The Durable Clearance of the T315I BCR-ABL Mutated Clone in Chronic Phase Chronic Myelogenous Leukemia Patients on Omacetaxine Allows Tyrosine Kinase Inhibitor Rechallenge

2010 ◽  
Vol 10 (5) ◽  
pp. 394-399 ◽  
Author(s):  
Franck E. Nicolini ◽  
Jean-Claude Chomel ◽  
Lydia Roy ◽  
Laurence Legros ◽  
Kaddour Chabane ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia

scholarly journals Treatment Free Remission for Chronic Phase Chronic Myelogenous Leukemia Patients Who Stopped Tyrosine Kinase Inhibitor Therapy Due to Intolerance

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5919-5919
Author(s):  
Daulath Singh ◽  
Sucha Nand ◽  
Hanh Mai
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Median Treatment ◽  
The Past ◽  
Treatment Free Remission

Introduction: Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm that is often diagnosed in adults between the ages of 25-60. The outcome of the chronic phase CML has dramatically changed due to Tyrosine Kinase Inhibitor (TKI) therapy. There are well established guidelines from NCCN and ESMO on stopping TKI for patients achieving prolonged remissions with TKIs. We report clinical outcomes from a single tertiary care center in patients who stopped TKI therapy for reasons other than prolonged remission status. Methods: We retrospectively reviewed all the CML patients who were treated at our institution in the past 10 years (January 1st,2009 - December 31st,2018). We excluded patients who had accelerated or blast phase CML, atypical CML, patients on non-TKI therapy, and patients who received an allogeneic stem cell transplant. Results: A total of 117 patients were diagnosed with chronic phase CML at our institution in the past 10 years. Among the 117 patients, 12 of these discontinued TKI therapy. Six patients stopped TKI after achieving prolonged remission with TKI therapy and the remaining patients discontinued due to intolerance to treatment, fear of side effects, and loss of insurance. The median age of the whole cohort is 66 years (range 42-85). Six patients were male and 6 were females. Six patients were diagnosed with CML prior to year 2009 and rest after 2009. Prior to stopping, six patients received only 1 kind of TKI, 2 patients were treated with 2 types of TKIs, 2 patients received 3 types of TKIs, and 2 patients had 4 lines of TKIs (See Table). Cohort 1: 6 patients who stopped due to prolonged remission, median major molecular remission - MMR4 (BCR-ABL <0.01% IS by RT-PCR testing) prior to stopping TKI is 6 years (range 3-13 years). Of the six, only 1 relapsed (within 1 month of stopping) and was initiated back on the same TKI (imatinib). The relapsed patient has not achieved MMR4 level remission to date. Median treatment free remission for this cohort is 13 months (range 1-24 months). Cohort 2: Of those 6 patients who stopped TKI for other reasons: 4 stopped due to side effects/intolerance, 1 stopped due to fear of side effects after FDA label was updated, and 1 patient discontinued due to a loss of insurance. Median duration of MMR4 prior to stopping is 4 years (range 1-11 years). 5 of these 6 patients relapsed in the median time of 6 months (range 3-16 months). Of these 5, 4 were started back on the TKI therapy (three on the same TKI and one on a different TKI). Median treatment free remission for this cohort is 4 months (range 2-16 months). Conclusion: In this small cohort from a single institution's experience, CML patients who discontinued TKI therapy after achieving MMR4 for reasons other than prolonged remission have experienced poor outcomes including a higher rate of relapse and a shorter treatment free remission. We need studies with larger samples sizes and longer follow up to assess outcomes in patients stopping TKI therapy for various reasons. Disclosures No relevant conflicts of interest to declare.

Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2808-2816 ◽  
Author(s):  
Nicholas C. Wolff ◽  
Robert L. Ilaria
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Murine Model ◽  
High Efficiency ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Leukemic Cells

Abstract The murine bone marrow retroviral transduction and transplantation model of chronic myelogenous leukemia (CML) imperfectly mimics human CML because the murine CML-like disease causes death of all animals from an overwhelming granulocytosis within 3 to 4 weeks. In this report, mice reconstituted with P210BCR/ABL-transduced bone marrow cells received posttransplantation therapy with either the tyrosine kinase inhibitor STI571 or placebo. Compared with the rapidly fatal leukemia of placebo-treated animals, 80% of the STI571-treated mice were alive on day 74, with marked improvement in peripheral white blood counts and splenomegaly. There was decreased tyrosine phosphorylation of STAT5, Shc, and Crk-L in leukemic cells from STI571-treated animals, consistent with STI571-mediated inhibition of the Bcr/Abl tyrosine kinase in vivo. In some STI571-treated animals Bcr/Abl messenger RNA and protein expression were markedly increased. In contrast to the polyclonal leukemia of placebo-treated mice, STI571-treated murine CML was generally oligoclonal, suggesting that STI571 eliminated or severely suppressed certain leukemic clones. None of the STI571-treated mice were cured of the CML-like myeloproliferative disorder, however, and STI571-treated murine CML was transplanted to secondary recipients with high efficiency. These results demonstrate the utility of this murine model of CML in the evaluation of novel therapeutic agents against Bcr/Abl-induced leukemias. This improved murine chronic-phase CML model may be a useful tool for the study of STI571 resistance, CML progression, and the anti-CML immune response.

Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia

2017 ◽  
Vol 35 (2) ◽  
pp. 175-184 ◽  
Author(s):  
Sieghart Sopper ◽  
Satu Mustjoki ◽  
Deborah White ◽  
Timothy Hughes ◽  
Peter Valent ◽  
...  
Keyword(s):  
T Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Independent Validation ◽  
Tyrosine Kinase Inhibitor Therapy

Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry–based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts. Results T cells of patients with CML at diagnosis expressed low l-selectin (CD62L) levels, which was not a result of proportional aberrations of T-cell subsets. Low numbers of CD62L-expressing CD4+ and CD8+ T cells correlated with higher Sokal score, increased spleen size, and high leukocyte and peripheral-blood blast counts. At month 6 during nilotinib therapy, CD62L expression returned to levels of healthy individuals. The level of CD62L loss on T cells directly correlated with the extent of soluble CD62L (sCD62L) elevation. In parallel, the proteolytic activity of tumor necrosis factor α–converting enzyme (TACE; ADAM17, CD156b), the metalloproteinase shedding CD62L, was increased at diagnosis and significantly decreased during nilotinib treatment. High CD62L+ expression on both CD4+ and CD8+ T cells and, vice versa, low sCD62L levels at CML diagnosis were linked to superior molecular responses. These findings were corroborated in independent validation cohorts. Conclusion We demonstrate the prognostic impact of CD62L shedding from T cells and increased sCD62L plasma levels at CML diagnosis on molecular response to tyrosine kinase inhibitor therapy in early chronic-phase CML. Functionally, decreased CD62L may be a consequence of increased TACE-mediated CD62L cleavage and potentially impairs immune-cell function. Larger prospective studies are ongoing to confirm the prognostic relevance of this finding.

scholarly journals The Bone Phenotype and Pain Response to Pamidronate in Tyrosine Kinase Inhibitor–Treated Chronic Myelogenous Leukemia

2019 ◽  
Vol 3 (5) ◽  
pp. 857-864 ◽  
Author(s):  
Declan C T Lavoie ◽  
Marie-Eve Robinson ◽  
Donna Johnston ◽  
Marika Pagé ◽  
Victor N Konji ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Pain Response ◽  
Bone Phenotype
Sign in / Sign up

Export Citation Format

Share Document