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Treatment of hairy cell leukemia

Treatment of hairy cell leukemia
Author:
Martin S Tallman, MD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Rebecca F Connor, MD
Literature review current through: Dec 2022. | This topic last updated: Mar 07, 2022.

INTRODUCTION — Hairy cell leukemia (HCL) is an uncommon lymphoid neoplasm characterized by the accumulation of small mature B cell lymphoid cells with abundant cytoplasm and "hairy" projections within the peripheral blood, bone marrow, and splenic red pulp. This accumulation of neoplastic cells typically results in splenomegaly; a variable reduction in the production of normal red blood cells, platelets, mature granulocytes, and monocytes; and complications of anemia, bleeding, and infection.

The treatment of HCL will be reviewed here; clinical features and diagnosis of this disorder are discussed separately. (See "Clinical features and diagnosis of hairy cell leukemia".)

PRETREATMENT EVALUATION — The initial evaluation of patients with HCL must establish the precise diagnosis, the extent of disease, and the performance status of the patient. Particular attention should be paid in the history and physical examination to palpable enlargement of the spleen, liver, and/or lymph nodes and history of recent infections.

Our pretreatment evaluation also includes the following studies, some of which are performed as part of the diagnostic evaluation (see "Clinical features and diagnosis of hairy cell leukemia", section on 'Evaluation'):

Laboratory studies include a complete blood count with differential and evaluation of the peripheral smear, chemistries with liver and renal function and electrolytes, uric acid, and lactate dehydrogenase. Hepatitis B and C serology should be obtained, especially for patients whose planned treatment includes rituximab.

Flow cytometry of the peripheral blood to confirm the immunophenotype of the circulating mononuclear cells.

Unilateral bone marrow biopsy is recommended for all patients; an aspirate should be attempted, but is often not attainable (dry tap). This sample should be sent for pathologic review with morphologic evaluation and immunohistochemistry. All cases should be evaluated for the BRAF V600E mutation using a highly sensitive technique (ie, allele-specific polymerase chain reaction or next-generation sequencing). If a highly sensitive technique is not available, immunohistochemical staining for VE1 may identify this mutation on bone marrow biopsy.

Imaging is not a standard part of the evaluation of patients outside of a clinical trial, but is appropriate for the evaluation of suspected complications such as infection or symptoms related to organomegaly or lymphadenopathy.

Women of childbearing age should have a serum pregnancy test if chemotherapy or radiation therapy is planned.

THERAPEUTIC STRATEGY

Goals of care — While not curative, modern therapy for HCL can alleviate symptoms, reverse cytopenias, and prolong survival to a near normal lifespan. Most patients can achieve durable remissions with long treatment-free periods followed by further therapy when symptomatic relapse occurs.

Indications for treatment — Many patients with HCL are asymptomatic and can be observed for months or years after the diagnosis is established before requiring treatment. There is no clear advantage to early treatment; therapy is indicated only when the patient develops one or more of the following problems or symptoms [1]. (See "Clinical features and diagnosis of hairy cell leukemia", section on 'Presenting symptoms or signs'.)

Significant cytopenias; typical peripheral blood counts that warrant treatment include an absolute neutrophil count <1000/microL, hemoglobin concentration <11 g/dL, or platelet count <100,000/microL

Symptomatic splenomegaly (common) or symptomatic adenopathy (uncommon)

Constitutional symptoms (eg, fever, night sweats, fatigue, weight loss)

Treatment may also be appropriate for patients with less severe cytopenias that are symptomatic (eg, repeated infections, bleeding) and for those with progressive lymphocytosis [1].

Asymptomatic patients — As described above, immediate treatment is indicated in patients with active disease manifest as significant cytopenias, symptomatic splenomegaly or adenopathy, or severe disease-related constitutional symptoms. Otherwise, a period of observation is recommended.

During this observation period, the frequency of visits depends on the severity and tempo of disease. Most patients can be seen in clinic every three months for the first year and then every three to six months thereafter until indications for therapy arise. At these visits we perform a history, physical examination, and a complete blood count with differential.

Infections — Historically, infection has been a major cause of death in patients with HCL [1-4]. These patients have an increased risk of infection due to a combination of disease-related immunosuppression (eg, neutropenia and/or monocytopenia) and treatment-related immunosuppression. In addition to increased rates of bacterial, viral, and fungal infections, patients with HCL appear to be at increased risk of nontuberculous mycobacterial infections [5].

