Cause of death in patients with newly diagnosed chronic lymphocytic leukemia (CLL) stratified by the CLL-International Prognostic Index

Wang, Yucai; Achenbach, Sara J.; Rabe, Kari G.; Shanafelt, Tait D.; Call, Timothy G.; Ding, Wei; Kenderian, Saad S.; Muchtar, Eli; Leis, José F.; Koehler, Amber B.; Schwager, Susan M.; Cerhan, James R.; Slager, Susan L.; Kay, Neil E.

doi:10.1038/s41408-021-00532-1

Cited by 7 publications

(4 citation statements)

References 8 publications

(8 reference statements)

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“…Rates of transformation to aggressive lymphomas were in keeping with other population data [8]. This data suggests that patients requiring treatment for CLL are more likely to die as a consequence of the disease itself or from complications of CLL-mediated immune suppression such as second cancers and infections, as suggested by Wang et al, where higher-risk patients have a 3-fold risk of dying from CLL and its complications [65]. Second malignancy rates with BTKi are an ongoing concern.…”

Section: Discussionsupporting

confidence: 78%

Clinical Outcomes in a Large Canadian Centralized CLL Clinic Based on Treatment and Molecular Factors over a Decade

Yang

Tordon

et al. 2023

Current Oncology

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FISH cytogenetics, TP53 sequencing, and IGHV mutational status are increasingly used as prognostic and predictive markers in chronic lymphocytic leukemia (CLL), particularly as components of the CLL International Prognostic Index (CLL-IPI) and in directing therapy with novel agents. However, testing outside of clinical trials is not routinely available in Canada. As a centralized CLL clinic at CancerCare Manitoba, we are the first Canadian province to evaluate clinical outcomes and survivorship over a long period of time, incorporating the impact of molecular testing and the CLL-IPI score. We performed a retrospective analysis on 1315 patients diagnosed between 1960 and 2018, followed over a 12-year period, where 411 patients had molecular testing and 233 patients had a known CLL-IPI score at the time of treatment. Overall, 40.3% (n = 530) of patients received treatment, and 47.5% (n = 252) of patients received multiple lines of therapy. High-risk FISH and CLL-IPI (4-10) were associated with higher mortality (HR 2.03, p = 0.001; HR 2.64, p = 0.002), consistent with other studies. Over time, there was an increase in the use of targeted agents in treated patients. The use of Bruton’s tyrosine kinase inhibitors improved survival in patients with unmutated IGHV and/or TP53 aberrations (HR 2.20, p = 0.001). The major cause of death in patients who received treatment was treatment/disease-related (32%, n = 42) and secondary malignancies (57%, n = 53) in those who were treatment-naïve. Our data demonstrate the importance of molecular testing in determining survivorship in CLL and underpinning the likely immune differences in outcomes for those treated for CLL.

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Section: Discussionsupporting

confidence: 78%

Clinical Outcomes in a Large Canadian Centralized CLL Clinic Based on Treatment and Molecular Factors over a Decade

Yang

Tordon

et al. 2023

Current Oncology

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“…In CLL, circulating malignant B cells deleteriously affect the T cell anti-tumor immunity [44,45]. CLL-associated mortalities are mainly due to disease progression, secondary solid malignancy, and/or infections [46] that are governed by the compromised immune system in predisposed patients [47,48]. T cell impairment/exhaustion is one aspect of the compromised anti-tumor immunity in CLL patients.…”

Section: Introductionmentioning

confidence: 99%

Depletion of polyfunctional CD26highCD8+ T cells repertoire in chronic lymphocytic leukemia

