scholarly journals Multicenter, Prospective and Retrospective Observational Cohort Study of Ponatinib in Patients with CML in Italy: Primary Analysis of the Oiti Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3603-3603
Author(s):  
Massimo Breccia ◽  
Luigia Luciano ◽  
Mario Annunziata ◽  
Imma Attolico ◽  
Alessandra Malato ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Survival Rates ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Primary Analysis ◽  
Medical Decisions ◽  
Safety And Efficacy ◽  
T315i Mutation

Abstract Background. Ponatinib is a third-generation tyrosine kinase inhibitor indicated for adults with resistant or intolerant chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia, or those carrying the T315I mutation. Ponatinib has been commercially available since January 2015, yet there is a paucity of data on its use in the real-world setting. The goal of the Observational study of Iclusig ® (ponatinib) Treatment in patients with CML in Italy (OITI) was to evaluate treatment patterns and outcomes, including safety and efficacy, in patients with CML treated in Italy since the approval of ponatinib. Methods. This noninterventional study included patients aged ≥18 years with CP, AP, or BP CML who initiated ponatinib treatment in routine clinical practice across 26 Italian centers (academic and hospital settings). The study population comprised a prospective cohort, including patients who started treatment with ponatinib after site activation during the 12-month enrollment period; a retrospective cohort, including patients who started treatment with ponatinib but died or were lost to follow-up prior to site activation; and a retrospective/prospective cohort, including patients who started treatment with ponatinib prior to site activation and were still on treatment or in follow-up at the end of the study. Demographic, efficacy, and safety data were collected from patient medical charts at study entry and routine visits. The primary endpoint was the complete cytogenetic response (CCyR) rate in CP CML patients 6 months after starting ponatinib. In the absence of cytogenetic evaluation, molecular assessment was used, considering patients in MR2 or better to be in CCyR. Here, the primary analysis of all evaluable patients for the primary endpoint (median follow-up, 23.7 months [range, 1.3-70.8]) is presented. Results. A total of 119 patients (110 CP, 6 AP, and 3 BP CML) were analyzed. Fifty-nine (49.6%) received ponatinib in second-line (2L), 41 (34.4%) in 3L, and 19 (16.0%) in ≥4L. Prior cardiovascular disease/hypertension was recorded in 56 (47.1%) patients. Median age at ponatinib start was 60 years (range, 19-93). Of 68 evaluated patients, 24 (35.3%) had a confirmed ABL1 mutation, including 7 (10.3%) with the T315I mutation. Starting doses of ponatinib were 45 mg (37.0%), 30 mg (41.2%), or 15 mg (21.8%). Median treatment duration was 22.8 months (range, 1.4-73.6). At baseline, 56 patients with CP CML had less than CCyR and 53 were in CCyR. For 1 patient, assessment was not available. At 6 months, 80/107 evaluable patients with CP CML were in CCyR; 29/56 (51.8%) achieved and 50/50 (100%) maintained CCyR compared to baseline, respectively. For 1 patient, baseline data were unavailable. Additionally, 37 (34.6%) and 19 (17.8%) patients with CP CML achieved a major molecular response (MMR; MR3) and a deep molecular response (MR4-MR5), respectively (Table 1). Progression-free survival rates estimated for patients with CP CML at 12 and 24 months were 92.6% (95% CI, 87.8-97.7%) and 84.6% (95% CI, 77.2-92.6%), respectively. Corresponding overall survival rates were 95.4% (95% CI, 91.6-99.4%), and 88.4% (95% CI, 81.7-95.7%). Seventy-one (59.7%) patients had treatment-related adverse events (AEs), most commonly rash, hypertension (Grade 1-2), and thrombocytopenia (Grade 3). Treatment-related arterial occlusive events occurred in 2 (1.7%) patients. Dose modifications occurred in 77 patients: 37.1% were due to AEs, 13.5% were reductions after at least major cytogenetic response, 10.6% were increases due to lack of efficacy, 1.7% were medical decisions, and 37.1% were for other reasons. Thirty-three patients discontinued ponatinib due to AEs (33.3%), medical decisions (24.2%), and other reasons (42.4%), such as death, progression, and hematopoietic stem cell transplantation. Conclusions. This observational study demonstrates that ponatinib has a favorable efficacy and safety profile in patients with CML treated in standard clinical practice. By 6 months, 74.8% of evaluable patients were in CCyR and 52.3% achieved at least MMR. Further, the probability of survival at 2 years was >88%. No new safety signals emerged with ponatinib treatment compared to prior studies. The early use of ponatinib and careful dose selection appear key to the safety and efficacy outcomes observed in this real-world study. Figure 1 Figure 1. Disclosures Breccia: Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Bonifacio: Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria. Castagnetti: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Inctye Bioscience Italy Srl: Current Employment. Iurlo: Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

scholarly journals Multicenter, Prospective and Retrospective Observational Cohort Study of Ponatinib in Patients with CML in Italy: Interim Analysis of the OITI Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1652-1652
Author(s):  
Alessandra Iurlo ◽  
Mario Annunziata ◽  
Francesco Albano ◽  
Luigia Luciano ◽  
Raffaele Spadano ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Board Of Directors ◽  
Interim Analysis ◽  
Survival Rates ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
History Of ◽  
T315i Mutation

