Real World Efficacy Evaluation of Branded and Copy Imatinib in Chronic Myeloid Leukemia: A Retrospective Multicentric Study from Argentina

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Ana Ines Varela ◽  
Georgina Bendek ◽  
Carolina Pavlovsky ◽  
Maria Josefina Freitas ◽  
Veronica Ventriglia ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Molecular Response ◽  
Advisory Committees ◽  
Free Survival ◽  
Safety And Efficacy ◽  
Kaplan Meier ◽  
Sokal Score

Background: Data on the safety and efficacy of copy drugs is usually unavailable. Imatinib mesylate is used to treat chronic myeloid leukemia (CML) patients in Argentina since 2002. During the last decade more than ten different imatinib copies are marketed by the different health-care systems in the country, usually for cost issues. In spite of the undoubted benefit of this tyrosine-kinase inhibitor indication in CML, there is no solid evidence that supports copy drug equivalent outcomes for this patient population. Aim: To compare the clinical presentation, treatment response and outcome of a chronic phase (CP) CML patient cohort treated with branded and copy imatinib in the real-life setting. Methods: Multicentric, retrospective trial based on data obtained from medical charts of adult CP CML patients treated with imatinib in 9 centers in Argentina from 2002 to 2020.We analyzed demographic characteristics and clinical characteristics described for branded and copy imatinib treated cohorts. Frequency of complete cytogenetic response (CCyR) at 12 months, Major molecular response or better(≥MMR) at 12, 18 and 24 months and overall MR4.0, MR4.5 and deep molecular response (MR4.0 +MR4.5 IS) were analyzed. Event was defined as failure, progression or CML related death. Kaplan Meier comparison of event free, progression free and overall survival. Statistics: IBM SPSS version 1. Results: A total of 568 CP CML adult patients (pt) treated with imatinib were included. Mean age at diagnosis: 45.7 years (range 18 - 85). Male 55.6% (316/568). Sokal Score was recorded in 471 pt: 57% (269/471) low, 26% (122/471) intermediate and 17% (80/471) high-risk. Median follow-up 107 months (RIQ: 36-149). Branded imatinib treatment 330 (58%) and imatinib copies 238 (42%). For branded and copy imatinib cohorts mean age 46,1 (18-85) and 45.3(18-80), male 53% (175/330) and 59% (141/238), median follow up 102 (RIQ 101-130) and 61 (RIQ 62-146) respectively. Sokal score low 58% (164/284) and 56% (105/187), intermediate 27% (77/284) and 24% (45/187) and high 15% (43/284) and19% (37/187). Frequency of CCyR at 12 months 71% (67/94) and 69% (41/59), ≥MMR at 12 months 57% (79/138) and 43% (39/89), ≥MMR 18m 66 % (61/92) and 71% (43/60), ≥MMR 24m 65% (96/147) and 79% (58/73). Overall MR4, MR 4.5 and Deep MR with branded imatinib 62.4% (186/298), 42% (118/276) and 63% (189/300), compared to 45(97/214), 24% (50/207) and 46% (99/215) with copies. Difference in evaluation throughout the treatment periods with loss of data did not allow response rate statistical comparison in predetermined timepoints. Kaplan Meier Event free survival median 229 months vs 75 months p 0.001, Progression free survival mean 318 months vs 208 pt 0.034 and Overall Survival mean 275 months vs 206 months for branded and copy imatinib respectively. Discussion: Several case reports have shown poor outcomes in patients treated with imatinib copy drugs, including loss of responses previously attained with branded imatinib. This study reports data from a large cohort of CP CML patients treated in daily practice during a long period of time. Treatment results at determined timepoints is comparable. Although management and treatment decisions were performed in different time periods, results show different outcomes in EFS and PFS between patients treated with branded vs copy imatinib. Overall survival in both cohorts is comparable. As studies assesing the safety and efficacy of the copy drugs compared with branded imatinib will hardly be performed this evidence calls for careful attention and strict follow up measures when managing CML patients with copy imatinib. Figure Disclosures Varela: Novartis: Consultancy, Speakers Bureau. Pavlovsky:Pint Pharma: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Freitas:Pfizer: Consultancy, Other: Advisory Board. Pavlovsky:Varifarma: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau. Moiraghi:Novartis: Speakers Bureau; BMS: Speakers Bureau.

