Results of Imatinib Therapy In Patients with Early and Late Chronic-Phase Chronic Myeloid Leukemia In a South Brazilian Cohort.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4487-4487
Author(s):  
Marcelo Capra ◽  
Mariza Shaan ◽  
Katia Fassina ◽  
Mario Sérgio Fernandes ◽  
Marco Antônio Schilling ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Sokal Score ◽  
Hasford Score

Abstract Abstract 4487 Background: Imatinib treatment for Chronic Myeloid Leukemia (CML) was first introduced in Brazil in 2001, initially used as second line therapy for patients resistant or intolerant to interferon (IFN). In 2008 imatinib was adopted as front-line therapy for chronic-phase (CP-CML) and clinical experience is improving since then, but little is known about the result of its introduction in our clinical practice. Aims: To evaluate the impact of imatinib treatment in the outcomes of a cohort of CP-CML and the prognostic significance of Sokal and Hasford scores and late-onset treatment. Methods: We conducted a retrospective study in a cohort of patients with CP-CML from a south Brazilian database. All patients received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the European LeukemiaNet. The outcomes were response to treatment, event-free survival (EFS) and overall survival (OS). Results: We analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 years (4 – 85). The median time from diagnosis to imatinib was 7 months (0 – 178) and 29% of pts had more than 12 months lapse. Prior therapy with IFN was used in 70% pts. All pts had a minimum follow-up of 12 months. At baseline, 57 pts (31%) were in complete hematological response (CHR) due to the use of previous treatment. Of the 127 pts not in CHR at baseline, 98% achieved CHR early during imatinib treatment. 177 pts had cytogenetic evaluation during treatment and 9 pts were in complete cytogenetic response (CCyR) due to the use of previous IFN. Of the 168 pts not in CCyR at baseline, 86,4% achieved a major cytogenetic response (MCyR) during imatinib treatment (84% had a CCyR and 2,4% had a partial cytogenetic response). The rate of pts achieving MCyR any point during treatment differed significantly in the low, intermediate and high risk Sokal score groups (97%, 81% and 78% respectively, P=0,04), but not in the Hasford score groups (90%, 85% and 72%, P=0,22). Minor cytogenetic response was seen in 3,6% of pts, minimal cytogenetic response in 6% and 9,5% had no cytogenetic response. The median time to a MCyR was 9 months, with 62% of pts achieving MCyR at 12 months. The rate of pts achieving MCyR in 12 months differed significantly between pts who start imatinib before 12 months from diagnosis (68%) and those late treated (47%, P=0,02). Evaluation of minimal residual disease at the molecular level was available for 155 pts: 25,5% of pts had a complete molecular response (CMR), 43% had a major molecular response (MMR) and 2 pts were in MMR at baseline due to previous IFN. The projected EFS and OS rates at 4 years were, respectively, 68% and 92% after a median follow-up time of 4 years. The rate of EFS differed significantly in the low, intermediate and high risk Sokal score groups (80%, 66% and 52% respectively, P=0,04), but not in the Hasford score groups (78%, 62% and 44%, P=0,09). During treatment with imatinib, 120 pts (65%) had a register of any grade hematologic adverse event (21% being grades 3 or 4) and 165 pts (90%) had a register of any grade nonhematologic adverse event (9,3% being grades 3 or 4). Of the 185 pts who received treatment, 134 (72%) continue to receive imatinib and 51 (28%) discontinued treatment. The reasons for discontinuation were: 11 (6%) pts had drug-related adverse events (3 [1,6%] hematologic and 8 [4,3%] nonhematologic), 17 (9,2%) had disease progression (5 [2,7%] loss of CHR, 10 [5,4%] loss of CCyR, 2 [1%] had progression to accelerate or blastic phase), 22 (11,9%) had treatment failure (3 [1,6%] had no CHR, 13 [7%] had no CCyR and 6 [3,2%] had no MMR), 1 pt (0,5%) discontinued due to comorbidity. For the 51 (100%) pts that discontinued imatinib, 31 (61%) switched to dasatinib, 17 (33%) to nilotinib, 1 (2%) to hydroxyurea, 1 (2%) to other treatment and 1 (2%) remained without treatment. Sixteen pts (8,6%) died during imatinib treatment or during long-term follow-up after discontinuation of imatinib. Conclusions: In our population of CP-CML pts treated with imatinib, a majority of patients achieved complete cytogenetic and major molecular responses, with a prolonged of OS and EFS and good safety profile. Sokal score showed better prognosis prediction than Hasford. Early onset of imatinib therapy led to better outcomes and justifies imatinib as front-line treatment of our patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Imatinib in Children with Chronic Myeloid Leukemia in Chronic Phase: Long-Term Results of the French National Phase IV Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4147-4147
Author(s):  
Hélène Deutsch ◽  
Andre Baruchel ◽  
Joelle Guilhot ◽  
Arnaud Petit ◽  
Thierry Leblanc ◽  
...  
Keyword(s):  
Median Time ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Second Line Therapy ◽  
Blastic Crisis ◽  
Line Therapy ◽  
Phase Iv

