Treatment of large granular lymphocyte leukemia

INTRODUCTION — Large granular lymphocyte (LGL) leukemia is characterized by peripheral blood and marrow lymphocytic infiltration with clonal LGLs, splenomegaly, and cytopenias, most commonly neutropenia.

The LGL is a morphologically distinct lymphoid subset that is larger than most circulating lymphocytes and has characteristic azurophilic granules containing acid hydrolases (picture 1). LGLs comprise 10 to 15 percent of normal peripheral blood mononuclear cells. The absolute number of LGLs in the peripheral blood of normal subjects is 200 to 400/microL.

LGLs arise from two major lineages [1,2]. Approximately 85 percent of normal LGLs have a natural killer (NK) cell phenotype and only 15 percent are derived from T cells. The phenotypes of LGLs in LGL leukemia, however, are just the opposite:

●CD3-positive T cell lineage – Approximately 85 percent of circulating LGLs are CD3 positive (+), CD8+, CD57+, CD56 negative (-) T cells, representing in vivo antigen-activated effector-memory cytotoxic T cells.

●CD3-negative NK cell lineage – The remaining 15 percent of circulating LGLs are CD3-, CD16+, and/or CD56+ NK cells. It had been postulated that such NK cells mediate non-major histocompatibility complex (MHC)-restricted cytotoxicity. It is now established that NK cells possess specific receptors for MHC class I molecules named "killer-cell Ig-like inhibitory receptor" (KIR) and "killer-cell activating receptor" (KAR). Interactions between these receptors and MHC class I molecules on target cells may inhibit or activate NK cell-mediated cytotoxicity.

LGL leukemia can arise from the clonal proliferation of LGLs of T cell or NK cell lineage. The management of LGL leukemia will be discussed here.

The etiology, clinical features, and diagnosis of T cell LGL leukemia and the diagnosis and management of NK cell LGL leukemia are discussed separately.

●(See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia".)

●(See "Large granular lymphocyte leukemia in rheumatoid arthritis".)

●(See "Natural killer (NK) cell large granular lymphocyte leukemia".)

PRETREATMENT EVALUATION — Patients with LGL leukemia should undergo a pretreatment evaluation to determine the extent of disease, patient performance status (table 1A-B), and assessment of comorbidities that are likely to have an impact on treatment options.

In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with LGL leukemia:

●Complete blood count with differential.

●Unilateral bone marrow aspirate and biopsy is recommended if the diagnosis is uncertain. The specimen should be evaluated microscopically and by immunophenotyping, cytochemistry, and conventional cytogenetics. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia".)

●Patients with childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

MANAGEMENT — Not all patients with LGL leukemia require treatment at the time of diagnosis.

Asymptomatic patients — For newly diagnosed patients with asymptomatic LGL leukemia, we suggest observation rather than immediate treatment.

During the period of observation, we perform a complete blood count (CBC) with differential every 6 to 12 months, along with a clinical examination. Patients are encouraged to contact their health care providers sooner if they have symptoms worrisome of disease progression (eg, recurrent infections, fatigue, dyspnea, bleeding).

Symptomatic patients — Treatment is typically reserved for patients with symptomatic disease because LGL leukemia cannot be cured by current treatments and most cases have an indolent clinical behavior (median survival >10 years). Two-thirds of patients ultimately require therapy, most commonly because of recurrent infection secondary to severe neutropenia [3]. Rare spontaneous remissions of LGL leukemia have been documented.

The main goal of treatment for patients with LGL leukemia is the relief of symptoms, and especially a reduction in infections associated with neutropenia. Although intuitively sensible, it remains unclear whether achievement of hematologic improvement prolongs survival.

Treatment is indicated for relief of symptoms or life-threatening peripheral blood cytopenias:

●Severe neutropenia (absolute neutrophil count <500/microL)

●Moderate neutropenia (absolute neutrophil count <1000/microL) with recurrent infections

●Symptomatic or transfusion dependent anemia

●Severe thrombocytopenia (<50,000/microL), which is a very rare event

●Associated autoimmune conditions (eg, rheumatoid arthritis) requiring therapy

Some patients with severe neutropenia as their only symptom may be reluctant to start treatment with immunosuppressive agents. Most experts initiate immunosuppressive therapy in such patients. A less attractive alternative is the intermittent use of antibiotics and granulocyte colony-stimulating factor (G-CSF) during febrile episodes. G-CSF can result in a transient partial correction of the neutropenia in such settings [4].