The following specific issues related to infectious complications are discussed separately:

Purine analogs suppress immune effector cells and induce a profound neutropenia and prolonged lymphopenia. Risk of infection with purine analogs and antimicrobial prophylaxis is discussed separately. (See "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Purine analog therapy' and "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Other purine analogs'.)

Patients who develop neutropenic fever require prompt evaluation and immediate administration of parenteral antibiotics tailored to the prominent organisms and resistance patterns of the institution. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

The use of granulocyte colony-stimulating factors must take into account the expected incidence of neutropenia and patient age. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

Prevention of infection through vaccination is important in patients with HCL. However, many patients with impaired immunity are unable to mount a protective immune response to active vaccination, and immunization with live virus vaccines may result in unchecked proliferation of attenuated strains. Most patients with HCL should be vaccinated with inactivated vaccines (eg, inactivated influenza vaccine), as indicated. Those receiving chemotherapy should not receive live virus vaccines (eg, vaccines for varicella; measles, mumps, rubella; measles, mumps, rubella, and varicella). Further details, including the appropriate timing of vaccination in patients with cancer, are discussed separately. (See "Immunizations in adults with cancer".)

Patients with serologic evidence of hepatitis B virus (HBV) infection (HBsAg-positive or anti-HBc-positive) are at risk for HBV reactivation and severe hepatitis if they receive immunosuppressive therapy. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Patients previously treated with purine analogs should receive irradiated blood products, if transfusion is indicated, to prevent transfusion-associated graft-versus-host disease. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Irradiation'.)

Variant hairy cell leukemia — HCL variant (HCL-v) is a rare chronic B cell lymphoid neoplasm that was previously thought to be a subtype of HCL, but is now considered to be an entity that is biologically distinct from HCL. (See "Clinical features and diagnosis of hairy cell leukemia", section on 'HCL variant'.)

For most patients with HCL-v, we suggest either five daily infusions of cladribine or seven days of continuous infusion cladribine, each followed approximately one month later by eight weekly treatments of rituximab. The choice between the five- and seven-day schedules can be based on feasibility in the clinic and clinician preferences. We administer the rituximab as consolidation rather than concurrently with the cladribine as cladribine frequently causes fever, which can complicate concurrent rituximab administration. Those who achieve normal peripheral blood counts are observed until progression. (See 'Administration' below.)

Support for cladribine plus rituximab comes from small prospective studies that report complete remission rates (CR) of at least 90 percent [6-8]. In the largest of these, 20 patients with HCL-v were treated with five daily infusions of cladribine plus eight weekly infusions of rituximab beginning on day 1 of cladribine [8]. Patients received a second eight-week course of rituximab if and when their blood had detectable minimal residual disease (MRD) at least six months after the first course. CR was achieved in 70 percent at four weeks and in 95 percent at six months. Eleven patients received a second course of rituximab. After a median follow-up of 70 months, estimated five-year progression-free survival (PFS) and overall survival (OS) were 63 and 74 percent, respectively. PFS and OS were shorter for HCL-v with mutated TP53 and/or detectable MRD at six months.

In contrast, most cases of HCL-v are poorly responsive or resistant to treatment with purine analogs alone and/or splenectomy [9-11].

MANAGEMENT

Our approach — Our initial approach to treatment is generally consistent with that proposed by an international consensus guideline supported by the Hairy Cell Leukemia Foundation [1], the British Society for Haematology [12], and the National Comprehensive Cancer Network [13].

When selecting a management strategy (algorithm 1), the following principles apply:

Therapy should be reserved for patients with symptomatic disease since asymptomatic patients may do well without therapy and treatment has potential short- and long-term complications. (See 'Indications for treatment' above.)

Purine analogs (ie, cladribine or pentostatin) are the preferred initial treatment for most patients with symptomatic HCL and normal renal function. Durable responses are seen in >90 percent of patients with a median progression-free survival (PFS) of 9 to 11 years. Because of ease of administration, we often prefer a single cycle of cladribine. For most patients with HCL, we offer either five daily infusions of cladribine or seven days of continuous infusion cladribine. The choice between the five- and seven-day schedules can be based on feasibility in the clinic and clinician preferences. Following initial treatment with cladribine, we offer a short course of rituximab consolidation. (See 'Purine analogs' below.)

