A Prospective Study of Imatinib 400 mg vs 800 mg Frontline in High Risk Ph+ Chronic Myeloid Leukemia (CML) Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 26-26 ◽  
Author(s):  
Michele Baccarani ◽  
Fausto Castagnetti ◽  
Kimmo Porkka ◽  
Johan L. Nielsen ◽  
Henrik Hjorth-Hansen ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Phase ◽  
Good Clinical Practice ◽  
Cytogenetic Response ◽  
Risk Category ◽  
Fish Analysis ◽  
Molecular Response ◽  
Primary Efficacy Variable ◽  
Primary Efficacy ◽  
Front Line

Abstract Background: imatinib mesylate (IM) is the drug of choice for the front-line treatment of Ph+ CML, at a dose of 400 mg daily (M. Baccarani et al Blood2006;108:1809–1820). Several biological and clinical observations suggest that increasing the dose may improve the results. The cytogenetic response to IM 400 mg daily is significantly related with Sokal relative risk. High risk patients could benefit of a dose increase front-line. Aim: to compare the effects of 400 mg and 800 mg daily in previously untreated, early chronic phase patients, high Sokal risk. The primary efficacy variable of the study is the complete cytogenetic response (CCgR) rate after 12 months, on an intention-to-treat analysis. Patients and Methods: this is a multicentric international study running in Italy, Sweden, Denmark, Finland, Norway, Turkey and Israel, approved by the local Ethic Committees, conducted according to Helsinki Declaration and Good Clinical Practice. 215 patients with confirmed Ph+ CML previously untreated, high risk according to Sokal formulation (J. Sokal et al Blood1984;63:789–799) were enrolled over a 3-year period and were randomized (1:1) to receive IM 400 or 800 mg daily. Cytogenetic response was assessed by conventional cytogenetics and FISH analysis after 3, 6 and 12 months. Molecular response was evaluated every three months. Results: as of August 2007, 137 patients are evaluable for CCgR rate at 12 months (primary efficacy variable). Patients in CCgR at that time were 78/137 (57%). Treatment failures during the study (no complete hematologic response or 100% Ph+ at 6 months, or loss of response) were 24/137 (17%), patients off-treatment for protocol violations or refusal were 10/137 (7%), patients off-treatment for toxicity were 7/137 (5%). Conclusions: the results of this preliminary analysis show that the CCgR rate at 12 months is overall 57%, in line with the results of the IRIS trial (imatinib 400 mg daily - T. Hughes et al, NEJM 2003, 349;15: 1423–1432) in the same risk category (69% all risks, 49% high Sokal risk). At the time of writing is too early to analyze the results by arm: a second analysis will be performed in November (datalock, October 31) and the results will be presented on site.

Cytogenetic and Molecular Response to Imatinib in High Risk (Sokal) Chronic Myeloid Leukemia (CML): Results of An European Leukemianet Prospective Study Comparing 400 Mg and 800 Mg Front-Line

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 185-185 ◽  
Author(s):  
Michele Baccarani ◽  
Fausto Castagnetti ◽  
Bengt Simonsson ◽  
Kimmo Porkka ◽  
Ibrahim C. Haznedaroglu ◽  
...  
Keyword(s):  
High Risk ◽  
Fish Analysis ◽  
Molecular Response ◽  
Front Line ◽  
Intention To Treat ◽  
International Scale ◽  
Daily Dose ◽  
Median Daily Dose ◽  
Marrow Cells

