Case Study 1112 LGL Leukemia
Photo Credit: Pathpedia
By: C. Andrew Kistler, MD, PharmD, RPh
A 63-year-old man presents to the hospital with a history of recurrent infections that include cellulitis, pneumonias, and upper respiratory tract infections. He reports subjective fevers at home along with unintentional weight loss and occasional night sweats. The patient has a remote history of arthritis, which was diagnosed approximately 20 years ago and treated intermittently with methotrexate (MTX) and prednisone. On physical exam, he is found to be febrile at 102°F, rather cachectic, pale, and have hepatosplenomegaly. Several swollen joints that are tender to palpation and have decreased range of motion are also present. His laboratory values show pancytopenia with the most severe deficiency in neutrophils.
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This patient received the diagnosis of large granular lymphocyte (LGL) leukemia, which is a rare malignancy that is often associated with autoimmune diseases such as rheumatoid arthritis (RA), Sjogrens syndrome, and hemolytic anemia. It also appears to be associated with patients with multiple myeloma and myelodysplastic syndrome.1 LGL leukemia is a type of peripheral T- cell and natural killer (NK) cell malignancy. The median age of disease onset is approximately 60 years of age, and it represents about 2% to 5% of all lymphoproliferative disorders in the United States. The overall incidence in the general United States population is extremely rare: approximately 1 in 10 million people.2 In addition to symptoms associated with their autoimmune disease, patients can present with the typical symptoms of fevers, night sweats, and weight loss. Interestingly, up to 35% of all patients with LGL leukemia will be asymptomatic and only have an incidental finding of neutropenia, anemia, or thrombocytopenia. Between 200 to 400 LGLs per microliter is considered normal, although most patients with LGL leukemia have greater than 2,000 per microliter.3
The cell signaling behind the development of LGL leukemia is complex; however, it appears that IL-12 and IL-15 are upregulated and represent the key cytokines involved. In addition to these cytokines, LGL leukemias are also relatively resistant to apoptosis secondary to over-expression STAT3, which is an important transcription factor in the cell cycle.4,5
LGL leukemia has a median survival of about 10 years, and even with treatment, remission is very rare. Therefore, depending on the clinical scenario, treatment can be held until the patient becomes symptomatic, has associated autoimmune conditions that also need treatment, or significant neutropenia, anemia, or thrombocytopenia. Patients will usually require treatment at some point secondary to progressive neutropenia causing recurrent infections. Asymptomatic patients can be observed for a specified amount of time as long as their blood counts and clinical status are being closely monitored. There is no consensus on the best treatment regimen; however, the mainstays of LGL leukemia treatment include MTX, cyclosporine, or cyclophosphamide with or without prednisone.6,7
Although LGL leukemia is a relatively rare diagnosis, it warrants further consideration and investigation in patients with concurrent autoimmune diseases found to have splenomegaly and neutropenia. The signaling pathways involved in LGL leukemia appear to include several specific cytokines and transcription factors, which could provide niche and orphan indications for medications being developed for current and future malignancies.
1. Lamy T et al. Cancer Control. 1998; 5:25.
2. Yamamoto JF, et al. Cancer Causes Control. 2008; 19:379.
3. Loughran TP Jr. Blood. 1993; 82:1.
4. Zambello R et al. Br J Haematol. 1996; 92:308.
5. Chen J et al. Blood. 2012; 119:137.
6. Lamy T et al. Blood. 2011; 117:2764.
7. Dearden CE et al. Br J Haematol. 2011; 153:451.