Patients with an active infection are treated with antimicrobials in an attempt to control the infection prior to starting a purine analog. (See 'Infections' above.)

If it is not possible to control the infection and there is need for immediate treatment, alternative therapies or dosing not associated with myelosuppression (eg, low dose pentostatin [14,15], vemurafenib) may be offered until the infection is controlled. Treatment with standard dose purine analogs is not suggested in the setting of active infection since it is associated with a decline in neutrophils prior to hematologic recovery. (See 'BRAF inhibition (vemurafenib or dabrafenib)' below.)

Purine analogs must be used with caution in patients with renal impairment. There are no dose adjustments provided in the manufacturer's labeling and these agents have not been adequately studied in this population. Some authorities suggest dose adjustments for cladribine (75 percent dose for creatinine clearance [CrCl] 10 to 50 mL/min; 50 percent dose for CrCl <10 mL/min).

Splenectomy may be offered as a palliative therapy in patients with symptomatic splenomegaly (massive enlargement, pain, infarction, rupture); as a temporizing measure in symptomatic pregnant women; or as a salvage therapy in patients with pancytopenia which is still present after other therapies. (See 'Splenectomy' below.)

In the immediate post-treatment period, patients are monitored with serial complete blood counts for count recovery and clinically for fever and signs/symptoms of infection. Response should be formally assessed four to six months after the conclusion of primary therapy. (See 'Response assessment' below.)

Purine analogs — The purine analogs pentostatin (2'-deoxycoformycin, 2'-DCF) and cladribine (2-chlorodeoxyadenosine, 2-CdA) are naturally targeted to lymphocytes and are cytotoxic to both resting and dividing cells. Both drugs induce durable complete remissions (CR) in the overwhelming majority of patients with HCL. Equally high rates of durable CRs are achieved with these two agents in both untreated and previously treated patients [16,17] and those with large or minimal tumor burdens. For these reasons, these agents are the initial treatment of choice for patients with HCL. There are no large series of patients with HCL treated with the other major purine analog fludarabine.

Choice of purine analog — The choice between cladribine and pentostatin must take into account the ease of administration and patient-related factors. For most patients, we prefer cladribine because of the shorter duration of therapy required (five to seven days versus several months), and general tolerability. Pentostatin has a boxed warning for severe renal toxicities with doses higher than recommended; do not exceed the recommended dose. Serum creatinine elevations occurring at recommended doses are usually minor and reversible.

The majority of patients achieve durable remissions with either multiple cycles of pentostatin or a single cycle of cladribine [18,19]. In one study of 233 patients followed for a median period of 16 years, cladribine and pentostatin resulted in similar overall response rates (100 versus 96 percent), rates of CR (76 versus 82 percent), and 10-year survivals (100 versus 96 percent) [16,17]. Patients achieving a CR with either agent showed significantly longer median disease-free survival (DFS) than those attaining only a partial remission (PR; not reached at 14 years versus 5.5 years).

The following illustrates the differences in administration:

Cladribine is administered with a defined endpoint. It is most often given as a two-hour infusion for five daily doses or as a continuous infusion over seven days. Cladribine should not be used in patients with active infection as trials excluded these patients. (See 'Cladribine' below.)

Pentostatin is administered intravenously once every two weeks as an outpatient. Pentostatin dose can be titrated to reduce the depth and duration of myelosuppression. Pentostatin has been used with active infection [14,15]. (See 'Pentostatin' below.)

Cladribine

Administration — Cladribine (2-CdA) is our preferred initial therapy for most patients with previously untreated HCL. Cladribine should not be used in patients with active infection as trials excluded these patients and cladribine is myelosuppressive. Cladribine is administered on a defined schedule. For most patients with HCL, we offer five daily infusions of cladribine or seven days of continuous infusion cladribine. Following initial treatment with cladribine, we offer a short course of rituximab consolidation.

