317 region (13%), and activation loop (9%). In addition, mutations were also found to cluster at high frequency to 4 novel AKD regions. One of them spans the residues flanked by amino acid positions 295 and 312 and contained 18% of AKD mutations. In addition to 5 pts who developed the highly dasatinib-resistant mutation V299L, 16/61 (25%) other pts harbored mutations within 295–312 prior to dasatinib start. Eleven (69%) of them never achieved any cytogenetic response on dasatinib and this was associated with significantly worse overall survival than that of patients expressing any other AKD mutation (p=0.02), except for T315I (Figure 1). Structurally, 295–312 mutations can potentially interfere with the N-lobe:helix αC interface. Although the exact energetic consequences of mutations at these residues are difficult to predict, structural analysis appears to indicate that these may hinder the outward torsion of the adjacent helix αC, potentially hampering the transition to the inactive conformation (“αC-Glu In” conformation) to which imatinib binds. Alternatively, the 295–312 region may serve as the structural scaffold for amino acid position 299, a direct dasatinib contact residue. Mutations mapping to 295–312 might distort the topography surrounding 299, thus altering the 299/dasatinib interface. Notably, 5/16 (32%) of these pts carried clones expressing more than 1 mutation within 295–312. All but 1 (80%) of these pts are dead. In summary, the use of techniques with higher sensitivity than conventional DS reveals that AKD mutations are highly prevalent (95%) in pts failing imatinib therapy, which could explain TKI resistance in pts not found to carry resistant mutations by conventional DS. We present evidence supporting the deleterious effect of mutations mapping to the novel 295–312 region. Experiments designed to prove these hypotheses are ongoing. Survival of 295–312 mutants Survival of 295–312 mutants

Overcoming Resistance in Chronic Myelogenous Leukemia

2013 ◽  
pp. 306-312
Author(s):  
Michael J. Mauro
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Kinase Domain ◽  
Drug Binding ◽  
Myelogenous Leukemia ◽  
Novel Therapy ◽  
Abl Kinase ◽  
Clinical Resistance

Resistance in chronic myelogenous leukemia is an issue that has developed in parallel to the availability of rationally designed small molecule tyrosine kinase inhibitors to treat the disease. A significant fraction of patients with clinical resistance are recognized to harbor point mutations/substitutions in the Abl kinase domain, which limit or preclude drug binding and activity. Recent data suggest that compound mutations may develop as well. Proper identification of clinical resistance and prudent screening for all causes of resistance, ranging from adherence to therapy to Abl kinase mutations, is crucial to success with kinase inhibitor therapy. There is currently an array of Abl kinase inhibitors with unique toxicity and activity profiles available, allowing for individualizing therapy beginning with initial choice at diagnosis and as well informed choice of subsequent therapy in the face of toxicity or resistance, with or without Abl kinase domain mutations. Recent studies continue to highlight the merits of increasingly aggressive initial therapy to subvert resistance and importance of early response to identify need for change in therapy. Proper knowledge and navigation amongst novel therapy options and consideration of drug toxicities, individual patient characteristics, disease response, and vigilance for development of resistance are necessary elements of optimized care for the patient with chronic myelogenous leukemia.

Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or ALL who failed imatinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7006-7006 ◽  
Author(s):  
C. Gambacorti-Passerini ◽  
T. Brummendorf ◽  
H. Kantarjian ◽  
G. Martinelli ◽  
D. Liu ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Low Grade ◽  
Imatinib Resistant ◽  
Philadelphia Chromosome Positive

