Abstract : T-cell large granular lymphocyte leukemia (T-LGLL) is
a rare clonal lymphoproliferative disorder. Because of its low incidence
rate and few cases, there is no standard treatment guideline. We report
on a case of T-LGLL with severe anemia [hemoglobin (HGB): 36 g/L].
After 4 months of treatment with cyclosporine A, the response was
suboptimal, and the patient still had transfusion-dependent anemia (HGB:
47 g/L). After six cycles of FND (fludarabine, mitoxantrone,
dexamethasone) regimen, the hematological response was complete (HGB:
143 g/L) and the monoclonallymphocytes were nonexistent. Therefore, an
FND regimen may be an option for treating refractory T-LGLL.
Keywords: Large granular lymphocyte leukemia;
Fludarabine;Treatment
T-cell large granular lymphocytic leukemia (T-LGLL) is a kind of
lymphoproliferative disease with an inert process. It is rare,
accounting for 2%–3% of lymphocytic leukemia. Most T-LGLL occur in
45–75-year-old patients, and the male-to-female ratio is 1:1[1].The
clinical manifestations of the disease are anemia, neutropenia, repeated
infections, and splenomegaly. Without clinical specificity, it is easy
to miss and misdiagnose. Due to the small number of cases and the lack
of systematic clinical research, there is no standard treatment. A case
of T-LGLL treated successfully with FND (fludarabine, mitoxantrone,
dexamethasone) is reported as follows.
A 34-year-old male presented to hospital on June 20, 2018, with
‘dizziness and fatigue for nearly 3 months’. There was no obvious cause
for the dizziness, fatigue, sweating, and other discomforts during the
previous 3 months. He did not have palpable peripheral lymphadenopathy,
splenomegaly, or hepatomegaly. The laboratory workup revealed the
following: white blood cell (WBC) count:13.46 × 109/L, neutrophil (NEU) count: 1.08 × 109 /L, lymphocyte
(LYM) count: 11.75 × 109 /L, HGB: 36 g/L, platelet
(PLT) count: 260 × 109 /L. Hepatitis B surface
antibody, anti-hepatitis C virus , anti-human immunodeficiency virus,
cytomegalovirus, and Epstein-Barr virus were negative, as was the
antinuclear antibody spectrum. Direct and indirect Coombs tests were
negative. Liver and kidney function, thyroid function, and
immunoglobulin were not significantly abnormal. VitB12 and ferritin were
normal. Peripheral blood smears showed that the proportion of
lymphocytes were significantly increased, and granules could be seen in
most of their cytoplasm (Figure 1 ). Bone marrow smears showed
that erythroid proliferation was active, and mature erythroblasts were
slightly different in size. The percentage of lymphocytes was normal,
and a large number of granules were observed. Bone marrow flow cytometry
(FCM) showed an abnormal mature T lymphocyte group, accounting for about
91.53% of the lymphocytes, with a phenotype of
TCRαβ+, CD8+,
CD5+, CD3+, CD2+,
CD57- , CD56-,
CD4-, CD30-,
HLA-DR-, CD38-,
CD20-, TCRβ/γ-. TCRVβ repertoire
analysis showed that Vβ3 accounted for 81.05% of the lymphocytes and
was considered to be a monoclonal lymphocyte cell. The STAT3 gene was
negative for mutations, TCR gene rearrangement was positive, and no
obvious abnormality was found from the bone marrow biopsy. Chromosome:
46, XY [20]. No abnormality was found in 41 genes related to
myelodysplastic syndrome. Therefore, T-LGLL was diagnosed.
During hospitalization, the patient was initially treated with
cyclosporine A (CsA) 100 mg once every 12 h for 4 months. However, the
response was suboptimal and the patient was still transfusion dependent.
Routine blood showed the following: WBC count: 11.53 ×
109 /L, NEU count: 1.28 × 109 /L,
LYM count: 9.88 × 109 /L, HGB: 47 g/L, PLT count: 270
× 109 /L. Bone marrow FCM demonstrated persistent
LGLs, with 86.02% involvement in lymphocytes. Considering the poor
effect of CsA and the patient not tolerating the severe anemia, an FND
regimen was given, which consisted specifically of the following:
fludarabine (25 mg/m2/d d1-d3), mitoxantrone (10
mg/m2 d1), and dexamethasone (20 mg/d d1-d5), repeated
every 4 weeks for six courses (Table 1 ). After the second cycle,
HGB was 71 g/L and LGLs decreased to 60.37% of the lymphocytes by bone
marrow FCM, part of the hematological reaction was obtained. After the
fourth cycle, HGB was 123 g/L, bone marrow FCM showed that LGLs about
25.96% of the lymphocytes. The patient obtained a complete
hematological response. More important, the abnormal monoclonal cells
were significantly reduced compared with before. And after the sixth
cycle, all the hematological parameters were in the normal range, no
monoclonal cells were found by bone marrow FCM.TCR gene rearrangement
was negative. The patient experienced no adverse reactions except for
mild nausea and transient mild leukopenia during the treatment. At 18
months follow-up, the patient remained in complete remission without any
other therapy.
T-LGLL is a rare lymphoproliferative disorder that is caused by
sustained immune stimulation and dysregulation of apoptosis [2].
Immunosuppressive agents such as methotrexate (MTX), cyclophosphamide
(Cy), and CsA are the main treatments for T-LGLL. The three latest
retrospective studies show the overall response rate (ORR) of the three
immunosuppressants are nearly 47%–53% [3-5]. Although the ORRs
are similar, the ORR with Cy is higher than CsA and MTX. Cy as a
second-line treatment after failure of MTX treatment has a certain
effect. Therefore, Cy may be a more effective first-line treatment for
T-LGLL[3, 4]. However, the complete response rate of these
immunosuppressants is limited, recurrence is common, and the long-term
medication will lead to infection and an increased risk of cancer. Thus,
a more effective and persistent treatment is needed. Alemtuzumab, a
monoclonal antibody against CD52, has shown certain efficacy. A phase 2
study shows that the remission rate is about 67% in 21 patients with
T-LGLL [6]. Splenectomy can be used for splenomegaly with
hemocytopenia, the total response rate is 58% [3]. In addition, it
is reported that calcitriol can reduce the activation of STAT1 and STAT3
and the output of inflammatory cytokines, so the vitamin D
supplementation may be a feasible treatment option for T-LGLL[7]. A
STAT3 inhibitor is also promising. Fludarabine has also shown good
efficacy with the potential to clear LGL cell clones. Costa et
al.[8] reports that all six T-LGLL patients who received fludarabine
treatment has a hematological response, while five cases (83.3%)
achieve absence of monoclonal populations as assessed by PCR. The
adverse reactions are tolerable. In addition, it is reported that three
patients with T-LGLL receive a complete hematological response after
first-line treatment with the FND regimen [9]. Fludarabine as a
cytotoxic drug not only can reduce the tumor cells but also can modulate
distinct functions of the immune system to improve post-treatment tumor
control [10].So we chose the FND regimen as the second-line
treatment for this patient, who achieved complete hematological response
and an eradication of LGL clones (Table 1 ).
In conclusion, FND has rapid response and good compliance, and may lead
to persistent relief by eradicating the LGL clones. it may be a feasible
alternative therapy for refractory T-LGLL and more particularly in
patients who cannot tolerate long-term use of immunosuppressants. But it
still needs further clinical research.