Seven-year follow-up of patients receiving imatinib for the treatment of newly diagnosed chronic myelogenous leukemia by the TARGET system

2011 ◽  
Vol 35 (5) ◽  
pp. 585-590 ◽  
Author(s):  
Tetsuzo Tauchi ◽  
Masahiro Kizaki ◽  
Shinichiro Okamoto ◽  
Hideo Tanaka ◽  
Mitsune Tanimoto ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Target System ◽  
Newly Diagnosed

Seven-Year Follow-up of Patients Receiving Imatinib for the Treatment of Chronic Myelogenous Leukemia by the TARGET System

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2287-2287
Author(s):  
Tetsuzo Tauchi ◽  
Masahiro Kizaki ◽  
Shinichiro Okamoto ◽  
Hideo Tanaka ◽  
Mitsune Tanimoto ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Myelogenous Leukemia ◽  
Imatinib Therapy ◽  
Target System ◽  
High Survival ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Number Of Patients

Abstract Abstract 2287 The TARGET system is an online database that can be easily accessed by physicians. The TARGET system is operated by the Japanese Society of Hematology. The registration of one's own chronic myeloid leukemia (CML) patients in the TARGET system makes it possible to share experiences among physicians, and, thus, may facilitate appropriate treatment for patients. Patients participating in clinical trials are usually selected according to strict eligibility criteria. Previous publications have questioned the use of other overly restrictive exclusion criteria in clinical oncology trials. In practical situations, however, the clinical features of patients are much more heterogeneous than those defined by the selection criteria in clinical trials. From this point of view, the TARGET system might provide more practical and general features compared with the IRIS study. Patients were registered in the TARGET system from October 2003 to March 2010 in Japan. A total of 1,236 patients from 176 hospitals were registered in Japan. We analyzed data from 639 CML chronic phase patients not receiving prior therapy registered in this system. After 90 months follow-up, high survival rates were demonstrated for imatinib-treated newly diagnosed CML patients, with event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) rates of 79.1, 94.8, and 95.1%, respectively. A landmark analysis of 296 patients who showed a complete cytogenetic response (CCyR) at 12 months after the initiation of imatinib treatment revealed that, at 90 months, 99% of patients (95% CI, 98 to 100) had not progressed to accelerated phase (AP) or blastic crisis (BC). The patients showing a CCyR and a reduction of at least 3 log levels of BCR-ABL transcripts after 18 months of treatment had an estimated survival rate without CML progression of 100% at 84 months.By 84 months, 315 patients had achieved an MMR. A total of 226 of 315 patients (71.7%) achieved undetectable BCR-ABL by 84 months. We therefore analyzed the probability of achieving undetectable BCR-ABL based on the molecular response at 12 and 18 months. The probability of achieving undetectable BCR-ABL by 72 months in patients with an MMR at 12 months was 86.5%, compared with 64.7% for those without an MMR (P<0.0001). Also, the probability of achieving undetectable BCR-ABL based on the molecular response for patients with an MMR at 18 months was 91.9%, compared with 65.3% for those without an MMR (P<0.0001). Therefore, having an MMR at 12 or 18 months of imatinib therapy is highly predictive of subsequent undetectable BCR-ABL. However, the TARGET data indicate a marked increase in the number of patients with undetectable BCR-ABL without an MMR at 12 months compared with IRIS sub-meta-analysis (64.7 vs. 5%, respectively). There were no new safety issues. In summary, based on this 7-year TARGET analysis, imatinib showed a continual clinical benefit as first-line therapy for newly diagnosed CML. The data from TARGET shows that Japanese patients contain a large number of late responders to imatinib therapy. The TARGET system may represent a more practical and general feature compared with the IRIS study. Disclosures: Tauchi: Novartis Pharma KK: Research Funding.

Incidence of Late Chronic Anemia in Newly Diagnosed Patients with Chronic Myelogenous Leukemia Responsive to Imatinib

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3769-3769
Author(s):  
Paola Volpicelli ◽  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Federico Vozella ◽  
Paola Finsinger ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Prolonged Treatment ◽  
Imatinib Treatment ◽  
Newly Diagnosed ◽  
Chronic Anemia ◽  
Significant Difference ◽  
Sokal Score

