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Am J Hematol. 2015 Oct;90(10):910-4. doi: 10.1002/ajh.24120. Epub 2015 Sep 10.

Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study.

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Department of Health Sciences, University Of Milano-Bicocca, Monza, Italy.
Department of Haematology And Oncology, Charité - Humboldt-Universität, Campus Virchow, Berlin, Germany.
Department of Haematology, S. Eugenio Hospital, Tor Vergata University, Roma, Italy.
Department of Haematology, Bianchi Melacrino Morelli Hospital, Reggio Calabria, Italy.
Department of Haematology, Niguarda Ca' Granda Hospital, Milano, Italy.
Department of Molecular Medicine, University of Pavia, Pavia, Italy and Department of Haematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Haematology Clinic, IRCSS AOU S. Martino-IST, University Of Genova, Genova, Italy.
Division of Haematology, Jewish General Hospital, McGill University, Montreal, QC, Canada.
Haematology, San Bortolo Hospital, Vicenza, Italy.
Haematology, AOU Careggi, University Of Firenze, Firenze, Italy.
Haematology, Hospital Universitario Miguel Servet, Zaragoza, Spain.
Haematology, University Of Catania, Catania, Italy.
Oncohaematology Division, IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, University Of Milano, Milano, Italy.
Haematology Department, Cancer Research Institute, The Catholic University Of Korea, Seoul, South Korea.
Clioss S.R.L., Nerviano (MI), Italy.
Clinical Research Unit, Haematology, San Gerardo Hospital, Monza, Italy.


Imatinib is effective for the treatment of chronic myeloid leukemia (CML). However even undetectable BCR-ABL1 by Q-RT-PCR does not equate to eradication of the disease. Digital-PCR (dPCR), able to detect 1 BCR-ABL1 positive cell out of 10(7) , has been recently developed. The ISAV study is a multicentre trial aimed at validating dPCR to predict relapses after imatinib discontinuation in CML patients with undetectable Q-RT-PCR. CML patients under imatinib therapy since more than 2 years and with undetectable PCR for at least 18 months were eligible. Patients were monitored by standard Q-RT-PCR for 36 months. Patients losing molecular remission (two consecutive positive Q-RT-PCR with at least 1 BCR-ABL1/ABL1 value above 0.1%) resumed imatinib. The study enrolled 112 patients, with a median follow-up of 21.6 months. Fifty-two of the 108 evaluable patients (48.1%), relapsed; 73.1% relapsed in the first 9 months but 14 late relapses were observed between 10 and 22 months. Among the 56 not-relapsed patients, 40 (37.0% of total) regained Q-RT-PCR positivity but never lost MMR. dPCR results showed a significant negative predictive value ratio of 1.115 [95% CI: 1.013-1.227]. An inverse relationship between patients age and risk of relapse was evident: 95% of patients <45 years relapsed versus 42% in the class ≥45 to <65 years and 33% of patients ≥65 years [P(χ(2) ) < 0.0001]. Relapse rates ranged between 100% (<45 years, dPCR+) and 36% (>45 years, dPCR-). Imatinib can be safely discontinued in the setting of continued PCR negativity; age and dPCR results can predict relapse.

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