Background. Ponatinib is a third-generation tyrosine kinase inhibitor indicated for adult patients with resistant or intolerant chronic phase (CP), accelerated phase (AP) or blast phase (BP) chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia, or for those carrying the T315I mutation. In the real-world setting, there is a paucity of data regarding the use of ponatinib. The goal of the Observational study of Iclusig® (ponatinib) Treatment in patients with CML in Italy (OITI) is to evaluate treatment patterns and outcomes, including the safety and efficacy of ponatinib, in patients with CML treated in hematology centers in Italy since January 2015, when ponatinib became commercially available. Methods. This ongoing, non-interventional study includes patients aged ≥18 years with CP, AP or BP CML who initiated ponatinib treatment in routine clinical practice across 40 centers (academic and hospital settings) as of October 2018. The study population consists of a prospective cohort, including patients who started treatment with ponatinib after site activation during the ongoing enrolment period; a retrospective cohort, including patients who started treatment with ponatinib but who died or were lost to follow-up prior to site activation; and a retrospective/prospective cohort, including patients who started treatment with ponatinib prior to site activation and are still on treatment. Demographic, efficacy and safety data are collected from patient medical charts at study entry and at routine care visits. The primary endpoint is complete cytogenetic response (CCyR) rate in patients with CP CML 6 months after starting ponatinib treatment. Here, the first interim analysis after ≥6 months' observation is presented for the retrospective and retrospective/prospective cohorts. Results. At time of data analysis (02 July 2019), 56 patients (53 CP, 1 AP and 2 BP CML) had been enrolled across 21 Italian centers. Twenty-eight (50.0%) patients had received ponatinib as second-line (2L) treatment and 33.9% received ponatinib in third-line (3L). Twenty (35.7%) patients had a history of cardiovascular events and 23 (41.1%) had a history of hypertension. Among patients with CP, AP and BP CML, median age at study entry was 59.1, 33.7 and 48.5 years, respectively; among 37 evaluable patients, 12 (32.4%), 1 (2.7%) and 1 (2.7%) patient(s) had a confirmed BCR-ABL1 mutation. Of evaluable patients, 4 (10.8%) had the T315I mutation. The starting dose of ponatinib for patients with CP CML was 45 mg once daily in 41.5% of patients, 30 mg in 39.6% of patients and 15 mg in 17.0% of patients; 1 (1.9%) patient started ponatinib at another dose. Median treatment duration was 23.9 months (range, 3.3-49.9 months) at the time of analysis. At Month 6, 88.6% of patients with CP CML achieved a CCyR. Additionally, 37.5% and 15.0% of evaluable patients with CP CML achieved a major molecular response (MMR; MR3.0) and a deep molecular response (MR4.5), respectively (Table 1). Estimated progression-free survival rates for patients with CP CML at Months 12 and 24 were 86.6% (95% CI, 77.8-96.4%) and 83.7% (95% CI, 73.8-94.9%), respectively. Corresponding overall survival rates were 96.2% (95% CI, 91.1-100.0%) and 93.1% (95% CI, 85.6-100.0%), respectively. Thirty (53.6%) patients had treatment-related adverse events (TRAE). The most frequent TRAEs were hypertension (n=6), skin lesion (n=2), increased lipase (n=2), rash (n=2) and pain in extremity (n=2). The only hematologic TRAE reported was thrombocytopenia (n=1). Dose interruptions occurred in 13 patients: for TRAEs (n=5, 38.5%), medical decision (n=4, 30.8%) or other causes (n=4, 30.8%; comprising death in 3 cases and 1 attempt at treatment-free remission). Conclusions. Data show that ponatinib has a favorable efficacy and safety profile in patients with CML treated in standard clinical practice in Italy. By Month 6, most patients had achieved CCyR and 44% of patients achieved MMR in 2/3L. Furthermore, the probability of survival at 2 years was more than 90%. No new safety signals emerged with ponatinib treatment than those previously reported. The early use of ponatinib (84% of patients received it as 2/3L treatment) as well as careful dose selection appear key to the safety and efficacy outcomes observed in this preliminary study evaluation. Disclosures Iurlo: Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria; Novartis: Other: Speaker Honoraria. Annunziata:Pfizer: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Albano:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Spadano:Incyte: Speakers Bureau; Pfizer: Speakers Bureau. Bonifacio:BMS: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Pellegrino:Inycte Biosciences Italy S.R.L: Employment. Galimberti:Inycte Biosciences Italy S.R.L: Employment. Foà:Celltrion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees. Breccia:Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

