The Use of Statin Enhances Chance of Achieving MR4.5 in Chronic Myeloid Leukemia Patients in Chronic Phase Following Imatinib Therapy

Abstract BACKGROUND: HMG-CoA reducatase inhibitors, or statins, are commonly prescribed medications which improve life expectancy in general population. They are known to improve hypercholesterolemia and decrease the incidence of cardiovascular events including myocardial infarction or stroke, but also suggested for cancer prevention even though the mechanism is not fully elucidated. Recent studies emphasized the potential role of statins in the cancer treatment to increase response rate to chemotherapy and to improve survival of cancer patients. Statin family of drugs is known to trigger tumor specific apoptosis and to result in growth arrest in leukemias (Penn, Leukemia 2002). The promising result of STIM (STop Imatinb) trial suggested that successful discontinuation of tyrosine kinase inhibitor (TKI) in patients with chronic myeloid leukemia (CML) is possible when patients attain deeper molecular response (defined as 4.5 log reduction or deeper) for 2 years or longer. However, with our current knowledge, there is no known additive intervention facilitates the achievement of MR4.5. We hypothesized that the use of statin improves response rate to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML), thus increasing MR4.5 achievement and increasing the chance of being attempted TKI discontinuation. METHODS: A total of 503 patients treated with TKI for CML treatment were initially evaluated for the response to TKI therapy with respect to complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response at 4.5 (MR4.5) and statin use. The inclusion criteria confined the patients with chronic phase (CP) treated with imatinib at the dose of 400mg daily, thus excluding 95 patients. Finally, 408 patients were entered into the final analysis. The statin group was defined as those on statin for cholesterol control at the time of imatinib commencement and remaining on statin while on at least 3 years or longer. Cumulative incidence method considering competing risk was adopted to calculate the incidences of MCyR, CCyR, MMR and MR4.5. Discontinuation of imatinib was accounted as competing risk in the analysis. Treatment failure, progression free- and overall survival was also evaluated. RESULTS: With a median follow-up duration of 6 years (range 3 months to 14 years), 88 patients (21.3%) were defined as statin group. Types of statin includes atorvastatin (n=44, 50%), rosuvastatin (n=26, 30%), simvastatin (n=10, 11%), pravastatin (n=6, 7%) and fluvastatin (n=2, 2%). The MCyR and CCyR achievement was not significantly different between the 2 groups (p=0.769 for MCyR and p=0.091 for CCyR). No difference of CCyR at 12 months was noted: 70.1% in statin vs 62.8% in non-statin group. The statin group showed a higher response rate than non-statin group for MMR (p=0.005) and MR4.5 (p=0.001): 67.3% vs 49.2% for MMR at 18 months; 55.8% vs 41.0% for MR4.5 at 5 years (Figure). Multivariate analysis was successful to confirm the use of statin as an independent clinical factor for improving MR4.5 (HR 1.785, 95% CI [1.260-2.530], p=0.001), but other clinical factors were not identified such as Sokal risk, age, gender or additional cytogenetic abnormalities (ACAs) at presentation. For MMR, the use of statin was also confirmed as independent factor for MMR (HR 1.541 95% [1.015-2.341], p=0.043) in addition to ACAs (HR 0.381, p=0.0038) and high sokal risk (HR 0.687, p=0.042). The use of statin was not found to be associated with improvement in treatment failure (p=0.580), progression free survival (p=0.731) or overall survival (p=0.542) in the present study. CONCLUSION: The use of statin suggested to improve deeper molecular response following imatinib therapy in CML-CP patients, therefore is promising to increase chance of attempt to TKI discontinuation. Statin appears to improve the chance of MR4.5 achievement by 78.5%. Careful interpretation is required and replication study in an independent cohort is strongly warranted to reach a clear conclusion on this promising effect of statin. The use of statin to deepen the molecular response of TKI therapy should be evaluated in the context of clinical trial. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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

Clinical Management Issues ◽

10.7175/cmi.v4i6s.1098 ◽

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.