Because of the rarity of Chronic Myeloid Leukemia (CML) in children and adolescents, only few studies reported on efficacity and tolerance of imatinib in the pediatric population and scant data are available regarding long-term follow-up. The aim of our analysis was to assess, the long-term efficacity and safety of imatinib in children with CML in early chronic phase included in the French multicentric prospective Glivec Phase IV trial (Millot et al, J Clin Oncol 2011). Methods: Children aged 0 to 18 years with newly diagnosis CML in chronic phase were eligible to received daily imatinib 260 mg/m² according the trial. Long-term analysis included overall survival (OS), progression-free survival (PFS), response to treatment and adverse events. Results: Between March 2004 and December 2008, 44 patients (median age 13.4 years; range 0.8 - 16.7 years) were included in the trial. As of April 2019, with a median follow-up of 10.6 years (range 1.8 - 13.4 years), 2 patients (pts) progressed to blastic crisis and only one death was recorded. The median age was 21.8 years (range 9.3 - 28.8 years) at the last follow-up. The median duration of imatinib therapy was 10.5 years (range 0.2 - 12.5 years) for the entire cohort. To date, 13 pts (29.5%) are still treated with imatinib. Thirty-one pts (70.5%) had discontinued first line treatment with imatinib after a median time of treatment of 2.4 years (range 0.2 - 10.6 years) for the following reasons: 10 pts did not achieve major molecular response (MMR), 1 pt developed blast crisis, 2 pts had unsatisfactory level of molecular response (MR) according to the clinician, 10 pts lost their response (loss of complete hematological response n=1, complete cytogenetic response [CCR] n=6 and MMR n=3), 4 pts attempted treatment free remission (TFR), 3 pts were intolerant to imatinib and 1 pt stopped because of pregnancy. Among these 31 pts who discontinued imatinib, 2 pts are still in TFR, and 29 pts switched to a second line therapy: second generation tyrosine kinase inhibitors (2TKI) (n=25), allogeneic hematopoietic stem cell transplantation (HSCT) (n=3), polychemotherapy (n=1). Sixteen of these 31 pts (51.6%) required subsequent lines of therapy including a second pt who transformed to blastic crisis under a second line therapy with dasatinib. Overall 11 pts (25%) underwent HSCT. Overall, regarding the best response, during the study follow-up 11 pts (25%) achieved MMR after a median time of 2.3 years (range 0.8-5.1), 7 pts (13.6%) achieved MR4 after a median time of 5.1 years (range 2.5-7.8), 25 pts (56.8%) achieved MR4.5 after a median time of 2.92 years (range 1.1-10.4) and 1 pt (2.3%) achieved CCR only. At last follow-up, 43 out the 44 pts were alive : 3 pts (7%) were in CCR, 12 pts (27.9%) in MMR, 6 pts (13.9%) in MR4 and 22 pts (51.2%) in MR4.5. Among the 13 pts still treated with imatinib, 1 pt (7.7%) was in CCR, 6 pts (14%) in MMR, 3 pts (23.1%) were in MR4 and 3 pts (23.1%) in MR4.5. Among the 11 transplanted patients, all pts except one are alive, in at least MR4.5. The death was related to post transplant infection. On an intention to treat basis, the 10-year OS of 44 patients treated was 97.7% (CI 95% 93.3-100). The 10-year PFS was 95.5% (CI 95% 89.3-100). We collected also the long-term safety of imatinib in the 25 pts who have received this therapy for more than 4 years. Newly occurring or worsening grade 3 or 4 hematologic or biochemical adverse events were infrequent after 4 years of imatinib. There is a decrease in the frequency of hematologic and extra hematologic sides effects reported during the first year and those reported after the fourth year of treatment with imatinib: musculoskeletal events 80 vs 24% (p<0,0001), abdominal pain 44% vs 16% (p=0,03), nausea 48% vs 16% (p=0,02), diarrhea 24% vs 0% (p=0,01) and neutropenia 84% vs 28% (p<0,0001), respectively. Conversely, the incidence of lymphopenia appeared with duration of imatinib treatment (p=0,04). Conclusion: With more than 10 years of follow-up, we showed that imatinib remains effective in one third of children included in the Glivec phase IV study with acceptable adverse effects and a low impact over time. Despite the notable proportion of switches, the OS and the PFS remain satisfactory in this pediatric cohort. Disclosures No relevant conflicts of interest to declare.