Abstract Sokal risk formulation was elaborated 25 years ago, based on very simple factors (age, spleen size, platelet count, and percentage of myeloblasts in the peripheral blood), based on patients treated with conventional chemotherapy. In spite of that, Sokal risk score is still the major prognostic factor for response to treatment with the tyrosine kinase inhibitor, Imatinib mesylate (IM). Since several preclinical, pharmacokinetic and clinical studies suggested that the therapeutic efficacy of IM may be concentration/dose–dependent, we assigned prospectively 217 adult patients with Ph pos CML, Sokal high risk (SHR), to be treated front line with IM 400 mg or 800 mg (Clin.Trials Gov. NCT00514488), comparing the cytogenetic and the molecular response rates at 3, 6, and 12 months. Cytogenetic response was evaluated by chromosome banding analysis (CBA) of marrow metaphases, and by FISH analysis of marrow cells in case of insufficient metaphase number. Molecular response was evaluated by RT-Q-PCR (PB), according to the international scale. The results are shown in Table 1. No difference between the two arms was significant at any time point. In the 400 mg arm, the median daily dose of IM was 400 mg, with 87% of patients receiving 350 to 400 mg. In the 800 mg arm, the median daily dose of IM was 720 mg, with 63% of patients receiving 600 to 800 mg. The CCgR rate was 86%, vs 66% in the patients who received a median daily dose of 600 to 800 or less than 600 mg daily, respectively (p=0.013). With a median follow up of 31 months (range 1–49 months), progression-free and overall survival are higher than 90% in both arms. Based on an intention-to-treat analysis, this study did not show a significant benefit of 800 mg over 400 mg in SHR patients, but the patients who could comply with the high dose had a better cytogenetic outcome. 3 months 6 months 12 months 400 800 400 800 400 800 (1)Refusal, or lost to follow-up, or protocol violations (2)Failure was defined according to the ELN recommendations (Baccarani et al, Blood2006;108:1809–1920) (3)No Ph pos metaphases out of at least 20 marrow cell metaphases, by CBA, or < 1% BCR-ABL positivity out of at least 200 marrow cells, by FISH (4)BCR-ABL:ABL < 0.10 and < 0.005 by RT-Q-PCR, converted to the International Scale. No. of pts 109 108 109 108 109 108 Dropouts(1) 4% 4% 5% 7% 5% 8% D/C adverse events 1% 2% 4% 4% 4% 7% Failure(2) 1% 1% 9% 10% 16% 15% CCgR(3) 19% 25% 49% 52% 58% 64% MolR>3.0 log(4) 7% 12% 25% 31% 33% 40% MolR>4.5 log(4) 1% 2% 3% 9% 10% 19% Transcript level (median) 2.085 1.122 0.378 0.108 0.084 0.036 Table 1: Summary of cytogenetic and molecular results. All percentages are calculated based on all randomized patients, according to the intention-to-treat principle. p-values are > 0.10 for all comparisons.

scholarly journals Correlations between Mutations in Cancer-Related Genes, Therapy Responses and Outcomes of the 3 rd Generation Tyrosine Kinase-Inhibitor (TKI) in Persons with Chronic Myeloid Leukemia Failing Prior TKI-Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 308-308
Author(s):  
Xiaoshuai Zhang ◽  
Zongru Li ◽  
Yazhen Qin ◽  
Robert Peter Gale ◽  
Xiaojun Huang ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Functional Enrichment ◽  
Molecular Response