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

Current Pharmacogenomics and Personalized Medicine ◽

10.2174/1875692117666190925115852 ◽

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.

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A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation

Journal of Clinical Medicine ◽

10.3390/jcm9113692 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3692

Author(s):

Matteo Dragani ◽

Giovanna Rege Cambrin ◽

Paola Berchialla ◽

Irene Dogliotti ◽

Gianantonio Rosti ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Molecular Response ◽

Molecular Monitoring ◽

Delay In Diagnosis ◽

Number Of Patients

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported—281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months—65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

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Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽

10.1182/blood.v114.22.1128.1128 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1128-1128 ◽

Cited By ~ 2

Author(s):

Hanna Jean Khoury ◽

Michael J. Mauro ◽

Yousif Matloub ◽

Tai-Tsang Chen ◽

Erkut Bahceci ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Duration ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Phase Iii ◽

Hematologic Toxicity ◽

Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

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Dasatinib Induces a Higher Molecular Response in Japanese Patients with Chronic Myeloid Leukemia After Imatinib Failure Than in Western Populations: Kanto CML Study

Blood ◽

10.1182/blood.v118.21.4448.4448 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4448-4448

Author(s):

Yoshihiro Hatta ◽

Koiti Inokuchi ◽

Takashi Kumagai ◽

Kazuteru Ohashi ◽

Atsushi Shinagawa ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tumor Cells ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Japanese Patients ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Resistance ◽

Dasatinib Treatment

Abstract Abstract 4448 Background Dasatinib is a potent tyrosine kinase inhibitor and is highly effective against chronic myeloid leukemia (CML). In Japan, dasatinib was approved in 2009 as a second-line therapy for CML after imatinib failure. Therefore, we conducted a phase II study to investigate the efficacy and safety of dasatinib treatment in Japanese CML-chronic phase (CP) patients with intolerance or resistance to imatinib. Patients and method CML-CP patients who were unable to continue imatinib therapy (400 mg/day) because of adverse events were registered as being intolerant to imatinib. Resistance to imatinib was defined as failure to achieve a partial cytogenetic response (PCyR) after three months of therapy or a complete cytogenetic response (CCyR) after six months of therapy or the expression of over 100 copies/μg RNA of BCR-ABL after 12 months of therapy. For these patients, dasatinib (100 mg) was administered once daily. Patients with T315I and F317I mutations in BCR-ABL were excluded. Major and complete molecular responses (MMR and CMR) were centrally evaluated using RQ-PCR at the BML laboratory. When the study was designed, a conversion factor (CF) had not been introduced to Japan for the adoption of international scale (IS). Subsequently, 0.1% IS (MMR) was defined as being equivalent to 731 copies/μg RNA based on the BML laboratory specific CF obtained in 2011, and 11 patients were identified as having an MMR at the time of study enrollment. Results A total of 61 patients were accrued from 21 centers: 26 with intolerance, and 35 with resistance. The median age was 58 years (range, 16 – 91 years). The median follow-up duration was nine months (range, 0.5 – 18 months). An MMR+CMR was observed in 27 out of 45 patients (60.0%, 13 CMR and 14 MMR) at six months and in 22 out of 31 patients (71.0%, 8 CMR and 14 MMR) at nine months after treatment with dasatinib, respectively. Excluding the patients with an MMR at the time of registration, dasatinib had induced an MMR+CMR in 21 out of 39 patients (53.9%, 11 CMR and 10 MMR) at six months and 19 out of 28 patients (67.9%, 7 CMR and 12 MMR) at nine months, respectively. The response rates in intolerant and resistant patients were comparable. Twelve patients discontinued dasatinib treatment because of drug toxicity (four patients), patient request (one), disease progression or the development of a T315I mutation (three), or unknown causes (four). Although grade 1 – 2 pleural effusion was observed in five patients, no severe cases were observed. Ten mutations in BCR-ABL occurred in eight patients during dasatinib treatment; a low IC50 of dasatinib against tumor cells in five of these mutations (M244V, M351T, F359I, F359V, H396R), an intermediate value against tumor cells in one of these mutations (Q252H), a high value against tumor cells in two of these mutations in three patients (T315I in two patients and E459K), and an unknown sensitivity against tumor cells in one of these mutations (A397P). Patients with M244V+Q252H, H396R, or T315I did not respond to dasatinib treatment. Conclusion Dasatinib is a safe and efficacious alternative for the treatment of CML following imatinib failure. Because MMR rate in the global study was 31% at one year and 44% at 5 years, the molecular response rate among Japanese patients was higher than that in western populations. Mutation in BCR-ABL remains a major issue. Disclosures: Okamoto: Bristol-Myers Squibb: Research Funding.

