Nilotinib 800 Mg Daily as Frontline Therapy of Ph + Chronic Myeloid Leukemia: Dose Delivered and Safety Profile for the GIMEMA CML Working Party.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2205-2205 ◽  
Author(s):  
Gianantonio Rosti ◽  
Fausto Castagnetti ◽  
Francesca Palandri ◽  
Massimo Breccia ◽  
Luciano Levato ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Safety Profile ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Working Party ◽  
Great Majority ◽  
Molecular Response ◽  
The European Union ◽  
Frontline Treatment

Abstract Abstract 2205 Poster Board II-182 Nilotinib is an effective and registered treatment of chronic myeloid leukemia (CML) after imatinib failure. Its efficacy as frontline treatment has been explored in phase 2 trials from MDACC and Italian GIMEMA , whose results have been presented recently (Cortes ASH Rosti, EHA). Here we present a detailed analysis of the safety profile of nilotinib 800 mg daily in the CML early chronic phase (ECP) setting. Briefly, 73 ECP patients (median age 51 yrs, range 18-83 yrs, 21/73 – 29% - ≥ 65 yrs at enrolment) received nilotinib at a dose of 400 mg BID. With a median follow-up of 15 months (range 12-24 months), the CCgR rate at 1 yr was 96%, and the major molecular response (MMolR) rate 85%. During the first 365 days, the treatment was interrupted at least once in 38 patients (52%; overall, 86 interruptions), with a median cumulative duration of drug interruption of 19 days (5.2% of 365 days) per patient (range 3-169 days); 35 pts (48%) received the full prescribed dose. The proportion of patients with ≥ 1 interruption decreased during the first and second quarter and second half (37%, 25% and 22% respectively). The mean daily dose was 600-800 mg, 400-599 mg, and less than 400 mg in 74%, 18% and 8% of patients, respectively. Four AEs (≥ grade 2) accounted for the great majority of dose interruptions: bilirubin increase (38%, no gr. 4), skin rash and/or pruritus (37%, no gr. 4), asymptomatic amylase and/or lipase increase (16%, gr. 4: 4%) (no pancreatitis), transaminases increase (19%, no gr. 4). Notably, only 3 events of peripheral edema/fluid retention have been recorded so far (2 gr 1, 1 gr. 2). No pleural or pericardial effusion. Only one pt permanently discontinued nilotinib for recurrent amylase and lipase increase gr. 3-4 after 7 months on nilotinib, without pancreatitis (normal ECO scan and MRI): the pt. is on imatinib 400 mg daily from 12 months, maintaining the CCyR but loosing MMolR on imatinib. The transient hyperglicemia (gr. 2 and 3: 6%) did not lead to any treatment discontinuation. The hematopoietic toxicity (grade 3-4) was negligible: only 5 events (3 neutropenias and 2 thrombocytopenias) in 5 pts (7%) (all within 3 months from treatment start: 431/438 q2weeks scheduled blood counts evaluable). Nilotinib 800 mg daily is feasible, safe and very effective in ECP CML (ClinicalTrials Gov.NCT00481052). ACKNOWLEDGEMENTS: The Italian Association Against Leukemia-lymphoma and myeloma (BolognAIL), The Fondazione del Monte di Bologna e Ravenna, The Italian Ministery of Education (PRIN 2005, No. 20050 63732_003, and PRIN 2007, No 2007F7 AE7B_002), The University of Bologna, The European Union (European LeukemiaNet). Disclosures: No relevant conflicts of interest to declare.