INITIAL TREATMENT

Choice of therapy — There is no standard treatment regimen for symptomatic LGL leukemia. Although experts prefer different specific regimens, there is general agreement that immunosuppressive therapy (ie, methotrexate, cyclophosphamide, cyclosporine) is the cornerstone of initial treatment [5-8]. The various immunosuppressive treatments have not been directly compared with one another in a prospective fashion, and data come primarily from small, retrospective case series. These series have used different response criteria and provide little information regarding time to response, response and treatment duration, and time to treatment failure.

The most promising results have been reported following the use of low-dose oral methotrexate, cyclosporine, or cyclophosphamide, either as single agents or in combination with prednisone [2,9-11]. Prednisone may hasten the initial response when administered as adjunctive therapy with another first-line immunosuppressive agent. However, treatment with single-agent prednisone is inadvisable because it has a low response rate and does not reduce LGL clones [12].

A choice among immunosuppressive treatments is primarily made based upon the clinical setting and clinician experience [5]:

●Neutropenia – We prefer oral methotrexate (10 mg/m² weekly) with or without prednisone for patients with neutropenia as their primary symptom. For patients with an absolute neutrophil count (ANC) <200/microL, oral prednisone (1 mg/kg per day) is administered in addition to the methotrexate for the first month and tapered off by the end of the second month.

●Autoimmune disorders – We prefer methotrexate (10 mg/m² weekly), with or without prednisone, for patients with an associated autoimmune disorder (eg, rheumatoid arthritis). In this setting, the use of prednisone is dictated by the accompanying autoimmune disorder. As an example, prednisone may help control joint pain related to rheumatoid arthritis.

●Anemia – We prefer either oral methotrexate (10 mg/m² weekly) or oral cyclophosphamide (100 mg daily) for patients with anemia. While both agents have activity in this setting. Some clinicians favor cyclophosphamide for patients with anemia due to its activity for pure red cell aplasia and for its activity in patients with LGL leukemia who progress after methotrexate; however, treatment with oral cyclophosphamide is limited to no more than 6 to 12 months. Other clinicians favor methotrexate because it can be continued indefinitely.

Response rates with the regimens are described in the following sections. The initial immunosuppressive regimen is continued until disease progression or until the maximum length of treatment is reached. (See 'Response evaluation' below.)

Methotrexate — Weekly low-dose oral methotrexate (10 mg/m² weekly) with or without prednisone is the preferred initial therapy for most patients with LGL leukemia, especially for patients with neutropenia as their primary abnormality and for patients with an associated autoimmune disorder. When compiling all the results reported in the literature, responses are seen in approximately half of patients, with a time to response ranging from 2 to 12 weeks [5]. The median duration of response ranges from two to four years.

The following are the largest studies investigating methotrexate in this population:

●An initial prospective study evaluated the efficacy of oral low-dose pulse methotrexate in 10 patients with T-LGL leukemia [13]. Methotrexate was started at a dose of 5.0 to 7.5 mg orally, given once per week in split AM and PM doses, and gradually increased to 15 to 20 mg/week (10 mg/m² per week) over one to three months. In patients receiving prednisone prior to starting methotrexate (in doses of 20 to 60 mg/day orally), the addition of methotrexate allowed reduction of the daily dose of prednisone to as low as 0 to 10 mg/day, without losing its effectiveness on reversal of neutropenia. The complete remission rate was 50 percent; a molecular remission was observed in three of the five patients achieving complete remission.

●A subsequent retrospective case series of patients with LGL leukemia, which included 201 patients with T-LGL leukemia, reported an overall response rate (ORR) of 55 percent (21 percent complete) in 62 patients treated with methotrexate [12].

●In a phase II Eastern Cooperative Oncology Group (ECOG) study of 55 patients with LGL leukemia, initial treatment consisted of weekly oral methotrexate plus daily oral prednisone, which was replaced by daily oral cyclophosphamide and prednisone for those not responding after four months of treatment [9]. The ORR after methotrexate was 38 percent. Those not responding to methotrexate had an ORR of 64 percent to cyclophosphamide. Serum biomarkers confirmed the inflammatory milieu of LGL leukemia but were not predictive of response. A gene expression profile correlated with response to methotrexate and appeared to be STAT3 mutation driven.