Abstract Background Most, but not everyone with chronic myeloid leukaemia (CML) responds to imatinib or 2 nd-generation tyrosine kinase-inhibitors (TKIs). Mutations in cancer-related genes and in other than ABL1 may explain variable responses and outcomes to the 3 rd-generation TKIs including ponatinib and olverembatinib. Aim Interrogate correlations between mutations in cancer-related genes and therapy responses and outcomes to 3 rd-generation TKIs. Methods We used deep targeted sequencing for cancer-related mutations and Sanger sequencing for BCR::ABL1 on DNA samples from 167 subjects with CML failing to the prior imatinib and/or 2 nd-generation TKI-therapy and just before receiving a 3 rd-generation TKI. Gene ontology (GO) analysis was used to evaluate functional enrichment in GO terms among mutated genes. Optimal cut-offs for variant allele frequencies (VAFs) of the common mutations were determined by analyzing receiver-operator characteristic (ROC) curves. A Cox multi-variable regression model was used to identify correlations between mutations in cancer-related genes and therapy responses and outcomes of 3 rd-generation TKI-therapy. Results 167 subjects in chronic phase (n = 125) and accelerated phase (n = 42) received ponatinib (n = 28) or olverembatinib (n = 139) therapy. 27 subjects were exposed to imatinib; 79, a 2 nd-generation TKI; 61, imatinib and a 2 nd generation TKI. 142 (85%) subjects had ABL1 mutations including ABL1T315I (n = 116) or others (n = 26). 163 subjects had other cancer-related mutations which were evaluated in epigenetic regulators (n = 150), transcription factors (n = 84), cell signaling (n = 42), tumor suppressors (n = 39), protein kinases (n = 27), chromatin modification (n = 9) and DNA damage repair (n = 3) related-genes according to functional enrichment. The top 10 mutations were ASXL1 (n = 115), RUNX1 (n = 12), KMT2D (n = 12), PHF6 (n = 8), KMT2C (n = 8), IKZF1 (n = 8), STAT5A (n = 8), DNMT3A (n = 7), TET2 (n = 6) and BCOR (n = 6). 20 subjects had high-risk additional chromosomal abnormalities (ACAs). Frequency of BCR::ABL1 mutations was inversely- (p < 0.001) and of cancer-related mutations directly-related (p = 0.009) to increasing exposure to prior TKI therapies. These relationships were especially so for mutations in KMT2C (p = 0.06), DNMT3A (p = 0.09), KDM6A (p = 0.06) and TNFAIP3 (p = 0.08). BCR::ABL1 (82% vs. 95%, p = 0.03), RUNX1 (5% vs. 14%, p = 0.04), KMT2C (3% vs. 10%, p = 0.08) and IKZF1 (3% vs. 10%, p = 0.10) were more common in accelerated phase. With a median follow-up of 34 months (interquartile range [IQR], 12-40 months), 95 and 71 subjects achieved a complete cytogenetic response (CCyR) and major molecular response (MMR). 18 subjects transformed to accelerated (n = 8) or blast (n = 10) phases, 16 died of disease progression (n = 12) or other causes (n = 4). 3-year cumulative incidences of CCyR and MMRwere 65% (95% Confidence Interval [CI], 58, 71%) and 52% (43, 61%). 3-year probabilities of progression-free survival (PFS) and survival were 88% (81, 92%) and 91% (85, 95%). Mutations in tumor suppressor genes were more common in subjects not achieving a CCyR (27% vs. 19%, p = 0.01). In multi-variable analyses ASXL1 mutation with a VAF ≥ 17% and a PHF6 mutation were significantly associated with lower cumulative incidences of CCyR (p < 0.001 and p = 0.032) and MMR (p < 0.001 and p = 0.04). Moreover, subjects with BCR-ABL1T315I mutation had significantly higher cumulative incidences of CCyR (p = 0.07) and MMR (p = 0.04) than those with no BCR-ABL1 mutation and other BCR-ABL1 non-T315I mutation. Increasing age, more Ph 1-chromosome-positive cells, the best prior therapy-response < partial cytogenetic response (PCyR) and more TKI-therapies were associated with poor responses. STAT5A mutation was significantly associated with worse PFS (p = 0.002) and survival (p < 0.001), RUNX1 mutation (p = 0.006), high-risk ACAs (p = 0.07) and accelerated phase (p = 0.002) with worse PFS and increasing age (p = 0.05) and comorbidity(ies) (p = 0.05) with wosre survival. Conclusions ASXL1 mutations with a VAF ≥ 17% and PHF6 mutations were associated with poor responses of the 3 rd-generation TKI-therapy. STAT5A and RUNX1 mutations and high-risk ACAs were also associated with worse outcomes in persons receiving a 3 rd-generation TKI. These data should help physicians select people to receive 3 rd-generation TKIs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Better Molecular Response (MR) to Imatinib (IM) in Early Chronic Phase (CP) Versus Late CP Chronic Myeloid Leukemia (CML) Patients (pts) in Complete Cytogenetic Response (CCR): A Comparison at 24 Months of 2 Clinical Trials of the GIMEMA Working Party on CML on Behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia (GIMEMA-CML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1096-1096 ◽  
Author(s):  
Angela Poerio ◽  
Marilina Amabile ◽  
Ilaria Iacobucci ◽  
Simona Soverini ◽  
Sabrina Colarossi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Nested Pcr ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Working Party ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Molecular Response ◽  
Front Line ◽  
Log Reduction

