EDUCATION
Each month in “ You Make the Call ,” we pick a challenging clinical question submitted through the Consult a Colleague program and post the expert ’ s response , but we also want to know what you would do . Send in your response to next month ’ s clinical dilemma and see how your answer matches up to the expert ’ s in the next print issue .
This month , Richard Furman , MD , discusses management of a patient with T-cell large granular lymphocytic leukemia .
CLINICAL DILEMMA :
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 × 10 9 / 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 gammapositive 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 ?
Expert Opinion
Richard Furman , MD Director , CLL Research Center Weill Cornell Medicine New York , NY
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
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asymptomatic lymphocytosis , with neutropenia and red cell aplasia being the most typical . Previous guidelines required an LGL count above 1.5 × 10 9 / L for more than six months in order to establish a diagnosis , but with the average LGL count being 1.7 × 10 9 / 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 ,
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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 .
Reference
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 .
Next Month ’ s Clinical Dilemma :
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 ?
How would you respond ? Email us at ashclinicalnews @ hematology . org .
18 ASH Clinical News August 2021