Drug Toxicities in Second-Line Treatment of Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5173-5173
Author(s):  
Tarcila S Datoguia ◽  
Hugo R C Silva ◽  
Amauri M C R Junior ◽  
José Salvador Oliveira ◽  
Monika Conchon
Keyword(s):  
Side Effects ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Hematological Toxicity ◽  
Molecular Response ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Cutaneous Rash

Abstract Introduction Chronic myeloid leukemia (CML) is known to be a myeloproliferative neoplasm that involves a genetic abnormality defined as Philadelphia chromosome. Part of chromosome 9 becomes attached to chromosome 22, forming the BCR-ABL fusion gene, which is an oncogenic tyrosine kinase. The rise of the tyrosine kinase inhibitors (TKIs) has transformed the outcome of CML. Imatinib was the first TKI approved for treating patients diagnosed with CML in 2001. Dasatinib and Nilotinib were accredited as second-line therapy in 2006 and 2007, respectively, for patients who had failed previous therapy. Although these new drugs improved response compared with imatinib, they also have important side effects that can lead to non-adherence to treatment. Given the importance to maintain regular treatment to avoid disease progression, this paper aims to discuss the drug toxicities in patients undergoing second-line therapy. Patients and methods This study was an observational analysis using medical records in Santa Marcelina Hospital, a public service located in São Paulo, Brazil. Results A total of 58 CML patients taking second-line therapy were included, 28 with dasatinib and 30 with nilotinib. In dasatinib group, only 3 patients were diagnosed accelerated phase and each one had different side effects, as hematological toxicity, pleural effusion and ulcerative colitis. Of 25 chronic phase patients taking dasatinib, 12 (48%) presented with clinical and laboratorial abnormalities: 3.5% had hematological toxicity (2% with severe bleeding), 4% had cutaneous rash, 10.7% with ulcerative colitis (confirmed in bowel biopsy) and 18% developed pleural effusion. 25% of all dasatinib patient with side effects lost molecular response and started a third TKI. In nilotinib cohort, 7 patients were diagnosed with CML accelerated phase and only two developed liver toxicity. 23 patients were chronic phase and 60% presented with several side effects: 3% hypertriglyceridemia, 6% had hematological toxicity, 6% with dyspepsia, 10% had cutaneous rash and 27% presented with higher liver transaminase. 7% of all nilotinib patients who developed side effects lost molecular response and had to discontinue therapy. Discussion Several examples of side effects can be described with all TKI including cytopenias, fatigue, pain, fluid retention, GI disorders, skin complains, cardiac and liver toxicities but grade 3-4 occurs in less than 2-3% of patients as Jabour et al reported. Despite of important adverse effects, dasatinib and nilotinib induce rapid and durable hematologic and cytogenetic response. In general, the most related toxicities are self-limited and manageable as Kantarjian related. Comparisons between these two second-line therapy using intolerance criteria can be difficult to represent because studies published until now have two different types of population in terms of cytogenetic response achieved previously with imatinib, for example. So, to have a successful treatment, it is important to consider other variables as comorbidities and mutational status as referred Mathisen et al. Individualized risk assessment, between CML and patients characteristics, should influence treatment choices and clinical management. In conclusion, the efficacy and safety of dasatinib and nilotinib have been confirmed by long-term outcome. Clearly these drugs have unique pharmacologic profiles and response patterns in every single patient, but the goal of treating these patients is the correct management of adverse events without losing molecular response. Disclosures No relevant conflicts of interest to declare.

