Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl–positive cells

Abstract Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem cell, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activity against Bcr-Abl–positive cells and is currently in Phase II clinical trials. As it is likely that resistance to a single agent would be observed, combinations of STI571 with other antileukemic agents have been evaluated for activity against Bcr-Abl–positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyurea (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferation assays that use Bcr-Abl–expressing cells lines, the combination of STI571 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. However, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. These data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consideration of clinical trials of these combinations.

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Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl–positive cells

Blood ◽

10.1182/blood.v96.9.3195.h8003195_3195_3199 ◽

2000 ◽

Vol 96 (9) ◽

pp. 3195-3199 ◽

Cited By ~ 11

Author(s):

J. Tyler Thiesing ◽

Sayuri Ohno-Jones ◽

Kathryn S. Kolibaba ◽

Brian J. Druker

Keyword(s):

Clinical Trials ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Single Agent ◽

Myelogenous Leukemia ◽

Hematopoietic Stem ◽

Abl Tyrosine Kinase ◽

Abl Tyrosine Kinase Inhibitor

Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem cell, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activity against Bcr-Abl–positive cells and is currently in Phase II clinical trials. As it is likely that resistance to a single agent would be observed, combinations of STI571 with other antileukemic agents have been evaluated for activity against Bcr-Abl–positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyurea (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferation assays that use Bcr-Abl–expressing cells lines, the combination of STI571 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. However, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. These data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consideration of clinical trials of these combinations.

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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 ◽

10.1182/blood-2007-03-080689 ◽

2007 ◽

Vol 110 (10) ◽

pp. 3540-3546 ◽

Cited By ~ 507

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.

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Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia

Blood ◽

10.1182/blood-2007-04-083196 ◽

2008 ◽

Vol 111 (4) ◽

pp. 1834-1839 ◽

Cited By ~ 188

Author(s):

Philipp le Coutre ◽

Oliver G. Ottmann ◽

Francis Giles ◽

Dong-Wook Kim ◽

Jorge Cortes ◽

...

Keyword(s):

Adverse Events ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Chronic Myelogenous Leukemia ◽

Kinase Inhibitor ◽

Myelogenous Leukemia ◽

Abl Tyrosine Kinase ◽

Imatinib Resistant ◽

Abl Tyrosine Kinase Inhibitor ◽

Grade 3

Patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia (CML-AP) have very limited therapeutic options. Nilotinib is a highly selective BCR-ABL tyrosine kinase inhibitor. This phase 2 trial was designed to characterize the efficacy and safety of nilotinib (400 mg twice daily) in this patient population with hematologic response (HR) as primary efficacy endpoint. A total of 119 patients were enrolled and had a median duration of treatment of 202 days (range, 2–611 days). An HR was observed in 56 patients (47%; 95% confidence interval [CI], 38%-56%). Major cytogenetic response (MCyR) was observed in 35 patients (29%; 95% CI, 21%-39%). The median duration of HR has not been reached. Overall survival rate among the 119 patients after 12 months of follow-up was 79% (95% CI, 70%-87%). Nonhematologic adverse events were mostly mild to moderate. Severe peripheral edema and pleural effusions were not observed. The most common grade 3 or higher hematologic adverse events were thrombocytopenia (35%) and neutropenia (21%). Grade 3 or higher bilirubin and lipase elevations occurred in 9% and 18% of patients, respectively, resulting in treatment discontinuation in one patient. In conclusion, nilotinib is an effective and well-tolerated treatment in imatinib-resistant and -intolerant CML-AP. This trial is registered at www.clinicaltrials.gov as NCT00384228.

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Bcr-Abl tyrosine kinase inhibitor imatinib as a potential drug for COVID-19

10.1101/2020.06.18.158196 ◽

2020 ◽

Cited By ~ 1

Author(s):

Nirmitee Mulgaonkar ◽

Haoqi Wang ◽

Samavath Mallawarachchi ◽

Sandun Fernando ◽

Byron Martina ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Infectious Agent ◽

Cell Surface Receptor ◽

Inhibition Mechanism ◽

Abl Tyrosine Kinase ◽

Fusion Inhibition ◽

Abl Tyrosine Kinase Inhibitor

AbstractThe rapid geographic expansion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent of Coronavirus Disease 2019 (COVID-19) pandemic, poses an immediate need for potent drugs. Enveloped viruses infect the host cell by cellular membrane fusion, a crucial mechanism required for virus replication. The SARS-CoV-2 spike glycoprotein, due to its primary interaction with the human angiotensin-converting enzyme 2 (ACE2) cell-surface receptor, is considered as a potential target for drug development. Based on in silico screening followed by in vitro studies, here we report that the existing FDA-approved Bcr-Abl tyrosine kinase inhibitor, imatinib, inhibits SARS-CoV-2 with an IC50 of 130 nM. We provide evidence that although imatinib binds to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein with an affinity at micromolar, i.e., 2.32 ± 0.9 μM levels, imatinib does not directly inhibit the spike RBD:ACE2 interaction – suggesting a Bcr-Abl kinase-mediated fusion inhibition mechanism is responsible for the inhibitory action. We also show that imatinib inhibits other coronaviruses, SARS-CoV, and MERS-CoV via fusion inhibition. Based on promising in vitro results, we propose the Abl tyrosine kinase inhibitor (ATKI), imatinib, to be a viable repurposable drug against COVID-19.

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Effect of a selective Abl tyrosine kinase inhibitor, STI571, on in vitro growth of BCR-ABL-positive acute lymphoblastic leukemia cells

Leukemia ◽

10.1038/sj.leu.2402068 ◽

2001 ◽

Vol 15 (4) ◽

pp. 590-594 ◽

Cited By ~ 10

Author(s):

Y Kawaguchi ◽

I Jinnai ◽

K Nagai ◽

F Yagasaki ◽

Y Yakata ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Lymphoblastic Leukemia ◽

Leukemia Cells ◽

In Vitro Growth ◽

Abl Tyrosine Kinase ◽

Abl Tyrosine Kinase Inhibitor

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A case report of bosutinib-induced interstitial granulomatous drug reaction in a patient with chronic myelogenous leukemia: a case report

SAGE Open Medical Case Reports ◽

10.1177/2050313x18795075 ◽

2018 ◽

Vol 6 ◽

pp. 2050313X1879507 ◽

Cited By ~ 1

Author(s):

Alexander B Aria ◽

Leon Chen ◽

Auris O Huen

Keyword(s):

Drug Reaction ◽

Case Report ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Chronic Myelogenous Leukemia ◽

Kinase Inhibitor ◽

Philadelphia Chromosome ◽

Myelogenous Leukemia ◽

Abl Tyrosine Kinase ◽

Abl Tyrosine Kinase Inhibitor

Bosutinib is a BCR-ABL tyrosine kinase inhibitor approved for the treatment of Philadelphia chromosome–positive chronic myelogenous leukemia. We report a case of bosutinib-induced interstitial granulomatous drug reaction in a 50-year-old Caucasian female with chronic myelogenous leukemia. Histologic analysis of a punch biopsy showed diffuse interstitial granulomatous infiltrates consisting of histiocytes amid thickened collagen accompanied by eosinophils. Her lesions improved with clobetasol 0.05% cream. No cases describing BCR-ABL tyrosine kinase inhibitor–associated interstitial granulomatous drug reaction were found in a search of the literature. It is important for physicians to be aware of the risk of interstitial granulomatous drug reaction associated with bosutinib treatment.

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