Ricerca Progetti nazionali, regionali, internazionaliStemCMLcure

The achievable cure in Chronic Myeloid Leukemia: unravelling CD26+ leukemia stem cell features to enable safe tyrosine kinase inhibitor discontinuation

Following treatment of Chronic Myeloid Leukemia (CML) with tyrosine kinase inhibitors (TKIs) active against the BCR ABL1 oncogenetic protein, responsible for the disease, between 10 to 40% of patients achieve a deep molecular response (DMR), which allows them to attempt to discontinue therapy.

However, after treatment withdrawal, only half of DMR patients remain stably in treatment free remission (TFR), which means that only about 20% of CML patients overall can discontinue TKI treatment (after 5 years on average) without recurrence of disease. Albeit this result is extraordinary considering the fatal natural course of CML, the life long treatment of the remnant 80% of patients is a heavy burden for both patients (due to side effects of treatment) and health care system (due to the drug price).

In CML patients, residual disease during TFR is represented by TKI insensitive leukemia stem cells (LSCs). We and others showed that CD26+ is a CML specific LSC marker, and we recently demonstrated that CD26+LSCs circulate in peripheral blood (PB) at diagnosis and can be detected in patients in DMR and even during stable TFR, being therefore unrelated to BCR ABL1 mRNA load. As DMR is not per se warranty of TFR, to unravel inmost characteristics of LSC reservoir could provide crucial information to select patients suitable for treatment discontinuation irrespective of treatment duration or grade of molecular response achieved. This project involves 3 hematology laboratories in Tuscany with long experience in CML research, integrated with 3 other clinical hematology centers contributing significantly to the accrual of CML patients. This task force will focus on the characterization of CD26+LSCs, as for: 1) proliferative properties (expression of Ki67 antigen and BMI1 gene); 2) capacity to survive in the low oxygen hematopoietic environment; 3) interaction with the immune system (expression of PD L1 antigen on LSCs, presence of PD L1 polymorphisms and serum level of Torquetenovirus as surrogate of patient’s immune competence). Newly diagnosed patients will be studied at baseline and after 3, 6 and 12 months of TKI treatment. Patients on TKI treatment meeting the current criteria for TKI discontinuation will be evaluated just before discontinuation and at the time of TFR failure, if any (BCR ABL1/ABL1 ratio >0.1% IS). Results will be correlated to the response to TKI at 3, 6, and 12 months and to the achievement of DMR (newly diagnosed patients) or to the outcome of TKI discontinuation (patients on treatment).

The main goal of the project is to shape the phenotype of CD26+LSCs to reveal features linked to a better or worse CML outcome, with a dual intent: 1) to increase the number of patients in which treatment can be safely discontinued, with advantages in terms of patient care and health system sustainability, and 2) to identify up front those patients in which treatment must be continued indefinitely, and then to select the best tolerated/less costly TKI.

 

Responsabile: Elisabetta Rovida

Data inizio: 03.08.20

Data conclusione: 02.05.24

CUP n. I74I18000180002

Progetto finanziato dalla Regione Toscana nell'ambito del Bando regionale Ricerca Salute 2018

 

COSTO COMPLESSIVO	CONTRIBUTO REGIONE	BENEFICIARI	PARTNER	COSTO COMPLESSIVO PER PARTNER	CONTRIBUTO REGIONE PER PARTNER
350.000,00	280.000,00	AOU SENESE	capofila	130.000,00	104.000,00
		AOU PISANA	partner	120.000,00	96.000,00
		Università degli studi di Firenze	partner	100.000,00	80.000,00