Abstract We sought to determine the differences in molecular response between early and late CP pts with CML who achieved a CCR after treatment with IM at the standard dose of 400mg/d. We studied 2 different cohorts of patients in CCR: 67/191 (35%) pts after α-Interferon (α-IFN) failure enrolled on the CML/002/STI571 protocol 53/76 (70%) pts treated front line with a combination of IM and pegilated IFN-α (PEG-IFN) enrolled on the CML/011/STI571 protocol Cytogenetic response was monitored on bone marrow (BM) metaphases and molecular response was assessed by real time RT-PCR (TaqMan) BM and peripheral blood (PB) samples, collected at baseline, 3, 6, 9 and 12 months during the first year, and every 6 months thereafter. Molecular response was expressed as the ratio between BCR/ABL and β2-microglobulin (β2-M) x100. The lowest level of detectability of the method was 10−5. Negative results (i.e. undetectable transcript) were confirmed by nested PCR performed 4 times (sensitivity 10−6). For the purpose of this analysis, a major molecular response (MMR) was defined as a BCR-ABL/β2M value <0.0001%, which turned out to be roughly equivalent to a 3-log reduction and a complete molecular response (CMR) was defined as negative (undetectable) BCR/ABL levels confirmed by nested PCR. We observed a progressive decrease of the amount of BCR/ABL transcript in pts who achieved a CCR. At 24 months the median reduction in BCR/ABL transcript level was: a 3-log reduction in late CP pts a 4-log reduction in early CP pts In the latter group of pts MR was assessed also at 36 months. So we observed that 36 months after the first dose of IM and PEG-IFN pts who were still in CCR had the median value of BCR/ABL transcript of 0.00001% both in BM and PB. Therefore all these pts achieved a MMR. However only 8/53 (4%) pts were in CMR (undetectable BCR/ABL at least once as assessed by nested PCR). We conclude that front-line treatment with IM results in a better quality MR (4-log reduction in BCR/ABL transcript levels in early CP pts, as against a 3-log reduction in late CP pts). Figure Figure

High Efficacy and Particular Safety Profile of Imatinib Mesylate (Glivec®) in Elderly Patients with CML in Chronic Phase: Results of the AFR04 Prospective Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1039-1039
Author(s):  
Philippe Rousselot ◽  
Franck Nicolini ◽  
François Xavier Mahon ◽  
Delphine Réa ◽  
Jérome Jaubert ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Prospective Study ◽  
Imatinib Mesylate ◽  
Cardiac Failure ◽  
Cumulative Incidence ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Level 3