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Efficacy Of Different Therapeutic Approaches In Blastic Phase Of Chronic Myeloid Leukemia: Single Centre Experience

Blood ◽

10.1182/blood.v122.21.5173.5173 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5173-5173

Author(s):

Elza Lomaia ◽

Ekaterina Romanova ◽

Larisa Girshova ◽

Yulia Alexeeva ◽

Eugenia Sbityakova ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Median Time ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Molecular Response ◽

Line Therapy ◽

Advanced Phase ◽

Blastic Phase

Abstract Dramatic changes in overall survival of patients (pts) with chronic myeloid leukemia (CML) in chronic phase (CP) have occurred since tyrosine kinase inhibitors (TKIs) were implemented in the treatment strategy. But there are still many issues in therapy of advanced phase disease, especially in blastic phase (BP). Allogeneic stem cell transplantation (alloSCT) is still the only curative option for CML BP, so all efforts should be focused on bringing pts to alloSCT. Thus optimal approach to obtain at least stable hematologic response before alloSCT is needed. Since 2008, 14 pts (4 more pts with isolated extramedullary BP were not included) with CML BP were admitted to our clinic. These were 8 males and 6 females with a median age of 44 years (range; 21-63) at the time of BP. The types of BP were: biphenotypic (n=1), undifferentiated (n=1), myeloid (n=8) and lymphoid (n=4). All pts except 2 (1 with BP and 1 with accelerated phase) were initially diagnosed as CP. Median time from diagnosis to BP was 37 months (range; 0-83). Before BP all pts except 2 were pretreated with imatinib and 6 of them, after failing imatinib, received one or more new TKIs. First line therapy in BP was monotherapy with new TKI (n=5) or chemotherapy (“7+3”, “RACOP”, low doses of Ara-C, “Hyper-CVAD”, “Dexa+VCR”) with or w/o TKI (n=9). Responses are specified in table 1. FLAG regimen was subsequently given to 5 pts as second or more line therapy after failure of previous monoTKI (n=1) or Rx + TKI (n=4). Median time from BP to FLAG was 3,5 months (range; 1,5-21). The best response to FLAG therapy was complete hematologic (n=1), complete cytogenetic with (n=1) or w/o (n=1) major molecular response. There were no responses in 2 cases. All responders maintain their response after median follow up (FU) of 2 months (range; 1,5-5). All patients treated with FLAG are alive (2 after alloSCT, 3 pending alloSCT). Only 1 ptn reached alloSCT w/o any Rx after monoTKI. AlloSCT was successful in 4/5. Median FU time for patients alive after alloSCT is 12 months (range; 3,5-25). For whole group after a median FU of 14 months, 7/14 (50%) pts are alive, including 4 pts after alloSCT. Estimated 3-year overall survival for all pts is 54% (fig. 1). Conclusion All CML BP patients treated with TKIs alone lost their response in a short time. Responses were much more durable in pts treated with Rx +/- TKIs. FLAG regimen was effective even in pts with failure to previous Rx+TKIs. The majority of pts after alloSCT are alive. Chemotherapy, including FLAG with concomitant or subsequent TKIs, had advantage over monoTKI both in overall and progression free survival in CML BP. Disclosures: Lomaia: Novartis: Honoraria, Travel grants Other; Bristol-Myers Squibb: Honoraria, Travel grants, Travel grants Other. Zaritskey:University of Heidelberg: Research Funding.

