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993 Increased Inflammatory Cytokines in Plasma Are Associated with Sustained Treatment-Free Remission in Chronic Myeloid Leukaemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Alternative Laboratory Predictors of Outcome
Hematology Disease Topics & Pathways:
Research, Adult, Translational Research, Clinical Research, Health outcomes research, CML, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies, Human
Monday, December 9, 2024: 5:00 PM

Chung Hoow Kok, PhD, BSc1,2,3, Verity A Saunders4*, Naranie Shanmuganathan, MBBS, PhD, FRACP, FRCPA5,6,7,8,9,10, Liu Liu11*, Yazad Daruis Irani, BSc, MSc, PhD11,12*, Jade Clarson11*, Phuong Dang4*, David T Yeung, MBBS, PhD, BSc, FRACP, FRCPA13,14,15,16, Agnes S. M. Yong, MD, PhD5,17, Susan Branford, PhD8,18,19, Javier Pinilla-Ibarz, MD, PhD20, Richard A. Larson, MD21, Jorge E. Cortes, MD22, Michael J. Mauro, MD23, James E Thompson, MD24, Neil P. Shah, MD, PhD25, Martha Wadleigh, MD26, Ehab L. Atallah, MD27, Jerald P. Radich, MD28, Timothy P Hughes, MD, MBBS, FRACP, FRCPA13,15,29,30 and David M Ross, MD, PhD, FRACP, FRCPA5,16,31,32,33*

1Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia
2Centre for Cancer Biology and SA Pathology, Adelaide, Australia
3Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia
4Precision Cancer Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia
5South Australian Health and Medical Research Institute, Adelaide, Australia
6Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia
7School of Medicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia
8School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia
9Department of Haematology, Central Adelaide Local Health Network, Adelaide, SA, Australia
10Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia
11Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia
12Department of Anatomical Pathology, Flinders University, Adelaide, Australia
13South Australian Health and Medical Research Institute, Adelaide, SA, Australia
14University of Adelaide, Adelaide, SA, Australia
15Australasian Leukaemia and Lymphoma Group (ALLG), Melbourne, Australia
16Royal Adelaide Hospital, Adelaide, SA, Australia
17Haematology Department, Royal Perth Hospital, Perth, Australia
18SA Pathology, Adelaide, SA, Australia
19Centre for Cancer Biology, Adelaide, Australia
20Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
21Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
22Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
23Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center, New York, NY
24Leukemia Service, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
25University of California San Francisco, San Francisco, CA
26Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
27Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI
28Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Rsch. Ctr., Seattle, WA
29Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
30Department of Haematology and Bone Marrow Transplantation, Royal Adelaide Hospital, Adelaide, Australia
31Royal Adelaide Hospital and SA Pathology, Adelaide, SA, Australia
32Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia
33Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia

Background: The immune status at the time of tyrosine kinase inhibitor (TKI) cessation may play a critical role in achieving sustained treatment-free remission (TFR) in chronic myeloid leukaemia (CML). Cytokine profiles may provide a measure of host immune activation against residual leukaemia.

Aim: To investigate the expression of plasma cytokines at the time of TKI cessation (TOC) and assess their predictive significance for sustained TFR in two TFR cohorts from Australia (AU) and US.

Methods: Blood was collected from 113 CML patients (pts) at TOC from an AU discovery cohort, 72 pts in the LAST study (US) as an independent validation cohort, and 20 healthy donors. The levels of 38 cytokines, chemokines and growth factors were measured in plasma samples using a MILLIPLEX Human Cytokine & Chemokine 38-plex panel and a Luminex 200 instrument. All samples were measured in duplicate and averaged. Unsupervised analysis was performed using t-Distributed Stochastic Neighbour Embedding. Multivariable model was performed with Cox proportional hazards regression. Hazard ratios (HR) and 95% confidence interval (CI) were reported for covariates, along with P values from the Wald test. All statistical analyses were conducted using the R v.4.1.1 and Prism GraphPad v9.

Results: In the AU cohort most pts were treated with imatinib (51%), followed by nilotinib (31%) and dasatinib (17%) prior to TOC. The median duration of TKI and MR4 was 6 years (range 4.3-10) and 4 years (range 3.2-6.5), respectively. Median follow-up after TKI cessation was 24.2 months (mths; range 20.7-26.8). The probability of sustained MMR after TKI cessation at 12 and 36 mths was 54% (95% CI 46-64%) and 47.6% (95% CI 36-62%), respectively.

