Thanks for your help this week. We had a case of T-LGL associated with rheumatoid arthritis. In our case her planned surgery was postponed. She was given GCSF and responded to this and this was used pre operatively for optimisation. She commenced MTX weekly and continues on this with a reasonable Blood count response: HB 95, plt 200, wcc 2.5, neu 1.7. She has not had any infective complications from her T- LGL
T cell Large granular lymphocyte leukaemia is a rare disorder accounting for around 2- 5% of cases of chronic lymphoproliferative disorders in the USA. It is usually diagnosed in older patients >60 years with an equal proportion of men and women affected. 85% of cases are of a more indolent T cell type but an agressive NK cell LGL is recognised particularly in the far east where it is linked to EBV infection and has a poor prognosis. In this summary we will discuss T LGL only.
T-LGL provides an interesting insight into the working of T cell mediated immunity. The response of the disease to immune suppression has lead researchers to feel that this was a condition caused by dysregulation of the immune system. This is also supported by the proponderance of this disorder in patients with pre-existing immune conditions.
T-LGL is derived from CD 8 positive cytotoxic T cells. In healthy patients these function as part of the immune system and are activated via the TCR interacting with peptides expressed on MHC. Activated cytotoxic T cells then proliferate and cause cell death through perforin and granzyme release killing virally infected cells.
In the case of T LGL it is postulated that chronic antigen expression causes initial oligoclonal cytotoxic T cell expansion. Then a subclone is selected for over time in cases where antigen is chronically expressed. This hypothesis is backed up by detailed PCR of T-LGL cells TCR (T cell receptor) that show limited diversity of the TCR LGL suggesting they are clonal.
A recent blood article by Lamy et al 2017 describes 28-75% of T-LGL patients have a STAT3 mutation. This finding is an important step in understanding the pathogenesis of T-LGL. This STAT 3 signalling may also predict the patients who will respond to MTX therapy though this is still under investigation.
Here the expansion of a sub-clone of cytotoxic T cells that has a STAT 3 signalling mutation leads to increased cytokine production and cytotoxic granule release causing anaemia, neutropenia and fatigue. The faulty STAT 3 signalling allows the clone to escape the normal apoptotic mechanism via a variety of mechanisms including increased production of platelet derived growth factor and IL15 and also the cells secrete excessive amounts of soluble FAS ligand to act as decoy allowing these cells to evade apoptosis.
Diagnosis of T LGL requires the following
Appropriate clinical context:
Splenomegaly (50% cases)
Cytopenias (85% Neutropenia, 50% Anaemia and 20% Thrombocytopenia)
Lymphocytosis (though often this is mild)
History of an autoimmune disease (up to 40% cases linked RA but also associations with Red cell aplasia, post BMT, Post solid organ transplant, CML, Cyclical Neutropenia, Pulmonary hypertension, HIV infection).
Large granular lymphocytes with prominent auzorophillic granules >0.5 x10^9. It should be stressed that on morphology alone these cant be distinuguished from usual LGL cells.
An excess of Large granular lymphocytes that express CD 3 and CD8, CD 57 and or CD16
PCR of TCR gama gene.
Rarely there will not be a lymphocytosis and there is not a good clinical background, in these cases a bone marrow is recommended as trephines can highlight areas of infiltration of LGL. It may also help exclude MDS or Aplastic anaemia as a cause for cytopenias.
When to treat LGL?
Watch and wait is a valid option if cytopenias are asymptomatic. Prognosis is often good >70% at 10 years. Many patients may never require any treatment and lamy et al point out that mortality from infection in LGL is low.
How I treat authors describe four situations where they feel treatment is valid:
- Recurrent infections and neutrophils <1
- Systemic treatment needed for other autoimmune condition
- Transfusion dependent anaemia
- Severe neutropenia neu <0.5
It should be noted that large scale trials are lacking in T LGL treatment and many of the treatment evidence bases are built on small case series. These recommendations are from the Blood How I treat paper 2011 and recent Lamy et al paper 2017.
- Not a longterm option but may be useful as adjunct while other therapy taking time to have effect. How I treat authors advocate its use if neu <0.5 at initiation of therapy suggesting 1mg/k for a month and then tapering.
- Proven treatment benefit as DMARD in RA hence useful treatment in this context.
- Starting dose 10mg/m2 weekly
- Around 50% ORR
- 2-12 weeks for response
- May not be durable beyond a few years?
- lamy et al describe recent data that suggests STAT3 mutated patients respond better to MTX
- Monitoring for Liver toxicity and pulmonary complications important
- 50-100mg daily
- ORR 50-60%
- Up to 4 months response
- Adinistration beyond a six months to a year not recommended due to carcinogenesis and bladder toxicity. Need to re-start if progressing cytopenias after treatment break.
- Possibly useful if severe anaemia/ red cell aplasia or in context of a solid organ transplant where ciclosporin may already be required
- Needs level monitoring
- Problematic if Hypertension or pre-existing renal impairment
If above options fail:
- Campath – Need to be fit and usually older demographic affected. Lower CD 52 expression on T LGL cells compared to usual cytotoxic T cells hence only about 60% response rates seen.
- Purine analogues – Need to be fit and usually older demographic affected. Up to 70% ORR and these can be durable lasting several years.
- Splenectomy – very limited evidence for benefit.
- ?JAK/Stat inhibitors – Lamy et al describe early data showing use of JAK 3 inhibitor Tofacitinib citrate used in 9 patients T LGL and 6 patients responded.
Assessment of Treatment response
- Assess after 4 months
- CR – Normalisation of FBC
- PR – Improvent in FBC
- PD – No response to cytopenias at 4 months
Many thanks for your help with the case this week. Please feel free to tweet any questions or comments.
Lamy et al. LGL Leukaemia:from pathogenesis to treatment. Blood 2017;129 (9) 1082-1094.
Lamy T, Loughran T. How I treat LGL leukaemia. Blood 2011;117 (10) 2764-2774.
Rose M, Berlinder N. T cell large granular lymphocyte leukaemia and related disorders. The Oncologist 2004;9:247-258