Chronic Myeloid Leukemia (CML) Patients with “Suboptimal” Response to Imatinib (IM) According to European LeukemiaNet Criteria Have a Poorer Outcome with Respect to “Optimal” Responders: A GIMEMA CML WORKING PARTY Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2196-2196 ◽  
Author(s):  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Francesca Palandri ◽  
Massimo Breccia ◽  
Marilina Amabile ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Working Party ◽  
Lower Probability ◽  
Molecular Response ◽  
Grey Zone ◽  
Long Term Outcome ◽  
Free Survival

Abstract Abstract 2196 Poster Board II-173 BACKGROUND: Imatinib (IM) 400 mg daily is the standard treatment for Chronic Myeloid Leukemia (CML) in early chronic phase (ECP). The European LeukemiaNet (ELN) recommendations were designed to help identify ECP CML patients responding poorly to front-line IM, suggesting, at given time points, when the treatment strategy should be changed (”failure”), or when “the long-term outcome of the treatment would not likely be as favourable” (“suboptimal response”). Suboptimal response is a “grey zone”: the patient may still have substantial benefit from continuing IM, but other therapies should be considered. AIM: To assess the outcome of “failure” and “suboptimal responders” Philadelphia-positive (Ph+) CML patients in a large multicentric, nationwide experience. METHODS: Between January 2004 and April 2007, 559 patients were enrolled in an observational study and in 2 independent intervention studies of the GIMEMA CML WP (Clin Trials Gov. NCT00514488 and NCT00510926). Response monitoring was based on conventional cytogenetic examination of bone marrow cell metaphases every 6 months and RT Q-PCR evaluations of blood cells after 3, 6, 12 months, and every 6 months thereafter. Definitions: major molecular response (MMR): BCR-ABL/ABL ratio < 0,1%IS; failure (according to ELN criteria): no hematologic response (HR) at 3 months, no complete HR (CHR) at 6 months, no cytogenetic response (CgR) at 6 months, no partial CgR (PCgR) at 1 year, no complete CgR (CCgR) at 18 months, loss CHR or CCgR, progression or death; suboptimal response (according to ELN criteria): no CHR at 3 months, no PCgR at 6 months, no CCgR at 12 months, no MMR at 18 months ; optimal response: non-suboptimal and non-failure at each time-point; event: failure or treatment discontinuation for any reason. All the calculations have been made according to the intention-to-treat principle. RESULTS: The patients who fitted the ELN criteria for failure had a significantly lower probability of subsequently achieving a CCgR and a MMR, and had a significantly lower overall survival (OS), failure-free survival (FFS) and event-free survival (EFS). The patients who fitted the ELN definitions of suboptimal response at 6 months (data not shown) and at 12 months (figure 1) had a significantly lower probability than “optimal” responders of subsequently achieving a CCgR and a MMR, and a significantly poorer FFS and EFS (figure 1), while the OS was not different in the two groups (90% and 95%, p= 0.35). CONCLUSIONS Our data confirms that suboptimal responders at 6 and at 12 months have a poorer outcome with respect to “optimal” responders, comparable to the outcome of failure patients. Acknowledgments: European LeukemiaNet, COFIN, University of Bologna and BolognAIL. Disclosures: No relevant conflicts of interest to declare.

High and Early Rates of Cytogenetic and Molecular Response with Nilotinib 800 Mg Daily as First Line Treatment of Ph-Positive Chronic Myeloid Leukemia in Chronic Phase: Results of a Phase 2 Trial of the GIMEMA CML Working Party

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 181-181 ◽  
Author(s):  
Gianantonio Rosti ◽  
Fausto Castagnetti ◽  
Angela Poerio ◽  
Massimo Breccia ◽  
Luciano Levato ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Working Party ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Average Dose ◽  
Open Label ◽  
Grade Iii