Various regimens have been used in clinical trials and the following two options are widely accepted:

Cladribine administered as a continuous intravenous infusion 0.1 mg/kg per day for seven days [20-26]

Cladribine 0.14 mg/kg/day intravenously over two hours once per day for five days [27-29]

Alternative off-label routes and schedules of administration of cladribine have included weekly two-hour infusions [30,31], oral administration [27,28,32], and subcutaneous administration [27,28,33,34]. Subcutaneous administration appears to be safe and to achieve drug levels similar to those achieved with intravenous administration [27,28,34]. Although prospective trials that used this route report excellent survival (similar to the normal population), there were relatively high rates of second primary malignancy (20 percent after a median of 5.7 years) and need for second-line treatment (required by 24 percent after a median of five years) [33].

The seven-day infusion of cladribine may be more myelosuppressive but has added convenience since it can be administered as an outpatient with a portable pump. The five daily infusions require more frequent visits to the clinic but allow for an in-person assessment of toxicity by the clinical team. As described below, deeper responses have been achieved using sequential cladribine followed by rituximab; it is not known yet whether this strategy will lead to greater long-term DFS compared with cladribine alone. Following initial treatment with cladribine, we offer a short course of rituximab consolidation. (See 'Rituximab' below.)

Fever occurs in the majority of patients treated with cladribine, coinciding with a rapid decline in the number of circulating hairy cells and neutrophils [35]. In some series, no viral, fungal, or other opportunistic infections were observed other than a single case of dermatomal herpes zoster 16 months after treatment. Infections are rarely documented, and it is believed that the fever may reflect cytokine release from hairy cells.

A phase II trial of granulocyte colony-stimulating factor (G-CSF) explored the relationship between cladribine-induced fever and neutropenia [35]. Treatment with G-CSF shortened the period of neutropenia, as compared with historical controls treated with cladribine alone. However, the incidence of febrile patients, number of febrile days, or frequency of admission for treatment with antibiotics was not changed. These data support the hypothesis that most fever is cytokine-mediated and not due to infection.

Cladribine therapy may be associated with the development of unexpected foci of hypoplasia and aplasia in bone marrow biopsies performed as part of their evaluation [36]. These foci are present in patients in CR with normal peripheral blood counts; their long-term significance is unclear [36].

Efficacy

Single-agent cladribine — A single cycle of cladribine will achieve a durable remission in the vast majority of patients with HCL. Cladribine has not been evaluated in randomized trials. Support for its use comes from case series and retrospective analyses.

The largest single institution experience with cladribine (0.1 mg/kg per day for seven days by continuous intravenous infusion) consisted of 349 evaluable patients with previously treated or untreated HCL [23,24]. The CR and PR rates were 91 and 7 percent, respectively. At four years, the overall survival (OS) was 96 percent; the relapse rates for patients achieving CR and PR were 16 and 54 percent, respectively. Of the 53 patients in first relapse after a cladribine-induced remission, retreatment with cladribine yielded CR and PR rates of 62 and 26 percent, respectively.

Extended follow-up from the same institution of 88 young adults (≤40 years) treated with cladribine and followed for a median of 21 years reported an 88 percent CR rate with a median duration of CR of 57 months (range 7 to 246 months) [37]. A PR was achieved in 12 percent with a median duration of response of 20 months (range 7 to 108 months). There was great variation in the length of response and, except for the degree of response (partial versus complete), the study could not identify clinical or pathologic features that were associated with longer or shorter duration of response. Data regarding measurable residual disease after treatment were not available. Of interest, the median duration of response in this population of younger adults was shorter than the median duration of response in an age-unrestricted population from the same center (57 versus 98 months, respectively).

In most other studies, including our own, 76 to 80 percent of assessable patients with HCL treated with cladribine achieved CR, and 7 to 24 percent achieved PR, with minimal toxicity [16,21,22,38]. The majority of patients remained disease-free for a prolonged period of time, with relapse rates of 14 to 20 percent at 24 to 30 months and 36 percent at 9.7 years [38]. PFS and OS at four years have been 72 to 84 percent and 86 to 96 percent, respectively [21,23-25,39,40]. OS in three series, including our own, was 79 to 87 percent after 12 years [33,38,41].

Cladribine plus rituximab — As described below, incorporation of rituximab into the initial therapy deepens responses and results in long remission durations; however, rituximab is also associated with immunosuppression and longer follow-up is needed to confirm superiority in long-term outcomes. Starting four to six weeks after initial treatment with cladribine, we offer four weekly doses of rituximab consolidation.