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

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

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

scholarly journals Efficacy and Safety of Ponatinib in CML and Ph+ ALL Patients in Real-World Clinical Practice: Data from a Belgian Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1744-1744 ◽  
Author(s):  
Timothy Devos ◽  
Koen Theunissen ◽  
Fleur Samantha Benghiat ◽  
Alain Gadisseur ◽  
Stef Meers ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Median Time ◽  
Real World ◽  
Research Funding ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Best Response ◽  
History Of ◽  
T315i Mutation

Abstract Background Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) indicated for adult patients with resistant or intolerant chronic phase (CP), accelerated phase, or blast phase chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), or those with the T315I mutation. In Belgium, ponatinib has been commercially available since March 2016. The goal of this registry was to collect efficacy and safety data in CML and Ph+ ALL patients and to evaluate ponatinib in routine clinical practice in Belgium. Methods This ongoing, prospective, multi-center registry includes patients ≥18 years of age with CML or Ph+ ALL, who have initiated ponatinib treatment. Demographic, efficacy and safety data were collected for patients enrolled from March 2016 (day 0) onwards. Results up to study month 24 are presented. Data were analyzed by descriptive statistics. Ethics Committee approval was obtained and all patients provided informed consent. Results At time of data analysis, 34 patients (21 CP-CML and 13 Ph+ ALL) were enrolled. The median age of CP-CML and Ph+ ALL patients was 57 and 55 years, respectively. Patients were heavily pretreated: 90% of CML and 92% of Ph+ ALL patients had received ≥2 prior TKIs. Several patients had one or more risk factors for TKI cardiovascular toxicity: hypertension (10), history of cardiovascular disease (11), smoker (10), hypercholesterolemia (5), and diabetes (4). Median follow-up was 539 days for CML and 135 days for Ph+ ALL patients. The reasons for starting ponatinib therapy were related to refractoriness to previous TKIs (36%), progression (18%), presence of the T315I mutation (18%) or intolerance (29%). Eighty percent (8/10) of the patients who started ponatinib due to intolerance to previous TKIs had received ≥3 prior TKIs. At entry, 17 of the 34 patients (50%) had a confirmed BCR-ABL mutation. Of these 17, 10 (59%; 5 CML and 5 Ph+ ALL) had the T315I mutation. Starting doses of ponatinib in CML patients were 45 mg (76%), 30 mg (10%) and 15 mg (14%) once daily. Starting doses in Ph+ ALL patients were 45 mg (85%), 30 mg (8%) and 15 mg (8%). At latest follow up, the median treatment duration for the 21 CML patients was 531 days (range 15 - 2483) and for the 13 Ph+ ALL patients it was 123 days (range 13 - 1945). Best response was a major molecular response (MMR), which was obtained in 71% of CML patients and 38% of Ph+ ALL patients. The median time-to-best response was 175 days in CML and 35 days in Ph+ ALL patients. In the 10 patients (7 CML and 3 Ph+ ALL) who started ponatinib because of intolerance to several previous TKIs, 80% achieved MMR. The median time to achieve best response in these patients was 192 days for CML and 31 days for Ph+ ALL patients. Treatment-related adverse events (AEs) were reported in 20 patients (59%); the most common were rash (26%), dry skin (9%) and constipation (9%). Three patients reported ≥1 treatment-related serious AE (SAE): thrombocytopenia (n=1), cholecystitis (n=1) and hepatocellular injury (n=1). Three serious cardiovascular events were observed in 1 patient, who had a history of congenital cardiomyopathy and aortic prosthesis. They were scored as not related to ponatinib. Dose reductions or interruptions occurred in 33 cases (20 in CML and 13 in Ph+ ALL patients), with the following reasons most frequently mentioned: AEs (76%), to prevent AEs (18%) and other (6%). Dose increases occurred in 12 cases (10 in CML and 2 in Ph+ ALL patients), for the following reasons: good tolerance of treatment (58%), no or low response (33%) or other (8%). At time of analysis, 19 patients (9 CML and 10 Ph+ ALL) had discontinued treatment, of which 32% due to AEs, 5% due to an SAE, 21% due to planned allogeneic transplant, 16% due to disease progression and 26% due to other reasons. [Note: Percentages may not total 100 due to rounding] Conclusion Real-world evidence from this Belgian registry shows that ponatinib has a favorable efficacy and safety profile in, and supports its use in CML and Ph+ ALL patients who are resistant or intolerant to previous therapies or those with the T315I mutation. Deep molecular responses were obtained in the majority of patients. No new safety signals emerged with ponatinib treatment than those previously reported. Funding: Incyte Biosciences Benelux BV Disclosures Devos: Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Theunissen:Incyte: Honoraria. Van Eygen:Janssen: Consultancy, Research Funding; Roche: Research Funding; Amgen: Research Funding. Kuipers:Incyte Biosciences Benelux BV: Employment.