Abstract Imatinib (IM) 400 mg daily is the standard treatment for chronic myeloid leukemia in early chronic phase (ECP): the results of the IRIS trial have shown a 72 months overall survival of 95%; EFS and PFS were 83% and 93%, respectively; the cumulative rate of complete cytogenetic response (CCgR) for the IM 400 mg arm was 25% at 3 months (at 6, 12, 18 and 60 months it was 51%, 69%, 76% and 87%, respectively). Nilotinib, a second generation TKI, has a higher binding affinity and selectivity for Abl with respect to IM, being 20 to 50 times more active in IM-sensitive cell lines and is highly effective in IM resistant patients, across every disease phase. To investigate the therapeutic efficacy and the safety of nilotinib 400 mg BID in untreated, ECP, Ph-pos CML patients, the italian GIMEMA CML Working Party is conducting an open-label, single stage, multicentric, phase II study trial (ClinicalTrials.gov. NCT00481052); all patients provided written informed consent. The primary endpoint is the CCgR rate at 1 year; the kinetic of molecular response is studied by Q-PCR baseline and after 1, 2, 3, 6, 9 and 12 months from treatment start. PATIENTS Seventy-three patients have been enrolled from 20 Centres between June, 2007 and February, 2008. The median age was 51 years (range 18–83), 45% low, 41% intermediate and 14% high Sokal risk. Median follow-up is currently 210 days (range 68–362). RESULTS All 73 patients and 48/73 (66%) completed 3 and 6 months on treatment, respectively. Response at 3 and 6 months (ITT): the CHR rate was 100% and 98%, the CCgR rate 78% and 96%, respectively. A MMR, defined as a BCR-ABL:ABL ratio &lt; 0.1% according to the International Scale, was achieved by 3% of all treated patients after 1 month on treatment, but this proportion rapidly increased to 22% after 2 months, 59% after 3 months and 74% after 6 months. One patient progressed at 6 months to accelerated-blastic phase with the T315I mutation. NILOTINIB DOSE AND COMPLIANCE No dose escalation was permitted in case of resistance; the median daily average dose was close to the intended dose, 789 mg (range 261 – 800); 34/73 patients (47%) interrupted nilotinib at least once, with a median duration of dose interruption of 15 days (range 2–98). The dose of nilotinib at the last visit was 400 mg BID for 52 patients (71%), 400 mg daily for 20 patients (27%) and 200 mg daily for 1 patient (1%). ADVERSE EVENTS: AEs (grade III/IV) were manageable with appropriate dose adaptations: hematologic toxicity was recorded so far in 4 pts (5% - only 1 event grade IV neutropenia); the most frequent biochemical laboratory abnormalities (grade III) were total bilirubin increase (15%), GOT/GPT increase (11%) and lipase increase (4%). Only 1 episode of grade IV lipase increase was recorded. It is noteworthy, considering the 48 cases with at least 6 months of follow-up, that the incidence of any grade II and III nonhematologic adverse event, decreased from 50% and 8% (first 3 months) to 23% and 6% (second trimester), respectively. ECG monitoring: in 16 patients (22%), transient and not clinically relevant ECG abnormalities have been recorded; 2 more patients (3%) revealed a transient and uneventful QTc prolongation (&gt;450 but &lt;499 msec). CONCLUSIONS: The results that have been achieved in these unselected patients and within a multicentric trial, strongly support the notion that in ECP Ph-pos CML patients both cytogenetic and molecular responses to nilotinib are substantially faster than the responses to IM. Acknowledgments: Work supported by European LeukemiaNet, COFIN, University of Bologna and BolognAIL.

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.

Frontline flumatinib versus imatinib in patients with chronic myeloid leukemia in chronic phase: Results from the China randomized phase III study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7004-7004
Author(s):  
Zhang Li ◽  
Li Meng ◽  
Yanli Zhang ◽  
Huanling Zhu ◽  
Jiuwei Cui ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Phase Iii ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Primary Endpoints ◽  
Study Results ◽  
Frontline Treatment ◽  
Phase Iii Study