Low-dose oral methotrexate is generally well tolerated and can be continued long term. Common toxicities associated with methotrexate include (see "Major side effects of low-dose methotrexate"):

●Gastrointestinal problems such as nausea, stomach upset, and loose stools

●Stomatitis or soreness of the mouth

●Macular punctate rash that usually occurs on the extremities and spares the trunk

●Central nervous system problems including headache, fatigue, or impaired ability to concentrate

●Alopecia

●Fever, but infection should be excluded

●Hematologic abnormalities, particularly macrocytosis

One or more of these side effects are seen in some form, at some time, in most patients. Less common, but potentially serious, side effects include hepatotoxicity, pulmonary toxicity, myelosuppression, and nephrotoxicity. Prior to initiating methotrexate therapy, patients should be screened for hepatitis B and hepatitis C virus infections and should undergo a baseline chest radiograph. Hepatic function and complete blood counts should be monitored every four to eight weeks while on therapy. We do not routinely administer folic acid to most patients receiving weekly methotrexate; however, we supplement folic acid at a dose of 1 mg/day for patients who develop mouth sores or other toxicities. (See "Major side effects of low-dose methotrexate".)

Cyclophosphamide — Low-dose oral cyclophosphamide (50 to 100 mg daily) has demonstrated an ORR of 55 to 65 percent in patients with previously untreated LGL leukemia [3,11,14-16]. This agent, along with prednisone, may be particularly effective in patients with LGL leukemia and pure red cell aplasia [3,14,17,18]. Preliminary data from United States, Italian, and French registries suggest that oral cyclophosphamide used as first-line therapy may be a good option either in neutropenic or anemic patients [19]. In addition, responses have been reported in a majority of patients who have failed treatment with methotrexate [12]. The time to response ranges from one to four months. The median duration of response is unknown. Cyclophosphamide should not be administered for longer than 6 to 12 months for responders because the risk of toxicity is related to the cumulative dose of medication.

Major toxicities associated with long-term cyclophosphamide therapy include bone marrow suppression with accompanying cytopenias, increased risk of infection, infertility, and an increased risk of developing secondary malignancies. Cyclophosphamide is teratogenic and contraindicated in pregnant females. Both cystitis and bladder cancer are associated with cyclophosphamide therapy. To minimize bladder toxicity, patients should be advised to take cyclophosphamide in the morning and to drink at least eight glasses (240 mL each) of water daily. (See "General toxicity of cyclophosphamide in rheumatic diseases".)

Cyclosporine — Cyclosporine A, administered at varying doses, has demonstrated an ORR of 56 percent with response rates ranging in different case series from 21 to 100 percent [5]. Responses are seen despite survival of the leukemic LGL clone, and relapses on therapy are not uncommon [20,21]. Responses have been reported in patients with pure red cell aplasia and in patients with resistant disease. One series reported higher response rates among patients with an HLADR4 phenotype (present in 32 percent of LGL leukemia and 90 percent of LGL leukemia associated with rheumatoid arthritis) [22].

The following case series reported on cyclosporine for the treatment of LGL leukemia [11,12,15-17,21-26]:

●A case series of 229 patients with LGL leukemia (201 patients with T-LGL) reported an ORR of 21 percent (4 percent complete) in 24 patients treated with cyclosporine [12].

●In another study, cyclosporine (5 to 10 mg/kg per day orally in two divided doses for at least three months, adjusted to a therapeutic blood level of 200 to 400 ng/mL) was given to 25 subjects with anemia and/or neutropenia associated with T-LGL leukemia [22]. Fourteen patients responded with sustained improvement in neutrophil counts or transfusion independence, seven of whom had complete normalization of blood counts. On multivariate analysis the presence of HLA-DR4 was highly predictive of response to cyclosporine.

●Cyclosporine (initial dose 1.0 to 1.5 mg/kg orally every 12 hours), with or without low-dose granulocyte-macrophage colony-stimulating factor (GM-CSF), has led to a return of normal neutrophil counts in five severely neutropenic subjects with initial absolute neutrophil counts <500/microL [20,21]. Abnormal LGL populations persisted in these patients and neutropenia returned when cyclosporine was discontinued. Two of these patients were able to maintain normal neutrophil levels for eight years with continuous cyclosporine therapy.

●In one study, clonal cytogenetic abnormalities were associated with a poor response to immunosuppressive therapy [17]. However, five patients were successfully treated, with starting doses of 12 mg/kg per day in divided doses for four patients, and 150 mg twice daily for the remaining patient.