Characteristics and Outcome of Patients with Chronic Myeloid Leukemia (CML) and T315I Mutation Following Failure of Imatinib Mesylate Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1943-1943
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Srdan Verstovsek ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Cell Transplant ◽  
2Nd Generation ◽  
Hematologic Response ◽  
T315i Mutation

Abstract Background. T315I is an imatinib pocket binding mutation within the Bcr-Abl kinase domain that is highly resistant, both in vitro and in vivo, to imatinib and to 2nd generation tyrosine kinase inhibitors (TKIs). Several studies have suggested that patients with T315I have a poor outcome. Study Aims. The objectives of this study were to define the clinical characteristics of patients harboring the T315I mutation, and to assess their outcome after imatinib failure. Results. T315I was detected in 27 pts: 20 among a series of 186 pts assayed after imatinib failure (11% of all pts; 21% of all mutations detected) after a median of 37 months (mos) from start of imatinib, and 7 among 23 pts who developed new mutations after a median of 10 mos on therapy with a 2nd generation TKI. Median age was 52 years. Median time from diagnosis to T315I was 41 mos, and the median follow-up from the detection of mutation is 18 mos. At the time of T315I detection, 10 pts were in CP, 9 in AP, and 8 in BP. Fifteen pts (56%) had transformed to accelerated or blast phase at the time of T315I detection. Best response to TKI immediately preceding development of T315I (20 imatinib, 2 nilotinib, 2 dasatinib, 2 bosutinib, 1 INNO-406) was CHR in 13 (48%) and CyR in 9 (33%; complete in 6, partial in 1, minor in 2). The median duration of response was 44 mos. Except for the lack of response to a second TKI (p=0.001), there was no difference in pt characteristics between pts with or without T315I, other mutations, or no mutations. Among the 20 pts with T315I present prior to start of 2nd TKI, 5 responded, all hematologic (3 complete hematologic response -CHR-, 2 partial hematologic response -PHR-, 1 return to chronic phase); in contrast all 5 pts without T315I prior to 2nd TKI, responded (1 major molecular response -MMR-, 2 Minor cytogenetic response -CyR-, 1 CHR, 1 PHR); and among the 2 pts with unknown T315I status at start of 2nd TKI 1 had PHR and 1 complete cytogenetic response -CCyR-. Responses were usually transient but 3 pts had sustained responses for some time despite presence of T315I: 1 pt in AP harboring simultaneously F317L and G250E acquired a T315I mutation 5 mos after the start of nilotinib and achieved MMR that was sustained for 21 mos eventually lost to major CyR. A 2nd pt in AP treated with bosutinib acquired a T315I mutation 6 months after the start of bosutinib, but nonetheless achieved a minor CyR that has been sustained for more than 8 mos. A third patient with Y253H mutation developed T315I 1 mo after therapy with INNO-406 for CML AP; at the last follow-up, 4 months into therapy, he maintained a PHR. 4/14 pts (38%) treated with T315I-directed agents (aurora kinase inhibitors, homoharringtonine) responded. 4 pts received allogeneic stem cell transplant (ASCT) and 2 are alive: 1 in CMR 24+ months after ASCT and 1 in CCyR 9 months after ASCT, wit molecular relapse and recurrence of T315I. 11/27 pts with T315I (40%) died. Patients in CP had better outcome with 87% 2-year survival, compared to 45% in AP and 20% in BP. Survival of patients with T315I was similar to those with other mutations or without mutations (p=0.64). Conclusion. Altough T315I is a mutation highly resistant to conventional BCR-ABL TKI, occasional responses can be observed. Overall survival of patients with T315I mutations is mostly dependent on the stage of the disease.

Phase II Clinical Trial Results of Dasatinib for Frontline Therapy in Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4565-4565 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Gautam Borthakur ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Significant Activity ◽  
Long Term Outcome ◽  
Free Survival ◽  
Complete Cytogenetic Response ◽  
T315i Mutation

