scholarly journals Hematopathologic and cytogenetic findings in imatinib mesylate treated chronic myelogenous leukemia patients: 2.5 years' experience

2010 ◽  
Vol 67 (10) ◽  
pp. 802-806 ◽  
Author(s):  
Irena Cojbasic ◽  
Lana Macukanovic-Golubovic
Keyword(s):  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Median Time ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Specific Activity ◽  
Chronic Phase ◽  
Previous Treatment ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia

Background/Aim. Imatinib mesylate, a tyrosine kinase inhibitor with specific activity against the breakpoint cluster region - Abelson murine leukemia (BCR-ABL) tyrosine kinase has been developed for treatment of chronic myelogenous leukemia (CML). Its hematologic and cytogenetic effects have been evaluated in a series of clinical trials. The aim of this study was to report hematologic and cytogenetic response in CML patients during the treatment with imatinib mesylate. Methods. A total of 21 patients were treated and observed from July 2006 to December 2008. The median time from CML diagnosis was no more than 12 months, so all the patients received previous treatment with hydroxyurea for which the median time was 3 months. The patients received imatinib mesylate in an effective oral dose of 400 to 800 mg daily, which was followed with peripheral blood counts, bone marrow examination, and cytogenetic studies at 6, 12, 18 and 24 months. Results. Complete hematologic responses were reported for 19 (90.48%) of 21 patients studied. Among 19 patients who had a response, 16 (86%) did so within 3 months. The best cytogenetic response rate at any time during the study treatment with imatinib mesylate, among 14 patients in which cytogenetic response evaluated was: complete cytogenetic response in 7 (50%) patients, partial cytogenetic response in 6 (42.9%) patients and minor cytogenetic response in 1 (7.1%) patient. No patients had progressed to accelerated or blastic phase. The most frequent adverse effects that seemed to be related to treatment with imatinib mesylate were edema and musculosceletal pain; overall, most were mild. Only one patient discontinued treatment because of hematologic toxic effects. Conclusion. The results obtained in this study confirm that imatinib mesylate induces a complete hematological and cytogenetic response in a high percentage of patients with chronic-phase CML.

Hematopathologic and cytogenetic findings in imatinib mesylate–treated chronic myelogenous leukemia patients: 14 months' experience

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 435-441 ◽  
Author(s):  
Rita M. Braziel ◽  
Teresa M. Launder ◽  
Brian J. Druker ◽  
Susan B. Olson ◽  
R. Ellen Magenis ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Treatment Interruption ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Cytogenetic Changes ◽  
Polymerase Chain

Abstract Imatinib mesylate, an Abl kinase inhibitor, produces sustained complete hematologic responses (CHRs) in chronic myelogenous leukemia (CML) patients, but the sequence and timing of morphologic and cytogenetic changes in CML patients during prolonged imatinib mesylate treatment has not been described. In this report, we document sequential hematologic and bone marrow findings in 19 interferon-refractory/interferon-intolerant chronic phase CML patients on imatinib mesylate for at least 14 months. Patients treated at an effective oral dose (300 to 600 mg per day) were followed with peripheral blood (PB) counts, marrow examination, and cytogenetic studies at 0, 2, 5, 8, 11, and 14 months. By 2 months, 17 of 19 patients achieved CHR; 1 reached CHR by 5 months, and 1 at 11 months. Five of 19 patients developed cytopenias requiring treatment interruption and/or dose reduction, but all were able to continue in CHR on study. In contrast to interferon-alfa treatment, imatinib mesylate–treated CML patients achieved not only CHR but complete morphologic marrow response. Normalization of marrow lagged behind PB response; however, by 8 months, all marrows showed normal or reduced cellularity without morphologic evidence of CML. Eighteen of 19 patients continued in CHR and morphologic marrow remission at 14 months; 1 patient relapsed with chronic phase CML. Although hematologic and marrow responses were uniform, cytogenetic responses were variable. Complete cytogenetic responses occurred in 6 patients, with 4 also in remission by fluorescent in situ hybridization and/or reverse-transcription–polymerase chain reaction. Six of 19 had partial and 7 of 19 no cytogenetic response. Several patients acquired additional clonal cytogenetic abnormalities during therapy, a finding with significant implications for prognosis and laboratory monitoring in imatinib mesylate–treated CML patients.