In a phase II trial, 59 patients with newly diagnosed HCL requiring treatment received an initial cycle of cladribine followed approximately one month later by eight weekly treatments of rituximab [7,42,43]. All patients achieved a CR and there were no severe (grade 3/4) toxicities. At a median follow-up of 60 months, the estimated rates of five-year failure-free survival and OS were 95 and 97 percent, respectively. Two patients required subsequent therapy, one for hematologic relapse at 12 months and the other for measurable residual disease (MRD) recurrence at 52 months. One patient died due to an unrelated cancer.

In a second phase II trial, 68 patients with purine analog-naïve classic HCL requiring treatment were randomly assigned to receive cladribine plus concurrent or delayed rituximab [44]. Those assigned to concurrent rituximab received eight weekly doses of rituximab starting on the first day of cladribine. Those assigned to delayed rituximab received rituximab if they had MRD in the blood six months or more after the cladribine. Both treatment groups could receive a second course of rituximab if MRD was detected in the blood six months or more after the first rituximab. When compared with a delayed rituximab strategy, concurrent rituximab resulted in:

Higher rates of blood MRD negativity at six months (100 versus 50 percent).

Fewer patients requiring two courses of rituximab (3 versus 18 percent).

Higher likelihood of maintaining MRD negativity long term (94 versus 12 percent with a median follow-up of 96 months). Ten patients maintained MRD negativity for more than five years after cladribine monotherapy.

Higher rates of grade 3 or 4 thrombocytopenia (59 versus 9 percent) and need for platelet transfusions (35 versus 0 percent).        

This study design raises several questions regarding the timing of treatment and the schedule and number of doses of rituximab. The study compared concurrent treatment versus treatment of blood MRD-positive disease six months after initial therapy. The latter arm is more reflective of treatment of resistant disease rather than consolidation of initial therapy. The design also used eight doses of concurrent rituximab rather than four doses of consolidation rituximab. Concurrent use of rituximab with cladribine adds toxicity. In addition, infusion-related reactions seen with rituximab may be confounded by the fever commonly seen with cladribine alone. It is also unlikely that eight doses of rituximab are necessary given the long periods of disease control seen with four doses when given as consolidation.

Pentostatin — Pentostatin is an acceptable alternative to cladribine for the initial treatment of HCL given its similar efficacy. When compared with interferon alfa (IFNa), pentostatin results in superior response rates and longer remissions.

Administration — Pentostatin is administered as 4 mg/m2 intravenously (IV) once every two weeks until maximal response. Infusions can be given in the outpatient setting. The dose of pentostatin can be titrated to reduce the depth and duration of myelosuppression. Unlike cladribine, pentostatin has been used with active infection [14,15].

Pentostatin has a boxed warning for severe renal toxicities with doses higher than recommended; do not exceed the recommended dose. Serum creatinine elevations occurring at recommended doses are usually minor and reversible. Data regarding risk of nausea or emesis are limited, but risk appears to be low.  

While clinicians often administer two consolidation doses of pentostatin after induction is complete, there is no evidence that this is necessary. Failure to obtain clinical evidence of an objective response by six months should lead to a change in therapy. Patients who show objective evidence of response by six months can be treated for up to a year in an attempt to achieve an optimal response.

Pentostatin is associated with a decrease in the total lymphocyte count, with a reduction in T cells proportionately greater than that for B cells or natural killer cells [45]. Absolute numbers of CD4+ and CD8+ cells fall to less than 200 cells/microL for at least six months after pentostatin is discontinued. In two studies, the median time to recovery of CD4+ cell counts following cessation of therapy was 54 months with pentostatin [46] and 40 months with cladribine [40].

Despite this degree of immunosuppression, opportunistic infections, other than an occasional case of herpes zoster, are uncommon unless purine analog treatment is associated with concomitant glucocorticoid exposure [47]. Prophylaxis against Pneumocystis carinii pneumonia may be reasonable if glucocorticoids are being given for a separate indication. (See "Prevention of infections in patients with chronic lymphocytic leukemia" and "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Other purine analogs'.)

Efficacy — The majority of patients achieve durable remissions with either multiple cycles of pentostatin or a single cycle of cladribine. When compared with IFNa, pentostatin results in superior response rates and longer remissions. In addition, pentostatin is usually effective in patients who are refractory to treatment with IFNa [48].