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.

scholarly journals FINAL Analysis of a PAN European STOP Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 633-633
Author(s):  
Francois-Xavier Mahon ◽  
Johan Richter ◽  
Andreas Hochhaus ◽  
Panayiotis Panayiotidis ◽  
Antonio Medina de Almeida ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Final Analysis ◽  
Molecular Response ◽  
Molecular Test ◽  
Advisory Committees ◽  
Free Survival ◽  
Tki Treatment

Abstract Background: With the dramatic success of tyrosine kinase inhibitors (TKI) to treat Chronic myeloid leukemia (CML), the life expectancy of CML patients is now close to that of the general population. In addition, treatment cessation is now a realistic goal for some CML patients. This was shown by several clinical trials such as the STIM study leading to the concept of TFR (treatment free remission). Around 40-60% of patients with stable DMR [deep molecular response, corresponding to &lt;0.01% BCR-ABL (IS)] can stop the TKI successfully, e.g. in accordance with recommendations from the European LeukemiaNet. In the interim analysis of the first 200 patients of the EURO-SKI (European Stop TKI) trial, 62% were in major molecular response (MMR: &lt;0.1% BCR-ABL1 IS) at 6 months. DMR duration before TKI stop was most predictive for maintenance of MMR. Here we present the final analysis of the EURO-SKI trial after 3 years of follow-up. Aims: The main objectives of The EURO-SKI trial were the evaluation of molecular recurrence-free survival (MRecFS) after Stopping TKI in a large Pan-european cohort of CML patients and definition of prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims are the evaluation of harmonized methods of molecular monitoring. Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed DMR for at least one year (confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. DMR confirmation was performed in standardized laboratories. Primary endpoint was maintenance of MMR after stopping TKI. According to protocol, a 36 months follow-up was planned. The null hypotheses were that MMR maintenance at 6 and 36 months was less or equal than 40% and less or equal than 35%, respectively. Results: Between May 2012 and December 2014, 868 patients were pre-registered by 61 centers from 11 countries. 140 pts were excluded (consent withdrawal n=1, protocol violation n=38, not eligible n=74, DMR not confirmed n=11, atypical/unknown transcript n=15, missing data n=1) resulting in 728 eligible patents. Of these, 46.8% were female. Median age at diagnosis was 52 years (range, 11 to 85 years). Median duration of TKI treatment was 7.5 years (range, 3.0-14.1 years) and median duration of MR4 before TKI cessation was 4.7 years (range, 1.0-13.3 years). Nine patients died without MMR loss (none CML related), 15 patients restarted TKI without MMR loss. At 6 months, 713 patients were available (without molecular test at 6 months: n=6, TKI restart without relapse: n=9). Since 434 patients (61%) [95% CI: 57-64] remained without relapse during the first 6 months, the null hypothesis was rejected (p&lt;0.0001). At 36 months, 678 patients could be analyzed (TKI restart without relapse: n=17, no molecular test at 36 months: n=33). With 309 patients in MMR, corresponding to 46% [95% CI: 42-49], the null hypothesis of 35% or less was rejected (p&lt;0.0001). MRecFS at 36 months resulted in 48% (CI: 44-52%) and molecular recurrence- and treatment-free survival (MRecTFS) in 46% (CI: 43-50%) (Fig 1). No blast crisis occurred. Regarding prognostic factors, we confirmed that TKI treatment duration and DMR duration were still the most important factors to predict MMR loss at 6 months. For the late recurrence, i.e., between 6 and 36 months (57 patients), TKI treatment duration before stop was the only relevant variable in a preliminary univariate logistic analysis. Summary/Conclusion: With this final analysis of the largest TFR trial, we confirm the MRecFS and MRecTFS rates at 6 months previously obtained from the interim analysis. However, late molecular recurrence (15% between 6 and 36 months) occurred and the underlying mechanisms need to be discussed. Nevertheless, 46% of the patients, were still in MRecTFS at 3 years. Figure 1 Figure 1. Disclosures Hochhaus: Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Hjorth-Hansen: AOP: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Mustjoki: Novartis: Research Funding; BMS: Research Funding; Janpix: Research Funding; Pfizer: Research Funding. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 207-207 ◽  
Author(s):  
Timothy P. Hughes ◽  
Andreas Hochhaus ◽  
Giuseppe Saglio ◽  
Dong-Wook Kim ◽  
Saengsuree Jootar ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
Superior Efficacy ◽  
Rate Of Progression

