Subclinical Large Granular Lymphocyte Clone in Myelodysplastic Syndrome: A Case Report and Literature Review
Authors: Ng Jun Yen , Edwards Danielle , D'Souza Melanie , Choi Philip Young-Ill 
Published: December 2024

Introduction
Large Granular Lymphocyte (LGL) clones are common in patients with MDS. They may be subclinical and revealed by identifying a STAT3 mutation. LGL leukemia arises from the clonal proliferation of LGLs, most commonly T-cells (T-LGL), followed by natural killer (NK) cells (NK-LGL). Identifying an LGL clone in patients with MDS may suggest a component of cytopenia amenable to immunosuppressive therapy. However, there is no clear treatment guideline in these cases.
Case
A 68-year-old male was referred to hematology with mildly progressive anemia and neutropenia, on the background of chronic kidney disease (CKD). This remained stable for 6 years, then progressed to severe macrocytic anemia with hemoglobin (Hb) of 63 g/L, mean corpuscular volume of 104 fL, neutrophil 1.06 x 10^9/L, and a normal platelet count. The total lymphocyte count was 0.78 x 10^9/L. There were no blasts nor increased LGL on the blood film. He commenced darbepoetin titrated to 150 micrograms fortnightly but remained transfusion-dependent.
Bone marrow examination showed myelodysplastic syndrome (MDS) with low blasts and multilineage dysplasia. Immunophenotyping showed T-cells with normal antigen expression and 15% of cells with an NK-cell phenotype. Next-generation sequencing (NGS) identified a STAT3 D661Y variant (read frequency 10%) without other mutations seen in MDS. His Hb continued to fall to 41 g/L despite frequent transfusions, and he commenced methotrexate starting at 10 mg and up to 15 mg weekly from the third week. He became transfusion-independent within four weeks with a Hb of 130 g/L after four months of treatment. He is now off methotrexate and remains transfusion-independent.
Discussion
LGL clones may be observed in over 30% of MDS cases. The detection of a STAT3 mutation may identify some cases of MDS with a subclinical LGL clone.
The presence of LGL clones in MDS may be more commonly associated with older age and hypocellular bone marrow. Moreover, STAT3 mutations may be associated with lower leucocyte counts and bone marrow cellularity. Less is known about the clinical impact of NK cell-predominant clones in these patients.
The National Comprehensive Cancer Network (NCCN) guidelines recommend considering flow cytometry, T-cell receptor polymerase chain reaction (PCR), and STAT3 mutation testing to evaluate for LGL in MDS. There are no clear guidelines on the management of these cases and currently, there is conflicting data in the limited literature. However, as in our case, identifying a STAT3 mutation with an LGL clone in patients with MDS suggests a degree of immune-mediated cytopenia which may improve with IST.
Saunthararajah et al. evaluated the effect of IST in patients with T-LGL (n=15), MDS (n=76), or both (n=9). Three of the nine patients with both T-LGL and MDS who received cyclosporin or anti-thymocyte globulin attained a clinically significant improvement in cytopenia, either as neutrophil recovery (&lt; 0·5 x10^9/L to &gt; 1 x10^9/L), sustained for at least six weeks within six months of initiating treatment, or reversal of transfusion-dependence for at least six weeks. This response rate is similar to patients with MDS only (28%) but lower than patients with T-LGL only (67%, P=0·01).
Zhang et al. did not observe any difference in the overall survival between MDS patients with T-LGL treated with IST and erythropoietin-agonists (n=10) and untreated patients (n=25). In Stahl et al.'s study with 207 MDS cases, the presence or absence of LGL clones (n=16 and 28, respectively) did not predict response to IST.
Our case contributes to the literature on STAT3 mutations revealing subclinical NK-LGL clones in MDS. While NGS is commonly performed in MDS, STAT3 may not be universally included in targeted panels for myeloid disease. We highlight the opportunity for a profound clinical response to IST in MDS with STAT3 mutation and an associated NK-LGL clone. The marked improvement in cytopenia noted is consistent with some reported cases. However, more studies are required to better select appropriate patients for IST, and to provide evidence-based treatment strategies.
Conclusion
We present a case of IST-responsive subclinical NK-LGL causing cytopenia diagnosed by screening for STAT3 mutations in MDS. Our case contributes to the limited literature reporting the successful use of IST in this setting. More research is needed to identify targeted IST algorithms in MDS with STAT3 mutations and NK or T-LGL clones.