7006 Background: Bosutinib (SKI-606) is an orally available, dual Src/Abl kinase inhibitor. To assess safety and preliminary clinical activity of bosutinib, we conducted a phase 1/2 study in patients (pts) with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who were imatinib resistant/intolerant. Methods: In part 1, 18 pts with imatinib- relapsed/refractory chronic phase (CP) CML received bosutinib 400 mg/day (3 pts), 500 mg/day (3 pts), or 600 mg/day (12 pts). Part 2 was an expanded cohort of 51 pts with all phases of Ph+ CML and ALL dosed at 500 mg daily. Timed blood samples were collected on days 1–3, 15 for PK analysis. Results: Of 69 pts, median age was 59 yrs; 48 were CP; 90% imatinib resistant. Drug-related grade 1/2 adverse events (AEs) occurring in =10% of CP pts: diarrhea (69%), nausea (44%), vomiting (19%), abdominal pain (13%), rash (13%). Grade 3/4 AEs occurring in =5% of CP pts: rash (6%), thrombocytopenia (6%). 17 pts required dose reductions. In evaluable imatinib-resistant CP-CML pts with no prior exposure to other Abl inhibitors, 16/19 (84%) had complete hematologic response (CHR); 4/21 had partial and 7/21 had complete cytogenetic responses for major cytogenetic response (MCyR) rate of 52%. Of 58 pts evaluable for mutations, 13 different imatinib-resistant mutations were found in 32 pts. 12/14 CP pts with non-P-loop mutations and 3/3 with P-loop mutations achieved CHR. 5/11 CP pts with non-P- loop mutations and 1/1 with P-loop mutation achieved MCyR. 4/9 evaluable advanced leukemia pts had CHR, 2 had MCyR. After oral administration, steady state exposure of bosutinib was nearly 2-fold higher than single-dose exposure. Mean elimination half-life was approximately 22–27 hours, supporting a once-daily dosing regimen. Conclusions: Bosutinib was well tolerated in pts with CML, with primarily low-grade gastrointestinal and dermatologic AEs. Bosutinib showed clinical activity in imatinib-resistant pts with cytogenetic responses and CHR across a range of mutations. Durability of response continues to be assessed. [Table: see text]

Bosutinib (BOS) for chronic phase (CP) chronic myeloid leukemia (CML) after imatinib (IMA) failure: ≥8-y update of a phase I/II study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7549-7549
Author(s):  
Tim H. Brümmendorf ◽  
Jorge E. Cortes ◽  
Yeow Tee Goh ◽  
Musa Yilmaz ◽  
Rebecca B. Klisovic ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Term Treatment ◽  
Prior Therapy ◽  
Long Term Treatment ◽  
New Treatment

7549 Background: BOS is approved for newly diagnosed CP CML and CML resistant/intolerant to prior therapy. In a phase I/II study, BOS showed durable efficacy and manageable toxicity in patients (pts) with CP CML after IMA failure. We report an ≥8-y update of this phase I/II and ongoing extension study. Methods: Pts with CP CML resistant/intolerant to IMA (CP2L) or IMA + dasatinib and/or nilotinib (CP3L) or with accelerated/blast phase (AP/BP) CML or Philadelphia chromosome+ acute lymphoblastic leukemia with prior tyrosine kinase inhibitor (TKI) therapy (ADV) received BOS starting at 500 mg/d. Results: 54/284 (19%) CP2L pts were still on BOS after ≥9 y and 8/119 (7%) CP3L and 5/167 (3%) ADV pts after ≥8 y; 61 CP2L pts discontinued BOS since y 5 and 21 CP3L and 12 ADV pts since y 4. Overall, the most common reason for discontinuation was disease progression/lack of efficacy in CP2L (27%), CP3L (42%) and ADV (50%) pts; last dose before discontinuation was ≥500 mg/d in 59 (21%), 28 (24%) and 46 (28%) pts, respectively. In CP2L pts, median (range) of follow-up was 54 (1–155) mo, treatment duration 26 (<1–155) mo and dose intensity 438 (87–599) mg/d; responses were durable (Table) and overall survival (OS) at 9 y was 74% vs 84% at 5 y. OS at 8 y was 69% in CP3L, 54% in AP CML and 23% in BP CML pts vs 78%, 59% and 23% at 4 y. 55 CP2L, 29 CP3L and 98 ADV pts died on study (10, 3 and 2 since the 4/5-y reports); 15, 5 and 3 had on-treatment transformations to AP/BP. Most common new treatment-emergent adverse events since y 5 in CP2L pts were pleural effusion (n=13), arthralgia (n=12) and increased blood creatinine (n=11). Conclusions: After ≥8 y, BOS continued to show durable efficacy and no new safety signals in pts with CP CML on long-term treatment, providing further support for BOS use after prior TKIs. Clinical trial information: NCT00261846 and NCT01903733 . [Table: see text]

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