We used an unsupervised analysis to group samples based on the similarity of their 38 cytokine expression profiles. Two distinct clusters in the AU samples were identified. Cluster 1 (n=62) had lower global 38-cytokines expression compared to cluster 2 (n=51, median 84 vs 104 pg/mL, p<0.001). Herein, we defined cluster 1 as a “cold” cluster and cluster 2 as “hot”. This dichotomy of cytokine expression was also seen in 20 healthy controls in similar proportions. 11 pts had pre-TOC and TOC matched samples several weeks apart. Only 1 pt (9%) had a different cytokine cluster profile between timepoints suggesting that the cluster category was generally stable for each pt in the short term.

At 12 mths, the hot cluster pts had a higher probability of sustained MMR (73%) compared to the cold cluster (39%, p<0.001). This difference was more pronounced at 36 mths, with the hot cluster group maintaining a sustained MMR rate of 73%, compared to 18% in the cold cluster (p=0.000035). We did not identify statistically significant differences in sex (p=0.92), age (p=0.12), MR4 duration (p=0.45), BCR::ABL1 transcript types (p=0.46), initial BCR::ABL1 halving time (HT, p=0.26), TKI type prior to TOC (p=0.48), or TKI duration (p=0.77) between hot and cold clusters. Multivariable analysis showed that cytokine expression clusters (HR 2.7; p=0.007), HT (HR 2.5; p=0.007) and BCR::ABL1 transcript type (HR 2.1; p=0.02) were independent predictors of TFR.

The US LAST cohort (n=72; 50% TFR at 12 mths) was used as an independent validation cohort. We identified hot and cold clusters in this cohort using the same criteria. At 12 mths, the hot cluster group (n=21) had a higher probability of sustained MMR (76%) compared to the cold cluster group (39%, n=51, p=0.0095). The hot:cold cytokine cluster sample ratio was 1:2.4 for the US cohort, and 1:1.2 for the AU cohort.

We identified 6 cytokines (IL-15, TNFb, IL-13, IL-6, IL-1a and G-CSF) as the most discriminating to define hot and cold clusters. The expression levels of all six cytokines were higher in the hot cluster compared to the cold cluster. Using this restricted set of predominantly inflammatory cytokines, at 12 mths the hot cluster pts had a higher probability of sustained MMR compared to the cold cluster both in AU (69% vs 43%, p=0.008) and US (75% vs 40%, p=0.017) cohorts.

Conclusion: Pts with higher levels of inflammatory cytokine expression have higher rates of sustained TFR. We postulate that the two distinct clusters of cytokine expression at the TOC reflect distinct states of immune activation. These findings support the development of predictive cytokine-based biomarkers to guide TFR treatment strategies and further support the case for immune activation as a strategy to enhance TFR outcomes for CML pts.

Disclosures: Shanmuganathan: Enliven: Other: travel support; Novartis: Honoraria, Other: travel support, Research Funding; Janssen: Honoraria, Other: travel support; Takeda: Honoraria. Yeung: BMS: Research Funding; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Takeda: Honoraria; Ascentage: Honoraria. Yong: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Celgene: Research Funding. Branford: Novartis: Honoraria, Research Funding, Speakers Bureau; Cepheid: Research Funding; Terns Pharmaceuticals: Research Funding. Pinilla-Ibarz: Eli Lily: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Bristol Meyers Squibb: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Novartis: Honoraria; Secura Bio: Consultancy, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy, Speakers Bureau. Larson: UpToDate: Patents & Royalties: royalties; Astellas, Celgene, Cellectis, Daiichi Sankyo, Forty Seven/Gilead, Novartis, and Rafael Pharmaceuticals: Research Funding; AbbVie, Amgen, Ariad/Takeda, Astellas, Celgene/BMS, Curis, CVS/Caremark, Epizyme, Immunogen, Jazz Pharmaceuticals, Kling Biotherapeutics, MedPace, MorphoSys, Novartis, and Servier: Honoraria. Cortes: Syndax: Consultancy; Nerviano: Consultancy; Sun Pharma: Consultancy, Research Funding; Lilly: Consultancy; Biopath Holdings: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy; AbbVie: Research Funding; Pfizer: Consultancy; Ascentage: Research Funding; Novartis: Consultancy, Research Funding. Mauro: Takeda: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Sun Pharma/SPARC: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Shah: Novartis: Honoraria; Bristol-Myers Squibb: Research Funding. Atallah: Novartis Pharmaceuticals Corporation: Honoraria. Radich: ThermoFisher: Honoraria. Hughes: Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Ross: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Keros: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH