Dose Changing and Discontinuation of Imatinib In Patients Affected by Philadelphia Positive Chronic Myeloid Leukemia: a Longitudinal Analysis, a Single Centre Experience.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4478-4478
Author(s):  
Serena Merante ◽  
Cristiana Pascutto ◽  
Ester Orlandi ◽  
Lara Pochintesta ◽  
Marina Boni ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Intermittent Therapy ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Increased Risk ◽  
Risk Of Progression ◽  
Tk Inhibitors ◽  
Complete Molecular Response

Abstract Abstract 4478 Introduction: Imatinib mesylate (IM) therapy is effective in patients with chronic myeloid leukemia (CML). However, its discontinuation or dose variation in patients who experience sustained molecular response is debated. The possibility of treating patients with an intermittent therapy could also be applied to the second-generation TK-inhibitors. We describe our single institute experience in patients with undetectable levels or in major molecular response of BCR-ABL transcript who reduced or were discontinued from IM therapy. We applied a model for the analysis of longitudinal data to study the BCR/ABL variation according to dose change or discontinuation. Methods: One hundred forty CML patients came to our observation between 1985 and 2009. Among these, 89 patients in chronic phase were eventually treated with IM. Fifty-five patients were treated with IM as naive patients. Each patient's treatment history was subdivided into time periods at constant dosage. Fifty-nine patients were followed-up for a total of 288 periods at constant dosage. At the end of each period, cytogenetic and/or molecular responses were evaluated. Thirty-eight progressions were recorded: 22 molecular, 6 cytogenetic and 10 of both types. The association between progression (molecular, cytogenetic or either) and treatment dose was assessed with the aid of generalized estimating equations (GEE) models, i.e. regression models designed to account for correlation due to repeated measurements over time on the same subject. Ten patients discontinued IM therapy for a period which ranged from three to 60 months, after the patient's individual request and informed consent. Results: We found no association between dose and progression, not even after accounting for period length. Discontinuation of treatment was not associated to an increased risk of progression. No association with a higher risk of progression was found for periods at reduced dosage (<400mg). Four of the 10 patients who discontinued IM are still in complete molecular response and off treatment. Conclusions: It is unclear whether IM can “cure” chronic myeloid leukemia but according to our data this therapy can be safely stopped or its dose varied in patients with complete cytogenetic and major molecular response of up to 18 months. Our experience suggests that withdrawal of IM therapy in CP-CML patients after achievement of a complete molecular response may result in divergent molecular outcomes. The prompt improvement seen after the restart of therapy argues against the development of resistance. The selection of resistant clones after IM exposure, and the emergence of Ph negative clones with secondary cytogenetic abnormalities, are matters of concern, particularly in patients receiving long-term IM. The improved quality of life while off therapy, and the prompt response to restart of IM therapy, suggest that the subset of patients who have sustained complete molecular response may be candidates for a tailored approach to intermittent therapy. We suggest that the same statistical analysis can also be used for other TK-inhibitors that are under study for both retrospective or prospective trials in CML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy

Blood ◽  
2009 ◽  
Vol 113 (25) ◽  
pp. 6315-6321 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Jianqin Shan ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
High Dose ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Increased Risk ◽  
Risk Of Progression

AbstractPatients not in complete cytogenetic response (CCyR) continuously face the competing possibilities of eventually achieving a cytogenetic response versus progressing. We analyzed the probability of achieving a CCyR, major molecular response, and progression in 258 patients with chronic myeloid leukemia in early chronic phase at 3, 6, and 12 months from imatinib start. The initial imatinib dose was 800 mg/day in 208 (81%) and 400 mg/day in 50 (19%) patients. For patients not in CCyR, the probability of achieving CCyR (P = .002) or major molecular response (P = .004) significantly decreased, whereas the risk of progression increased (P = .16) at each time point. Patients with a BCR-ABL1/ABL1 ratio greater than 1% to 10% after 3 months of imatinib had a 92% probability of achieving CCyR with continued therapy, similar to the 98% for those with 1% or less, but their risk of progression (11%) was almost 3-fold that of patients with a BCR-ABL1/ABL1 transcript ratio of 1% or less (4%) and similar to that of patients with transcript levels more than 10% (13%). These results suggest that patients not in CCyR after 12 months on imatinib have a higher risk of progression. This risk is discernible as early as 3 months into imatinib therapy by molecular analysis and may provide the rationale to institute therapies that render higher rates of early response.