Low-dose oral cyclosporine can be continued long-term, but its use is limited by drug interactions and side effects. Cyclosporine is metabolized by the hepatic cytochrome P450 3A enzymes and has a variety of important drug interactions. Toxicities with long-term use include gastrointestinal distress, nephrotoxicity, hypertension, neurotoxicity, and secondary malignancies. Blood pressure, creatinine, blood urea nitrogen, blood glucose, liver function tests, potassium, and magnesium should be monitored every two weeks for the first three months of therapy and every one to two months thereafter. Plasma creatinine is adequate for follow-up of the renal function; an increase above baseline by more than 30 percent (even if it is still in the normal range) requires a decrease of the dose or a temporary discontinuation of the drug. Similarly, hypertension during therapy should prompt reduction in dose or initiation of antihypertensive therapy. (See "Pharmacology of cyclosporine and tacrolimus".)

RESPONSE EVALUATION — Four months following the initiation of therapy, the response to treatment should be evaluated by history, physical examination, and complete blood count with differential [5]:

●Complete response – A hematologic complete response is defined as the complete normalization of blood counts (ie, hemoglobin >12 g/dL; platelets ≥150,000/microL; absolute neutrophil count >1500/microL; absolute lymphocyte count <4000/microL) in the setting of a circulating LGL count of less than 500/microL.

●Partial response – A hematologic partial response is defined as an improvement in blood counts that does not meet criteria for complete remission (eg, an absolute neutrophil count >500/microL or decreasing transfusion requirements).

●Treatment failure – Treatment failure is defined as an inability to achieve an at least partial response after four months of therapy.

●Progressive disease – Progressive disease is defined as a worsening of cytopenias, hepatomegaly, or splenomegaly.

Patients who achieve an at least partial response should continue treatment until treatment failure or until the maximum number of months has elapsed for that regimen, whichever is shorter. Methotrexate and cyclosporine can be continued indefinitely, as tolerated. In contrast, cyclophosphamide should not be administered for longer than 6 to 12 months for responders. Patients who fail to attain an at least partial response should be considered for a new therapy.

A decision to continue treatment in a patient with a complete remission must balance the toxicity of treatment with the risk of recurrence. There are no formal studies that have addressed this question. Some clinicians choose to discontinue methotrexate in patients who have maintained a complete remission (especially a molecular remission) for one or two years. In our experience, cessation of methotrexate usually leads to eventual slow recurrence of the clinical manifestations of LGL leukemia. Retreatment with methotrexate at that time is usually successful again. In contrast, cessation of cyclosporine is associated with rapid recurrence of cytopenias. Therefore, a drug holiday from cyclosporine is not recommended.

TREATMENT OF RELAPSED OR RESISTANT DISEASE — The treatment of patients with relapsed, resistant, or refractory disease depends upon the initial treatment regimen and the timing of progression. For our purposes [5]:

●Relapsed disease refers to the progression of disease after an initial response.

●Resistant disease refers to the inability to achieve an at least partial response after four months of therapy.

●Refractory disease refers to the failure of the three major immunosuppressive drugs (ie, methotrexate, cyclophosphamide, and cyclosporine).

Relapsed disease — The treatment of patients with LGL leukemia that relapses after an initial response depends upon the timing of relapse. Patients not receiving active treatment at the time of relapse may respond to a second trial of the initial treatment regimen. More commonly, such patients and those who relapse on active therapy may respond to a trial of another one of the three major immunosuppressive drugs (ie, methotrexate, cyclophosphamide, and cyclosporine). (See 'Initial treatment' above.)

Resistant disease — Patients with LGL leukemia that is refractory to initial treatment should undergo a trial of another one of the three major immunosuppressive drugs (ie, methotrexate, cyclophosphamide, and cyclosporine). As described above, responses to cyclophosphamide have been reported in a majority of patients who have failed treatment with methotrexate [12]. Some experts prefer cyclosporine for the treatment of patients with resistant disease manifesting as anemia. (See 'Initial treatment' above.)

Refractory or aggressive disease — Refractory disease refers to those patients who have persistent LGL leukemia despite trials of the three major immunosuppressive drugs (ie, methotrexate, cyclophosphamide, and cyclosporine). The optimal treatment of such patients is unknown and often the best option is to enroll on a clinical trial. Purine analogs and alemtuzumab have demonstrated activity in LGL leukemia and may be considered. Splenectomy may correct neutropenia, hemolytic anemia, or provide symptomatic relief from splenomegaly, but may induce high-risk secondary infections.