Abstract Background: Dasatinib is approximately 300 times more potent than imatinib (IM) in vitro and has significant activity in patients (pts) with CML-CP resistant to or intolerant of IM. In 2005, we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP. Objective: To determine the long-term outcome of pts with CML-CP treated with front-line dasatinib. The primary endpoint was achievement of major molecular response (MMR) at 12 months (mos). Methods: Pts with previously untreated CML-CP within 6 mos from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg twice daily (BID) or 100 mg once daily (QD). After 66 pts were accrued, the BID arm was closed and all subsequent pts were treated with 100 mg QD. No prior therapy was allowed except for IM for <1 month, or hydroxyurea. Results: From November 2005 to August 2014, a total of 155 pts have been enrolled. For this analysis, we included only those pts with a minimum of 12 mos follow-up: 107 pts (77 QD, 30 BID). Median age was 48 years (yrs) (range 16–83 yrs). Median baseline counts: WBC 26.4 K/uL, peripheral blood blasts 0%, bone marrow blasts 2%, and platelets 333 K/uL. Twenty-seven pts (25%) had brief prior exposure to IM. Sokal score by distribution: Low (76%), Intermediate (21%), High (4%). Median follow-up is 62.9 mos (11.7 - 104.1 mos). Of the 99 evaluable pts who were not in CHR at the start of therapy, 99 (100%) achieved CHR. Of 105 evaluable pts (ie, followed for at least 3 mos), 105 (100%) achieved complete cytogenetic response (CCyR). MMR has been achieved in 94 pts (90%), including 59 pts (56%) with complete molecular response (CMR; minimum 100,000 ABL copies). BCR-ABL/ABL <10% at 3 mos occurred in 100/106 evaluable (94%) and at 6 mos in 98/104 evaluable (94%). At 6 mos, 93/102 evaluable (91%) pts had achieved a CCyR and 69/101 evaluable (68%) an MMR; corresponding figures at 12 mos are 92/97 pts evaluable (95%) and 73/95 pts evaluable (77%), respectively. Fifty-eight pts (54%) have required at least one dose reduction (most common reasons: 22 pts had dose reductions due to pleural effusions, 8 due to neurologic/headaches, 4 due to thrombocytopenia). The actual median daily dose for all pts was 80mg (20–140mg). Five pts lost CCyR: (2/5 of these pts who lost CCyR ultimately progressed to accelerated phase (CML-AP)). The 3-yr and 5-yr overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS) are shown in the Table. There have been two deaths on study (1 pt: 74 yr-old woman with sepsis/infection; 1 pt: 53 yr-old man with morbid obesity and hypertension who died of unknown causes). Twenty-six (24%) pts have discontinued therapy: 11 due to toxicity (most commonly due to pleural effusion in 7 pts), 5 pt choice, 5 lost CCyR, 2 died on study, 2 pt non-adherence, 1 due to development of T315I mutation. Conclusion: Rapid CCyR occurs in nearly all pts, and MMR was achieved in 90% of pts with previously untreated CML-CP treated with frontline dasatinib therapy with a favorable toxicity profile. Deep responses occur early. Only two patients experienced transformation to CML-AP, and only one patient developed T315I mutation. These results confirm the sustained efficacy of dasatinib as initial therapy for CML-CP. Table: Outcomes at 3-year and 5-year timepoints in patients with CML treated with frontline dasatinib Total Events 3-Year 5-Year OS 107 5 98% 95% EFS 107 8 95% 92% TFS 107 4 99% 95% FFS 107 24 84% 76% *Definitions: EFS: includes, at any time on study: International Randomized Study of Interferon and STI571 trial (IRIS)-defined events, which includes loss of major cytogenetic response, loss of complete hematologic response, transformation to accelerated or blast phase, death from any cause while on study. FFS: includes loss of complete cytogenetic response, failure to achieve response at set times as defined by European Leukemia Net, treatment intolerance, or treatment discontinuation for any reason while on study. TFS: measured from start of therapy to date of transformation to accelerated or blast phases while on therapy or to date of last follow-up. Disclosures Kantarjian: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Ravandi:BMS: Honoraria, Research Funding. Verstovsek:Incyte Corporation: Research Funding. Jabbour:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

scholarly journals Plasma concentration guided dosing of drugs used for the treatment of childhood leukaemias: protocol for a systematic review

BMJ Open ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. e053308
Author(s):  
Madelé van Dyk ◽  
Chelsea Boylan ◽  
Robin Michelet ◽  
Anna M Mc Laughlin ◽  
Ganessan Kichenadasse ◽  
...  
Keyword(s):  
Systematic Review ◽  
Plasma Concentration ◽  
Clinical Outcomes ◽  
Survival Rates ◽  
Cytogenetic Response ◽  
Small Sample ◽  
Childhood Leukaemia ◽  
Molecular Response ◽  
Large Variability ◽  
Dose Individualisation