scholarly journals Safety and efficacy of nilotinib after 10 years of interferon

2015 ◽  
Vol 6 (2S) ◽  
pp. 19-22
Author(s):  
Filippo Russo
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Interferon Alfa ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Safety And Efficacy ◽  
Optimal Response ◽  
Complete Molecular Response

Here we describe a case of a woman with chronic myeloid leukemia at high risk, according to the Sokal Index. The patient started interferon alfa-2b (IFN) at standard dose obtaining a major molecular response after about four years of treatment. After about 10 years the patient presented a toxicity from IFN and different comorbidities, so she was switched to nilotinib and achieved a complete molecular response (MR4). This case shows how nilotinib is effective and tolerable also in patients with multiple comorbidities. Keywords: Chronic myeloid leukemia; Optimal response; Nilotinib; Interferon alfa-2b

Multicenter Retrospective Study on the Development of Peripheral Lymphocytosis During Second-Line Dasatinib Therapy for Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2275-2275
Author(s):  
Ha Yeon Lee ◽  
Su Jin Lee ◽  
Boram Ha ◽  
Jun Ho Yi ◽  
Chul Won Jung ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Second Line ◽  
Major Molecular Response ◽  
The Republic

Abstract Abstract 2275 Background: Dasatinib is known to induce large granular lymphocyte (LGL) expansion, which correlates with better clinical efficacy. The current retrospective study attempted to investigate the incidence of lymphocytosis following second-line dasatinib therapy in chronic myeloid leukemia (CML) and to analyze the clinical factors predictive of the development of lymphocytosis, as well as association with treatment outcomes. Method: Fifty CML patients who failed imatinib treatment and received dasatinib for 3 months or more, were enrolled from 9 centers in the Republic of Korea. The cumulative incidence of lymphocytosis was assessed, and cytogenetic and molecular response, treatment failure, loss of response, progression to advanced disease, and survival were evaluated and analyzed according to the development of lymphocytosis. Results: After a median of 17 months of dasatinib therapy, complete cytogenetic (CCR) and major molecular response (MMR) was noted in 23 and 16 patients, respectively. Twenty three patients (46%) developed lymphocytosis following dasatinib therapy (median onset 4 months). No clinical predictive factor for the development of lymphocytosis was found. The cytogenetic response was significantly better in the group that developed lymphocytosis (LC+), as compared to the group without lymphocytosis (LC-); the LC+ group showed a higher complete cytogenetic response (CCyR; 78.3% vs. 29.6%, p=0.001) and major molecular response (MMR; 52.2% vs. 14.8%, p=0.005), in comparison to the LC- group. The development of lymphocytosis after dasatinib was identified as a favorable independent marker for predicting a CCyR (p=0.002) or MMR following dasatinib therapy (p=0.003). Conclusion: The present study suggested that 1) lymphocytosis following dasatinib therapy is not rare phenomenon with incidence of 46%; 2) it might be associated with higher response following dasatinib therapy. Further study is necessary to identify which subset of lymphocytes was expanded and to reveal the exact mechanism by which dasatinib induces lymphocyte expansion. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chronic myeloid leukemia: successful therapy with nilotinib in a young patient with high Sokal risk and in sub-optimal response with imatinib

2015 ◽  
Vol 4 (6S) ◽  
pp. 13-16
Author(s):  
Fausto Palmieri
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Young Patient ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Chronic Phase ◽  
Molecular Response ◽  
Optimal Response ◽  
Increased Risk

