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995 FATE and Role of Peripheral Blood CD26+ Leukemia STEM CELLS at Diagnosis in Chronic Myeloid Leukemia Patients: FINAL Results of Prospective Flowers Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Alternative Laboratory Predictors of Outcome
Hematology Disease Topics & Pathways:
CML, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
Monday, December 9, 2024: 5:30 PM

Anna Sicuranza, PhD1*, Adele Santoni, MD2*, Paola Pacelli3*, Sara Freducci, MD4*, Emanuele Pacini5*, Elisabetta Abruzzese, MD6, Daniele Cattaneo7*, Alessandra Iurlo, MD, PhD8*, Luigiana Luciano, MD9, Sara Galimberti, MD10*, Valentina Giai, MD, PhD11*, Olga Mulas, MD12*, Giovanni Caocci, MD13, Federica Sorà14*, Isabella Capodanno, MD15*, Monica Crugnola, MD16*, Antonella Gozzini, MD17*, Sabina Russo, MD18*, Mario Annunziata, MD19,20*, Claudio Fozza, MD21*, Anna Marina Liberati, MD22, Alessandra Cartocci23*, Elisabetta Zappone24*, Emanuele Cencini, MD25*, Vincenzo Sammartano5*, Elena Bestoso26*, Cristina Marzano27*, Dania Tocci28*, Teresa Miracapillo4*, Camilla Turriziani28*, Donatella Raspadori24* and Monica Bocchia, MD29*

1Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy, Siena, Italy
2UOC Ematologia, Azienda ospedaliero-universitaria Senese, Siena, Italy
3Hematology Unit, Department of Medical Science, Surgery and Neuroscience, Univer, Siena, ITA
4Dept of Medical sciences, surgery and neurosciences., Hematoly Unit. University of Siena, Siena, Italy
5University of Siena, Siena, Italy
6Department of Hematology, S. Eugenio Hospital, Tor Vergata University, ASL Roma 2, Roma, I, Italy
7FONDAZIONE IRCCS CA' GRANDA OSPEDALE MAGGIORE POLICLINICO, MILANO, ITA
8Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
9Hematology Unit, Federico II University, Napoli, Italy
10Department of Clinical and Experimental Medicine, Hematology, University of Pisa, Pisa, Italy
11Hematology, AOU Città della Salute e della Scienza di Torino, Turin, Italy
12Department of Medical Sciences and Public Health, University of Cagliari, Businco Hospital, Cagliari, Italy
13University of Cagliari, Monserrato, Italy
14Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
15Hematology Unit, Azienda Unità Sanitaria Locale-IRCCS, Reggio Emilia, Italy
16Hematology Unit and BMT, University Hospital of Parma, Parma, Italy
17Hematology, AOU Careggi, University of Florence, Florence, Italy
18Division of Hematology, Dipartimento di Patologia Umana dell'Adulto e dell'Età Evolutiva,, Hematology Section, AOU Policlinico "G Martino", University of Messina, Italy, Messina, Italy
19Azienda Ospedaliera Di Rilievo Nazionale Antonio Cardarelli, Napoli, ITA
20Hematology, San Giuseppe Moscati Hospital, Aversa, Italy
21Hematology Unit – Azienda Ospedaliera Universitaria of Sassari, University of Sassari, Sassari, Italy
22A.O. Santa Maria di Terni – Università degli Studi di Perugia, Terni–Perugia, Italy
23Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, ITA
24Hematology Unit, Azienda Ospedaliera Universitaria Senese, Siena, ITA
25Division of Hematology, Azienda Ospedaliera Universitaria Senese & University of Siena, Siena, Italy
26Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy, Siena, Italy
27University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, ITA
28Dept of Medical sciences, surgery and neurosciences., Hematoly Unit. University of Siena, Siena, Italy
29Hematology, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy

Background: In a cross-sectional study we previously demonstrated that in peripheral blood (PB) of chronic myeloid leukemia (CML) patients leukemia stem cells (LSCs) CD26+ are detectable by flow-cytometry at diagnosis, during TKI therapy and during treatment free remission (TFR). No prospective data are available regarding the behavior of PB CD26+LSCs from diagnosis and the correlation, if any, between the bulk of this staminal compartment at diagnosis with the attainment of molecular response.

Methods: We here present final results of a prospective Italian multicenter study including newly diagnosed chronic phase (CP) CML patients centrally monitored by flow-cytometry for PB CD26+LSCs quantification from diagnosis up to 24 months of TKI treatment.