Abstract Abstract 207 Background: Results from the phase 3, international, randomized ENESTnd trial have demonstrated the superior efficacy of nilotinib over imatinib with significantly higher rates of major molecular response (MMR), complete cytogenetic response (CCyR), and with significantly lower rates of progression to AP/BC on treatment. Here, we present data with a median follow-up of 18 months. Methods: 846 CML-CP patients were randomized to nilotinib 300 mg twice daily (bid) (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg once daily (n=283). Primary endpoint was MMR (≤ 0.1% BCR-ABLIS) rate “at” 12 months, as previously presented. Key secondary endpoint was durable MMR at 24 months. Other endpoints assessed at 24 months include progression to AP/BC (with and without clonal evolution), event-free survival, progression-free survival, and overall survival (OS). Results: With a median follow-up of 18 months, the overall best MMR rate was superior for nilotinib 300 mg bid (66%, P < .0001) and nilotinib 400 mg bid (62%, P < .0001) compared with imatinib (40%). Superior rates of MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups (Table). The overall best rate of BCR-ABLIS ≤ 0.0032% (equivalent to complete molecular response, CMR) was superior for nilotinib 300 mg bid (21%, P < .0001) and nilotinib 400 mg bid (17%, P < .0001) compared with imatinib (6%). The overall best CCyR rate was superior for nilotinib 300 mg bid (85%, P < .001) and nilotinib 400 mg bid (82%, P=.017) compared with imatinib (74%). The superior efficacy of nilotinib was further demonstrated using the 2009 European LeukemiaNet (ELN) 12-month milestone in which fewer patients had suboptimal response or treatment failure on nilotinib 300 mg bid (2%, 3%) and nilotinib 400 mg bid (2%, 2%) vs imatinib (11%, 8%). Rates of progression to AP/BC on treatment were significantly lower for nilotinib 300 mg bid (0.7%, P=.006) and nilotinib 400 mg bid (0.4%, P=.003) compared with imatinib (4.2%). The rate of progression on treatment was also significantly lower for nilotinib when including clonal evolution as a criteria for progression (Table). There were fewer CML-related deaths on nilotinib 300 mg bid (n=2), and 400 mg bid (n=1) vs imatinib (n=8). Estimated OS rate (including data from follow-up after discontinuation) at 18 months was higher for nilotinib 300 mg bid (98.5%, P=.28) and nilotinib 400 mg bid (99.3%, P=.03) vs imatinib (96.9%). Both drugs were well-tolerated. Discontinuations due to adverse events or laboratory abnormalities were lowest for nilotinib 300 mg bid (7%) compared with nilotinib 400 mg bid (12%) and imatinib (9%). With longer follow up there has been minimal change in the occurrence of AEs. Minimum 24-month follow-up data for all patients will be presented. Conclusions: With longer follow-up, nilotinib was associated with a significantly lower rate of progression to AP/BC on treatment and lower rates of suboptimal response or treatment failure vs imatinib. Nilotinib resulted in fewer CML-related deaths and a higher OS rate vs imatinib. Nilotinib induced superior rates of MMR, CMR, and CCyR vs imatinib in patients with newly diagnosed CML-CP. Taken together, these data support nilotinib as a new standard of care for patients with newly diagnosed CML. Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Clark:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Honoraria, Research Funding. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp:Novartis Pharma AG: Employment. Haque:Novartis: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

scholarly journals Increased Monocytic Myeloid-Derived Suppressor Cells in the Marrow of Relapsed/Refractory Acute Myeloid Leukemia Patients Following Induction Chemotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5270-5270
Author(s):  
Amanda Przespolewski ◽  
Paul K. Wallace ◽  
Tara Cronin ◽  
Eunice S. Wang
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Potential Role ◽  
Suppressor Cells ◽  
Advisory Committees ◽  
Free Survival ◽  
Relapsed Disease