Abstract Abstract 3769 Anemia has been reported in about 5–8% of newly diagnosed patients with Chronic Myelogenous Leukemia (CML) treated with imatinib in the first 6 months of therapy, and has been generally regarded as transient like neutropenia and thrombocytopenia: in patients responsive to imatinib, however, it is still unclear if the prolonged treatment could induce the appearance of a late chronic anemia. To highlight this issue, we revised 104 CML patients (M/F 54/50, median age at diagnosis 58.0 years, interquartile range 43.3 – 70.2) treated at our Institution with 1st line imatinib therapy for at least 36 months and in stable complete cytogenetic response (CCyR). At the 36th month of imatinib treatment, a late chronic anemia (defined as Hb levels < 11 g/dl for > 6 months) was present in 16/104 patients (15.4%): the anemia was severe (Hb < 10 g/dl) in 10 patients (9.6%) and moderate/mild (Hb ≥ 10 < 11 g/dl) in 6 patients (5.8%). Clinical features at diagnosis of patients who had late chronic anemia at the 36th month compared to the remaining 88 patients without late anemia are shown in the Table: Hb < 11 g/dl at the 36th month Hb ≥ 11 g/dl at the 36th month p M/F 6/10 48/40 0.209 Median age (yrs) (IR) 68.0 (58.9 – 75.4) 56.6 (43.1 – 69.1) 0.016 Sokal Score: Low 3 44 0.002 Int 8 39 High 5 5 Median Hb (g/dl) (IR) 11.6 (10.4 – 13.3) 12.7 (11.2 – 13.8) 0.098 Median WBC (× 109/l) (IR) 79.0 (33.2 – 136.6) 60.5 (31.8 – 112.4) 0.423 Median PLTS (× 109/l) (IR) 624 (299 – 835) 412 (296 – 557) 0.122 All patients with late chronic anemia had a low reticulocyte count and 7/16 a condition of iron deficiency with reduced serum ferritin but no clinical and instrumental sign of chronic blood loss: in this latter group, oral iron supplementation was always ineffective. Four out 16 patients (25%) needed 1 or more red cell transfusions during the follow-up. At landmark analysis from the 36th month of imatinib treatment, there was no significant difference in the cumulative 4-year overall survival for patients with and for those without late chronic anemia (80%, 95% CI 44.8 – 100%, vs 94%, 95%CI 85.8 – 100%, respectively; p=0.068). In conclusion, the occurrence of a late chronic anemia during long-lasting treatment with imatinib has been observed in > 15% of our responsive patients and was severe in about 10% of cases: its occurrence seems more common in elderly patients with higher Sokal score at diagnosis. Late chronic anemia does not seem to affect OS, but the real impact should be evaluated on a large cohort of patients. Disclosures: Tafuri: Sigma Tau Pharmaceuticals: Research Funding.

scholarly journals How to Monitor Patients with Chronic Myelogenous Leukemia

2003 ◽  
Vol 1 (4) ◽  
pp. 513-517
Author(s):  
Michael E O'Dwyer
Keyword(s):  
At Risk ◽  
Disease Progression ◽  
Chronic Myelogenous Leukemia ◽  
Treatment Options ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Optimal Response ◽  
Risk Of Disease

The introduction of imatinib has radically altered the treatment options and, perhaps, prognosis for patients with newly diagnosed chronic myelogenous leukemia (CML). However, although the majority of patients appear to benefit from this agent, it is important to recognize as early as possible the patients who experience a sub-optimal response and those who may be at risk of disease progression. This article reviews current available methods of monitoring and provides recommendations for appropriate follow up of imatinib-treated patients.

Real world treatment patterns in chronic myeloid leukemia patients newly initiated on tyrosine kinase inhibitors in an U.S. integrated healthcare system

2017 ◽  
Vol 24 (4) ◽  
pp. 253-263
Author(s):  
Nazia Rashid ◽  
Han A Koh ◽  
Kathy J Lin ◽  
Brian Stwalley ◽  
Eugene Felber
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Index Date ◽  
Stem Cell Transplant ◽  
Study Time ◽  
Myelogenous Leukemia ◽  
Prior History ◽  
Cell Transplant ◽  
Time Period ◽  
History Of