Results: 242 consecutive CP-CML patients were enrolled (132 imatinib, 72 nilotinib and 38 dasatinib). The bulk of CD26+LSCs at diagnosis varied between patients with a median value of 7,1454 cells/µl (range 0,0126-698,746 cells/µl; IQR 2,18-33,26 cells/µl). During TKI treatment, we observed a consistent and rapid reduction of them achieving median values of 0,0132 cells/µl (IQR 0-0,034 cells/µl), 0,011 cells/µl (IQR 0-0,031 cells/µl) and 0,0071 cells/µl (IQR 0-0,0259 cells/µl) at 3, 12 and 24 months, respectively. No statistically significant differences in terms of CD26+LSCs log-reduction were noted according to the type of TKI treatment at any time points evaluated. However, a significant correlation between a low amount of CD26+LSCs at diagnosis and an optimal molecular response at 3, 12 and 24 months (BCR::ABL1<10% and BCR::ABL1<0.1%, respectively) was documented. Indeed, CML patients with optimal molecular response at 3 months had a median CD26+LSCs of 6,21 cells/µl (IQR 1,79-31,50 cells/µl) while suboptimal responders patients showed a median of 19,87 cells/µl (IQR 5,37-39,81 cells/µl) (p=0.03); moreover, patients with BCR::ABL1<0.1% at 12 and 24 months, revealed median CD26+LSCs at diagnosis of 5,50 cells/µl (IQR 1,81-22,64 cells/µl) and 6,05 cells/µl (IQR 1,79-29,90 cells/µl) respectively, compared to suboptimal responders showing 16,87 cells/µl (IQR 2,82 -71,77) and 20,52 cells/µl (IQR 4,24-106,91) (p=0.004, p=0.009). Additionally, evaluating the cohort of CML patients who switched TKI treatment after failure with respect to patients who did not change TKI, we observed that the former had a significantly higher median CD26+LSCs at diagnosis (14,59 cells/µl; IQR: 3,76-46,00 cells/µl) compared to the no-switch group (median of 5,82 cells/µl; IQR: 2,35-26,70 cells/µl) (p=0.034). Three ranges of CD26+LSCs correlating to molecular response were identified: <3,21 cells/µl (1° tertile); between 3,21-19,21 cells/µl (2° tertile); >19,21 cells/µl (3° tertile). In particular, considering the molecular response at 3 months the incidence of CML patients with BCR::ABL1<10% was 93.5% in the first CD26+LSCs tertile, while 78.8% in the third tertile (p=0.027). At 12 months the incidence of optimal response in the first tertile was 78.5% and 62.8% in the third one (p=0.015). At 24 months the two incidences were 90.8% and 77.9%, respectively (p=0.079).

Conclusions: This prospective study demonstrated a rapid rate of reduction of CD26+LSCs during TKI treatment, however confirming their long-lasting persistence even if at very low levels. For the first time, a correlation between the amount of CD26+LSCs at diagnosis and the response to TKI treatment, was documented. Given these results, the bulk of CD26+ LSCs at diagnosis could represent an easily and rapidly measurable, new prognostic tool for predicting TKI response.

Disclosures: Abruzzese: Novartis: Consultancy; Ascentage: Consultancy; MorphoSys: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; BMS: Consultancy. Iurlo: Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; GSK: Consultancy, Honoraria; BMS: Consultancy, Honoraria; AOP: Consultancy, Honoraria. Galimberti: Celgene: Honoraria; Roche: Honoraria, Other: support for attending meetings; Incyte: Honoraria; Novartis: Honoraria, Other: support for attending meetings; Jazz: Honoraria, Other: support for attending meetings; AstraZeneca: Honoraria, Other: support for attending meetings; AbbVie: Honoraria, Other: support for attending meetings; Pfizer: Honoraria; Janssen: Honoraria. Giai: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mulas: Novartis: Speakers Bureau. Crugnola: BMS: Speakers Bureau; Novartis: Speakers Bureau. Fozza: Soby: Consultancy; Amgen: Research Funding; BMS: Research Funding; Sanofi: Research Funding. Liberati: Bristol Myers Squibb: Honoraria, Other: Support for travel, Research Funding; BeiGene: Research Funding; LoxoOncology: Research Funding; Dr. Reddy's Lab.: Research Funding; Fibrogen: Research Funding; Archigen: Research Funding; Onconova: Research Funding; Karyopharm: Research Funding; Oncopeptides: Research Funding; GlaxoSmithKline: Research Funding; Morphosys: Research Funding; Novartis: Other: Support for travel, Research Funding; Verastem: Other: Support for travel, Research Funding; Sanofi: Other: Support for travel, Research Funding; Janssen: Honoraria, Other: Support for travel, Research Funding; Millennium: Research Funding; AbbVie: Honoraria, Other: Support for travel, Research Funding; Celgene: Honoraria, Other: Support for travel, Research Funding; Roche: Other: Support for travel, Research Funding; Takeda: Other: Support for travel, Research Funding; PSI: Research Funding; IQVIA: Honoraria, Other: Support for travel; Incyte: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Bocchia: Novartis: Honoraria, Other: travel grant; Incyte: Honoraria, Other: travel grant; Abbvie: Honoraria, Other: travel grants.

*signifies non-member of ASH