Abstract The reported median age of the chronic myelogenous leukaemia (CML) patients (pts) enrolled in the pivotal IRIS trial was 50y. Subgroup analysis have been already published focusing on pts over 60y with the conclusion that imatinib is efficient and well tolerated. We report here the first prospective study dedicated to imatinib in elderly pts with CML in chronic phase (CP). Patients aged 70y and over were eligible if they were diagnosed with CP CML for less than 12 months. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) comorbidity index was calculated for all pts. Hydroxyurea was the only treatment accepted before inclusion. Imatinib mesylate (IM, Novartis Pharma) was administered at the dosage of 400 mg QD. Cytogenetic response was assessed for each patient every 6 months during 2 years and every year thereafter. BCR-ABL analysis were performed in reference laboratories every 3 months and results expressed according to the ENL recommendations. Thirty pts with newly diagnosed CP CML were enrolled from March 2002 to October 2004. Median age was 74.8 years (70 to 90). Sex ratio (M/F) was 1.72. Thirty percent of the pts were classified as high risk, 35% intermediate risk and 35% low risk according to the Sokal score stratification. The mean severity CIRS-G index value was 1.47. Two pts had categories at level 3 (cardiopathy and nephropathy). Interval between diagnosis and imatinib initiation was 51 days (13 to 312). Median follow up was 45 months. Grade 2 to 3 neutropenia was observed in 22% of the patients (one patient received G-CSF). Grade 2 to 3 anemia was noted in 31.8% of the pts, 86% of them received rHU-EPO with a complete resolution of anemia. The most commonly reported extra haematological toxicity was oedema (71%, only one grade 3) followed by gastrointestinal symptoms (38%). Of note, 65% of the pts had cardiovascular comorbidities. The 2 pts who presented a cardiac failure episode were those with a CIRS-G cardiac categorie at level 3. Three pts stopped IM (2 already mentioned for cardiac intolerance and one for cutaneous intolerance). The median daily dose of IM was 392 mg (256 to 445), as calculated from the patients records. A transient or permanent dosage reduction was noted in 52.3% of the patients. Cumulative incidence of complete cytogenetic response (CCR) was 71.4% and 77% at 12 and 24 months respectively. One patient lost CCR after imatinib discontinuation. The cumulative incidence of major molecular response (MMR) was 25%, 56% and 59% at months 12, 24 and 36 respectively. Among pts in MMR at month 36, 25% were in complete molecular response. There was no correlation between the CIRS-G score or index and response. Among the 3 pts who stopped the treatment, 2 had CIRS-G categories at level 3. In conclusion, the toxicity of imatinib mesylate appeared more pronounced on the red cell lineage in elderly patients that reported in younger patients. Oedema are also very common but easily treated with diuretics. We observed 2 cases of cardiac failure in this cohort of high risk patients in the 2 patients with a previous level 3 CIRS-G category, suggesting a non favourable benefit/risk ratio in patients with severe comorbidity. For all other elderly patients, a high level of sustained cytogenetic and molecular responses was observed irrespective of age.

Determinants of Choice of Front-Line Tyrosine Kinase Inhibitor for Chronic Phase CML: A Study from the "Registro Italiano LMC & Campus CML"

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Mario Tiribelli ◽  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Isabella Capodanno ◽  
Maria Cristina Miggiano ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Multivariable Analysis ◽  
Chronic Phase ◽  
Front Line ◽  
Line Therapy ◽  
Concomitant Medications

Introduction : therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice. Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib. Results: median age at diagnosis was 59.9 years [interquartile range (IQR) 47.1 - 71.7], with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively. Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start. As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged <45 (69.1%) while imatinib was used in 76.9% of patients over 65 (p<0.001). There was a predominance of imatinib use across all Sokal (51.1% in low, 61.3% in intermediate and 51.4% in high) and ELTS (50.3% in low, 60.4% in intermediate and 66.5%) risk categories. We observed a prevalent use of 2G-TKIs in patients presenting with higher WBC counts (55.1% if WBC >100,000/mm3 vs 38.2% if WBC <100,000/mm3; p<0.001), lower Hb (53.8% if Hb <10 g/dl vs 41.9 if Hb >10 g/dl; p=0.001) and bigger spleen (65.1% if spleen >5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p<0.001). There was a decreasing use of 2G-TKIs with higher number of concomitant drugs: 64.4% for 0, 47.7% for 1-2, 27.0% for 3-5 and 13.6% for >5 drugs, respectively (p<0.001). Concordantly, there was a significant higher use of imatinib in patients with hypertension (69.8%), diabetes (70.0%), COPD (73.7%), previous neoplasms (73.0%), AMI (86.3%) or stroke (97.2%) history (p<0.001 for all conditions). Lastly, we observed a wider use of imatinib (61.1%) in patients diagnosed in years 2018-19, compared to those of the period 2012-17 (53.7%; p=0.01). In multivariable analysis, factors correlated with imatinib use were age > 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications. Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib. Figure Disclosures Breccia: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.