Evaluation of the Imatinib Treatment of Patients with Chronic Myeloid Leukemia (CML). a Retrospective Study from Algerian Working Group on CML (GAT-LMC)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5454-5454
Author(s):  
K Djouadi ◽  
A Bouchakour ◽  
S Taoussi ◽  
MT Abad ◽  
Z Ouchenane ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Free Survival ◽  
Sokal Score ◽  
Eutos Score

Abstract Introduction: The advent of anti-tyrosine kinase has revolutionized the treatment of chronic myeloid leukemia. Indeed, from 2000, the IMATINIB has become internationally the gold standard of treatment for CML chronic phase, while the allogeneic bone marrow transplant was previously, the 1st intention choice, when an HLA-matched donor is available. The aim of this study is to evaluate the efficiency and the toxicity of a treatment with Imatinib(copy), drug used in Algeria to treat patients with a CML chronic phase. The main objective is to evaluate the overall survival and the progression-free survival to these patients. Materials and methods: This is a longitudinal study, National, multicenter, retrospective, which included Algerian patients with chronic phase CML and treated with Imatinib between January 2007 and December 2013. A technical form was established and distributed to different hematology services nationwide, to collect and analysis the following data: Patient's general characteristics, disease circumstances of discovery, clinical and para-clinical examinations at diagnosis (blood count, blood smear, bone marrow aspiration, karyotype, molecular biology, Sokal prognostic classification score and Eutos score). The treatment: Imatinib 400 mg / d, a therapeutic assessment is made according to the ELN recommendations adapted to our conditions and capabilities in Algeria: The complete hematologic response (CHR) at 03 months and molecular response and / or cytogenetic and / or Fish at 03, 06.12, 18.24 months and more according to capabilities. At 03mois and / or 6 months we search a bcr / abl rate <10%. At 12 months we research a major molecular response (MMR), defined by a bcr / abl ratio lower than 0, 1% according to the ELN. A ratio between 0.1 to 1% is considered a good response according to GAT-LMC (the CML study Algerian group) so the Imatinib treatment is continued. The median follow-up of patients in December 2014 is 48 months (12-84 months). Overall survival and progression-free survival are determined by using the Kaplan-Meier method. The descriptive analysis of the quantitative variables by calculating averages, medians and the qualitative variables, by using percentages and 95% confidence interval. The Chi2 test is used to compare between two variables. Results: From 1024 collated sheets, 1007 are assessable; the median age of patients was 45.7 years (06-87 years), it's about 516 men and 491 women with a sex ratio M / F 1.05. The Diagnosis of CML is done by cytogenetic examination in 337 patients (33%), by Fish 214 patients (21%) and by molecular biology in 401 patients (39%). The prognostic classification (PC), according to the Sokal score, found a low risk in 18.7%, 55.5% as intermediate and a high risk in 25.8%. The Eutos score is less than 87 in 97% and more than 87 in 03%. A CHR at 03mois was found in 907 patients (90.1%). There is no correlation between the RHC at 03 months and the SOKAL PC (p = 0.23), by cons we found a significant correlation with the Eutos score (p <10-3). Molecular assessment at 03 and 06 months is performed in 222 patients and a bcr / abl ratio <10% was found in 66.5%. A molecular evaluation at 12 months showed an MMR in 55.4%. Cytogenetic evaluation (FISH) has found a 28.6% CCyR at 3 months, 45% at 6 months, 64.2% at 12 months (IRIS = 68%), 75.7% at 18 months (IRIS = 76.2%) and 85% at 24 months. Overall survival was 84% at 08 years and it is significantly correlated to Sokal score (p <10-6). A failure to TRT was found in 11.5% of the cases and a 10, 1% relapse rate, related to non-adherence to TRT in 50% of the cases and a lack of monitoring by a regular molecular control in the other half of the cases. Event-free survival at 08 years was 76%. A good clinical and biological tolerance is noted in 90% of the cases. Only 8% of patients were switched to a 2nd generation TKIs because of intolerance. A non-adherence to TRT was found in 14.4%. Conclusion: Imatinib, used in Algeria, is a very interesting molecule both efficiency side and tolerance level. However, we must ensure a molecular monitoring for a patients optimal follow up, and an adequate patient education for a better adherence. Disclosures No relevant conflicts of interest to declare.