Abstract Background: Acute myeloid leukemia (AML) is an aggressive malignancy associated with poor long-term outcomes. This malignancy arises in the context of an immunosuppressive milieu, which fosters immune escape and tumor growth. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous group of immature myeloid cells with immunosuppressive activity, the most potent of which are the monocytic MDSCs (mMDSCs). The presence of mMDSCs within the bone marrow microenvironment of patients with AML, along with their impact on disease relapse and overall survival has yet to be fully characterized. Therefore, we sought to address this unanswered question through a retrospective analysis of a cohort of AML patients (pts) at Roswell Park Comprehensive Cancer Center. Methods: Medical records were retrospectively reviewed under an IRB approved protocol in order to identify pts aged 18-70 years old with normal karyotype (NK) AML treated with standard cytarabine and anthracycline based chemotherapy with refractory or subsequent relapsed disease. Demographics, disease-specific variables, baseline clinical characteristics, treatment response, and adverse events were analyzed using descriptive statistics. Overall survival and relapse-free survival were estimated utilizing Kaplan-Meier (KM) analysis. Detailed analysis of previously collected clinical multiparameter flow cytometric data was performed utilizing WinList software to identify mMDSCs at serial clinical time points (diagnosis, after induction chemotherapy, and relapse). A mononuclear gate was created utilizing CD45 vs. SSC (blasts excluded), followed by FSC vs. SSC to eliminate dead cells and aggregates. Based on the scientific literature, mMDSCs were defined as the subset of marrow cells co-expressing CD14+ and HLA-DR dim, and was reported as the percentage of total monocytes in the marrow aspirate sample. Results: Six pts with NK-AML who received induction chemotherapy with cytarabine, daunorubicin, and etoposide (ADE) were identified. Mean age was 56 years (range 35 - 67), with 3/6 male pts (50%) (Table 1). NPM1 was mutated in 2/6 pts at diagnosis, with no FLT3-ITD mutations identified. In addition, 2 pts had an elevated WBC at presentation. Following induction therapy, 2 pts had primary refractory disease with four achieving complete remission (CR). Furthermore, each of the 6 pts relapsed. All 6 pts had marrow aspirate samples containing detectable mMDSCs by flow cytometry at multiple time points. Of note, 5 of 6 pts had elevated mMDSCs (average 76.2%; range 72.8% - 82.6% of total marrow monocytes) detected at time of response assessment following induction. Median relapse-free survival was 48 months (Figure 1). Overall survival not yet been reached. Mean duration of follow up was 85 months (range 61 - 119 months). Conclusions: This retrospective analysis suggests that high numbers of marrow mMDSCs (>72%) are associated with relapsed/refractory AML in a small patient cohort. Of note, other risk factors for refractory/relapsed disease (i.e. elevated WBC at presentation and FLT3 mutation) were not consistently present in our cohort, thus supporting a potential role of mMDSCs in promoting disease recurrence. Additional studies to further quantify and delineate the biological role of mMDSCs in a larger pt cohort are needed to corroborate these findings and determine the potential role of these immune cells in therapy resistant AML. Disclosures Wang: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3011-3011 ◽  
Author(s):  
Lucia Masarova ◽  
Jorge E. Cortes ◽  
Keyur P. Patel ◽  
Susan M. O'Brien ◽  
Graciela M. Nogueras González ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 2 ◽  
Advisory Committees ◽  
Free Survival ◽  
Genetics Research ◽  
Phase 2 Study ◽  
Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

scholarly journals Safety and Efficacy of Midostaurin in Combination with High-Dose Daunorubicin in 7+3 Induction for Acute Myeloid Leukemia with FLT3 Mutation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3896-3896
Author(s):  
Yehuda E. Deutsch ◽  
Robert Wilkinson ◽  
Amanda Brahim ◽  
Stephanie Boisclair ◽  
Jose Sandoval-Sus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Cancer Center ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Acute Myeloid

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease with varied outcomes dependent on patient cytogenetic and mutational status. Thirty percent of adults with newly diagnosed AML have a mutation in the fms-related tyrosine kinase 3 (FLT3) gene. Midostaurin is a small molecule inhibitor that acts on multiple receptor tyrosine kinases, including FLT3. The RATIFY trial showed improved overall survival (OS) and event-free survival in patients treated with daunorubicin and cytarabine (7+3) plus midostaurin (Stone et al, NEJM 2017). In this trial, a dose of daunorubicin 60 mg/m2 was administered. High dose (HD) 90 mg/m2 daunorubicin significantly improved the rate of complete remission and overall survival, including in patients with FLT3-ITD (Luskin et al, Blood 2016). HD daunorubicin has also been shown to be more effective than idarubicin in patients with FLT3-ITD AML (Lee et al, J Clin Oncol 2017). This data raises the question of whether the combination of midostaurin and HD daunorubicin would further improve outcomes of FLT3 mutated AML patients, while maintaining a tolerable safety profile. The objective of this study is to describe the safety and efficacy endpoints of FLT3 mutated AML patients treated with HD daunorubicin plus midostaurin as part of induction therapy. Methods: We retrospectively reviewed clinical and molecular data of patients at Memorial Healthcare System, Moffitt Cancer Center, and Sylvester Cancer Center with newly diagnosed FLT3 mutated AML treated from May 1st, 2017 to July 1st, 2019. Clinical data was abstracted in accordance with institutional review board approved protocol. All patients were induced with HD daunorubicin 90 mg/m2 on days 1-3, cytarabine 100 mg/m2 on days 1-7, and midostaurin 50 mg PO twice daily on days 8-21. Growth factor and antimicrobial support were used per institutional guidelines. Demographics were analyzed using descriptive statistics. OS was analyzed using Kaplan Meier method. Other efficacy outcomes were CR, CRi (assessed according to the European Leukemia Network Criteria for AML), proportion of patients needing re-induction, and proportion of patients who underwent hematopoietic stem cell transplant (HSCT). Safety outcomes were adverse events (AEs) and early (30- and 60-day) mortality. Results: Twenty-six patients were included in the final analysis. Patient characteristics are outlined in TABLE 1. All patients were FLT3 mutated, as confirmed with molecular studies. The FLT3 subtype was ITD (high) in 3 patients, ITD (low) in 16 patients, TKD in 5 patients, and both in 2 patients. Seventy-seven percent of patients achieved a CR/CRi after one induction cycle, and 96.2% attained CR after two induction cycles. Median time to ANC and platelet recovery was 28 and 26 days, respectively. One patient died during the first 60 days, due to Enterococcus sepsis. The most common non-hematological AEs were nausea (77%), diarrhea (62%), mucositis (58%), rash (54%), and increased ALT (54%). Cumulative incidence of relapse in the cohort was 28% (n=7). Four patients relapsed pre-transplant and achieved CR2 with additional therapy. All 7 of these patients had co-occurring mutations of various types. Of the 20 patients who were considered transplant eligible, 13 (65%) underwent HSCT and 4 (20%) are pending transplant. Of the 13 transplanted patients, 3 experienced relapse post-transplant. After a median follow up of 14.5 months, median OS has not been reached. Conclusion: In our multi-center experience, induction with HD daunorubicin, cytarabine, and midostaurin is clinically effective and seems to be well tolerated. Short term mortality was low and AEs were manageable, with no unexpected safety signals. Also, CR/CRi rates were higher than previously reported, suggesting that the combination of HD daunorubicin and midostaurin may improve the outcomes of patients with FLT3 mutated AML. Future analyses with larger patient samples and longer follow up are warranted to further evaluate long-term safety and efficacy for this regimen. Figure Disclosures Sandoval-Sus: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Bradley:AbbVie: Other: Advisory Board. Talati:Agios: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding.