Purpose To evaluate treatment patterns in patients diagnosed with incident chronic myelogenous leukemia (CML) newly initiating therapy with imatinib, dasatinib, or nilotinib. Patients were followed to determine switching and discontinuation rates. Factors associated with switching or discontinuation from index TKI therapy, reasons for discontinuation based on electronic chart notes, and frequency of laboratory monitoring were assessed during the follow-up period. Methods A retrospective cohort study was conducted in chronic myelogenous leukemia patients aged ≥ 18 years who were identified from the Kaiser Permanente Southern California (KPSC) Cancer Registry database during the study time period of 1 January 2007 to 12 December 2013. The index date was defined as the date of the first TKI prescription (imatinib, dasatinib, or nilotinib) identified during the study time period with no prior history of TKI use within 12 months. Patients had to have continuous membership with drug benefit eligibility and no prior history of stem cell transplant (SCT) or other cancers during the 12 months prior to the index date. Baseline characteristics were identified during 12 months prior to the index date and outcomes were identified during the follow-up period after the index date. All patients were followed from index TKI therapy until end of study time period (12 December 2014), death, stem cell transplant, or disenrollment from the health plan unless one of the following occurred first: a patient switched their index therapy, or a patient discontinued their index therapy. Forward stepwise selection multivariable logistic regression models were used to evaluate factors associated with patients who continued therapy compared to those who switched or discontinued therapy with the index TKI. Chart notes were reviewed 30 days prior and 30 days post index TKI discontinuation to evaluate reasons for discontinuation. Molecular and cytogenetic testing frequency was also assessed during the follow-up period among the different patient groups. Results Two hundred sixteen patients were identified with incident chronic myelogenous leukemia and use of TKI therapy: 189 (87.5%) received imatinib, 19 (8.8%) received dasatinib, and 8 (3.7%) received nilotinib. The mean age on index date was 53 years and 63% were male; 103 patients (48%) continued on their index therapy, while 62 patients (28%) switched, and 51 patients (24%) discontinued.

scholarly journals The Clinical Utility of Pharmacogenomics Testing in Assessing Tyrosine Kinase Inhibitor Therapy, Intolerance and Responses in Patients with Chronic Myelogenous Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5440-5440
Author(s):  
Darci Zblewski ◽  
Naseema Gangat ◽  
Michelle A. Elliott ◽  
Aref Al-Kali ◽  
Mark R. Litzow ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Chronic Myelogenous Leukemia ◽  
Metabolic Pathways ◽  
Research Funding ◽  
Small Sample ◽  
Poor Metabolizers ◽  
Myelogenous Leukemia ◽  
Second Line ◽  
Newly Diagnosed ◽  
First Line

Abstract Background: Chronic myelogenous leukemia (CML) is a BCR-ABL1 driven myeloid neoplasm, with excellent response rates to tyrosine kinase inhibitors (TKI). TKI such as imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) currently US FDA approved, have dramatically changed survival outcomes. That being said, two main challenges exist; suboptimal responses and TKI intolerance. The reason why some patients tolerate/respond to TKI better than others is unknown, but is potentially explainable based on drug metabolism. The field of pharmacogenomics (PGX) is rapidly evolving, with commercial panel's rapidly assessing metabolic pathways such as cytochrome P450 (CYP), UGTA1A, p-glycoprotein/ABCB1. We carried out this study using a 22 gene-PGX panel to assess potential causes of TKI related intolerance and suboptimal responses in compliant patients. Methods: Twenty-nine Mayo Clinic patients with CML were prospectively recruited after informed consent. Buccal swabs were utilized for PGX testing to assess variations/polymorphisms involving CYP3A4/5, 1A2, 2C9, UGT1A1, amongst others (www.Oneome.com). Three groups of patients were recruited, those with i) TKI intolerance, ii) suboptimal responses by ELN criteria, iii) and newly diagnosed cases, to assess if PGX testing could explain TKI intolerance or resistance, or alter choice of therapy in newly diagnosed cases. A pharmacology review was obtained to interpret reports in all cases. Results: 29 patients with CML were prospectively enrolled, median age 64 years, 15 (52%) male. At last follow up (median 21 months), 3 (10%) deaths and no disease progressions were documented. 82% received first line IM, whereas 18% received first line DAS. Major metabolic pathways assessed for IM included, CYP3A4 and 5, while minor pathways included 2C19, 2C9 and 2D6. Majority (83%) of IM patients had normal major pathways with 17% being intermediate-normal. With regards to the minor pathways, 25% were rapid metabolizers for 2C19, whereas 29% were intermediate and 4% poor metabolizers for 2C9 and 50% and 16% were intermediate and poor metabolizers for 2D6. In all IM treated patients PGX testing did not completely explain intolerance or resistance and did not change clinical decision making. Front line DAS was used in 18% and the major pathway assessed was CYP 3A4, with 80% being normal and 20% being intermediate metabolizers. Once again PGX testing did not completely explain intolerance/resistance and no therapeutic changes were based on PGX analysis. Seventeen (59%) patients received second line TKI therapy (50% each for intolerance and resistance), with DAS (58%) and NIL (29%), being the two most common. Once again for DAS, 90% had normal 3A4 metabolism while 10% were intermediate and for NIL 80% were normal and 20% intermediate. Only one of 2 NIL treated patients with UGTA1A polymorphisms developed indirect hyperbilirubinemia (grade 1). In the second line setting, PGX testing did not completely explain or alter treatment decisions. BOS was used as a third line agent in 3 (>10%) patients, 2 who remained refractory and one with intolerance, and all three were normal CYP3A4 metabolizers. None of these patients developed diarrhea a common side effect of BOS. PON was used in one patient with intermediate CYP3A4 metabolism as a 5th line agent and the patient continues to have refractory disease with no thrombotic events. In all cases, no changes were made to concomitant medications based on PGX testing. Conclusion: In conclusion, while PGX testing has rapidly evolved and become commercially available, in the context of TKI therapy for CML, while it offers useful insights on minor metabolic derangements and side effects like NIL induced hyperbilirubinemia, in our study, currently limited by a small sample size, it did not completely explain TKI intolerance or resistance. Recruitment of additional patients (n=100) and correlations with plasma drug levels are currently ongoing. Table. Table. Disclosures Al-Kali: Novartis: Research Funding. Stewart:Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding; Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy.