Aggressive forms of LGL leukemia have been described with a clinical behavior close to aggressive lymphoma. There is no consensus regarding the preferred treatment approach for such patients, and clinical practice varies. Some clinicians have proposed the use autologous or allogeneic hematopoietic cell transplantation (HCT). A retrospective study by the European Group for Blood and Marrow Transplantation (EGBMT) reported overall survival and progression-free survival at two years of 60 and 43 percent, respectively, for the entire cohort of 15 patients who underwent either autologous or allogeneic HCT (5 and 10 patients, respectively) [27].

Alemtuzumab — The monoclonal antibody alemtuzumab targets CD52 expressed on the surface of T cell LGL leukemia [28]. Case reports and small case series have demonstrated responses in half of patients with refractory disease [12,23,25,29-35]. As an example, a phase II trial of 25 patients demonstrated an overall response of 56 percent [36].

Patients treated with alemtuzumab are immunocompromised and are therefore at risk for potentially lethal opportunistic infections with organisms such as Pneumocystis jirovecii (previously P. carinii) and cytomegalovirus. All patients planning to receive alemtuzumab should undergo serology testing for cytomegalovirus (IgM and IgG), herpes simplex virus (IgM and IgG), hepatitis B (HBsAg and anti-HBc), and hepatitis C (anti-HCV). While prophylaxis for such infections is generally given, clinicians need to consider these organisms when patients become unwell. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV" and "Overview of diagnostic tests for cytomegalovirus infection".)

Autoimmune encephalitis (AIE) has been reported in association with alemtuzumab treatment [37]. Patients with symptoms such as subacute onset of memory impairment, altered mental status, psychiatric symptoms, neurological findings, and/or seizures should be evaluated for AIE. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

Purine analogs — Data regarding the efficacy of purine analogs (eg, 2-chlorodeoxyadenosine, pentostatin, and fludarabine) for the treatment of LGL leukemia are limited to less than 100 published cases [11,12,23,25,38-44]. The overall response rate in reported cases is approximately 80 percent with most remissions occurring after the first course of therapy [5]. Remissions lasting up to six years have been reported.

Patients receiving therapy with purine analogs are at increased risk for several opportunistic infections. The use of antimicrobials in these patients is presented separately. (See "Prevention of infections in patients with chronic lymphocytic leukemia" and "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Purine analogs'.)

Ruxolitinib — The JAK2 inhibitor, ruxolitinib, was reported to achieve durable remissions in patients with refractory LGL leukemia.

JAK-STAT signaling has been proposed as a potential therapeutic target in LGL leukemia [45,46]. Treatment with ruxolitinib achieved a durable complete remission in one patient and a very good partial response (>1 year) in another patient with refractory LGL leukemia; neither patient experienced adverse effects of ruxolitinib [47].

Prior to initiating ruxolitinib, patients should be counseled about the risk of ruxolitinib withdrawal syndrome and screened for tuberculosis, as described separately.

Splenectomy — Case reports and small case series of patients with LGL leukemia have noted responses in up to 56 percent, with the most recent case series demonstrating low response rates [3,5,12,15,48-52]. Splenectomy may be considered only for patients with resistant disease who have symptomatic splenomegaly or evidence of autoimmune cytopenias.

Other therapies — There is a paucity of data regarding the use of other treatment regimens for LGL leukemia. While occasional responses have been noted in case reports, more aggressive treatment, such as the use of allogeneic HCT or chemotherapy regimens used for more aggressive lymphomas (eg, CHOP or hyper-CVAD), has had disappointing results [1,53,54]. Response rates with these regimens are poor and most patients die within one year after the start of treatment. One possible reason for the adverse outcome is that LGL leukemic cells, like their normal counterparts (NK or T cell cytotoxic cells), constitutively express high levels of P glycoprotein (PgP), the product of the multidrug resistance gene (MDR1) [55-58].

A report from France described two cases of T cell LGL leukemia in patients with rheumatoid arthritis (RA) that responded to treatment with the B cell monoclonal antibody rituximab [59]. Rituximab appears somewhat counterintuitive for the treatment of a T cell malignancy; however, there are profound abnormalities in B cell function as evidenced by autoantibodies, circulating immune complexes, and hypergammaglobulinemia in LGL leukemia. Other cases showing efficacy of rituximab in the context of RA and LGL leukemia have been reported [60,61]. Further study is needed to determine whether there is a role for rituximab in this setting, especially in absence of associated RA.

