Once-Daily Dasatinib for Treatment of Patients with Chronic Myeloid Leukemia

2009 ◽  
Vol 43 (5) ◽  
pp. 920-927 ◽  
Author(s):  
Timothy Tyler
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Once Daily ◽  
Number Of Patients ◽  
Significant Difference ◽  
American Society

Objective To discuss the new dasatinib dosing regimen for the treatment of chronic phase chronic myelogenous leukemia (CP CML) in patients who failed or were intolerant to imatinib therapy. Data Sources Literature published between July 2008 and December 2008 was accessed via MEDLINE, the Proceedings of the American Society of Hematology, and the Proceedings of the American Society of Clinical Oncology using the key words chronic myelogenous leukemia, chronic myeloid leukemia, dasatinib, imatinib, nilotinib, pharmacokinetics, and regimen. Study Selection And Data Extraction Meeting abstracts and reports of major Phase 1–3 studies published in English are included. Data Synthesis Imatinib is the standard first-line therapy for CML; however, some patients develop resistance or are intolerant to the drug. Dasatinib was approved for the treatment of imatinib-resistant/intolerant patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia at the dosage of 70 mg twice daily. A Phase 3 dose-optimization study was performed to compare this regimen with others, including dasatinib 100 mg once daily, in patients with CP CML. Results of this study showed that there was no significant difference in efficacy between these 2 regimens. The safety profile was improved in the 100-mg once-daily dasatinib arm with significantly reduced frequencies of grade 3–4 thrombocytopenia and all-grade pleural effusions. The number of patients who had to discontinue, reduce, or interrupt their dosage was also less among patients taking dasatinib 100 mg once daily. Conclusions Dasatinib 100 mg once daily has a more favorable risk to benefit assessment compared with the previous 70 mg twice-daily regimen and is now the recommended schedule for patients with CP CML.

scholarly journals Philadelphia chromosome-negative chronic myelogenous leukemia without breakpoint cluster region rearrangement: a chronic myeloid leukemia with a distinct clinical course

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 445-452 ◽  
Author(s):  
R Kurzrock ◽  
HM Kantarjian ◽  
M Shtalrid ◽  
JU Gutterman ◽  
M Talpaz
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Course ◽  
Bone Marrow Failure ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Cell Counts

Abstract The hallmarks of chronic myelogenous leukemia (CML) include the Philadelphia chromosome (Ph) translocation [t (9;22)(q34;q11)] and consistent molecular genetic aberrations: a break within a restricted 5.8 kb DNA segment, bcr, on chromosome 22q11; transposition of the c- abl protooncogene from chromosome 9q34 to 22q11; and formation of a hybrid bar-abl gene encoding an abnormal 210 Kd bcr-abl protein with augmented tyrosine kinase enzymatic activity. These molecular phenomena may occur even in the absence of cytogenetic evidence of the Ph translocation. They are highly specific and sensitive markers for CML, and are presumed to play a significant role in the pathogenesis of this malignancy. Surprisingly, we have encountered 11 patients who lacked the Ph translocation, bcr rearrangement, and (in the four patients with available mRNA) a bcr-abl message, and yet had a disease phenotype at diagnosis that was a morphologic facsimile of classic chronic phase CML. These patients presented with high white blood cell counts, neutrophilia, occasional basophilia, splenomegaly, and a hypercellular bone marrow with granulocytic hyperplasia and a left shift in myeloid maturation. Despite the striking resemblance between the early stages of bcr-negative and bcr-positive CML, disease progression manifests distinctly in these two disorders. In contrast to the blastic transformation that inevitably complicates bcr-positive CML, the natural history of our 11 Ph-negative, bcr-negative CML patients was characterized by increasing leukemia burden with leukocytosis, pronounced organomegaly, extramedullary infiltrates, and eventual bone marrow failure (anemia and thrombocytopenia) without marked increases in blast cells. Our current observations suggest that a chronic myeloid leukemia process can develop without associated changes in the bcr or c- abl genes. Although the initial phase of this disease is indistinguishable from CML, the presence or absence of molecular markers may aid in the prediction of the clinical course of Ph-negative CML.

scholarly journals Philadelphia chromosome-negative chronic myelogenous leukemia without breakpoint cluster region rearrangement: a chronic myeloid leukemia with a distinct clinical course

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 445-452 ◽  
Author(s):  
R Kurzrock ◽  
HM Kantarjian ◽  
M Shtalrid ◽  
JU Gutterman ◽  
M Talpaz
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Course ◽  
Bone Marrow Failure ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Cell Counts