scholarly journals Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

2015 ◽  
Vol 4 (2S) ◽  
pp. 17-20
Author(s):  
Mario Annunziata
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Chronic Myeloid Leukemia Patient ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Cutaneous Rash

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome–positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Francis Giles ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Combination Regimens ◽  
Philadelphia Chromosome Positive

Abstract Fifty patients with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in early chronic phase received imatinib mesylate, 400 mg orally daily. After a median follow-up of 9 months, 49 patients (98%) achieved a complete hematologic response and 45 patients (90%) achieved a major cytogenetic response, complete in 36 patients (72%). Compared with similar patients who received interferon-α with or without hydroxyurea or other interferon-α combination regimens, those receiving imatinib mesylate had higher incidences of complete and major (Ph < 35%) cytogenetic responses at 3 months (34% and 74% versus 1%-4% and 9%-24%, respectively), 6 months (52% and 80% versus 3%-7% and 11%-28%, respectively), and 9 months (60% and 77% versus 5%-11% and 14%-30%, respectively; P < .001). Competitive quantitative polymerase chain reaction (QPCR) studies at 9 months showed a median QPCR value (ratio of BCR-ABL/ABL transcripts × 100) of 0.59% overall and of 0.24% (range, 0.001%-29.5%) for complete cytogenetic response.

Relationship between Clinical/Hematological Response and Increase of Plamacells in the Bone Marrow of Patients with Chronic Myelogenous Leukemia Imatinib Mesylate Treatment (631).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4552-4552
Author(s):  
Alessandro Poggi ◽  
Ivana Pierri ◽  
Silvia Catellani ◽  
Francesca Olcese ◽  
Antonella Marasco ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
B Lymphocytes ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Response To Treatment ◽  
Imatinib Treatment

Abstract Tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec, Novartis, formerly known as STI571) are the first line treatment of Chronic Myelogenous Leukemia (CML) and of a rare form of gastroenteric stromal cancer. It has been recently reported that in the latter case, tumor cells are refractory to imatinib antiproliferative effect in vitro and the response to the drug in vivo is due to immunocompetent cells, able to produce cytokines with antineoplastic activity. In this study, 20 CML patients, prior and during treatment with imatinib mesylate, underwent bone marrow (BM) aspirates every 6 months, including: morphologic and phenotypic analysis, cytogenetic and biomolecular evaluation, compared to peripheral blood. Plasma from BM and peripheral blood was also recovered for cytokyne-chemokine dosage. We report that in 12 out of 20 CML patients a significant increase in the percentage of BM lymphoplasmocytoid cells was observed upon treatment with imatinib mesylate, with >10% (range 10–16%) of CD20+CD126+cells. Among this population, two third of cells coexpressed IgM and one third was IgD+, while a smaller fraction of IgM+CD126+CD20– (3–4%) or IgD+CD126+CD20- (2–3%) cells was also found. The lasting 8 patients had<5% of CD20 +CD126+ lymphocytes (range2–4%), 2/3 coexpressing IgM and 1/3 coexpressing IgD. All patients with increased number of CD126+ B lymphocytes underwent hematologic remission, 7 of them with complete molecular and cytogenetic remission. On the other hand, among the patients with low or undetectable CD20+CD126+cells, only 4 underwent hemathological remission and none of them displayed stable cytogenetyc and molecular remission. In two patients relapsed after six months of treatment, the fraction of BM CD20+CD126+ lymphocytes decreased from 16% and 11% to 7 and 5%, respectively, with undetectable IgM+ CD126+CD20- or IgD+ CD126+CD20- cells. These data suggest that this population of lymphoplasmocytoid B cells depends on or contribute to the pharmacological response; by the way, this phenomenon might help in monitoring the outcome of disease and the response to treatment. To check this item and understand the biochemical mechanisms substaining the observed increase in BM lymphoplasmocitoid cells on imatinib treatment, we wonder if the production of cytokines able to induce B lymphocytes differentiation, such as interleukin (IL)-4, IL-6 (whose receptor is CD126), IL-3, IL10 or IL-21 was affected by imatinib administration. To this aim, both soluble cytokines (by ELISPOT) and their mRNA (by real time polymerase chain reaction) were evaluated in the BM of these patients: moreover, the expression of MCP-1, SDF-1, IP-10 and IL-8 were also measured, to verify whether the increse in BM CD20+ CD126+ lymphocytes was due to a redistribution rather than to “in situ” differentiation. Preliminary results seem to indicate that the latter hypothesis is unlikely; in addition, when CD20+ CD126+ were increased in the BM, they also raised in the peripheral blood. These immunological events might have a role in the response to tyrosine kinase inhibitor and need further investigations.

