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1479 Pro-Inflammatory and Pro-Oxidative Changes during Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study)

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Diseases, Adverse Events, Biological Processes, Pathogenesis, Myeloid Malignancies
Saturday, December 11, 2021, 5:30 PM-7:30 PM

Anna Sicuranza, PhD1*, Ilaria Ferrigno, PhD1*, Elisabetta Abruzzese, MD2, Alessandra Iurlo, MD, PhD3*, Sara Galimberti4*, Antonella Gozzini, MD5*, Luigiana Luciano, MD6, Fabio Stagno, MD, PhD7, Antonella Russo Rossi8*, Nicola Sgherza, MD9*, Daniele Cattaneo10*, Corrado Zuanelli Brambilla, MD1*, Cristina Marzano1*, Carmen Fava, M.D.11, Olga Mulas12*, Emanuele Cencini, MD13*, Alessandro Gozzetti14*, Luca Puccetti15* and Monica Bocchia15*

1Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy
2Hematology, S. Eugenio Hospital, Tor Vergata University, Rome, Italy
3Hematology Division, Foundation IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano, Italy
4Department of Clinical and Experimental Medicine, Hematology, University of Pisa, Pisa, Italy
5Hematology, AOU Careggi, University of Firenze, Florence, Italy
6Hematology Unit, Federico II University of Naples, Napoli, Italy
7Hematology Unit, AOU Policlinico “Rodolico – San Marco” Rodolico Hospital, Catania, Catania, Italy
8Hematology, University of Bari, Bari, Italy
9Hematology and Stem Cell Transplantation Unit, AOUC Policlinico, Bari, Italy, Bari, ITA
11Hematology Division, Ospedale Mauriziano, University of Turin, Torino, Italy
12Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
13Division of Hematology, Azienda Ospedaliera Universitaria Senese and University of Siena, Siena, Italy
14Hematology Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy
15Hematology, Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy

Background: Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, during treatment with nilotinib, a higher than expected incidence of arterial occlusive events (AOEs) was observed. We retrospectively showed an “inflammatory status” during nilotinib treatment that may explain this increased incidence of AOEs. Here, we report results of a prospective multicenter (KIARO) study including 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib) in which pro/anti-inflammatory cytokines were measured at diagnosis and during treatment, with the aim to investigate potential changes in each patient’s inflammatory status possibly favoring AOEs.

Aims: The aims of this study are: 1) to analyze prospectively inflammation status during TKI treatment; 2) to record AOEs; 3) to calculate the SCORE and evaluate its predictive role for AOEs; 4) to analyze possible associations of AOEs with altered inflammation status.

Methods: Inflammatory status was evaluated by measuring IL6, IL10, TNFα, oxLDL and hs-CRP plasma levels at diagnosis and during treatment (+1, +3, +6, +12 months); additionally, clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated.

Results: 186 newly-diagnosed CML patients starting either imatinib, nilotinib or dasatinib treatment, entered this study. Regarding the inflammation status, we observed that TNFα and IL6 levels were high at diagnosis and decreased during the first 12 months of treatment regardless the type of TKI; instead, IL10 levels were comparable among the 3 TKI cohorts at baseline, but showed a remarkably different evolution during treatment. In fact, IL10 levels were significantly higher after 6 and 12 months of imatinib (p=0.012 and p=0.009, respectively) and dasatinib (p=0.032 and p=0.014, respectively) compared to nilotinib. Consequently, TNFα/IL10 ratio was significantly higher in nilotinib cohort at 6 and 12 months respect to imatinib (p=0.044 at 6 months and p=0.041 at 12 months) and dasatinib (p=0.040 at 6 months and p=0.044 at 12 months). As well, IL6/IL10 ratio was significantly higher in nilotinib cohort compared to imatinib and dasatinib both at 6 (p=0.042 and p=0.049, respectively) and 12 months (p=0.040 and p=0.041, respectively) (Figure 1). OxLDL levels were similar in the 3 groups for the first 6 months. At 12 months we detected a significant increase of oxLDL levels in the nilotinib cohort (p=0.041), respect to imatinib and dasatinib. We did not find significant differences in hs-CRP levels across the 3 TKIs, although a trend for higher levels was observed in nilotinib cohort. Overall, these results suggest a TKI-driven pro-inflammatory status in nilotinib treated patients.

After a median follow-up of 23.3 months of TKI treatment, 10 patients (5.4%) suffered an AOE, specifically: 6 ACS, 2 PAOD, 1 TIA and 1 stroke. 5 events (50%) occurred in patients treated with nilotinib, either in first line (4 patients) or in third line (1 patient, after failure following brief treatment with imatinib and dasatinib). In this subgroup of 10 patients experiencing an AOE, we observed a trend of increased IL6 and TNFα median values both at diagnosis and at each time point, compared with the remaining no-AOE patients. IL10 and oxLDL had similar median concentrations in both AOE and no-AOE cohorts, except for oxLDL at 12 months which resulted higher in patients who experienced AOEs. Moreover, regarding AOEs, nilotinib treatment showed a 3.1 times increased risk compared to other TKIs (HR 3.1, 95% CI 2.6-4.4 p< 0.001), whereas 10-year SCORE was not predictive in the whole cohort (HR 0.6, 95% CI 0.33-0.94 p= 0.094) or in any subgroup (imatinib HR 0.8, 95% CI 0.49-1.03 p= 0.067; nilotinib HR 0.4, 95% CI 0.29-0.76 p= 0.112, dasatinib HR 0.6, 95% CI 0.37-0.92 p= 0.082).

Conclusions: Our results showed a pro-inflammatory/oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher IL6/IL10 and TNFα/IL10 ratios, higher levels of oxLDL and a trend for higher hs-CRP only in nilotinib cohort. However, due to the low number of observed events, a formal statistical analysis for any association between AOEs and pro/anti-inflammatory cytokines levels was not possible. Therefore, a longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis.

Disclosures: Abruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding.

*signifies non-member of ASH