You Make the Call: How would you manage this patient with T-cell large granular lymphocytic leukemia?

This month, Richard Furman, MD, discusses management of a patient with T-cell large granular lymphocytic leukemia.

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This case is regarding a patient with T-cell large granular lymphocytic leukemia (T-LGL). A 73-year-old-asymptomatic female was found to have severe neutropenia (absolute neutrophil count <0.3 × 109/L). On exam she did not have splenomegaly. A bone marrow biopsy showed diffuse extensive replacement of the marrow architecture with T-cell large granular lymphocytic leukemia. T-cell receptor gene rearrangement analyses were identified both beta- and gamma-positive clones. A metaphase karyotype done on the bone marrow aspirate was normal, and fluorescence in-situ hybridization testing for del6q was negative. Molecular testing identified a point mutation in STAT3 (Y640F).

Her T-LGL responded briefly (1 week) to prednisone. She was then treated with methotrexate (20 mg/week for 3 months) without improvement in her disease. Likewise, her disease did not respond to oral cyclophosphamide. She has now started cyclosporin. How would you recommend this patient be managed? Is there a role for tofacitinib? Are there any novel or clinical trial options?

Classic large granular lymphocyte (LGL) leukemia is a collection of three lymphoproliferative disorders that under the WHO Classification of Lymphoid Neoplasms are termed T-cell granular lymphocytic leukemia (T-LGLL), chronic lymphoproliferative disorder of NK cells (CLPD-NK), and aggressive NK-cell leukemia. T-LGLL and CLPD-NK are indolent and represent what previously was termed T-LGL, T-CLL, or NK-LGL, and represent more than 95% of the LGLs. Typical presentations include cytopenias, autoimmune disorders, or an asymptomatic lymphocytosis, with neutropenia and red cell aplasia being the most typical. Previous guidelines required an LGL count above 1.5 × 10⁹/L for more than six months in order to establish a diagnosis, but with the average LGL count being 1.7 × 10⁹/L, it is now recognized that lower counts in the correct clinical setting qualify.

Treatment of LGL leukemia is only required for those patients who are symptomatic, with approximately 50% requiring therapy at presentation. First-line treatment options include methotrexate, cyclosporine, or cyclophosphamide, with response rates typically high. Some investigators report on a possible improved response to cyclosporine in those with red cell aplasia and there is a randomized phase II study investigating methotrexate versus cyclophosphamide (NCT01976182). Many patients are characterized as non-responders due to not receiving treatment of sufficient duration. In a 2014 study reporting on oral cyclophosphamide, the median time to response was four months.¹ An additional observation is that sometimes a prolonged course of lower dose prednisone (up to 20 mg daily) for longer durations might yield successful results.

Subsequent therapy for those demonstrating poor responses to cyclophosphamide, methotrexate, or cyclosporine include alemtuzumab, purine analogs, and cytarabine. When using alemtuzumab, it is important to use as low a dose as necessary to achieve a response. In my personal experience, I have found efficacy with more experimental agents, including thalidomide and phosphoinositide 3-kinase inhibitors. Finally, looking to potential future treatments, a publication reported on nine patients treated successfully with tofacitinib, a JAK inhibitor, given the presence of the STAT3 mutations in many LGL leukemias.2 Interestingly, there seemed to be no correlation with the presence of a STAT3 mutation, perhaps indicating a universal hyperactive JAK-STAT pathway present in all patients and not just those with STAT mutations.

References

1. Moignet A, Hasanali Z, Zambello R, et al. Cyclophosphamide as a first-line therapy in LGL leukemia. Leukemia. 2014;28(5):1136.
2. Bilori B, Thota S, Clemente MJ, et al. Tofacitinib as a novel salvage therapy for refractory T-cell large granular lymphocytic leukemia. Leukemia. 2015;29(12):2429.

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I was called for an opinion regarding the management of a 28-year-old man who has a history of Budd-Chiari syndrome in 2015. He did not have any other significant past medical history. However, on review of his chart, I found that PCR testing of the peripheral blood came back positive for JAK2 V617F in August of 2020. The variant allele frequency was 0.06%. Is there a quantitative cutoff for which the allele burden is considered clinically significant? Should I attribute his hepatic vein thrombosis to the JAK2 positivity?

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