Large Granular Lymphocytic Leukemia

[stumpedNSJ]

I am looking for more information on LGL leukemia. I would like to know how this is diagnosed.... What are the numbers, test results doctors are looking for to make an actual diagnosis?

I am a 37 year old female, recently diagnosed with Autoimmune Neutropenia but the Hematologist told me I do not have LGL Leukemia "YET". Certain test results I had led him to believe that this could turn into LGL later on. Specifically, what would prompt a diagnosis of LGL in the future for me?

Thanks for your response.

Stumped

[Dr. Safaa Mahmoud]

Dear stumpedNSJ,

Large granular lymphocytes (LGLs) are lymphocytes with a size larger than that of the normal lymphocytes and contain azurophilic cytoplasmic granules. LGLs are classified phenotypically (cell membrane markers) into Natural killer NK cell or T-cell phenotype.

There are four lymphoproliferative disorders affecting LGLs:
reactive/transient LGL expansion,
chronic LGL lymphocytosis,
indolent LGL leukemia, and
aggressive LGL leukemia.
80% of LGL leukemia are due to clonal expansion of the T-cell phenotype. The T-cell variant of chronic lymphocytic leukemia CLL represents 25% of all CLL cases.

Different viruses have been implicated in the pathogenesis of LGL leukemia like: Human T-cell leukemia-lymphoma virus-I-II (HTLV I-II), Epstein-Barr virus (EBV), Human immunodeficiency virus (HIV) and Human Herpes virus type-8 (HHV8). However no direct relation between the infection with any of these viruses and the development of T-LGL leukemia.

Any case of unexplained cytopenias and high numbers of LGLs should be investigated for LGL leukemia.

Laboratory investigation: complete blood picture CBC and blood smear show any of the following:
Neutropenia in almost 85% of cases (counts of 500/µl in 50% of patients).
Anemia in 50% of the cases.
Moderate thrombocytopenia in 20% of them.

The peripheral blood smear:
A normal lymphocytic count or a mild lymphocytosis ( 7,800/µl).
Increased number of the circulating granular lymphocytes up to 4,000/µl (N. 223 ± 99/µl).

Criteria for diagnosis of LGL leukemia:

Abnormal monoclonal proliferation of CD8+ T cells in patients with cytopenia.
Clonality is measured by gene rearrangement studies using Southern blotting or by polymerase chain reaction (PCR) on the DNA extracted from the proliferating large lymphocytes. PCR is the most commonly used for its convenience. Flow cytometry analysis is another procedure that can be also used.

The classic immunophenotype of the malignant T cell in LGL leukemia is CD3+CD4–CD8+CD16+CD27– CD45R0–CD57+CD94+.

Atypical lymphocytosis occurs in many conditions that should be excluded before the diagnosis of LGL leukemia.
The majority of these causes are viral infections.
In Epstein-Barr virus (EBV) infection the atypical lymphocytes are not CD57+.
In Cytomegalovirus infection in spite the mild increase in CD3+, CD57+ LGL; there is no evidence for TCR gene rearrangement.
In Human immunodeficiency virus infection, the LGL are polyclonally expanded.

A common association between LGL leukemia and other systemic diseases is common and include:
Autoimmune diseases, e.g. rheumatoid arthritis RA , Felty's syndrome
Hematologic disorders including, autoimmune thrombocytopenia, autoimmune hemolytic anemia, and
Other malignancies such as myelodysplasia and B-cell lymphoproliferative disorders.

Natural History, Prognosis, and Therapy of LGL Leukemia:
LGL leukemia is an indolent chronic disorder. Some patients with mild cytopenias and/or lymphocytosis remain asymptomatic for a long period. Spontaneous remissions have been reported in some studies.
In symptomatic cases (majority) treatment should be initiated. Being a rare malignancy, treatment recommendations are based on data coming from case reports and retrospective studies. Recurrent neutropenia and infections are the main concern in treatment of this disease.

Treatments for symptomatic cases include:
Growth factors:
Both G-CSF and GM-CSF are effective in the treatment of severe infections with netropenia

Immunosuppressive agents are used in patients with both neutropenia and anemia, they include
Methotrexate,
Cyclophosphamide, and
Cyclosporine
All of them have been used alone or in combination with prednisone.
Prednisone alone produced clinical improvement in neutropenia.
Fludarabine and pentostatin have been shown to induce clinical and not cytogenetic remission.

I hope you find this information helpful

Best regards,

[stumpedNSJ]

Thank you for the information. Based on what you told me, do you feel I fall into this category. My test results were as follows


My igG result came back high at 1770 mg/dl.

T-Cell clonality test came back positive.

The final report read as follows:
"Moderate Lymphocytosis"
"Modest increase in CD3+/CD8+/CD57+ Large Granular Lymphocytes, T-Cell"
"Lambda predominant Plasma Cells"
"No monoclonal B-Cell population"

Regards,
Stumped

[Dr. Safaa Mahmoud]

Dear stumpedNSJ,

In cases of LGL leukemia complete blood picture CBC shows any of the following:

Neutropenia in almost 85% of cases (with counts of 500/µl in 50% of patients).
Anemia in 50% of the cases.
Moderate thrombocytopenia in 20%.

The peripheral blood smear shows:
A normal lymphocytic count or a mild lymphocytosis ( 7,800/µl).
Increased number of the circulating granular lymphocytes up to 4,000/µl (N. 223 ± 99/µl).

Criteria for diagnosis of LGL leukemia includes abnormal monoclonal proliferation of CD8+ T cells in patients with cytopenia.

I am not a hematologist but as your doctor told you, your degree of your neutropenia is not the degree expected in cases of LGL leukemia, although your results are positive for monoclonality. I advise you to follow up with with the hematologist. Keep us updated.

Best regards,

[mimskeesuno,RPh]

Dear stumpedNSJ,

I too am a newbie to LGL Leukemia, in remission now for 7 months!! Also, Dr. Mahmoud, thank you for all your helpful information. What we have is rare, and not widely studied. I keep checking different chat boards to obtain info on this rare cancer. Keep up with your blood work, keep copies for all your future docs, that is really important.

The very ironic thing is, that I too am 37, and female. My current new mds (I have moved) are trying to figure out this 'Autoimmune Neutropenia.' I was lucky enough to go to Moffit Cancer Center in Tampa, FL, to see a specialist who found my LGL. After treatment, I am in remission, and not soo sick these days, only fatigued.....big time.

Keep in touch, I hope you do well. Hang in there!!!