7004 Background: Flumatinib (FM), a derivative of imatinib (IM), is a novel BCR-ABL1 tyrosine kinase inhibitor (TKI). The aim of this open-label phase III study was to validate the efficacy and safety of FM in comparison with IM as frontline treatment in Chinese patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in chronic phase (CML-CP). Methods: Randomization was stratified by Sokal score with a 1:1 allocation to each arm. Primary endpoints were major molecular response (MMR = BCR-ABL IS≤0.1%) rates at 6 and 12 months. Molecular responses were assessed at a central laboratory blinded to treatment allocations during the study. Efficacy endpoints were analyzed for the intention-to-treat populations. This study is registered with ClinicalTrials.gov, number NCT02204644. Results: 400 eligible patients were randomized and patient characteristics at baseline were similar in each arm. The full analysis set (FAS) consisted of 393 patients who received FM 600 mg (n = 196) or IM 400 mg (n = 197) tablets once daily. Compared with IM, FM resulted significantly higher induction of MMR rate (%; 95%CI) at 6 month (33.7; 27.06-40.29 vs 18.3; 12.88-23.67; P = 0.0005) and 12 month (48.5; 41.47-55.47 vs 33.0; 26.43-39.56; P = 0.0021) and also at 3 month (8.2; 4.33- 12.00 vs 2.0; 0.06-4.00; P = 0.0058). Significantly more patients in the FM than in the IM arm achieved a complete molecular response (BCR-ABL IS≤0.0032%) at 12 months. Early molecular response (BCR-ABL IS ≤ 10%) at 3 months and early CCyR at 6 months were also significantly higher with FM than IM (82.1; 76.78-87.50 vs 53.3; 46.33-60.27; P < 0.0001 and 60.71; 53.88-67.55 vs 49.75, 42.76, 56.73; P = 0.0332). FM has a safety profile similar to IM. The rates of grade 3/4 TEAEs of FM were similar to IM, 56.57% (112 of 198) vs 41.38% (87 of 196). However, the frequencies of some nonhematological and hematological adverse events were significantly lower in the FM than in the IM arm, such as rash (4.59% vs 12.63%, P = 0.0064) and eyelid edema (0.51 vs 14.65, P < 0.0001); leukopenia (30.61 vs 62.63, P < 0.0001) and neutropenia (30.10 vs 59.60, P < 0.0001). No specific TEAE was identified in each arm. Conclusions: This phase III study met its primary endpoints. Our study results suggest that FM is comparable to IM in its safety and superior in its efficacy profile at 3, 6 and 12 month time points. These results support FM as a frontline treatment option for patients with newly diagnosed CML-CP. Clinical trial information: NCT02204644.

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 &lt;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

Mutations of TET2, IDH1, IDH2 and ASXL1 In Chronic Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3377-3377
Author(s):  
Catherine Roche-Lestienne ◽  
Marceau Alice ◽  
Elise Labis ◽  
Olivier Nibourel ◽  
Valérie Coiteux ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Candidate Genes ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Haematopoietic Stem Cell ◽  
Molecular Response ◽  
Genetic Event ◽  
Myeloid Malignancies

Abstract Abstract 3377 It is generally accepted that the BCR-ABL oncoprotein transformes haematopoietic stem cell and initiates chronic myeloid leukemia (CML). However, leukemogenesis is a complex process, and genomic heterogeneity of the chronic phase (CP) of the disease has been reported. At the molecular level, this intrinsic heterogeneity could support a causative link with the varying response to treatment and disease progression. Genetic analysis of candidate genes in myeloid malignancies reported mutations of the ten-eleven translocation 2 (TET2), the isocitrate deshydrogenase (IDH) 1 and IDH2, and the additional sex combs like 1 (ASXL1) genes in myeloproliferative, acute myeloid and myelodysplasic neoplasms. Similarly, we can stipulate that these candidate genes may contribute to phenotypic heterogeneity of CML. To investigate whether TET2, IDH1, IDH2 and ASXL1 defect could represent a significant event in CML, we selected 91 CML patients (pts) treated with imatinib (IM) at first line and presenting five profiles of IM response at time of the analysis: 1) 25 pts in major molecular response (MMR) at 12 months of IM; 2) 11 pts in CCR but presenting additional Philadelphia (Ph) negative clonal evolution; 3) 20 pts in partial cytogenetic response at 18 months of IM, referred as primary resistant (R1); 4) 20 pts in acute transformation 4 to 72 months after onset IM; and 5) 15 pts relapsing in CP of the disease, referred as secondary resistant (R2). The search for mutation was performed by sequencing the entire TET2 coding region (11 exons), the IDH1 and IDH2 exon 4 and the ASXL1 exon 12. Analysis of paired samples from CML diagnosis, time of IM response and, when available, CCR revealed: 1) 2 pts (2.2%) in acute transformation presenting 3 TET2 stop mutations not located within conserved region (del at A2079, substitution T4893A - both also been detected at diagnosis -, and del at C4851 which has not been detected at diagnosis, even by mutation-specific ASO-PCR); 2) no IDH1 and IDH2 mutation; and 3) 8 pts (8.7%) presenting ASXl1 stop mutations at diagnosis. Among them, 3 pts (two ins at G646 and one ins at V751) have reached MMR without detected mutations at this time; one R1 pt presenting ins at G646 had major cytogenetic response with 5% Ph+ cells but the mutation was not found at this time and the pt have progressed to MMR 9 months later; one pt with 23 bp del at R634 has evolved in acute transformation with detected mutation at this time; and 3 R2 pts presenting either 4 bp del at S895, del at R860 or 2 pb ins at A752 have lost CCR associated with lost of hematologic response in one case. In this later group of 3 pts, except for del at R860, all ASXL1 mutations were found in samples at time of relapse. We therefore conclude that, contrary to what has been reported in other myeloid malignancies, TET2, IDH1 and IDH2 are not commonly acquired in CML and may not represent a major genetic event in CML transformation. However, ASXL1 alteration seems to be an early event in CML leukemogenesis but does not seem to participate in the disease transformation. Disclosures: No relevant conflicts of interest to declare.

