EHA Library - The official digital education library of European Hematology Association (EHA)

PONATINIB 15 MG DAILY, COMBINING EFFICACY AND TOLERABILITY. A RETROSPECTIVE SURVEY IN ITALY.
Author(s): ,
Gianni Binotto
Affiliations:
Dept. of Medicine, Hematology and Clinical Immunology,Padua School of Medicine,Padova,Italy
,
Fausto Castagnetti
Affiliations:
Institute of Hematology "L. and A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine ,"S.Orsola-Malpighi" University Hospital, University of Bologna,Bologna,Italy
,
Gabriele Gugliotta
Affiliations:
Institute of Hematology "L. and A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine,"S.Orsola-Malpighi" University Hospital, University of Bologna,Bologna,Italy
,
Elisabetta Abruzzese
Affiliations:
Hematology Unit,“S. Eugenio” Hospital,Roma,Italy
,
Alessandra Iurlo
Affiliations:
Hematology Division,IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, University of Milan,Milan,Italy
,
Fabio Stagno
Affiliations:
Chair of Hematology,University of Catania,Catania,Italy
,
Antonella Gozzini
Affiliations:
Haematology,AOU Careggi, University of Firenze,Florence,Italy
,
Patrizia Pregno
Affiliations:
Hematology Unit,Azienda Ospedaliero Universitaria Città della Salute e della Scienza,Turin,Italy
,
Sara Galimberti
Affiliations:
Department of Clinical and Experimental Medicine, Section of Hematology,University of Pisa,Pisa,Italy
,
Carmen Fava
Affiliations:
Hematology Division,Ospedale Mauriziano, University of Turin,Turin,Italy
,
Alessandro Isidori
Affiliations:
Hematology and Stem Cell Transplant Center,AORMN Hospital,Pesaro,Italy
,
Gaetano La Barba
Affiliations:
Department of Hematology, "Spirito Santo" Hospital,Pescara,Italy
,
Mario Tiribelli
Affiliations:
Division of Hematology and BMT, Department of Medical Area,University of Udine,Udine,Italy
,
Massimiliano Bonifacio
Affiliations:
Department of Medicine, Section of Hematology,University of Verona,Verona,Italy
,
Mario Annunziata
Affiliations:
Hematology Unit,Cardarelli Hospital,Naples,Italy
,
Luigia Luciano
Affiliations:
Hematology Unit,"Federico II" University of Naples,Naples,Italy
,
Isabella Capodanno
Affiliations:
Haematology Department,Arcispedale Santa Maria Nuova - IRCCS Reggio, Reggio emilia,Italy
,
Monica Bocchia
Affiliations:
Chair of Hematology,University of Siena,Siena,Italy
,
Francesca Lunghi
Affiliations:
Hematology and Bone Marrow Transplantation Unit,IRCCS San Raffaele Scientific Institute,Milano,Italy
,
Luciano Levato
Affiliations:
Hematology Unit,"Pugliese-Ciaccio” Hospital,Catanzaro,Italy
,
Malgorzata Monika Trawinska
Affiliations:
Hematology Unit,“S. Eugenio” Hospital,Roma,Italy
,
Fabrizio Pane
Affiliations:
Hematology Unit,"Federico II" University of Naples,Naples,Italy
,
Giuseppe Saglio
Affiliations:
University of Turin,Orbassano,Italy
,
Michele Baccarani
Affiliations:
Institute of Hematology "L. and A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine,"S.Orsola-Malpighi" University Hospital, University of Bologna,Bologna,Italy
,
Gianpietro Semenzato
Affiliations:
Dept. of Medicine, Hematology and Clinical Immunology,Padua School of Medicine,Padova,Italy
Gianantonio Rosti
Affiliations:
Institute of Hematology "L. and A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine,"S.Orsola-Malpighi" University Hospital, University of Bologna,Bologna,Italy
(Abstract release date: 05/17/18) EHA Library. Binotto G. 06/16/18; 215436; PS1122
Dr. Gianni Binotto
Dr. Gianni Binotto
Contributions
Abstract

Abstract: PS1122

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background

The third generation tyrosine kinase inhibitor ponatinib is effective as salvage treatment  for chronic phase (CP) Ph+ chronic myeloid leukemia (CML) patients resistant or intolerant to prior TKIs. Considering the demonstrated impact of ponatinib dose on the incidence of cardiovascular adverse events, a dose reduction to 15 mg daily is recommended in CP after the achievement of treatment milestones. Lower than 45 mg ponatinib dose strategies are currently under investigation in prospective clinical trials. There is a strong interest on independent data describing the efficacy and the safety of 15 mg daily ponatinib.

Aims

Describe and  assess the efficacy and toxicity of low doses of ponatinib in CML-CP resistant or intolerant to previous TKIs.

Methods

A retrospective analysis of consecutive, CML-CP patients treated with ponatinib 15 mg as starting or de-escalated dose has been performed. No pre-specified criteria to switch to ponatinib or to reduce the dose were indicated.