Dasatinib Efficacy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Pre-Existing BCR-ABL Mutations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 449-449 ◽  
Author(s):  
Martin C Müller ◽  
Jorge Cortes ◽  
Dong-Wook Kim ◽  
Brian J. Druker ◽  
Philipp Erben ◽  
...  
Keyword(s):  
Amino Acids ◽  
Median Time ◽  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Imatinib Resistant ◽  
Dasatinib Treatment

Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 &gt;3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 &gt;200 nM; n=21) achieved a response. Among 70 patients with &gt;1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 &gt;3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 &gt;3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 &gt;3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes. Table Analysis by dasatinib IC50 No BCR-ABL mutation BCR-ABL mutation BCR-ABL mutation treated with 100 mg QD &gt;3 nM (excl. T315I) 3 nM* Unknown IC50** Some patients had &gt;1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 &gt;3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50. Patients, n 641 402 49 44 254 83 Response rates (≥24 mos of follow-up), % CHR 93 90 90 82 94 96 MCyR 65 56 55 34 58 73 CCyR 56 44 41 25 47 54 MMR 45 33 36 18 34 43 Median time to MCyR, mos 2.8 2.9 2.8 5.7 2.9 2.8 Median time to CcyR, mos 3.0 5.3 3.0 5.7 5.4 3.4 24-mo PFS (95% CI), % 83 (79.8–86.5) 70 (65.3–75.2) 73 (60.1–86.3) 48 (31.2–64.7) 73 (66.6–78.9) 89 (82.3–96.3) 24-mo OS (95% CI), % 94 (91.4– 95.7) 89 (85.1– 92.1) 90 (81.2– 98.3) 81 (68.8– 93.8) 90 (85.8– 94.2) 96 (91.2–100)

Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3302-3302
Author(s):  
Massimo Breccia ◽  
Fabio Stagno ◽  
Roberto Latagliata ◽  
Paolo Vigneri ◽  
Laura Cannella ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Standard Dose ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

Clinical Outcome of CML Patients with Philadelphia Chromosome Complex Variants.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4499-4499
Author(s):  
Santiago del Castillo ◽  
Regina Garcia Delgado ◽  
Laura Entrena ◽  
Agustin M Hernandez ◽  
Arturo Campos ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Genetic Material ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Current State ◽  
Worse Prognosis

Abstract Abstract 4499 INTRODUCTION: The presence of translocation between chromosomes 9 and 22 that characterizes the chronic myeloid leukemia (CML) is occasionally accompanied by more complex variations involving additional exchange of genetic material with other chromosomes. This variants of Philadelphia chromosome have no worse prognosis than those others with the common translocation. MATERIAL: Since 1997 we have diagnosed in our hospital 5 CML patients who didn't show any of these variants. Three women 17, 23 and 76 years old and two men of 36 and 65. All of them diagnosed in chronic phase. Risk stage at diagnosis by Sokal were 1 high, 1 intermediate and 3 low. By Hasford 2 were intermediate end 3 low. Philadelphia chromosome variants involve a third chromosome in 4 cases (translocations 2;9;22, 9;22;12, 9;22;9 and 6;9;22) and in one case involving four chromosomes (translocation 1;2;9;22). Three patients diagnosed before the imatinib approval started treatment with IFN and Ara-C and subsequently changed to Imatinib treatment. Two others started treatment with imatinib directly. RESULTS: All patients had a good outcome with treatment being the current state of 2 patients in complete molecular response (105 and 60 months of follow-up) and 2 patients in Major Molecular Response (146 and 143 months). The 5th patient, a 17 years old woman, has been treated for three months with Imatinib and showed complete haematological response at first month and major cytogenetic response at third month. It is striking in this last patient the fact that two years earlier had been referred for study of myeloid moderate leukocytosis (20,000 leukocytes with circulating myeloid progenitors without anemia, thrombocytosis, or splenomegaly). The patient didn't come to clinic when Bone Marrow Test was cited and two years later resumes the visit continuing with the same leukocytosis in peripheral blood and without splenomegaly unchanged despite not having received any treatment. CONCLUSION: Our experience confirm that this type of patients with complex translocation variants have no worse prognosis than normal translocation under imatinib treatment and suggests that may have a more benign clinical behavior. Disclosures: No relevant conflicts of interest to declare.

Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1493-1493
Author(s):  
Kohei Yamaguchi ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with <0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Correlation between Hasford Score with Early Molecular Response in Patients with Chronic Myeloid Leukemia in Chronic Phase Treated with Imatinib

2019 ◽  
Vol 12 (1) ◽  
pp. 227-232
Author(s):  
I. Dewa Made Widi Hersana ◽  
Ugroseno Yudho Bintoro ◽  
Ami Ashariati ◽  
Made Putra Sedana
Keyword(s):  
Myeloid Leukemia ◽  
Risk Group ◽  
Chronic Phase ◽  
High Risk Group ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Test Results ◽  
Rt Pcr ◽  
Longitudinal Observational Study ◽  
Hasford Score

The aim of the study is to to determine correlation Hasford score and early molecular response in chronic phase BCR-ABL-Positive CML patients treated with imatinib. This is an longitudinal observational study in newly diagnosed patients of CML chronic phase BCR-ABL-Positive treated imatinib from Januari 2017 to September 2017. Patients were stratified according to Hasford score at diagnosis. Q-PCR(Quantitative RT-PCR) were used to monitor BCR-ABL transcription levels after 3 months of imatinib treatment. Correlation between Hasford score with early molecular response were analyzed using Koefisien Kontingensi’s correlation test. Results: Thirty five patients were enrolled in this study consist of 13 male and 22 female. After 3 months of imatinib treatment, EMR were 5 patients (83.3%), 11 patients (61.1%) and 2 patients (18.2%) in low, intermediate, and high risk group patients, respectively. Koefisien kontigensi test showed that there was significant correlation between Hasford score and EMR (p=0.018; r=0.431). The Hasford score correlated to early molecular response in chronic phase BCR-ABL-positive CML patients received imatinib.

BCR-ABL RNA Levels at the Time of a Complete Cytogenetic Response (CCR) Predict the Duration of CCR in Imatinib-Treated Chronic Myeloid Leukemia Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1098-1098
Author(s):  
Richard D. Press ◽  
Zac Love ◽  
Ashlie A. Tronnes ◽  
Gwen Kurilik ◽  
Michael J. Mauro ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Log P ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Log Reduction ◽  
Complete Cytogenetic Response ◽  
Rna Levels

Abstract Background : Imatinib induces a complete cytogenetic response (CCR) in the majority of patients with chronic phase CML. CCR is durable in the majority of patients, but relapse occurs in a subset. To determine the potential of quantitative RT-PCR (qPCR) of BCR-ABL to predict cytogenetic relapse, we serially monitored residual disease in 90 CML patients with an imatinib-induced CCR. Methods and patients : mRNA was prepared from total nucleated cells from blood or bone marrow, and cDNA was synthesized using random hexamer primers. Relative BCR-ABL expression was then measured by real-time fluorescent PCR normalized for G6PDH expression. This assay has a detection limit of 1 CML cell in 100,000 and an analytical precision of 6% (CV). At the start of imatinib therapy, 85% of patients were in chronic phase, at a median 9.5 months after diagnosis. Patients were treated with imatinib alone (64%) or in combination with interferon or cytarabine (32%). One patient each was treated with imatinib in combination with either the farnesyltransferase inhibitor tipifarnib, donor leukocytes (after allogeneic BMT), or an experimental heat shock protein (hsp70) vaccine. During the imatinib follow-up time of 28 months (median), disease monitoring occurred by cytogenetics and qPCR (median 6 samples per patient). The CCR was achieved after 9.7 months (median) of imatinib therapy. Results : At the time of first achieving CCR, BCR-ABL RNA levels had decreased by a median of 1.8 logs below the median baseline level. During further follow-up, 26 patients (29%) experienced cytogenetic relapse (defined as any Ph-positive metaphase cell) at a median 6.0 months after CCR and a median 20 months after starting imatinib. There was no difference in the imatinib treatment time, the time to achieve CCR, or the post-CCR follow-up period between the patients with and without subsequent cytogenetic progression. qPCR data at the time of first CCR were available for 78 patients, including 25 of 26 with a subsequent cytogenetic relapse. The reduction of BCR-ABL RNA at the time of first achieving CCR was significantly less in those patients with a subsequent cytogenetic relapse (median 1.4 log) compared to those with a sustained CCR (median 2.0 log) (P=0.002). In the 64 patients with a sustained CCR, the molecular response progressively improved over time to reach a median reduction of 4.0 log at 15 months after CCR. Of the 29 patients achieving at least a 2 log reduction of BCR-ABL RNA at the time of first reaching CCR, only 3 (10%) had a subsequent cytogenetic relapse. In comparison, 22 of 49 patients (45%) with a less than 2 log reduction at the time of achieving CCR had a subsequent cytogenetic relapse (odds ratio = 7.1; 95% CI 1.9–26). At the time of first achieving CCR, a reduction in BCR-ABL RNA of less than 2 logs thus had a diagnostic sensitivity of 88% and a diagnostic specificity of 49% for predicting subsequent cytogenetic relapse. Conclusions : We conclude that, in the majority of imatinib-treated CML patients reaching CCR, the level of BCR-ABL RNA at the time that the CCR is first achieved is a sensitive predictor of the durability of the CCR. The availability of a laboratory marker capable of stratifying the subsequent risk of disease progression (early in remission) will be useful in targeting additional (or alternative) therapies to those patients with the highest risk.