hOCT1 Gene Expression Might Predict Molecular Response In Patients with Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4838-4838
Author(s):  
Lurdes Zamora ◽  
Marta Cabezon ◽  
Concha Boqué ◽  
Silvia Marce ◽  
Jordi Ribera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Chronic Phase ◽  
Organic Cation Transporter ◽  
Initial Response ◽  
Molecular Response ◽  
Hematopoietic Malignancy

Abstract Abstract 4838 Introduction: Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy characterized by the presence of BCR/ABL fusion gene. The resulting protein has a high tyrosine kinase (TK) activity. The first-line treatment for CML is Imatinib, which allow the achievement of cytogenetic and molecular response in most of patients with CML in chronic phase. However, some patients do not respond to this treatment or lose their initial response. Imatinib has been reported to be incorporated into the cell through hOCT1 transporter (human organic cation transporter). The aim of this study was to determine whether the expression of hOCT1 at diagnosis of CML influenced the achievement of molecular response. Patients and Methods: We analyzed hOCT1 gene expression by quantitative PCR in 42 patients at diagnosis and 18 months after treatment with Imatinib. We compared the expression with the presence of compleat molecular response (CMR) at 18 months. We consider CMR when the Ratio (BCR-ABL/ABL)×100 was <0.1% (after International Scale correction). For statistical analysis methods we have used Kolmogorov-Smirnov and Mann-Whitney nonparametric methods. Results: Of the 42 patients, 2 were in hematological response, 22 were in cytogenetic response and 18 in CMR at 18 months. We found a higher hOCT1 gene expression at 18 month than at diagnosis (53.3 versus 29.6, p<0.001) in all patients (Figure 1). We have found some tendency of higher hOCT1 expression at diagnosis in patients with CMR at 18 months than in those who did not had (25.5 versus 18.8, p = 0.07) (Figure 2). Conclusions: Partially funded by FICJ-P-EF-09, RD06/0020/1056 de RTICC and Novartis. We want to thank Dr. David Marin for providing us plasmid for quantitative analysis. Disclosures: No relevant conflicts of interest to declare.

Evaluation Of hOCT1expression In Patients With Chronic Myeloid Leukemia (CML) Treated With Imatinib In First Line

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4041-4041
Author(s):  
Cintia Do Couto Mascarenhas ◽  
Maria Helena Almeida ◽  
Eliana C M Miranda ◽  
Bruna Virgilio ◽  
Marcia Torresan Delamain ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Taqman Probe ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
First Line ◽  
Transcript Levels