Results

62 patients are included, 53% males. Median age at ponatinib start was 57 (28-87) years. The median time from CML diagnosis to ponatinib treatment was 53.2 months (4.8-230). ABL1 mutations were detected in 29.3% patients (being 41% of them positive for the T315I mutation). Roughly half of the patients (45%) received ponatinib as 4th or 5th line of treatment. Ponatinib was started at 45, 30 and 15 mg, in 24, 13 and 25 patients, respectively. Resistance to prior TKIs was the reason for switch in all patients treated with higher than 15 mg dose, while 12/25 patients starting with 15 mg were purely intolerant or intolerant and resistant. The median treatment duration at any dose was 21.2 months, with 45/62 (72%) patients exposed to ponatinib for more than 12 months. Overall, 68% of patients improved response status. In patients treated with 45 or 30 mg the CCyR, MR3 and MR4/MR4.5 rates were 76%, 55% and 32% respectively. Responses were achieved after a median of 3.5, 4.3 and 6.7 months, respectively. Dose reduction to 15 mg was decided after a median time of 10 months, mostly due to adverse events (73%) and less frequently, to prevent toxicity and/or following response attainment (27%). Median duration of treatment was 32.4 months, with a discontinuation rate of 5/37 (1 cerebrovascular accident, 2 severe hematologic toxicities, two cases of resistance/progression). Two deaths were registered (both in the 45 mg group), one after blast crisis and one for a fatal cardiovascular event. Focusing the 25 patients started with ponatinib 15 mg, median duration of treatment was 15 months (4.3-58.1). CCyR was obtained in 55% of patients lacking CCyR and MR3 in 50% without MMR with a median time of 3.8 and 3.4 months, respectively. During follow-up, MR3 or deeper responses were maintained or improved in 80% of cases, while 7 patients lost their best acquired response (4 MR4/4.5 to MR3, 1 MR3 to MR2, 1 CCyR to PHR and 1 progression to accelerated phase). Three patients of this group discontinued the treatment (1 coronary vasospasm-induced acute coronary syndrome, 2 muscle skeletal pain). After a median follow-up of 21 months, 35/54 (65%) patients on ponatinib mantain a MR3 or deeper response; 48 (89%) are taking 15 mg or lower. 

Conclusion

This analysis confirms the efficacy of de-escalated ponatinib dose in CML patients resistant to prior TKIs, with acceptable toxicity profile. Promising data on 15 mg as a starting dose in selected patients (intolerant or with low level resistance) warrant further investigation in larger prospective trials.

Session topic: 8. Chronic myeloid leukemia - Clinical

Keyword(s): Chronic myeloid leukemia, Dose intensity, Tyrosine kinase inhibitor

Abstract: PS1122

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background

The third generation tyrosine kinase inhibitor ponatinib is effective as salvage treatment  for chronic phase (CP) Ph+ chronic myeloid leukemia (CML) patients resistant or intolerant to prior TKIs. Considering the demonstrated impact of ponatinib dose on the incidence of cardiovascular adverse events, a dose reduction to 15 mg daily is recommended in CP after the achievement of treatment milestones. Lower than 45 mg ponatinib dose strategies are currently under investigation in prospective clinical trials. There is a strong interest on independent data describing the efficacy and the safety of 15 mg daily ponatinib.

Aims

Describe and  assess the efficacy and toxicity of low doses of ponatinib in CML-CP resistant or intolerant to previous TKIs.

Methods

A retrospective analysis of consecutive, CML-CP patients treated with ponatinib 15 mg as starting or de-escalated dose has been performed. No pre-specified criteria to switch to ponatinib or to reduce the dose were indicated.

Results

62 patients are included, 53% males. Median age at ponatinib start was 57 (28-87) years. The median time from CML diagnosis to ponatinib treatment was 53.2 months (4.8-230). ABL1 mutations were detected in 29.3% patients (being 41% of them positive for the T315I mutation). Roughly half of the patients (45%) received ponatinib as 4th or 5th line of treatment. Ponatinib was started at 45, 30 and 15 mg, in 24, 13 and 25 patients, respectively. Resistance to prior TKIs was the reason for switch in all patients treated with higher than 15 mg dose, while 12/25 patients starting with 15 mg were purely intolerant or intolerant and resistant. The median treatment duration at any dose was 21.2 months, with 45/62 (72%) patients exposed to ponatinib for more than 12 months. Overall, 68% of patients improved response status. In patients treated with 45 or 30 mg the CCyR, MR3 and MR4/MR4.5 rates were 76%, 55% and 32% respectively. Responses were achieved after a median of 3.5, 4.3 and 6.7 months, respectively. Dose reduction to 15 mg was decided after a median time of 10 months, mostly due to adverse events (73%) and less frequently, to prevent toxicity and/or following response attainment (27%). Median duration of treatment was 32.4 months, with a discontinuation rate of 5/37 (1 cerebrovascular accident, 2 severe hematologic toxicities, two cases of resistance/progression). Two deaths were registered (both in the 45 mg group), one after blast crisis and one for a fatal cardiovascular event. Focusing the 25 patients started with ponatinib 15 mg, median duration of treatment was 15 months (4.3-58.1). CCyR was obtained in 55% of patients lacking CCyR and MR3 in 50% without MMR with a median time of 3.8 and 3.4 months, respectively. During follow-up, MR3 or deeper responses were maintained or improved in 80% of cases, while 7 patients lost their best acquired response (4 MR4/4.5 to MR3, 1 MR3 to MR2, 1 CCyR to PHR and 1 progression to accelerated phase). Three patients of this group discontinued the treatment (1 coronary vasospasm-induced acute coronary syndrome, 2 muscle skeletal pain). After a median follow-up of 21 months, 35/54 (65%) patients on ponatinib mantain a MR3 or deeper response; 48 (89%) are taking 15 mg or lower. 

Conclusion

This analysis confirms the efficacy of de-escalated ponatinib dose in CML patients resistant to prior TKIs, with acceptable toxicity profile. Promising data on 15 mg as a starting dose in selected patients (intolerant or with low level resistance) warrant further investigation in larger prospective trials.

Session topic: 8. Chronic myeloid leukemia - Clinical

Keyword(s): Chronic myeloid leukemia, Dose intensity, Tyrosine kinase inhibitor

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