Large granular lymphocyte (LGL) leukemia is a T or NK clonal disorder characterized
by the tissue invasion of marrow, spleen and liver. Clinical presentation is dominated
by recurrent infections associated with neutropenia, anemia, splenomegaly and autoimmune
diseases, particularly rheumatoid arthritis.
1, 2, 3, 4
Recently, STAT3 and STAT5 mutations have been detected in T-LGL and in NK-LGL leukemias.
5, 6, 7, 8
These somatic mutations, coupled to other intrinsic and extrinsic mechanisms, are
likely to induce constitutive activation of the JAK/STAT pathway thus contributing
to maintenance of leukemic LGL survival.
9
These findings strongly suggest a common specific pathogenic pattern in T-LGL and
NK-LGL leukemias and provide justification for consideration of the same treatment
options. Indications for treatment are severe or symptomatic neutropenia, symptomatic
or transfusion-dependent anemia or associated autoimmune diseases requiring therapy.
There is no standard treatment for patients with LGL leukemia. All the largest series
published in the literature (collecting data on more than 40 patients) are retrospective.
Data are very heterogeneous and treatment outcome per single agent is available for
very few patients. Immunosuppressive therapy remains the foundation of treatment including
single agents that is, methotrexate, oral cyclophosphamide or cyclosporine. On the
basis of an initial study showing very good overall response rate (ORR) using methotrexate,
this drug has remained the most recommended option in LGL leukemia.
10
Oral low dose cyclophosphamide was first used in pure red cell aplasia associated
with LGL leukemia.
11, 12
In a French series, cyclophosphamide was shown to be also efficient in neutropenic
patients and for those who failed methotrexate.
13
Those results suggested that cyclophosphamide used as first-line therapy could be
an interesting alternative to methotrexate.
In this letter, we describe the encouraging results of cyclophosphamide used in a
series of 45 previously untreated LGL leukemia patients. Patients suffering from LGL
leukemia and treated with cyclophosphamide as first-line therapy were included in
this retrospective study. Patients were screened from the Italian, French and USA
Penn State registries. Patients gave their informed consent for data collection. The
diagnosis of LGL leukemia was based on a chronic LGL peripheral blood expansion (>0.5
× 109/l), usually lasting for more than 6 months. Criteria for T-LGL leukemia included
expression of LGL surface markers compatible with a typical T-cell (commonly αβ+ or
γδ+/CD3+/CD8+/CD57+ and/or CD16+) phenotype associated with clonal rearrangement of
TCRγ gene using PCR or clonal Vβ expression using flow cytometry. Criteria for NK-LGL
lymphocytosis/chronic NK-LGL leukemia included expression of LGL surface markers compatible
with a NK-cell (commonly CD3−/CD8+/CD16+ and/or CD56+) phenotype with more than 0.75
× 109/l circulating cells.
14, 15
Response to treatment was determined periodically on blood cell count and only best
response was taken into account. Hematological complete response (CR) was defined
by a normal blood count (hemoglobin (Hb)>12g/dl, platelets>150 × 109/l, absolute neutrophil
count (ANC)>1.5 × 109/l and lymphocytosis<4 × 109/l) and LGL peripheral count in a
normal range (<0.3 × 109/l). Molecular CR was based on hematological CR associated
with a negative PCR analysis for CD3+ cases. Hematologic partial response was defined
as an improvement in blood count specified as follows: ANC increasing more than 50%
and reaching more than 0.5 but less than 1.5 × 109/l; Hb level increasing more than
2 g/dl and transfusion independent without reaching 12 g/dl level. Treatment failure
was defined as a progressive disease (worsening of cytopenia or organomegaly) or a
stable disease (none of the later given criteria met). Some patients received cyclophosphamide
because of symptoms not related to cytopenia. For those patients, response criteria
included clinical symptom resolution. Patients who received prednisone, granulocyte
colony-stimulating factor or erythropoiesis-stimulating agent before or at the same
time of cyclophosphamide were included in this retrospective study. For the descriptive
analysis, qualitative variables were described using numbers and percentage, whereas
medians and extremes were used to describe quantitative analyses. Qualitative variables
were compared using χ
2 or Fisher's test.