et al. 2023

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Background CD8+ T cells play an essential role against tumors but the role of human CD8+CD26+ T cell subset against tumors, in particular, haematological cancers such as chronic lymphocytic leukemia (CLL) remains unknown. Although CD4+CD26high T cells are considered for adoptive cancer immunotherapy, the role of CD8+CD26+ T cells is ill-defined. Therefore, further studies are required to better determine the role of CD8+CD26+ T cells in solid tumors and haematological cancers. Methods We studied 55 CLL and 44 age-sex-matched healthy controls (HCs). The expression of CD26 on different T cell subsets (e.g. naïve, memory, effector, and etc.) was analyzed. Also, functional properties of CD8+CD26+ and CD8+CD26− T cells were evaluated. Finally, the plasma cytokine/chemokine and Galectin-9 (Gal-9) levels were examined. Results CD26 expression identifies three CD8+ T cell subsets with distinct immunological properties. While CD26negCD8+ T cells are mainly transitional, effector memory and effectors, CD26lowCD8+ T cells are mainly naïve, stem cell, and central memory but CD26high T cells are differentiated to transitional and effector memory. CD26+CD8+ T cells are significantly reduced in CLL patients versus HCs. CD26high cells are enriched with Mucosal Associated Invariant T (MAIT) cells co-expressing CD161TVα7.2 and IL-18Rα. Also, CD26high cells have a rich chemokine receptor profile (e.g. CCR5 and CCR6), profound cytokine (TNF-α, IFN-γ, and IL-2), and cytolytic molecules (Granzyme B, K, and perforin) expression upon stimulation. CD26high and CD26low T cells exhibit significantly lower frequencies of CD160, 2B4, TIGIT, ICOS, CD39, and PD-1 but higher levels of CD27, CD28, and CD73 versus CD26neg cells. To understand the mechanism linked to CD26high depletion, we found that malignant B cells by shedding Galectin-9 (Gal-9) contribute to the elevation of plasma Gal-9 in CLL patients. In turn, Gal-9 and the inflammatory milieu (IL-18, IL-12, and IL-15) in CLL patients contribute to increased apoptosis of CD26high T cells. Conclusions Our results demonstrate that CD26+ T cells possess a natural polyfunctionality to traffic and exhibit effector functions and resist exhaustion. Therefore, they can be proposed for adoptive cancer immunotherapy. Finally, neutralizing and/or inhibiting Gal-9 may preserve CD26highCD8+ T cells in CLL.

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“…10 Similarly, in patients with CLL/SLL, deaths due to the underlying disease and disease-related complications are the principal CODs in the rituximab era. 11,12 Prospective data on cause-specific mortality are limited for other indolent B-cell lymphomas.…”

Section: Introductionmentioning

confidence: 99%

Causes of death in low-grade B-cell lymphomas in the rituximab era: a prospective cohort study

et al. 2022

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Low-grade B-cell lymphomas other than follicular and small lymphocytic lymphoma (LGBCL) account for 10% of all B-cell non-Hodgkin lymphomas. Despite improvements in survival outcomes for these patients, little is known about cause of death (COD) in the rituximab era. For a better understanding, we studied 822 newly diagnosed patients with marginal zone, lymphoplasmacytic, and unclassifiable low-grade B-cell lymphoma prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource from 2002-2015. COD was assigned based on medical record review using a standard protocol. At a median follow-up of 107 months, 219 (27%) patients had died. The incidence of lymphoma-related deaths when pooling across subtypes was lower than non-lymphoma related deaths (10-year incidence 8.0%, 95% CI: 6.2-10.4 vs 13.6%, 95% CI: 11.2-16.6). The incidence of lymphoma related deaths varied by subtype, ranging from 3.7% at 10 years in extranodal marginal zone lymphoma (EMZL) to 19.3% in lymphoplasmacytic lymphoma (LPL)/Waldenström Macroglobulinemia (WM). Patients with early progression or retreatment events, defined using event-free survival at 24 months from diagnosis (EFS24), had significantly higher likelihood of lymphoma related death compared to patients without early events (10-year estimate 19.1% vs 5.1% respectively, p<0.001), while the rates for non-lymphoma death were comparable in patients with or without early events (10-year estimates 11.0% vs 15.3%, respectively). In conclusions, the most common COD in LGBCLs in the first decade after diagnosis was for causes other than lymphoma. Progression or retreatment within the first 2 years of diagnosis was a strong predictor for risk of lymphoma-related death.

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Cause of death in patients with newly diagnosed chronic lymphocytic leukemia (CLL) stratified by the CLL-International Prognostic Index

Cited by 7 publications

References 8 publications

Clinical Outcomes in a Large Canadian Centralized CLL Clinic Based on Treatment and Molecular Factors over a Decade

Clinical Outcomes in a Large Canadian Centralized CLL Clinic Based on Treatment and Molecular Factors over a Decade

Depletion of polyfunctional CD26highCD8+ T cells repertoire in chronic lymphocytic leukemia

Causes of death in low-grade B-cell lymphomas in the rituximab era: a prospective cohort study

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