The hallmarks of chronic myelogenous leukemia (CML) include the Philadelphia chromosome (Ph) translocation [t (9;22)(q34;q11)] and consistent molecular genetic aberrations: a break within a restricted 5.8 kb DNA segment, bcr, on chromosome 22q11; transposition of the c- abl protooncogene from chromosome 9q34 to 22q11; and formation of a hybrid bar-abl gene encoding an abnormal 210 Kd bcr-abl protein with augmented tyrosine kinase enzymatic activity. These molecular phenomena may occur even in the absence of cytogenetic evidence of the Ph translocation. They are highly specific and sensitive markers for CML, and are presumed to play a significant role in the pathogenesis of this malignancy. Surprisingly, we have encountered 11 patients who lacked the Ph translocation, bcr rearrangement, and (in the four patients with available mRNA) a bcr-abl message, and yet had a disease phenotype at diagnosis that was a morphologic facsimile of classic chronic phase CML. These patients presented with high white blood cell counts, neutrophilia, occasional basophilia, splenomegaly, and a hypercellular bone marrow with granulocytic hyperplasia and a left shift in myeloid maturation. Despite the striking resemblance between the early stages of bcr-negative and bcr-positive CML, disease progression manifests distinctly in these two disorders. In contrast to the blastic transformation that inevitably complicates bcr-positive CML, the natural history of our 11 Ph-negative, bcr-negative CML patients was characterized by increasing leukemia burden with leukocytosis, pronounced organomegaly, extramedullary infiltrates, and eventual bone marrow failure (anemia and thrombocytopenia) without marked increases in blast cells. Our current observations suggest that a chronic myeloid leukemia process can develop without associated changes in the bcr or c- abl genes. Although the initial phase of this disease is indistinguishable from CML, the presence or absence of molecular markers may aid in the prediction of the clinical course of Ph-negative CML.

Philadelphia chromosome and terminal transferase-positive acute leukemia: similarity of terminal phase of chronic myelogenous leukemia and de novo acute presentation.

1983 ◽  
Vol 1 (11) ◽  
pp. 669-676 ◽  
Author(s):  
K Jain ◽  
Z Arlin ◽  
R Mertelsmann ◽  
T Gee ◽  
S Kempin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Leukocyte Antigen ◽  
Terminal Transferase

Twenty-eight patients with Philadelphia chromosome (Ph1)--positive and terminal transferase (TdT)--positive acute leukemia (AL) were treated with intensive chemotherapy used for adult acute lymphoblastic leukemia (L-10 and L-10M protocols). Fifteen patients had a documented chronic phase of Ph1-positive chronic myelogenous leukemia preceding the acute transformation (TdT + BLCML) while the remaining 13 patients did not (TdT + Ph1 + AL). An overall complete remission (CR) rate of 71% was obtained with a median survival of 13 months in the responders. Clinical presentation, laboratory data, cytogenetics, response to treatment, and survivals of the two groups of patients are compared. These results appear to be similar, suggesting a common or closely related origin. Since the overall survival of those receiving chemotherapy maintenance is poor, three patients underwent allogeneic bone marrow transplantation (BMT) from histocompatibility leukocyte antigen--matched siblings after they achieved CR. One of them is a long-term survivor (35 + months) with a Ph1-negative bone marrow. New techniques such as BMT should be considered in young patients with a histocompatibility leukocyte antigen--compatible sibling once a CR has been achieved.

BCR Rearrangement–Negative Chronic Myelogenous Leukemia Revisited

2001 ◽  
Vol 19 (11) ◽  
pp. 2915-2926 ◽  
Author(s):  
Razelle Kurzrock ◽  
Carlos E. Bueso-Ramos ◽  
Hagop Kantarjian ◽  
Emil Freireich ◽  
Susan L. Tucker ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Interferon Alfa ◽  
Myelogenous Leukemia ◽  
Disease Evolution ◽  
Number Of Patients ◽  
Significant Difference ◽  
Atypical Cml ◽  
Peripheral Blood Smears

PURPOSE: To document the characteristics of patients with major breakpoint cluster region (M-bcr) rearrangement–negative chronic myelogenous leukemia (CML). PATIENTS AND METHODS: The hematopathologist, who was blinded to patients’ molecular status, reviewed the referral bone marrows and peripheral-blood smears from 26 patients with Philadelphia (Ph) translocation–negative CML who lacked Bcr rearrangement (and other evidence of a Bcr-Abl anomaly) and 14 patients (controls) with chronic-phase Ph-positive CML. Clinical data was ascertained by chart review. RESULTS: Among the 26 M-bcr rearrangement–negative CML patients, three pathologic subtypes emerged: (1) patients indistinguishable from classic CML (n = 9), (2) patients with atypical CML (n = 8), and (3) patients with chronic neutrophilic leukemia (n = 9). Among the 14 patients with Ph-positive CML who were included in the blinded review, 13 were classified as classic CML, and one was classified as atypical CML. The only statistically significant difference between M-bcr rearrangement–negative subgroups was in the proportion of patients having karyotypic abnormalities, an observation common only in patients with atypical CML (P = 0.008). However, the small number of patients in each subgroup limited our ability to differentiate between them. Interferon alfa induced complete hematologic remission in five of 14 patients; four of these remissions lasted more than 5 years. Only one of 26 patients developed blast crisis. The median survival of the 26 patients was 37 months. CONCLUSION: Patients with M-bcr rearrangement–negative CML fall into three morphologic subgroups. Disease evolution does not generally involve blastic transformation. Instead, patients show progressive organomegaly, leukocytosis, anemia, and thrombocytosis. Some patients in each subgroup can respond to interferon alfa.

scholarly journals A Novel Methoxybenzyl 5-Nitroacridone Derivative Effectively Triggers G1 Cell Cycle Arrest in Chronic Myelogenous Leukemia K562 Cells by Inhibiting CDK4/6-Mediated Phosphorylation of Rb

2020 ◽  
Vol 21 (14) ◽  
pp. 5077
Author(s):  
Bin Zhang ◽  
Ting Zhang ◽  
Tian-Yi Zhang ◽  
Ning Wang ◽  
Shan He ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chronic Myeloid Leukemia ◽  
Cell Cycle Arrest ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
G1 Phase ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Chronic myeloid leukemia (CML) is a malignant tumor caused by the abnormal proliferation of hematopoietic stem cells. Among a new series of acridone derivatives previously synthesized, it was found that the methoxybenzyl 5-nitroacridone derivative 8q has nanomolar cytotoxicity in vitro against human chronic myelogenous leukemia K562 cells. In order to further explore the possible anti-leukemia mechanism of action of 8q on K562 cells, a metabolomics and molecular biology study was introduced. It was thus found that most of the metabolic pathways of the G1 phase of K562 cells were affected after 8q treatment. In addition, a concentration-dependent accumulation of cells in the G1 phase was observed by cell cycle analysis. Western blot analysis showed that 8q significantly down-regulated the phosphorylation level of retinoblastoma-associated protein (Rb) in a concentration-dependent manner, upon 48 h treatment. In addition, 8q induced K562 cells apoptosis, through both mitochondria-mediated and exogenous apoptotic pathways. Taken together, these results indicate that 8q effectively triggers G1 cell cycle arrest and induces cell apoptosis in K562 cells, by inhibiting the CDK4/6-mediated phosphorylation of Rb. Furthermore, the possible binding interactions between 8q and CDK4/6 protein were clarified by homology modeling and molecular docking. In order to verify the inhibitory activity of 8q against other chronic myeloid leukemia cells, KCL-22 cells and K562 adriamycin-resistant cells (K562/ADR) were selected for the MTT assay. It is worth noting that 8q showed significant anti-proliferative activity against these cell lines after 48 h/72 h treatment. Therefore, this study provides new mechanistic information and guidance for the development of new acridones for application in the treatment of CML.

scholarly journals Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia

Blood ◽  
1995 ◽  
Vol 85 (8) ◽  
pp. 2013-2016 ◽  
Author(s):  
H Sill ◽  
JM Goldman ◽  
NC Cross
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
P16 Gene ◽  
Number Of Patients ◽  
Wide Range ◽  
Homozygous Deletions

The p16 gene, also referred to as MTS1, INK4, CDK4I, or CDKN2, at chromosome 9p21 has recently been described as a tumor suppressor that may be involved in a wide range of tumors. We have used a semiquantitative multiplex polymerase chain reaction assay to search for deletions of the p16 gene in 34 patients with chronic myeloid leukemia in blast crisis (CML BC), 19 patients with acute lymphoblastic leukemia (ALL), and 25 patients with acute myeloid leukemia (AML). Homozygous deletions of p16 exons were found in 5 of 10 (50%) patients with CML in lymphoid BC and in 5 (26%) ALL patients, but in only 1 (2%) case with AML. No deletions were found in CML BC of nonlymphoid phenotype. Comparison of chronic phase DNA or remission DNA with acute leukemia DNA in 5 individuals showed that the p16 deletions were acquired and not inherited, directly implicating these lesions in the pathogenesis of the disease. We conclude that functional elimination of the p16 gene, or a closely mapping gene, is involved in a significant number of patients with CML in lymphoid transformation.

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