Novel Prognostic Markers in Previously Treated Chronic Lymphocytic Leukemia
Authors: Pabon Cindy M , Brander Danielle M. , Stewart Tiffany , Weinberg J. Brice 
Published: November 2021

Abstract
Background: We need new biomarkers that manage CLL patients receiving novel chemotherapeutic agent treatments. In our earlier pilot study, we reported an association of inferior outcomes in those with higher IgM density, or those with IgG isotype expression, not explained by traditional markers such as unmutated IGHV or TP53 aberrations (Brander, et al., ASH abstract 118, 2011). The International Prognostic Index for CLL (CLL-IPI) was developed to provide CLL risk stratification, but this tool was largely studied in those treated conventionally (Lancet Oncol 17:779-790, 2016). Here we report studies of CLL cell IgM expression and outcomes in CLL patients treated with novel agents. We hypothesized that high IgM expression is associated with poor progression free survival (PFS) in patients treated with novel agents.
Methods: We studied samples from 906 Duke University CLL patients. Fifty seven of 906 patients had received ibrutinib, acalabrutinib, and/or venetoclax. We classified CLL cell IgM expression surface isotype as low (&lt;30%), moderate (31-60%), or high (&gt;60%), and noted presence of class switching to IgG. We collected the following: social and geographical demographics, IGHV mutation status, CLL-IPI score, Rai staging, beta-2-microglobulin, FISH, cytogenetics, and treatment response per iwCLL definitions. PFS was defined as time from initiation of treatment with novel agents to progression of disease or death.
Results: Of 57 CLL patients, 42 were alive at the time of followup. Median time for followup was 62 months for patients on BTK-inhibitors and 32 months for those on the Bcl-inhibitor venetoclax. Social demographics were similar across all treatment groups. Deaths were noted in each group (2/7 acalabrutinib, 13/45 ibrutinib, 6/13 venetoclax), with progression of disease as the leading cause. Many patients were not treatment naïve before starting novel agents. Specifically, 14/19 patients most recently on venetoclax had been exposed to a novel inhibitor. PFS did not correlate with surface IgM expression and outcomes for those treated with BTK inhibitors or venetoclax. Previously, approximately 25% of CLL patients with TP53 mut/del17p relapsed within 24 months of initiating traditional chemoimmunotherapeutics. Our TP53 mut/del17p group treated with BTK inhibitors had improved PFS (p=0.005) (Figure 1). Similarly, by univariate cox regression, we found statistically significant PFS in patients with high risk mutations treated with BTK inhibitors (p=0.042). There was no statistically significant correlation between CLL-IPI score and PFS, nor high IgM expression density and PFS for those treated with BTK inhibitors.
Conclusions: We hypothesized that higher IgM expression density is associated with reduced PFS in patients treated with the novel agents. This was not identified in our study of 57 patients who had been treated with ibrutinib, acalabrutinib, or venetoclax. There was significantly shorter PFS for patients treated with BTK-inhibitors and TP53 mutand/or del17p compared to those without these genomic changes (p=0.005). This is consistent with prior studies. Historically, approximately 25% of CLL patients with TP53 mut/del17p relapsed within 24 months of initiating traditional chemoimmunotherapeutic agents. Our TP53 mut/del17p group treated with BTK inhibitors had improved PFS compared to the historical outcomes with a PFS of 66.5 months despite being a relapsed/refractory group. Our data supports prior studies identifying this as a high-risk subgroup of patients in need of investigational agent treatments (Catherwood MA, et al, J Clin Pathol, 72:343-346, 2019; and Gordon MJ, et al. Clin Cancer Res, In press, 2021). While the CLL-IPI score generally helps with prognostication of CLL patients, it was not significantly superior in our analyses in these patients. Other retrospective studies have also identified the limitations of the CLL-IPI score in the era of novel agents. Our work is limited by a small sample size of patients treated with the novel agents and by the retrospective nature of the study. With larger cohorts and longer followup, our future prospective studies will help clarify the role of surface immunoglobulin expression relative to CLL biology, and patient outcomes while receiving novel treatments.
Figure 1 Figure 1.

Disclosures
Brander: BeiGene: Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; AstraZeneca: Research Funding; Verastem: Consultancy; Genentech: Consultancy, Research Funding; ArQule: Research Funding; Ascentage: Research Funding; DTRM: Research Funding; ArQule/Merck: Consultancy; LOXO: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; NCCN: Other: panel member.