IntroductionChildhood leukaemia is the most common type of cancer in children and represents among 25% of the diagnoses in children <15 years old. Childhood survival rates have significantly improved within the last 40 years due to a rapid advancement in therapeutic interventions. However, in high-risk groups, survival rates remain poor. Pharmacokinetic (PK) data of cancer medications in children are limited and thus current dosing regimens are based on studies with small sample sizes. In adults, large variability in PK is observed and dose individualisation (plasma concentration guided dosing) has been associated with improved clinical outcomes; whether this is true for children is still unknown. This provides an opportunity to explore this strategy in children to potentially reduce toxicities and ensure optimal dosing. This paper will provide a protocol to systematically review studies that have used dose individualisation of drugs used in the treatment of childhood leukaemias.Methods and analysisSystematic review methodology will be applied to identify, select and extract data from published plasma guided dosing studies conducted in a paediatric leukaemia cohort. Databases (eg, Ovid Embase, Ovid MEDLINE, Ovid Cochrane) and clinical trial registries (CENTRAL, ClinicalTrials.gov and ISRCTN) will be used to perform the systematic literature search (up until February 2021). Only full empirical studies will be included, with primary clinical outcomes (progression-free survival, toxicities, minimal residual disease status, complete cytogenetic response, partial cytogenetic response and major molecular response) being used to decide whether the study will be included. The quality of included studies will be undertaken, with a subgroup analysis where appropriate.Ethics and disseminationThis systematic review will not require ethics approval as there will not be collection of primary data. Findings of this review will be made available through publications in peer-reviewed journals and conference presentations. Gaps will be identified in current literature to inform future-related research.PROSPERO registration numberCRD42021225045.

Molecular Response of CML Patients to INFα Based Treatment or to STI Based Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4872-4872
Author(s):  
Debora Luzi ◽  
Rosanna Capozzi ◽  
Annamaria Rauco ◽  
Roberta Pace ◽  
Emilio Donti ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Response Duration ◽  
Cytogenetic Response ◽  
The Other ◽  
Entire Group ◽  
Molecular Response ◽  
Rt Pcr ◽  
Molecular Remission ◽  
First Time

Abstract Introduction: Continous improving results have been obtained during last two decades in the control of Ph’positive chronic myeloid leukemia(CML). However the final goal of molecular remission remains difficult to obtain even in the STI age. Aims : Evaluation of the rate of molecular response to IFNα,IFNα based treatment,to STI or to STI-INFα combination was analized in 100 consecutive Ph+ CML patients observed in a single Institution over a period of 20 years. Patients, Methods and Results All patients were treated at the time of diagnosis (87) or late (13) during the course of their disease. Distribution according to treatment was: INFα,63pts (late or early:13,50);INFα-ARA-C combination,20pts;STI,14 pts;STI-INFα association, 3 pts. Two pts, both initially assigned to INFα-ARA-C combination, were crossed-over to STI, one because relapsing off-therapy after a long lasting continous (25 mths) molecular remission and the other in cytogenetic response because intolerant to the initial treatment. In addition, other 3 pts patients, with persistent complete cytogenetic, but not molecular remission to INFα or INFα-ARA-C combination were subsequentially trated with the STI-IFNα association. At present,99/100 pts are evaluable. The median times of follow-up for the entire group and form the different treatment subgroups are: late IFNα 154 months(42–263); early IFNα, 71 months(1–197); IFNα-ARA-C, 61 months(5–203); STI- IFNα,78 mths(11–47), STI,31 mths(3–41). A complete kariotypic remission(CKR) was observed in 15/63 IFNα treated pts, in 10/20 IFNα-ARA-C pts group, in 10/13 cases of STI group and in 3 /3 pts who received STI-IFNα. A molecular response(RT-nested PCR, JQ Guo, Leukemia: 2002,15,2447–53) was observed in 4/15,2/10,5/10 and in 2/3 CKR pts initially trated with the different modalities listed above. Response was confirmed from 2 to 7 consecutive or not consecutive times in the 2/4 cases responsive to INFα, in the 2 cases responsive to INFα-ARA-C combination,4/5cases responsive to STI and in 2/3 cases responsive to STI-IFNα association. The 2nd and the 3rd molecular remission to STI were obtained in the patient molecularly and cytogenetically relapsed off-therapy and, for the first time from the diagnosis, in the other patient in CKR to IFNα-ARA-C combination and crossed to STI treatment. Furthermore, all 3 cases, in CKR, but not molecular response to other treatments at the time of cross-over to STI-IFNα combination, achieved a persistent (in 2 to 3 tests over a period ranging from 6+ to 12+ mths) molecular remission. The first interval between the start of the treatment and the first molecular response varied from 12 to 52, from 3 to 22, from 11 to 24, from 5 to 11 mths in the groups initially treated with IFNα, IFNα-ARA-C, STI or STI-IFNα respectively. The 2 pts, crossed-over to STI alone, both, obtained a response after 29 mths of therapy. In addition in the 3 pts crossed-over to STI-IFNα therapy, the molecular response was obtained after 14,23 and 25 mths from the start of last treatment. Conclusion It is not possible to achieve any conclusion regarding the treatment effect on molecular response duration because of the different length of follow-up of various groups of patients. However in responsive patients to IFN alone or combined to ARA-C or STI, consecutive negative RT-PCR tests were observed more frequently than in patients receving STI alone.

Imatinib Mesylate Therapy in Late Ph+ Chronic Myeloid Leukemia Patients in Stable Complete Cytogenetic Response after Interferon-Alpha Results in a Very High Complete Molecular Response Rate.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2158-2158
Author(s):  
Giuliana Alimena ◽  
Massimo Breccia ◽  
Luigia Luciano ◽  
Fabrizio Quarantelli ◽  
Daniela Diverio ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Complete Molecular Response

Abstract Imatinib mesylate was given to 26 Philadelphia positive (Ph+) chronic myeloid leukemia (CML) patients who were in late chronic phase (CP) and in stable complete cytogenetic response (CCR) after interferon-alfa (IFN-α), but showed persistent positive residual disease at PCR analysis under this treatment. At diagnosis median age was 40 years (range 21–64) and according to Sokal’s score, 18 patients were low risk and 8 were intermediate risk. Median IFN treatment was 88 mo.s (range 15–202) and median CCR duration was 73 mo.s (range 10–148). Imatinib was administered at the standard dose of 400 mg/die, after stopping IFN for 1 week. Residual disease was measured on bone marrow (BM) cells at baseline, before starting Imatinib, at 3, 6, 12, 18 mo.s and at the last follow-up (median 32 mo.s, range 21–49), by assaying BCR-ABL transcripts using quantitative PCR (RQ-PCR). The copy number (CN) of BCR/ABL and ABL transcript were derived by the interpolation of CT values to the appropriate standard curve, and the result, for each sample, was expressed as ratio of BCR/ABL mRNA copies to ABL mRNA x 100 (normalized copy number - NCN). Imatinib treatment resulted in a progressive and consistent decline of residual disease in all but one patient, from a median of 0.89 at baseline to 0.01 at the end of follow-up. Major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%) and BCR/ABL transcripts were undetectable in 13 (50%). Achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response vs 18,97 for those who did not; p<0.001), but not with other clinical/biological patient characteristics. In all patients, imatinib was well tolerated with no side effects requiring drug dose reduction or dose discontinuation. Albeit obtained from an unusual subset of selected patients with favourable prognosis, and likely particularly sensitive to imatinib, present results confirm the efficacy of combining Imatinib and IFN-α and further support investigating treatment approaches employing these two drugs.

Clinical Characteristics and Outcome of Patients (pts) with F317L BCR-ABL Kinase Domain (KD) Mutation after Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1949-1949
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Susan O’Brien ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Mutation Detection ◽  
Point Mutations ◽  
Cytogenetic Response ◽  
In Vitro Mutagenesis ◽  
Molecular Response ◽  
Cell Transplant ◽  
Best Response

Abstract Background. Point mutations of the Bcr-Abl KD are the most frequently identified mechanism of resistance in pts with CML who failed TKI. The setting for outgrowth of different mutations and their subsequent response to different TKIs varies significantly. For example, mutations in codon 317, which would be predicted to impair dasatinib binding, have been generated during in vitro mutagenesis with dasatinib but not nilotinib, and the F317L, in particular, has been reported following treatment with dasatinib. Aims. We assessed the incidence and pattern of development F317L mutations in pts with TKI-resistant CML at our institution and responses following change in therapy. Results. F317L mutation was detected in 20 patients: 12 occurred among 99 pts (12%) after imatinib failure who had KD mutation assessment, and 8 among 16 pts (50%) who developed new mutations on dasatinib therapy (among 77 treated) (p=0.001). Median age for all pts with F317L was 49 years (range, 34–66 years). Pts had received imatinib for a median of 23 months (mo) (range, 2–69). Best response to imatinib was complete hematologic response in 11 and cytogenetic response in 8 (5 complete, 2 partial, 1 minor). One pt did not respond. At the time the mutation was detected, 8 pts were in chronic (CP), 6 in accelerated (AP) and 6 in blast phase (BP). Patients with F317L-mutated tumors developing on imatinib or dasatinib had similar characteristics as those who had KD mutations at other sites or no mutation detected. Among pts with F317L at start of 2nd TKI, 3 received dasatinib and all 3 had transient hematologic responses (best response) (1 partial -PHR-, 2 complete -CHR-) lasting 4, 12 and 19 mo;.4 were treated with nilotinib and 3 responded (1 CHR, 1 major molecular response-MMR-,1 complete molecular response -CMR-); 2 had imatinib dose escalation after appearance of F317L and both had a sustained complete cytogenetic response (CCyR) for 24+ and 26+ months; one pt received stem cell transplant and is in CMR 20 months after transplant; one pt did not respond to a combination of imatinib and farnesyl transferase inhibitor; and one pt was lost of follow-up with no further therapy. Among pts who developed F317L while on dasatinib (n=8), 4 never responded and 4 had an initial response to dasatinib (1 CHR, 3 CCyR) lost after a median of 15 months (range, 3 to 26); one pf these was then treated with nilotinib and achieved an ongoing CCyR for 3+ months and 2 received bosutinib after failing both nilotinib and dasatinib, achieving a transient CHR lasting 6 and 9 months, respectively. After a median follow-up of 29 months from treatment failure and 25 months from the detection of F317L, 10 pts (50%) are alive (7 CP, 2 AP, 1 BP at F317L). Median survival of pts with F317L from mutation detection was 19 mo. Survival of pts with F317L was similar to those with other mutations or without mutation when survival was dated from the time of treatment failure (p=0.51) or from mutation detection (p=0.92). Conclusion. F317L occurs more frequently after dasatinib therapy paralleling the findings of in vitro studies. TKIs showing differential in vitro activity against this mutation (e.g. nilotinib or INNO-406) may represent good candidates for treatment failure associated with F317L-mutated tumors.