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.

Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7009-7009
Author(s):  
Carlo Gambacorti-Passerini ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Yeow Tee Goh ◽  
Irina S Dyagil ◽  
...  
Keyword(s):  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Second Line ◽  
Prior Therapy ◽  
Kaplan Meier ◽  
Imatinib Resistant

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

scholarly journals Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1141-1145 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Francis J. Giles ◽  
Kapil N. Bhalla ◽  
Javier Pinilla-Ibarz ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Molecular Response ◽  
Open Label ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase

Abstract Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure. This trial was registered at www.clinicaltrials.gov as #NCT00109707.

Imatinib in Children with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (CP CML): AAML0123 COG Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2140-2140 ◽  
Author(s):  
Martin A. Champagne ◽  
Cecilia Fu ◽  
Myron Chang ◽  
Linda Cooley ◽  
Nyla A. Heerema ◽  
...  
Keyword(s):  
Liver Toxicity ◽  
White Cell Count ◽  
Phase 1 ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Minor Response ◽  
Complete Cytogenetic Response

Abstract Introduction. Our prior phase 1 study (P9973) established the safety profile and suggested efficacy of imatinib in children with CP CML at doses varying from 260–570 mg/m2. The purpose of this phase 2 study was to define the rates of response in children with previously untreated CP CML. Methods. Patients less than 22 years of age at study entry with newly diagnosed CP CML, with no prior therapy other than hydroxyurea, were eligible. Imatinib was administered orally at a dose of 340 mg/m2 daily, with courses defined as 28-day intervals. A hematological response (HR) was defined at the end of courses 1 and 2 as a reduction in the white-cell count to <10 x 109/L and in platelet count to <450 x 109/L, and was considered a complete response (CHR) when maintained for at least four weeks. Cytogenetic response is defined as follows, based on the absolute percent of Ph+ metaphase cells on marrow specimens: complete cytogenetic response (CCyR) 0% Ph+ cells; partial (PCyR)1–35%; minor 39–65%; minimal 66–95%; none 96–100%. Iterative cytogenetic analyses were performed every 3 months during therapy. Toxicities were reported prospectively using the NIH CTCv2.0 criteria. Results. 50 children (42% boys), with a median age of 11.8 years (range 2.3–19.1) completed more than one course of therapy and were evaluable for response. Median number of courses delivered was 22.5 (range 1–43), with a median follow-up of 795 days. 96% of the calculated dose was administered. Eleven patients experienced 14 non-hematological grade 2–4 adverse events, and one patient discontinued therapy because of toxicity. The HR and CHR rates were 78% and 12%, at the end of course 1, and 20% and 78%, respectively, at the end of course 2. Only one patient was reported as a hematologic non-responder at the end of course 2. At the end of the third course, 33 patients were evaluated for cytogenetic response. Twelve (36%) children were in CCyR; 10 (30%) in PCyR; 5 in minor response; 4 in minimal response; 2 with no cytogenetic response. Six patients did not have cytogenetic evaluation; while in 11 (33%) the study was not possible due to insufficient sampling. Overall, 33 (66%) CCyRs were documented, at a median time of 5.6 months (91% documented by 9 months). Only 1 patient achieved a CCyR after course 10. Thirty-three children were removed from protocol, of which 23 underwent stem cell transplantation. One patient progressed to blast phase while on therapy, while six additional patients had cytogenetic progression. Of the 3 remaining patients, two patients had difficulty with taking medications and one had grade 4 liver toxicity. At 1 year, the estimated event free and overall survivals are 96% and 98%, respectively. Conclusion. Imatinib is well tolerated in previously untreated children with CP CML and induces comparable rates of complete cytogenetic response to those observed in adults. Current evaluation of molecular response is being performed.