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Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial

Journal of Clinical Oncology ◽

10.1200/jco.2011.38.7522 ◽

2012 ◽

Vol 30 (28) ◽

pp. 3486-3492 ◽

Cited By ~ 280

Author(s):

Jorge E. Cortes ◽

Dong-Wook Kim ◽

Hagop M. Kantarjian ◽

Tim H. Brümmendorf ◽

Irina Dyagil ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Cytogenetic Response ◽

Phase Iii ◽

Molecular Response ◽

Newly Diagnosed ◽

Blast Phase ◽

End Point

Purpose Bosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML). Patients and Methods A total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day. Results The complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P = .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P < .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P < .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib. Conclusion This ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile.

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TKI Treatment Discontinuation: How Many Patients Could Stop Tyrosine Kinase Treatment According to Discontinuation Trials Criteria? Incidence and Prognostic Impact of Deep Molecular Response in a Cohort of Chronic Myeloid Leukemia Patients of South Brazil's Hematology Centers

Blood ◽

10.1182/blood.v124.21.5542.5542 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5542-5542

Author(s):

Laura Fogliatto ◽

Marcelo Eduardo Zanella Capra ◽

Mariza Shaan ◽

Tito Vanelli Costa ◽

Luis Carlos Zanandrea Contin ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Molecular Response ◽

Imatinib Treatment ◽

Event Free Survival ◽

Free Survival ◽

The Future ◽

Tki Discontinuation

Abstract Sustained deep molecular response (MR4.5) after imatinib treatment defines a subgroup of patients with chronic myeloid leukemia (CML) with better outcome and that probably would be able to stop treatment in the future, according to results of clinical TKI discontinuation trials. Most of these trials showed that patients with a long-term imatinib treatment and low Sokal risk have a higher probability of maintain a deep molecular remission after stopping treatment. OBJECTIVES The main objective is to review the molecular responses, overall survival and event free survival of CP CML patients that have been treated with imatinib in 14 hematology centers in South Brazil. Using our data basis we also would like to see how many of them present long-term imatinib treatment, sustained deep molecular remission and correlate these findings with the Sokal risk groups. These data would allow us to predict patient profile that could be able to discontinue the treatment in the future in a prospective clinical trial. PATIENTS AND METHODS This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) that have been treated in 14 hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. MR(4.5) was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction. All tests were performed at a central standardized according to ELN. Event-free-survival (EFS) was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Overall survival (OS) was measured from the start of imatinib until death of any cause or to the date patient was last known to be alive. RESULTS Data from 474 patients was analyzed. After a median observation time of 46 months, 5-year overall survival (OS) was 86%, 5-year event-free-survival was 53%. Of the 474 patients, 258 had adequate PCR evaluations during treatment. 118 of 258 (45,7%) patients achieved MR(4.5) and 69 of 258 (27%) had sustained response for at least two years after a minimum time of treatment of 3 years. The cumulative incidence of MR(4.5) after 9 years was 76% (median, 3 years). In the group that achieved MR(4.5), there was only 1 (0,8%) death and 1 (1,1%) progression compared to 8 deaths (5,7%) and 8 progressions (7,5%) in the group without MR(4.5); these differences were significant with p=0,03 and 0,02 respectively. In the subgroup of 69 patients that had had been treated with imatinib for 3 year or more and sustained deep response (RM4,5) for at least two years, 21 pts had low Sokal risk, 7 pts intermediate Sokal risk and only 4 pts a high Sokal risk. Unfortunately, in 37 pts the Sokal risk could not be accessed due to missing information. CONCLUSION In our series MR(4.5) is reached in the majority of patients with long-term imatinib treatment. MR(4.5) is a predictor of outcome with only one disease progression and one death due to CML in this group of patients. Unfortunatly PCR are not available for all patients in our clinical practice, but this situation are improving. Regarding the 69 patients with TKI discontinuation trial criteria, we find out that 21 patients fulfill such criteria. In the future, according to the results of current stop trials it could be possible include this selected group of CP CML patients in a prospective clinical trial. Disclosures No relevant conflicts of interest to declare.