Long-Term Follow-Up after Frontline Therapy with the Hyper-CVAD and Imatinib Mesylate Regimen in Adults with Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 9-9
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
De Novo ◽  
Survival Rates ◽  
Disease Recurrence ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Multiparameter Flow Cytometry ◽  
Molecular Response ◽  
Cell Transplant ◽  
Early Results

Historically, complete remission (CR) rates with hyper-CVAD (cyclophosphamide, vincristine [VCR], doxorubicin and dexamethasone alternating with methotrexate and cytarabine) in de novo adult Ph-ALL were 90% or better. There was no impact on survival since remissions were brief with median CR duration of 16 mos [Kantarjian, JCO18:547, 2000; Cancer101:2788, 2004]. CR rate of imatinib in relapsed/refractory Ph-ALL or chronic myelogenous leukemia in lymphoid blast phase was 20%, with rapid disease recurrence. A phase II trial of hyper-CVAD and imatinib for Ph-ALL was designed in 2001. Imatinib 400 mg was given days 1–14 of each course, followed by 12 months of continuous imatinib with monthly VCR and prednisone interrupted by 2 intensifications with hyper-CVAD and imatinib. Allogeneic stem cell transplant (SCT) was performed in first CR as feasible. Early results of 20 patients (pts) were encouraging and demonstrated feasibility [Thomas, Blood 103:4396, 2004]. Imatinib was then increased to 600 mg days 1–14 of course 1, continuously with courses 2–8, escalated to 800 mg during maintenance therapy (extended to 24 mos) then imatinib indefinitely. The study has completed accrual. Fifty-four pts with imatinib-naïve de novo or minimally treated Ph-ALL received therapy from April 2001 to September 2006. Forty-five pts had active disease, untreated (n=39) or refractory (n=6) to one induction course; 9 were in CR at start. Median age was 51 years (range, 17–84); 52% were male. Seven pts (13%) had CNS disease at presentation. Of 45 evaluable pts 42 (93%) achieved CR (1 CRp, 1 partial response, 1 died early from sepsis). Median days to response was 21. Molecular response rate (negative by nested PCR) was 52%. Allogeneic SCT was performed in 16 pts within a median of 5 mos from start of therapy (range, 1–13), and did not appear to improve survival (2-yr rates 63% vs 56% without SCT). After median follow-up of 4 years (range, 10–74 mos), eleven relapses (22%) were observed. Eight de novo pts relapsed at 8, 8, 10, 11, 11, 15, 16 and 42 mos from start of therapy (2 after SCT without imatinib maintenance); 2 CR at start at 16 and 19 months, and 1 primary refractory pt at 12 mos. Two pts changed therapy for persistent molecular disease or intolerance and relapsed at 6 and 10 mos. Relapse was preceeded by positive multiparameter flow cytometry with minimal increments in levels of quantitative RT-PCR for bcr-abl in a few cases. Non T315I ABL kinase domain (KD) mutations were identified at relapse in 3 of 8 pts tested. Deaths included 12 pts in CR (5 infections, 4 complications of allogeneic SCT, 1 pancreatitis, 1 intracranial hemorrhage, 1 unknown). The hyper-CVAD and imatinib regimen continues to demonstrate favorable 3-yr disease-free and overall survival rates for the de novo group compared with hyper-CVAD alone (66% vs 14% and 55% vs 15%, respectively, p<0.001). Development of ABL KD mutations was noted at disease recurrence in a few cases. Incorporation of the newer tyrosine kinase inhibitors into combination with therapy with hyper-CVAD is underway.

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