Association of Hydroxyurea to Imatinib Is Effective in Patients with Chronic Myelogenous Leukemia Resistant to Imatinib Alone.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4693-4693 ◽  
Author(s):  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Ida Carmosino ◽  
Chiara Sarlo ◽  
Rosa De Cuia ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chronic Phase ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Hematological Toxicity ◽  
Imatinib Treatment ◽  
Duration Of Response ◽  
Wbc Count

Abstract The introduction of Imatinib in the treatment of Chronic Myelogenous Leukemia (CML) leads to the achievement of Complete Cytogenetic Response (CCR) in about 70% of patients: however, in the remaining 30% of patients there is a persistance of Ph+ cells also after standard (400 mg/day) and increased (600 mg/day) dose of Imatinib. These patients are thus cytogenetically resistant to Imatinib alone and their management is at present unclear. From 11/2002 to 11/2003, 10 patients in chronic phase (6 male and 4 female, median age 52.5 years, range 29 – 68 years) with persistance of 100% Ph+ cells (9 patients) or BCR/ABL + cells (1 patient with Ph- BCR/ABL+ CML at onset) after standard (at least 6 months of treatment) followed by increased dose (at least 3 months of treatment) of Imatinib alone, were considered resistant and added Hydroxyurea (HU) to Imatinib. Seven patients have been pretreated with IFN before Imatinib; median times from diagnosis and from Imatinib treatment to HU addition were 51 months (range 23 – 151) and 14 months (range 10 – 31), respectively. HU was given according to WBC count: patients with WBC < 10 x 109/l started HU at the dose of 1 g/day, patients with WBC > 10 x 109/l at the dose of 1.5 g/day. Imatinib was continued at the same previous dosage (600 mg/day in 6 patients and 400 mg/day in 4 patients who did not tolerate increased dosage for hematological toxicity). Three patients achieved a complete response (2 CCR after 3 and 12 months respectively and 1 molecular complete response after 9 months in the patient Ph- BCR/ABL+ at onset) and 1 patient achieved a partial CR (Ph+ < 33%) after 9 months: the remaining 6 patients were resistant with persistance of 100% Ph+ cells. Toxicity was mild and only 1 patient discontinued for 2 weeks the association due to transient thrombocytopenia: no extra-hematological toxicity has been recorded. After a median follow-up of 14 months (range 20 – 10), 2 patients (1 resistant and 1 after 5 months from the achievement of CCR) evolved in Blastic Phase (BP), 5 patients are in stable chronic phase with 100% Ph+ cells and 3 patients are still in response after 4,6 and 7 months respectively. In conclusion, the association of HU with Imatinib seems capable to induce cytogenetic response in at least one third of patients resistant to Imatinib alone, with minimal toxicity: a longer follow-up and a comparison with other associations is needed to evaluate the quality and duration of response in such group of patients.