The BCR-ABL Transcript Levels At 3 and 6 Months Predict the Long-Term Outcome of Chronic Myeloid Leukemia Patients Treated Frontline with Imatinib Mesylate: A Gimema CML WP Analysis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1678-1678
Author(s):  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Massimo Breccia ◽  
Giorgina Specchia ◽  
Elisabetta Abruzzese ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Roc Curves ◽  
Molecular Response ◽  
Advisory Committees ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Free Survival ◽  
Transcript Levels

Abstract Abstract 1678 Background. Imatinib mesylate (IM) is the therapeutic standard for chronic myeloid leukemia (CML), but nilotinib and dasatinib, at least in selected patients, have the potential to replace it. The early prediction of poor outcome is important to optimize the treatment strategy. In IM-treated patients, BCR-ABL transcript levels according to the International Scale (IS) > 10% at 3 and > 1% at 6 months were able to identify high-risk groups (Marin et al, JClinOncol 2011; Hanfstein et al, Leukemia 2012). Similar analysis were performed within the IM arms of the ENESTnd trial (Hochhaus et al, EHA 2012) and the DASISION trial (Jabbour et al, EHA 2012). Methods. To investigate the prognostic impact of BCR-ABLIS levels at 3 and 6 months on the future response status and the long-term outcome of CML patients treated frontline with IM, we analyzed 559 patients enrolled within 3 trials of the GIMEMA CML WP (ClinTrialsGov NCT00514488/NCT00510926, observational trial CML023). Patients with evaluable QPCR sample at 3 and 6 months: 487/559 (87%) and 492/559 (88%), respectively. Definitions: major molecular response (MMR): BCR-ABLIS ratio <0.1%; molecular response with 4.0-log reduction (MR4.0): BCR-ABLIS <0.01%; failures: according to 2009 ELN recommendations. The rate of complete cytogenetic response (CCgR) and MMR at 1 year, the rate of MR4.0 at 2 years, the failure-free survival (FFS), the progression-free survival (PFS) and the overall survival (OS) according to the BCR-ABL transcript levels (≤10% vs >10 and ≤1% vs >1%) at 3 and 6 months were analyzed. Patients with events or censored within 3 or 6 months were excluded from the respective analysis. Receiver operating characteristic (ROC) curves were used for descriptive purposes. Results. Median age: 52 years (range 18–84). IM dose: 76% 400mg, 24% 800mg. Sokal score: 39% low, 39% intermediate, 22% high; EUTOS score: 93% low, 7% high. Median follow-up: 76 months (range: 7–99); 95% of patients had at least 5-year observation. BCR-ABLIS at 3 months: ≤1% in 336/487 (69%), >1% to ≤10% in 120/487 (25%) and >10% in 31/487 (6%). BCR-ABLIS at 6 months: ≤1% in 425/492 (86%), >1% to ≤10% in 54/492 (11%) and >10% in 13/492 (3%). Responses and outcomes according to transcript levels are presented in table 1. Patients with BCR-ABLIS >10% at 3 months achieved inferior CCgR and MMR rates at 1 year and inferior MR4.0 rate at 2 years, but the long-term outcome was comparable to patients with transcript levels < 10%. On the contrary, a BCR-ABLIS >1% at 3 months was associated, not only to lower subsequent response rates, but also to significantly inferior FFS, PFS and OS. The BCR-ABLIS levels able to predict for FFS, PFS and OS with maximal sensitivity and specificity (ROC curves) were 1.9%, 0.8% and 0.8%, respectively. Results were similar, with small differences, in the 6-month analysis. Conclusions. In a multicentric nationwide experience, the proportion of patients with BCR-ABLIS transcript levels >10% at 3 and 6 months was low. The risk distribution and the proportion of patients treated with high-dose IM may explain, at least in part, the differences with other published reports. At 3 and 6 months, a BCR-ABLIS cutoff of 1% was a reliable surrogate marker of response and outcome. A transcript level >10% identified a smaller cohort with inferior responses, but failed to predict the long-term outcome. A BCR-ABLIS level >1% at 3 and 6 months represents a warning, requiring a close monitoring. A switch to 2nd generation tyrosine kinase inhibitors should be considered. Acknowledgments. University of Bologna, BolognaAIL, COFIN, Fondazione Carisbo. Disclosures: Castagnetti: Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis Pharma: Consultancy, Honoraria, Speakers Bureau. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Abruzzese:Bristol Myers-Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzini:Novartis Pharma: Honoraria; Bristol Myers Squibb: Honoraria. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Martinelli:Bristol-Myers-Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.