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 &lt;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.

Efficacy of dasatinib in chronic phase chronic myelogenous leukemia patients after imatinib failure according to baseline BCR- ABL mutations

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7023-7023 ◽  
Author(s):  
A. Hochhaus ◽  
S. Branford ◽  
J. Radich ◽  
M. C. Mueller ◽  
N. Shah ◽  
...  
Keyword(s):  
Amino Acids ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Response Dynamics ◽  
The Individual

7023 Background: Dasatinib is an oral, multi-targeted BCR-ABL and SRC kinase inhibitor with preclinical activity against 20/21 imatinib (Im) resistant BCR-ABL mutations. Clinical efficacy was demonstrated in phase I, II, and III studies in patients (pts) with chronic myelogenous leukemia (CML) in all phases of the disease and BCR-ABL positive acute lymphoblastic leukemia (ALL). We sought to establish a relationship between type of BCR-ABL mutations associated with Im resistance and efficacy of dasatinib in chronic phase (CP) CML pts. Methods: Between 10/03 and 03/06, dasatinib was commenced in 1,093 CP-CML pts recruited for three consecutive trials and administered for a median of 8.7 months (range <1–25.9). BCR-ABL mRNA was screened for mutations of amino acids 207–517 by D-HPLC and/or regular sequencing and data are available from 961 cases (88%). ABL polymorphisms K247R and E499E were excluded from analysis. Results: Prior to dasatinib, 75 different BCR-ABL mutations involving 56 amino acids were detected in 18/240 Im intolerant (7.5%) and 324/721 (45%) Im resistant pts. 267 pts showed one, 53 pts two, 16 pts three, and six pts four mutations. In Im resistant pts, response was not different between 370 pts with and 351 pts without baseline mutations: Complete hematologic response (CHR) was achieved in 89% vs 92%; major cytogenetic response (MCR) in 48% vs 52% being complete (CCR) in 38 vs 36%, respectively. Response dynamics were associated with preclinical activity of dasatinib: classifying mutations for IC50 values <2, 2–20 and >1,000nM (T315I), CHR was achieved in 93, 85 and 28%; MCR in 48, 42 and 0%; and CCR in 37, 35 and 0% of cases, respectively. During follow up, new mutations were detected in 30 cases, predominantly T315I (n=10), Y253H/F (n=4), and F317L (n=3). Conclusions: We conclude that dasatinib is capable of inducing hematologic and cytogenetic remissions in a significant proportion of Im resistant pts associated with BCR-ABL mutations, except T315I, but also in pts with BCR-ABL independent causes of resistance. Quality of response depends on the individual type of the mutation which is consistent with preclinical observations. No significant financial relationships to disclose.

Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4298-4305 ◽  
Author(s):  
Martine Gardembas ◽  
Philippe Rousselot ◽  
Michel Tulliez ◽  
Magda Vigier ◽  
Agnès Buzyn ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Tyrosine Kinase Domain ◽  
Phase 2 ◽  
Phase 2 Trial

AbstractIn chronic myelogenous leukemia (CML) imatinib mesylate has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr-abl fusion protein. Using this agent alone high rates of cytogenetic responses were recorded. However, several mechanisms of resistance have been described. In vitro studies examining the effects of imatinib mesylate plus cytarabine have shown synergistic antiproliferative effects of this combination. Thus, the CML French Group decided to perform a phase 2 trial testing a combination of imatinib mesylate and low-dose cytarabine in 30 previously untreated patients in chronic phase. Treatment was administered on 28-day cycles. Patients were treated continuously with imatinib mesylate orally at a dose of 400 mg daily. Cytarabine was given on days 15 to 28 of each cycle at an initial dose of 20 mg/m2/d via subcutaneous injection. Adverse events were frequently observed with grade 3 or 4 hematologic toxicities and nonhematologic toxicities in 53% (n = 16) and 23% (n = 7) of patients, respectively. The cumulative incidence of complete cytogenetic response (CCR) at 12 months was 83% and at 6 months 100% of the patients achieved complete hematologic response (CHR). We concluded that the combination was safe and promising given the rates of response. (Blood. 2003;102:4298-4305)

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