Abstract Introduction The majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP), present satisfactory response to imatinib treatment. However, 25-30% of these pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The human organic cation transporter 1 (hOCT1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into chronic myeloid leukemia (CML) cells The aim of this study was to analyze hOCT-1 levels at diagnosis of CML patients and correlate with cytogenetics and molecular responses. Methods hOCT-1 expression was evaluated in 58 newly diagnosed CML pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis and RNA was obtained from total leucocytes. For cDNA synthesis, 3 ug of RNA was used. hOCT-1 expression was evaluated by real-time PCR with TaqMan probe SLC22A1 (Applied Biosystems) and endogenous GAPDH control. The results were analyzed using 2-ΔΔCT. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1%. Results 58 CML pts, 60% male, median age of 46 years (19-87) were evaluated, 71% in chronic phase (CP), 21% in accelerated phase (AP) and 5% in blast crisis (BC). The mean and median of hOCT-1 transcript levels in the total group was 2.03 and 0.961 respectively (0.008–19.039) and CP pts was 1.86 and 1.00 (0.008-10.34).The median duration of imatinib treatment was 27 months (1-109) and 96.6% achieved complete hematological response, 79.3% complete cytogenetic response and 69% major or complete molecular response. The regression analysis showed correlation between higher transcript levels of hOCT-1 and BCR-ABL transcripts<10%) at 3 months analysis (p<0.0001). Albeit, there was no influence of the hOCT-1 transcript levels at diagnosis in the achievement of cytogenetic and molecular response at 24 months of treatment. Conclusions In this report, we found that high hOCT-1 expression was predictive of BCR-ABL transcripts<10% at 3 months, although we did not find correlation between hOCT-1 levels at diagnosis and the achievement of molecular response at 24 months, studies show that there is correlation between BCR-ABL log reduction in the first months of treatment and the achievement of molecular response. Disclosures: No relevant conflicts of interest to declare.

Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party

Blood ◽  
2011 ◽  
Vol 117 (21) ◽  
pp. 5591-5599 ◽  
Author(s):  
Gabriele Gugliotta ◽  
Fausto Castagnetti ◽  
Francesca Palandri ◽  
Massimo Breccia ◽  
Tamara Intermesoli ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Age Groups ◽  
Chronic Phase ◽  
Working Party ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Long Term Outcome ◽  
Free Survival

AbstractThe median age of chronic myeloid leukemia (CML) patients is ∼ 60 years, and age is still considered an important prognostic factor, included in Sokal and EURO risk scores. However, few data are available about the long-term outcome of older patients treated with imatinib (IM) frontline. We analyzed the relationship between age and outcome in 559 early chronic-phase CML patients enrolled in 3 prospective clinical trials of Gruppo Italiano Malattie Ematologiche dell'Adulto CML Working Party, treated frontline with IM, with a median follow-up of 60 months. There were 115 older patients (≥ 65 years; 21%). The complete cytogenetic and major molecular response rates were similar in the 2 age groups. In older patients, event-free survival (55% vs 67%), failure-free survival (78% vs 92%), progression-free survival (62% vs 78%), and overall survival (75% vs 89%) were significantly inferior (all P < .01) because of a higher proportion of deaths that occurred in complete hematologic response, therefore unrelated to CML progression (15% vs 3%, P < .0001). The outcome was similar once those deaths were censored. These data show that response to IM was not affected by age and that the mortality rate linked to CML is similar in both age groups. This trial was registered at www.clinicaltrials.gov as #NCT00514488 and #NCT00510926.

scholarly journals Mutational Profiles during the Progression of Chronic Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3596-3596
Author(s):  
Mengxing Xue ◽  
Zhao Zeng ◽  
Qinrong Wang ◽  
Lijun Wen ◽  
Yi Xu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
The Other ◽  
Molecular Response ◽  
Dismal Prognosis