scholarly journals Combining Imatinib-Following-Nilotinib Treatment in First Line Therapy for Chronic Phase Chronic Myeloid Leukemia. Update from the PhilosoPhi34 Study at 24 Months of Follow-up

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5435-5435
Author(s):  
Maria Luisa Pioltelli ◽  
Ester Pungolino ◽  
Mariella D'adda ◽  
Chiara Elena ◽  
Lorenza Maria Borin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Sokal Score ◽  
First Line Treatment

Abstract Background Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder which molecular base is represented by the bcr-abl fusion gene, encoding for the constitutionally activated BCR-ABL tirosine-kinase. Three Tirosin-Kinase Inhibitors (TKI) are approved for first line treatment: Imatinib (IM) and the second generation (2G) TKI Nilotinib (NIL) and Dasatinib. 2G TKI are known to provide faster and deeper molecular responses (MR) compared to Imatinib, but serious toxicities may hamper long term treatment with these molecules. Furthermore, 2G TKI were usually employed as second line after IM failure, while the inverse sequence from second to first generation TKI (like an induction-maintenance model) has not been explored yet. We used this schedule in a small group of patients in the PhilosoPhi34 study (EudraCT: 2012-005062-34), a clinical trial designed by the REL (Rete Ematologica Lombarda) cooperative group. This study was composed by three consecutive phases: a Recruitment Phase, a Core Phase (CP) in which patients received NIL 300 mg BID for 12 month (mos), and an Observational Phase (OP), restricted for patients who obtained at least complete cytogenetic response at the end of the CP. During OP, treatment choice was up to the physician and any TKI approved for first line treatment could be used, including IM. In 2017 we presented preliminary data showing that a 12-mos-NIL treatment followed by IM appears as a safe and effective choice for first line therapy in chronic phase CML. Fluctuations in BCR/ABL ratio were similar between IM and NIL treated pts, and the probability of loss of MR4 or MR3 was the same in the two groups; furthermore, despite fluctuations, MR was maintained or improved over time in IM subgroup. Our purpose is to verify these data after 24 mos follow up (FU) at the end of OP. Methods We analyze PhilosoPhi34 database; MR is reported at 3, 6 and 12 mos during the CP and every 6 mos during the OP. The last pt completed the 24 mos of OP in June 2018. Database is still open, evaluations ongoing, and some data can be missing yet: our preliminary observations concern pts with available data of 24 mos OP. Results Seventy-nine pts started the OP. Fourteen pts switched to IM during the OP (Table 1) due to high cardiovascular risk or grade 1-2 chronic AEs . Only 11 pts started IM since the beginning of OP, and we consider these pts in our analysis. Sokal score was high in 2 pts (18%), intermediate in 5 (45.5%), low in 4 (36.5%). At the beginning of OP, 6 pts had a MR ≥ 4 (54.5%), 5 had MR3 (45.5%). At 12 mos of the OP, 7 had MR ≥ 4, 3 had MR3 and 1 had lost MR3 with PCR 0.192%IS (1/5, 20%). At 24 mos of the OP, 9 had MR ≥ 4 (81,8%), and 2 had MR3. Notably, none of pts lost MMR; 2/3 pts(66%) improved response from MR 3 to MR 4 and the pt who transiently lost MMR at 12 mos, recovered it at 24. Sixty-four pts maintained 2G TKI: 62 NIL, 2 other TKI (not considered for analysis). Of them, 4 were lost during this phase: 2 within the first year of OP, other 2 within 12 and 24 mos of OP. In the NIL group, Sokal score was high in 10 pts (16.6%), intermediate in 19 (31.6%) and low in 31 (51.6%). At the beginning of OP, 32 pts had MR ≥ 4 (51.6%), 21 had MR3 (33.8%) and 9 less than MR 3 (14.5%). Responses were improved over time: at 12 mos, 36 pts had MR ≥ 4 (60%), 20 had MR3 (33%) and 4 less than MR3 (6%). At 24 mos 46 pts had MR ≥ 4 (78%), 8 MR3 (13.5%) and 4 less than MR3 (8,5%), Among them, 1 pt experienced disease progression due to a mutation. In particular, during the second year of OP, 11 pts improved response from MR3 to MR ≥ 4(11/20, 55%). Discussion Our data show progressive MR improvement in both IM and NIL group. In particular, risk of loss of MMR is not increased in IM group. More data, more balanced groups and a longer FU are necessary to further confirmations, but after three years of FU, we consider this combination of NIL-followed-by-IM a possible strategy for first line treatment in chronic phase CML, in particular for pts with cardiovascular risk factors. Disclosures Rossi: Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Deep Molecular Response in Imatinib First-Line 418 Newly Diagnosed CP CML Patients.