Here we describe a case of a young patient with chronic myeloid leukemia, at high-risk according to the Sokal index, who started imatinib at standard dose and obtained a sub-optimal response at 12 months. This condition was not automatically an indication to change therapy, but considering the patient as suboptimal, we decided to switch to a second-generation tyrosine kinase inhibitor (TKI), nilotinib 800 mg/die, obtaining soon a complete cytogenetic response (CCYR), thereafter a major molecular response (MMolR). Delayed achievement of cytogenetic and molecular is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving imatinib therapy. Therefore we can hypothesise that this kind of patient could be elegible for an early switch to second-generation TKI.

Mutation Analysis of ABL1 Gene and its Relation to the Achievement of Major Molecular Response in Indonesian Chronic Myeloid Leukemia Patients

2020 ◽  
Vol 17 (1) ◽  
pp. 48-54
Author(s):  
Reni Widyastuti ◽  
Melva Louisa ◽  
Ikhwan Rinaldi ◽  
Riki Nova ◽  
Instiaty Instiaty ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Cross Sectional ◽  
Imatinib Resistance

Background: Imatinib mesylate is the first tyrosine kinase inhibitor approved for chronic myeloid leukemia (CML) therapy. Imatinib is an effective drug. However, previous studies have shown that about 20-30% of patients eventually would develop resistance to imatinib. Approximately 40% of imatinib resistance is associated with BCRABL kinase domain mutation. One of the most common and serious variations account for imatinib response is T315I of ABL1 gene. Objective: The study aimed to examine the association of T315I mutation with the ABL1 gene and its relation to major molecular response (MMR) achievement in CML patients. This study also examined other mutations adjacent to T315I, i.e., F311I, F317L, and different possible variations in the ABL1 gene. Methods: This was a cross-sectional study on Indonesian CML patients in chronic phase. We analyzed 120 blood samples from patients in chronic phase who have received imatinib mesylate (IM) for ≥12 months. Results: There were no T315I, F311I, and F317L mutations found in this study. However, we found another variation, which was 36 substitutions from A to G at position 163816 of ABL1 gene (according to NG_012034.1). Conclusions: We found no T315I, F311I, and F317L mutations in this study. Our findings suggest that there might be other factors that influenced the MMR achievement in our study patients. However, there were 36 substitutions from A to G at position 163.816 (according to NG_012034.1) that needed further examination to explore the significance of this mutation in clinical practice.

Imatinib Mesylate Therapy in Late Ph+ Chronic Myeloid Leukemia Patients in Stable Complete Cytogenetic Response after Interferon-Alpha Results in a Very High Complete Molecular Response Rate.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2158-2158
Author(s):  
Giuliana Alimena ◽  
Massimo Breccia ◽  
Luigia Luciano ◽  
Fabrizio Quarantelli ◽  
Daniela Diverio ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Complete Molecular Response

Abstract Imatinib mesylate was given to 26 Philadelphia positive (Ph+) chronic myeloid leukemia (CML) patients who were in late chronic phase (CP) and in stable complete cytogenetic response (CCR) after interferon-alfa (IFN-α), but showed persistent positive residual disease at PCR analysis under this treatment. At diagnosis median age was 40 years (range 21–64) and according to Sokal’s score, 18 patients were low risk and 8 were intermediate risk. Median IFN treatment was 88 mo.s (range 15–202) and median CCR duration was 73 mo.s (range 10–148). Imatinib was administered at the standard dose of 400 mg/die, after stopping IFN for 1 week. Residual disease was measured on bone marrow (BM) cells at baseline, before starting Imatinib, at 3, 6, 12, 18 mo.s and at the last follow-up (median 32 mo.s, range 21–49), by assaying BCR-ABL transcripts using quantitative PCR (RQ-PCR). The copy number (CN) of BCR/ABL and ABL transcript were derived by the interpolation of CT values to the appropriate standard curve, and the result, for each sample, was expressed as ratio of BCR/ABL mRNA copies to ABL mRNA x 100 (normalized copy number - NCN). Imatinib treatment resulted in a progressive and consistent decline of residual disease in all but one patient, from a median of 0.89 at baseline to 0.01 at the end of follow-up. Major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%) and BCR/ABL transcripts were undetectable in 13 (50%). Achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response vs 18,97 for those who did not; p<0.001), but not with other clinical/biological patient characteristics. In all patients, imatinib was well tolerated with no side effects requiring drug dose reduction or dose discontinuation. Albeit obtained from an unusual subset of selected patients with favourable prognosis, and likely particularly sensitive to imatinib, present results confirm the efficacy of combining Imatinib and IFN-α and further support investigating treatment approaches employing these two drugs.