The Impact of Cytogenetic Response At 6 Months of Therapy in Global Survival of Patients with Chronic Myeloid Leukemia Treated with Imatinib in the South of Brazil

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4453-4453
Author(s):  
Laura Fogliatto ◽  
Marcelo Capra ◽  
Mariza Schaan ◽  
Mario Sérgio Fernandes ◽  
Tito Vanelli Costa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Major Molecular Response ◽  
Global Survival ◽  
The Impact

Abstract Abstract 4453 Background Treatment of chronic myeloid leukemia with imatinib leads to disease remission in a majority of patient, but in some patients (pts) controlling the disease remains a challenge. One of the proposed prognostic factors for identifying this subset of pts is the treatment response in the first months of therapy. Objectives We conducted a study to evaluate the importance of the early complete cytogenetic response (CCyR) and the factors associated with its achievement. Methods This is a retrospective study in a cohort of pts with chronic-phase chronic myeloid leukemia (CP-CML) enrolled in 3 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months (mo) from diagnosis. Patient evaluation and response criteria followed the ELN recommendations. The ACE-27 (Adult Comorbidity Evaluation-27) is a 27 item comorbidity index for patients with cancer and assign weights from 1 to 3 based on the dysfunction grade of each condition (mild, moderate and severe, respectively). An ACE-27 score was applied to each patient. Imatinib suspensions were considered if superior to 20 days at any point during therapy. Global survival (GS) was measured from the start of imatinib to the date of death from any cause. Results We analyzed data from 181 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 yr (4 – 85) and 55% were male. The median time from diagnosis to imatinib was 7 mo (0 – 178) and 71% pts were early-imatinib treated. Prior therapy with interferon was used in 60% pts. The median of follow-up was 47 mo. With 6 months of imatinib therapy, 123 pts (68%) achieved CCyR, in this group the four year global survival was 97%. 58 (32%) were not in CCyR at 6 months of therapy, in this group the four year GS was 87%. This difference was significant (P=.024; Figure 1). The chance of achieving major molecular response (MMR) during follow up was 79% for the pts with CCyR at 6 months compared to 53% for the group with no CCyR at 6 months (P<0,001). Some factors were associated with reduced chance of CCyR at 6 months. In a multivariate analysis, the pts with late-onset imatinib treatment (more than 12 mo from diagnosis) had a CCyR rate of 31%, in contrast, the pts who started imatinib before 12 mo had a rate of 50% (P=0,02). The pts with good adherence to treatment had greater CCyR rate than those with poor adherence (interruption greater than 20 days), 51,4% and 35%, respectively (P=0,04). Comorbidity measured by ACE-27 score also influenced the CCyR rates at 6 months: 54% of score 0 (no comorbidity) patients achieved CCyR, compared to 30% of pts with score 1 (mild comorbidity), 33% of pts with score 2 (moderate) and 47% of pts with score 3 (severe) (P=0,009). The greater CCyR rate in the severe comorbidity group probably lacks significance due to the reduced number of pts in this group (22). Conclusions A great proportion of pts achieve CCyR after 6 months of imatinib therapy, nevertheless, the pts who achieve CCyR by 6 months of therapy have greater proportion of major molecular response and global survival. Imatinib therapy should be started as soon as possible and additional efforts must be taken to avoid nonadherence. Finally, special attention should be given to pts with comorbidities as their results tend to be worse. Disclosures: No relevant conflicts of interest to declare.

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