A total of 45 patients treated with cyclophosphamide as a first-line therapy for LGL
leukemia from 1989 to 2012 were retrospectively included in this series. Clinical
characteristics are described in Table 1. Starting doses were as follows: 100 mg/day
(n=36), 50 to 75 mg/day (n=8) taken orally and 1 g IV/month (n=1). Median time from
diagnosis to treatment was 3 months (range, 0–55). Treatment was initiated because
of severe isolated neutropenia (n=16, 36%), neutropenia and anemia (n=2, 4%), transfusion-dependent
anemia (n=15, 33%) and thrombocytopenia (n=5, 11% including three cases of idiopathic
thrombopenic purpura). Seven non-cytopenic patients (15%) were treated for disease-associated
LGL leukemia: neuropathy (n=3), vasculitis (n=1) and constitutive symptoms (n=3).
ORR was 71% (32/45): there were 21 CR (47%) including three molecular responses (mCR)
and 11 (24%) partial responses. ORR was 72% versus 68% for T-LGL and NK-LGL subtype,
and 72% versus 67% for neutropenic and anemic patients, respectively (P=not significant).
Patients treated for symptoms related to LGL leukemia had a 94% ORR (6/7). Eighteen
patients (40%) were initially co-treated with prednisone and no significant impact
was found for the response to cyclophosphamide (P=0.31). As well as, concomitant granulocyte
colony-stimulating factor administration with cyclophosphamide did not influence the
time to response and the ORR. The median time to reach best response was 4 months
(range 0.8–21) and patients were treated for a median time of 6.4 months (range 0.5–33).
Evidence of clinico-biological improvement was systematically observed within the
4 months following treatment initiation. Therefore, we assume that cyclophosphamide
should be given for at least 4 months before changing drug regimen. Median treatment
duration was 8.5 months (range 3.4–33) for responders, except one patient who received
several courses of cyclophosphamide for 7 years. With a median time follow-up of 35
months (range 3.8–277), four out of the 32 responders relapsed (13%): one of these
patients responded again to a short course of cyclophosphamide and was maintained
subsequently on cyclosporine decided thereafter. The three others were switched to
either methotrexate or cyclosporine. Eight patients experienced grade 1–2 toxicities
(18%). Only three patients (7%) stopped treatment: one because of worsened anemia
and two because of febrile neutropenia not obviously related to hematological toxicity.
One patient experienced temporary worsening of anemia without stopping therapy.
We previously mentioned that cyclophosphamide induces a very good ORR in LGL leukemia
in de novo or relapsing patients.
14
The ORR of 71% described in our series confirmed and emphasized what has been reported
in the literature with a total of 25 responders out of 38 patients treated as first
line with cyclophosphamide (66% ORR) (Table 2).
11, 12, 13, 17, 18
We show that cyclophosphamide compares favorably to methotrexate given as a first-line
therapy. In 1993, Loughran et al.
10
reported a 60% ORR in a prospective series of 10 patients receiving methotrexate at
a weekly dose of 10 mg/m2. These results were less encouraging in two larger series.
One comes from the prospective ECOG study showing a 37% ORR in 56 patients and the
other is retrospective from the French registry and reported a 44% ORR in 36 patients.
13, 19
Furthermore, molecular response is rarely obtained and the incidence of relapse following
methotrexate is, at least in French experience, estimated at 67%.
13
Our series demonstrates that cyclophosphamide used as first-line therapy is effective
in T/NK-LGL leukemia, in both neutropenic and anemic patients. ORR and response duration
seem encouraging. We recommend only 9–12 months of treatment. It seems sufficient
to induce durable remissions and to avoid the complication of myelodysplastic syndromes/acute
myeloid leukemia, which although rare is dependent on cumulative dose and length of
exposure. For responding patients, tapering dose to 50 mg per day would be a reasonable
option. Although recognizing the limits of a retrospective study, we suggest that
cyclophosphamide could be an interesting alternative to methotrexate as first-line
therapy in LGL leukemia. A prospective study comparing cyclophosphamide to methotrexate
as first-line therapy is currently ongoing in France.