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Second-Generation Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia Patients with Stable Deep Molecular Response: A Systematic Review and a Meta-Analysis

Computational and Mathematical Methods in Medicine ◽

10.1155/2021/3110622 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Qiongnan Di ◽

Huiyang Deng ◽

Yingxin Zhao ◽

Bo-ya Li ◽

Ling Qin

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Meta Analysis ◽

Chronic Phase ◽

Molecular Response ◽

Weighted Mean ◽

Deep Molecular Response ◽

Tki Discontinuation

The treatment with 2nd-generation tyrosine kinase inhibitors (2G-TKIs), namely, dasatinib and nilotinib, has been reported to have faster and deeper responses in newly diagnosed chronic phase-chronic myeloid leukemia (CP-CML) patients as compared with imatinab. A number of studies on the discontinuation of 2G-TKIs have been conducted and recently published. A meta-analysis was conducted in this study to assess the rate of treatment-free remission (TFR) rate as well as the long-term safety of 2G-TKI discontinuation in CML patients with stable deep molecular response (DMR). 517 patients were recruited in 5 single-armed, prospective cohort studies. The overall weighted mean TFR rate at the follow-up of 12 months reached 57% (95% CI 51-64%; I 2 = 56.4 %). The weighted mean TFR rate at the 24-month follow-up was 53% (95% CI 47-60%; I 2 = 47.1 %). The loss of TFR was primarily concentrated in the first 12 months. 96.5% of patients, having restarted TKI therapy after a molecular relapse, achieved major molecular response (MMR) rapidly. There were four deaths at the two-year follow-up. As suggested from the results of the final study, 2G-TKI discontinuation in CML patients with stable DMR was reported to be feasible. Relapsed patients were retreated with 2G-TKI, and over 95% of patients could reach MMR. Almost no deaths occurred due to adverse events in two years after discontinuation, and more than half of the patients could maintain a TFR.

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Krónikus myeloid leukaemiás betegek követése a Marosvásárhelyi Hematológiai és Csontvelő-átültetési Klinika beteganyagában 2008 és 2018 között

Orvosi Hetilap ◽

10.1556/650.2019.31250 ◽

2019 ◽

Vol 160 (2) ◽

pp. 67-72

Author(s):

Aliz-Beáta Tunyogi ◽

Erzsébet Lázár ◽

István Benedek jr. ◽

Johanna Sándor-Kéri ◽

Annamária Zsigmond ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Cumulative Probability ◽

Close Monitoring ◽

Molecular Remission ◽

Risk Patients ◽

Sokal Score

Abstract: Introduction and aim: Chronic myeloid leukemia is a clonal myeloproliferative disorder characterized by the BCR-ABL gene rearrangement with translocation between chromosomes 9 and 22. The constitutively active BCR-ABL tyrosine kinase inhibitor became the standard frontline therapy. The molecular monitoring is essential. Method: We studied the chronic myeloid leukemia patients at the Clinical Hematology and Bone Marrow Transplant Unit Tg-Mures between 2008 and 2018. Results: We followed 59 patients, median age of 45 years, female : male ratio 1.5 : 1. 80% of the patients were in chronic phase. Sokal score was low in 61%, intermediate 27% and high in 12% of the patients. The median follow-up time was 5 years and 9 months. 59% of the patients reached molecular remission (average time 11 months). The cumulative overall survival was 80% at 5 years and 76% at 10 years. The overall survival according to disease phase was 98%, 85%, 20%; according to Sokal score it was 91%, 66%, 51%. The cumulative progression-free survival was 75% at 5 years and 50% at 10 years. Only 8% of the low risk patients are progressing opposite to 77% of the high risk patients. The cumulative probability to maintain the molecular remission for 5 years is 100%, for 10 years 91% and for 15 years 52%. Conclusion: A rising level of BCR-ABL is an early indication of the loss of response identifying the patients who need close monitoring and therapeutic change. Orv Hetil. 2019; 160(2): 67–72.

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