Optimal Treatment Strategy with Nilotinib for Patients with Newly Diagnosed Chronic Myelogenous Leukemia in the Chronic Phase Based on Early Achievement of Deep Molecular Response (MR4.5) : First Report from N-Road, a Phase II Study in Japan

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1925-1925
Author(s):  
Kaichi Nishiwaki ◽  
Kei-Ji Sugimoto ◽  
Shigehisa Tamaki ◽  
Junichi Hisatake ◽  
Hisayuki Yokoyama ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Phase Ii ◽  
Dose Escalation ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Risk Scores ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Optimal Response ◽  
Deep Molecular Response

Abstract Background : Nilotinib is a potent and selective inhibitor of BCR-ABL. In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) trial, frontline nilotinib therapy at 300 mg twice daily (BID) resulted in a higher rate of deep molecular response (DMR) compared to imatinib therapy in patients with chronic myelogenous leukemia in the chronic phase (CML-CP). Furthermore, in the ENESTxtend study, many patients with suboptimal response or treatment failure achieved a major molecular response (MMR) after the nilotinib dose was increased to 400 mg BID from 300 mg BID. The present study was aimed at investigating a strategy of intra-patient nilotinib dose escalation for patients with newly diagnosed CML-CP in order to achieve MR4.5early. Methods : N-Road is a multicenter phase II clinical study for patients with newly diagnosed CML-CP, in which nilotinib was administered at 300 mg BID for 24 months. In this study, increasing the nilotinib dose to 400 mg BID was allowed if patients satisfied the criteria for no optimal response at any time points. The criteria for no optimal response were defined as follows: BCR-ABL1 > 10% on the International Scale [IS] after 3 months, BCR-ABL1 > 1% on the IS after 6 months, BCR-ABL1 > 0.1% on the IS after 12 months, BCR-ABL1 > 0.0032% on the IS after 18 months, two consecutive losses of MMR, and two consecutive losses of MR4.5 (BCR-ABL1 ≤ 0.0032% on the IS). The primary endpoint was the cumulative MR4.5rate by 24 months after the initiation of nilotinib treatment. Results: Between August 2012 and July 2015, 53 Japanese patients were enrolled, of whom 51 were evaluated in the study. The median patient age was 50 years. The ratio of men to women was 33:18. The numbers of patients with low, intermediate, high Sokal risk scores was 21 (41.2%), 21 (41.2%), and 6 (11.8%), respectively, and 3 (5.9%) had an unknown risk. The median duration of nilotinib treatment was 23.8 months (range, 4.1-26.3 months). Of the patients, 33 (64.7%) completed 24 months of treatment, 7 (13.7%) had ongoing treatment, and 11 (21.6%) discontinued treatment because of adverse events (AEs; n=4), protocol deviation (n=1), loss to follow-up (n=3), death (n=1), insufficient effect (n=1), or consent withdrawal (n=1). The cumulative MR4.5 rate (95% confidence interval [CI]) in the 46 evaluable patients was 52.0% (36.9-69.0%) by 24 months (Figure). The cumulative MR4.0 and MMR rates were 60.9% (46.1-76.0%) and 83.5% (69.6-93.5%) by 24 months, respectively. Among the 46 evaluable patients, 26 satisfied the criteria for no optimal response. The dose was increased in 6 of the 26 patients but not in the remaining 20 patients for the following reasons,: hematological AEs (n=3), non-hematological AEs (n=9), achievement of MR4 at 18 months (n=2), patient refusal (n=4), and unknown (n=2). Although 4 patients with no optimal response achieved MR4.5, all of them did not receive an increased treatment dose. The actual mean dose intensities in the patients with or without optimal response were 570 and 560 mg/day, respectively. None of the patients had disease progression, and 1 patient died of an unknown cause during the study. The estimated rates (95% CI) of progression free survival and overall survival at 24 months were 98% (84-100%) and 98% (84-100%), respectively. The most common (≥20%) non-hematological AEs of any grade were rashes (47%), headache (34.2%), fatigue (21.6%) and nausea (23.5%). The most common (≥5%) grade 3/4 laboratory abnormalities were increased lipase (10.6%), decreased phosphate (12.2%) and increased alanine aminotransferase (7.8%). Cardiovascular events were observed to be ischemic heart disease in 2 patients (3.9%). Conclusion: In this study, it was difficult to evaluate the efficacy of nilotinib dose escalation to achieve MR4.5 early because the dose could not be increased to 400 mg BID in many patients who did not show optimal response. However, as we were unable to increase the dose to 400 mg BID in many patients because of AEs and as nilotinib therapy demonstrated superior MR4.5, these results might support continuous nilotinib therapy using a dosage of at least 300 mg BID for newly diagnosed CML. Disclosures Nishiwaki: Novartis PHARMA: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document