Abstract Background: Despite significant improvements in the prognosis of chronic myeloid leukemia (CML) achieved by targeted therapy with tyrosine kinase inhibitors (TKIs), a small proportion of cases may not respond to TKIs or may relapse after an initial response, and then progress from chronic phase (CP) to blastic crisis (BC), characterized by a dismal prognosis. It remained uncertain whether the genetic lesions in addition to the BCR-ABL1 fusion could predict clinical outcomes of CML in the TKI era. Aim: To study the mutational profiles at each stage of CML and the prognostic significance of somatic mutations in addition to the BCR-ABL1 fusion in the TKI era. Patients and Methods: We performed targeted sequencing in 81 CML patients chosen retrospectively. 10 patients had optimal response to TKIs by European LeukemiaNet criteria and maintained durable major molecular response more than 5 years. 71 patients had progressed to accelerated phase (AP) or BC, of whom 43 had sequencing performed at paired CP and AP/BC samples, 28 at AP or BC samples. Totally, we analyzed 53 CP, 20 AP, and 61 BC samples. The targeted resequencing gene panel, covering 386 genes which were recurrently mutated in hematologic malignancies, were performed on a HiSeq 4000 NGS platform (Illumina). Results: Among the 53 CP samples, 20 (37.7%) had mutations involving 14 genes, and the number of mutated genes in each patient was 0-3 (median 0). ASXL1 was the most commonly mutated gene, 10/53 (18.9%) patients had this mutation, followed by KMT2D (4/53, 7.5%), PC (2/53, 3.8%), ERBB4 (2/53, 3.8%). ASXL1 mutation mainly existed in 43 patients with progressed disease , while only one case carried this mutation in 10 patients responsive to TKIs (20.9% vs 10%). 17/20 (85%) AP samples (including 10 patients progressed to AP and the other 10 patients who eventually progressed to BC from AP ) carried mutations involving 18 genes, the number of mutated genes in each patient was 0-6 (median 1.5). ABL1 was the most commonly mutated gene, and 8/20 (40%) patients had this mutation. The second was the ASXL1 mutation, 7 (7/20, 35%) patients carried this mutation. The other genes mutated in more than 2 patients included BCORL1 (3/20, 15%), RUNX1 (2/20, 10%), PHF6 (2/20, 10%), KMT2D (2/20, 10%), ATM (2/20, 10%). 54/61 (88.5%) BC samples (44 with myeloid crisis, 14 with lymphoid crisis, 3 with mixed phenotypic crisis) carried mutations, involving 41 genes, and the number of mutated genes in each patient was 0-9 (median 2). Similar to the mutation status in AP, the most commonly mutated gene was also ABL1, 24/61 (39.3%) patients carried this gene mutation, followed by ASXL1 mutation (13/61, 21.3%), and the other genes were in order, RUNX1 (11/61, 18.0%), WT1 (8/61, 13.1%), GATA2 (6/61, 9.8%), MED12 (5/61, 8.2%), IDH1 (5/61, 8.2%), TP53 (4/61 , 6.6%), KMT2D (4/61, 6.6%), etc. (Figure 1A) Among all the samples, 34 nonsynonymous variants in the ASXL1 gene were identified in 31 samples of 21 patients ( 3 samples with two variants). All the variants were frameshift and nonsense mutations, localized at the last exon of the ASXL1 gene. 13/21 patients with ASXL1 mutations had multi-stage samples. The median VAF of the ASXL1 mutations in the advanced stage was 31.4% (0-47.0%), which was significantly higher than that in CP at diagnosis (7.0%, 0-27.2%, P=0.033). Most of the ASXL1 mutations detected in CP expanded at the advanced disease, and were accompanied with other additional gene abnormalities, such as ABL1, RUNX1 and WT1 mutations, with the VAF similar to or lower than that of the ASXL1 mutations. In a few cases, the ASXL1 mutant clones in the CP disappeared, suggesting that some ASXL1 mutations may be clonal hematopoiesis unrelated to disease progression.(Figure 1B) In order to evaluate the effects of ASXL1 mutations on sensitivity to TKIs in vitro. We co-expressed P210-BCR-ABL1 fusion and ASXL1 mutation (G646Wfs*12) in Ba/F3 cells. Compared to Ba/F3 cells co-expressing BCR-ABL1 fusion and ASXL1 mutation (Ba/F3-BA/As), Ba/F3-BCR-ABL1 cells without ASXL1 mutation (Ba/F3-BA/Ve) showed higher sensitivity to TKIs, including imatinib, dasatinib and nilotinib.(Figure 1C) Conclusions: These results demonstrated the genetic lesions accumulated during the progression of CML from CP to BC. ASXL1 mutations were the most common genetic lesion in CP at diagnosis and may confer a poor prognosis, as it reduced the sensitivity to TKIs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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