Large Granular Lymphocytic Leukemia Coexists with Clonal Hematopoiesis of Indeterminate Potential
Authors: Durrani Jibran , Awada Hassan , Kishtagari Ashwin , Kerr Cassandra M , Adema Vera , Nagata Yasunobu , Kuzmanovic Teodora , Hong Sanghee , Kongkiatkamon Sunisa , Lichtin, MD Alan , Nazha Aziz , Patel Bhumika J. , Saunthararajah Yogenthiran , Carraway Hetty E. , Visconte Valeria , Sekeres Mikkael A. , Maciejewski Jaroslaw P. 
Published: November 2019

Large granular lymphocytic leukemia (LGL) is a lymphoproliferative cytotoxic T cell (CTL) that typically presents in elderly population. The spectrum of the disease ranges from semi-reactive oligoclonal to clonal CTL expansion, and from silent to a chronic leukemia with para-neoplastic manifestation. However the description of the disease still preceded the new genetic landscape mapping techniques. In lieu of this, we analyzed the genetic landscape of LGL using a set of 33 genes. Interestingly, not only did the deeper analysis help with a better understanding of the complex CTL proliferative processes but indicated a suspected association with conditions such as clonal hematopoiesis of indeterminate potential (CHIP). Association of LGL with age related CH has been described in the past by us and others. Our results indicate that LGL is often associated with the presence of myeloid mutations, generally consistent with the most common typical CHIP mutations (DNMT3A, TET2, ASXL1). We then analyzed a set of 13 patients with coexistent MDS/LGL. This observation raises the question that LGL is, at least in some cases, a tumor surveillance response. All LGL patients were diagnosed using a stringent single center diagnostic criteria and at the time of diagnosis, were also checked for other conditions including MDS to prevent any risks of overlooked diagnoses. A previously well described diagnostic standard of >3/5 positive criteria was used; (i) presence of large granular lymphocytes (>500/μL, by differential counts from complete blood count) for >6 months; (ii) abnormal cytotoxic T lymphocytes expressing CD2, CD56 and CD57 and lacking CD28; (iii) preferential usage of a TCR Vβ family by flow cytometry; and (iv) TCR gene rearrangement by PCR; (v) bone marrow infiltration with LGL is another diagnostic criterion but a designated marrow biopsy is often not performed in clear LGL which are otherwise asymptomatic.
Coexistent presence of MDS and LGL was confirmed in 13/240 (5%) of the patients. These patients displayed typical features of MDS including abnormal cytogenetics (8/13), dysmorphia of myeloid cells in the bone marrow (13/13), ringed sideroblasts (1/13) and the presence of highly clonal somatic myeloid mutations (8/13) with an average VAF of 28+3%. When compared to LGL only, the MDS/LGL series had 15% vs. 39% (P=0.014) STAT3/5b mutations. We detected the presence of mutant myeloid clones in 25% (41/161) of the patients with pure LGL with an average VAF of 35+ 2%. Suspecting that these mutations may be present early in MDS and CHIP, we compared the mutational spectrum of LGL against MDS (n=835) and CHIP. Indeed, an overlap between the typical CHIP mutations was noted with LGL; in addition the clonal burden in CHIP was observed to be lower, 13% vs. 33% in LGL indicating a more advanced myeloid disease in LGL. This could be due to overlapping demographics or through a common pathophysiologic link. Spliceosomal mutations, cohesion complex, PRC2 and RAS mutations were overrepresented in MDS and CHIP in comparison to LGL.
Our results indicate that LGL is often associated with myeloid mutations that are also typical in CHIP. Though, age-related changes or other mutagenic stressors, including inflammatory changes could be contributing factors to both LGL and CHIP outgrowth, conversely LGL may evolve as a consequence of a tumor surveillance response to myeloid neoplasms or CHIP. While the coexistence of MDS and LGL has been described in the past, and our analysis corroborates this, we observed that LGL may also coexist with CHIP in some patients. The implication of this would be beneficial to our understanding of, not only, the individual diseases but could also impact care in CHIP survivorship.

Disclosures
Nazha: MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Tolero, Karyopharma: Honoraria; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Saunthararajah:EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties; Novo Nordisk: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Novartis: Consultancy; Alexion: Consultancy.