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3014-3014
Author(s):  
Franck Emmanuel Nicolini ◽  
Vincent Alcazer ◽  
Pascale Cony-Makhoul ◽  
Stephanie Dulucq ◽  
Sandrine Hayette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Univariate Analysis ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Advisory Committees ◽  
Free Survival ◽  
Deep Molecular Response ◽  
Chi2 Test

Abstract Introduction Deep molecular response (DMR) are now highly desirable goals in the treatment of CP-CML, especially in the front-line setting, because it can lead to a definitive treatment-free remission (TFR). However, such a goal is difficult to attain and does not concern the majority of patients (pts), but currently the precise number of pts able to access to TFR is unknown. Aims We aim to determine the number or newly diagnosed CP-CML pts reaching DMR, stable DMR, and access to TFR, on Imatinib (IM, Glivec®) first-line. Methods We retrospectively analyzed in an observational study, a cohort of newly diagnosed CP-CML pts treated with IM first-line 400 mg daily alone in our 3 reference centers between 2000→2018. All pts were followed according to the ELN recommendations 2006, 2010 and 2013. Clinical data were extracted from medical files, and responses (hematologic, cytogenetic, molecular) were analysed according to standard methods. Molecular results were standardised according to the ELN/Eutos programs since 2003, and were all expressed as BCR-ABLIS in %. DMR have been defined according to the ELN (NCP. Cross et al., Leukemia 2015). Stability of DMR has been defined as a stable if ≥2 years at least on 4 datapoints. TFR has been proposed to pts presenting the only current recommended criteria: MR4.5 ≥2 years at least on 4 datapoints [(Rea et al., Cancer 2018)], in the 3 centers involved, within clinical trials, pioneered in our country, or now as a clinical routine recommendation. Loss of MMR was the trigger for TKI resumption after IM cessation for TFR. Overall survival (OS), progression-free survival (PFS), failure-free survival (FFS, defined as progression to advanced phases death, loss of CHR, CCyR, or MMR, discontinuation of IM for toxicity, primary cytogenetic resistance) were analysed since IM initiation in intention-to-treat. Results Four hundred and eighteen pts have been included in this study, with a median age of 60.7 (48-70) years at diagnosis, with 57% males and 43% females. Sokal score (n=401) was low in 32%, intermediate in 51% and high in 17%. ACA were present at diagnosis in 5.5% of the pts (NA in 1.44%). Major BCR transcripts were found in 98% of pts, and atypical transcripts in 1.9%. CHR was reached in a median of 1 (0.85 to 1.64) month of IM, <10% BCR-ABL transcript (IS) level at 3 months was found in 81% of the pts, and only 9.5% of pts were in MMR at 3 months. The median follow-up after IM initiation is 77.4 (0.9-231.5) months, 125 (30%) pts have switched to TKI2 for IM resistance or intolerance. Overall, 252 (60%) pts reached MR4, 127 (30%) stable MR4, 170 (41%) MR4.5, and 82 (20%) stable MR4.5. The median time on TKI necessary for obtaining stable MR4.5 is 15.6 (5.9-28) months. The cumulative incidence of MR4.5 at 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months were 12.5%, 23.4%, 31.6%, 36.72%, 43.55%, 48.7%, 48.3%, 52.98%, 54.03%, 59.18% respectively (Figure 1A.). The cumulative incidence of stable MR4.5 at 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months were 5.76%, 11.5%, 17.83%, 21.82%, 26.35%, 28.13%, 28.13%, 29.13%, 29.13%, 29.13% respectively (See figure 1B.). Seventeen (13%) and 10 (12%) pts have switched IM→TKI2 before obtaining a stable MR4 and a stable MR4.5 respectively. Overall, 41 (10%) pts have reached the TFR criteria and stopped their TKI and 23 (56%) never lost their MMR after cessation, with a median follow-up of 41.7 (9.4-121.8) months. In an univariate analysis, only gender (female vs male, 39% vs 61% for no MR4.5 and 53.66% vs 46.34% for stable MR4.5, p=0.028, Pearson's CHI2 test), and MMR at 3 months (yes vs no, 3.74% vs 96.26% for no MR4.5 and 17.46% vs 82.54% for stable MR4.5, p<0.001, Pearson's CHI2 test) were identified variables impacting on stable MR4.5. A multivariate analysis could not be performed on so few discriminant factors identified in the univariate analysis. Conclusions Only 42 out 418 (10%) of the newly diagnosed CP-CML pts on IM first-line in our study reach the TFR criteria we recommended, and only 22 over 418 pts (5%)will finally definitively stop any TKI durably within the limits of this retrospective observational study. Urgent strategies in order to increase the access to definitive TFR are needed. Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Incyte Biosciences: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; Incyte: Other: Travels for attending to Congress; Novartis: Consultancy, Other: Writing support, Travels for attending to Congress. Dulucq:BMS: Consultancy; Incyte: Consultancy. Hayette:Incyte: Consultancy. Mahon:BMS: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Incyte: Speakers Bureau. Etienne:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau.