Outcome of Patients with Chronic Myeloid Leukemia Who Recieved an Intermittent Imatinib Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1034-1034
Author(s):  
Hyun-Gyung Goh ◽  
Soo-Hyun Kim ◽  
Jeong Lee ◽  
Sae-Eun Jang ◽  
Wan-Seok Kim ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Oral Dose ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Intermittent Therapy ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
600Mg Daily

Abstract Diagnosis of chronic myeloid leukemia (CML) is based on detection of the BCR-ABL gene or Philadelphia chromosome, and the BCR-ABL tyrosine kinase inhibitor imatinib has been the standard therapy for CML patients. Although imatinib therapy is effective in CML, it is still unclear whether imatinib can be safely discontinued without relapse. This study was designed to investigate the outcome of 26 CML patients after discontinuation of imatinib and to determine whether intermittent imatinib therapy can be employed in CML patients. Between May 2001 and Jun 2007, 555 patients have been treated with imatinib in St Mary’s Hospital of the Catholic University of Korea, and 26 patients discontinued imatinib when they achieved either complete cytogenetic response (CCyR) or complete molecular response (CMR). These 26 patients were diagnosed as Philadelphia positive (Ph+) CML between November 1995 and May 2002, and 22 patients were in chronic phase (CP) and 4 patients were in accelerated phase (AP) at diagnosis. The median age was 35 years (22–56), and 12 patients (46%) were female and 14 (54%) were male. Among 26 patients, 7 received interferon prior to imatinib therapy and 7 underwent SCT. Five patients received both interferon and SCT before imatinib therapy, and the remaining 7 patients received the imatinib as a front line therapy. Imatinib was started at oral dose of 400mg and 600mg daily for patients in CP and AP, respectively, and when they achieved CCyR or CMR, imatinib was discontinued after informed consent of the patient. In case of cytogenetic or molecular relapse, patients in all phases were retreated with imatinib at 400mg daily. Bone marrow (BM) or peripheral blood (PB) samples were obtained at regular intervals from diagnosis for hematologic response (HR), cytogenetic response (CyR) and molecular response (MR) monitorings. Eleven patients discontinued imatinib when they achieved CCyR, and 15 patients discontinued imatinib after achieving CMR. After the median duration of 7 month (4–48) observation without imatinib therapy, hematologic, cytogenetic and molecular relapses occurred in 4, 7 and 10 patients, respectively, and imatinib at oral dose of 400mg daily was reintroduced to all patients except 2 who continued to remain in CMR after imatinib discontinuation. Except 1 patient who expired and 2 patients who are in persistent molecular remission, all of 23 patients are maintaining the best response achieved after imatinib resumption with a median duration of 38 months (16–58). In conclusion, although imatinib cannot be discontinued completely, intermittent therapy can be considered for the treatment of CML patients. Intermittent imatinib treatment should not be restricted to CP patients who achieve CMR, and AP patients or patients with CCyR also can be considered for intermittent imatinib treatment. We will continue the follow-up of the patients enrolled in this study, and long-term study of intermittent imatinib treatment with expanded pool of patients will enable us to determine the accurate consequences of discontinuation of imatinib and intermittent imatinib treatment.

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