PROGNOSIS — LGL leukemia is usually a chronic disease, and some patients may be asymptomatic for long periods of time [62]. The first large series published in the literature included 151 patients; survival was approximately 85 percent at a mean follow-up of two to four years [62]. Another study of 68 patients reported a median survival greater than 10 years [3].

In multivariate analyses, risk factors associated with poor clinical outcome were fever at diagnosis, low percentage of CD57+ cells, and low (<5000/microL) or high (>20,000/microL) peripheral LGL counts [62]. In another study, severe neutropenia or "B" symptoms (ie, fever, weight loss, night sweats) were associated with a lower probability of complete remission.

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

Ongoing studies are comparing available drugs (eg, methotrexate versus cyclophosphamide) and new drugs. Agents under investigation include some approved for other diseases (eg, Janus kinase inhibitor, tofacitinib), other novel drugs (eg, STAT3 inhibitors), and novel antibodies.

Considering the role of IL-15 in the pathogenesis of LGL leukemia, monoclonal antibodies targeting IL-15 were evaluated, but a phase I trial using a humanized MiK-beta-1 monoclonal antibody against the shared IL-2/IL-15R subunit (CD122) showed disappointing results [63,64].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Large granular lymphocyte leukemia".)

SUMMARY AND RECOMMENDATIONS

●Large granular lymphocyte (LGL) leukemia – LGL leukemia is characterized by peripheral blood and marrow lymphocytic infiltration with clonal LGLs, splenomegaly, and cytopenias, most commonly neutropenia. LGL leukemia can arise from the clonal proliferation of LGLs of T cell or natural killer (NK) cell lineage.

●Management – Not all patients with LGL leukemia require treatment at the time of diagnosis.

•Asymptomatic – For patients with asymptomatic T-LGL, we suggest close observation rather than immediate treatment (Grade 2C). (See 'Asymptomatic patients' above.)

•Symptomatic – We reserve treatment for patients with symptoms related to neutropenia, anemia, thrombocytopenia, or associated autoimmune conditions requiring therapy. (See 'Symptomatic patients' above.)

●Treatment – There is no standard treatment regimen for symptomatic LGL leukemia, but there is general agreement that immunosuppressive therapy (ie, methotrexate, cyclophosphamide, cyclosporine) is the cornerstone of initial treatment. A choice among immunosuppressive treatments is primarily made based upon the clinical setting and physician experience:

•Neutropenia – For patients with LGL leukemia and neutropenia as their primary symptom, we suggest methotrexate with or without prednisone rather than other immunosuppressive therapies (Grade 2C). We administer oral methotrexate 10 mg/m² weekly. For patients with an absolute neutrophil count <200/microL, oral prednisone (1 mg/kg per day) is administered in addition to the methotrexate for the first month and tapered off by the end of the second month. (See 'Methotrexate' above.)

•Autoimmune disorders – For patients with LGL leukemia and an associated autoimmune disorder, we suggest treatment with methotrexate, with or without prednisone (Grade 2C). In this setting, the use of prednisone is dictated by the accompanying autoimmune disorder. (See 'Methotrexate' above.)

•Anemia – For patients with LGL leukemia and anemia as their primary symptom, we suggest either oral methotrexate or oral cyclophosphamide, rather than cyclosporine (Grade 2C). While both of these agents have demonstrated activity in this setting, some clinicians prefer cyclophosphamide for patients with anemia at least partially due to its demonstrated activity in patients with pure red cell aplasia. Other clinicians prefer methotrexate because it can be continued indefinitely as long as it is tolerated, whereas treatment with oral cyclophosphamide is limited to no more than 6 to 12 months. (See 'Cyclophosphamide' above.)

●Response evaluation – Four months following the initiation of therapy, the response to treatment should be evaluated by history, physical examination, and complete blood count with differential. Patients with at least a partial response should continue treatment until treatment failure or until the maximum number of months has elapsed for that regimen, whichever is shorter. Methotrexate and cyclosporine can be continued indefinitely, as tolerated. In contrast, cyclophosphamide should not be administered for longer than 6 to 12 months for responders. (See 'Response evaluation' above.)

●Relapsed, refractory, or resistant disease – Treatment of patients with relapsed, resistant, or refractory disease depends upon the initial treatment regimen and the timing of progression. (See 'Treatment of relapsed or resistant disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas P Loughran, Jr, MD, who contributed to earlier versions of this topic review.