Does Previous Interferon Use Have Negative Effect on Imatinib Response in Chronic Myeloid Leukemia (CML)? A Single Center Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4821-4821
Author(s):  
Mustafa Yenerel ◽  
Reyhan Diz-Kucukkaya ◽  
Naciye Demirel ◽  
Mesut Ayer ◽  
Selim Yavuz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
First Line ◽  
Group I ◽  
Blastic Phase ◽  
Significant Difference ◽  
Group Ii ◽  
Ifn Treatment

Abstract Aim: Effectiveness of imatinib in CML was evaluated on a cohort of 104 patients with a median 29 months of observation time, recruited between 3/2002 and 2/2006. Patients and methods: 104 patients diagnosed as having CML between 1990–2006 were included in this study. Their median age was 44 years (19–77) and 55% of patients were male. Imatinib was used in a dose of 400mg/day for chronic phase and 600mg/day for accelerated and blastic phase. In chronic phase patients with no cytogenetic response in 1 year and in accelerated or blastic phase patients with no hematologic response in 3 months, doses were increased to 600mg/day and 800 mg/day respectively. Interferon (IFN) treatment had been used as α-IFN 5 MIU/m2 daily combined with or without monthly courses of cytosine arabinoside (Ara-C) 20 mg/m2 for 10 days in 50 patients before imatinib. Cytogenetic response (CR) was monitored on bone marrow metaphases collected at baseline, 3, 6, 9 and 12 months during the first year, and every 6 months thereafter. CR was quantified by 20 metaphases Ph in bone marrow: 0% as complete (CCR), 1–35% major as (MjCR) and > 95% as imatinib failure. Molecular response followed by PCR in bone marrow samples. We stratified the patients according to previous IFN treatment in two groups. CML patients who were treated with imatinib as a first line therapy were analyzed as Group I. Other patients who were treated initially with IFN and ara-C and those were switched to imatinib because of intolerance or unresponsiveness were accepted as Group II. Results: Age, sex distribution and disease phases of both groups were quite similar. Therapy responses are summarized in Table 1. Hematological response (HR) was seen in 90,4 % of the patients (94/104) in median 54 days (11–149) for Group I and 41 days (15–193) for Group II. There wasn’t any difference according to the time elapsed for HR (p=0,79). Cytogenetic data were interesting in our patients. As a total result, CR were achieved in 77,8 % of the patients in median 5,1 months (84 days– 2,7 years). CR rate was significantly higher in Group I (p=0.019). When we compared two groups according to early cytogenetic response in first 6 months, Group I had also much better results (p=0.049). CCR were achieved 35,6 % of the patients (37/104) and there wasn’t any difference between the groups (p=0,25). Molecular response was achieved in 19,2% of the patients followed by PCR (19/87) and there was no significant difference (p=0,15). We conclude that imatinib is highly effective as a first line agent in CML patients. Advanced disease age probably is the most important factor for the lower response rates in the second group. But, the role of previous IFN therapy should also be questioned. As a summary, imatinib should be used in every CML patient without any delay in order to get higher and sooner CR. Tablo 1. Imatinib response of the 104 patients with CML. HR (p=0.89) CR (p=0.019) MjCR in 6 months(p=0.049) CCR(p=0.25) Mol. Response(p=0,15) Imatinibfailure (p=0.03) Imatinib Follow-up Group I 90,7% (49/54) 77,8% (42/54) 57,4% (31/54) 40,7% (22/54) 30% (12/40) 22,2% (12/54) 22,1 months (3,7 months -3,5 yrs) Group II 88% (44/50) 56% (28/50) 38% (19/50) 30% (15/50) 17% (8/47) 40% (20/50) 3 years (9months-5,1 yrs)

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