Discontinuation of Imatinib in Children with Chronic Myeloid Leukemia: An International Registry of Childhood Chronic Myeloid Leukemia (I-CML-Ped) Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 53-54
Author(s):  
Frédéric Millot ◽  
Meinolf Suttorp ◽  
Stéphanie Ragot ◽  
Guy Leverger ◽  
Jean-Hugues Dalle ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Age At Diagnosis ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Advisory Committees ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Background: Imatinib, a tyrosine kinase inhibitor (TKI) is currently proposed as first line therapy in children with chronic myeloid leukemia (CML) in chronic phase (CP). Studies in adults with CML demonstrated that 40 to 50% of patients with prolonged deep molecular response under TKI could discontinue TKI permanently without molecular relapse. However, data regarding TKI discontinuation in children with CML are limited. Methods: Using the ELN criteria we identified in the International Registry of Childhood Chronic Myeloid Leukemia 18 patients less than 18 years of age at diagnosis with CML in CP exhibiting under imatinib treatment sustained deep molecular response &gt;MR4.0 (DMR) for ≥ 2 years and then discontinued the TKI. We retrospectively analyzed outcome of these patients and treatment-free remission rate (TFR) at various time points. Treatment with imatinib was resumed in case of molecular relapse defined as loss of major molecular response (MMR). Results: There were 11 boys and 7 girls. From diagnosis in CP until TKI discontinuation the 18 children showed no progression, resistance, warning or suboptimal response or switch to another TKI before discontinuation. Median age at diagnosis of CML was 11.9 years (range, 2.3 to 15.8 years) and median age at discontinuation of TKI was 16 years (range, 9 to 24 years). Median overall follow-up from diagnosis of CML was 107 months (range, 67-209 months). DMR was achieved after a median time of 12 months (range, 3 - 50 months) on imatinib. Before discontinuation median treatment duration of imatinib was 73.25 months (range, 32 to 109 months) and median duration of MR4.0 was 46.2 months (range, 23.9 to 98.6 months). Seven patients experienced molecular relapse 4.1 months (range, 1.9-6.4 months) after stopping and restarted imatinib. Two patient resumed imatinib 3.6 and 3.4 months after discontinuation because of increased in transcript level (from 0.001% to 0.01 and 0.012, respectively) but without loss of MMR. The median molecular follow up after discontinuation was 116 months (range, 71 to 209 months) for the patients without molecular relapse. The proportion of patients maintaining molecular free remission was 61% (95% CI, 38%-83%), 56% (95% CI, 33%-79%) and 56% (95% CI, 33%-79%) at 6, 12, and 36 months, respectively (Figure 1). Six of the 7 children who experienced molecular relapse after discontinuation again achieved MR4.0 at median of 4.7 months (range, 2.5-18 months) after restart of imatinib; the remaining patient achieved MMR but not DMR and was switched to Dasatinib. No withdrawal syndrome was observed in this cohort of 18 patients. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment duration before discontinuation and duration of DMR until imatinib discontinuation had no influence on treatment free remission. Conclusion: These data indicate that imatinib could be safely discontinued in children younger than 18 years of age at diagnosis of CML with sustained MR4.0 for at least 2 years under imatinib. Larger studies of TKI discontinuation in children with CML are needed in order to identify factors predicting treatment free remission. Disclosures Dalle: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria; Bellicum: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

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