Pentostatin was the first drug reported that induced a high rate of CRs in HCL [49,50]. Trials have used a variety of doses and schedules [14,32,48-58]. Higher doses have been associated with similar response rates, but greater toxicity. As examples:

In an study of 50 patients with HCL treated with pentostatin (5 mg/m2 per day for two consecutive days every two weeks until maximum response), overall response rate and CR rate were 84 and 64 percent, respectively, with the majority of patients achieving maximal response within six months [52]. Toxicities were moderate and included nausea, vomiting, skin rash, and conjunctivitis, as well as significant neurologic toxicities in four patients. "Life-threatening" neutropenia occurred in 70 percent of patients; however, this was limited to the first two to three cycles of therapy. Mortality as a result of therapy was attributable to infection in 6 percent of patients.

In another study, CR was attained in 20 of 23 patients (87 percent) treated with pentostatin (4 mg/m2 every other week) with infrequent infections and no treatment-related deaths [32]. CD4+ cells were significantly, but only temporarily, decreased after treatment, with no opportunistic infections or second malignancies being noted after two years of follow-up.

Another series evaluated a regimen of pentostatin at 4 mg/m2 IV weekly for three consecutive weeks, with therapy repeated every eight weeks [56]. CR was achieved in 25 of 28 patients (89 percent) after completion of two cycles of therapy. Transient neutropenia occurred only during the first cycle and 12 patients developed fever and/or infection; there were no deaths.

The relative efficacy of pentostatin and IFNa was evaluated in a prospective intergroup study that randomly assigned 313 patients with HCL to receive either pentostatin (4 mg/m2 IV every two weeks for six months) or IFNa (3 million units subcutaneously three times per week) [14]. Pentostatin therapy was associated with higher rates of confirmed CR (76 versus 11 percent) and confirmed CR or PR (79 versus 38 percent) and a longer median relapse-free survival (not reached versus 20 months after a median follow-up of 57 months). Survival outcomes were not significantly different between treatment arms, although this analysis was complicated by the cross-over design of the study. Estimated OS and relapse-free survival of patients achieving CR with pentostatin were 87 and 76 percent, respectively [59].

At a median follow-up of over nine years, 83 percent of patients treated with pentostatin on this protocol were still alive, and only 18 percent of those who achieved CR have relapsed [59]. Of the 40 deaths, two were related to HCL; the mortality rate for the cohort of pentostatin-treated patients was similar to age- and sex-specific mortality in the United States.

Splenectomy — Splenectomy is not routinely used for patients with HCL. Possible indications for splenectomy in HCL include:

Symptomatic splenomegaly (massive enlargement, pain, infarction, rupture)

Pancytopenia due to splenic sequestration that is still present after other treatments [60]

As a temporizing measure in symptomatic pregnant women [61]

Highly effective therapy with purine analogs generally obviates the need for splenectomy in other settings. (See 'Purine analogs' above.)

Removal of the spleen was the first effective therapy for HCL [62-64]. Although splenectomy does not produce pathologic remissions, peripheral blood counts return to normal in approximately 40 to 70 percent of patients [62]. The response to splenectomy is maintained for a median of 20 months, approximately one-half have disease progression within five years, and the OS at five years is 60 to 70 percent [62,65].

RESPONSE ASSESSMENT — Following initial treatment, patients should be evaluated to determine the response to therapy. This evaluation includes a complete physical examination, including an evaluation of spleen size, complete blood count with differential, and a bone marrow biopsy (table 1). Although post-treatment bone marrow biopsy is not mandatory outside of a clinical trial, it is required to document a complete response (CR) and has prognostic value.

The bone marrow biopsy looks for normal hematopoiesis and the eradication of the leukemic cells. Following the completion of therapy, there can be delayed and continuing improvement. Bone marrow biopsy should be delayed for four to six months following the completion of cladribine therapy. Following pentostatin, bone marrow biopsy is performed when there is near normalization of hematologic parameters.

Initial treatment aims to achieve a CR defined as [1]:

Near normalization of peripheral blood counts: hemoglobin >11 g/dL (without transfusion); platelets >100,000/microL; absolute neutrophil count >1500/microL.

Regression of splenomegaly on physical examination. Radiographic assessment of spleen size is not necessary for clinical practice.

Absence of morphologic evidence of HCL on both the peripheral blood smear and the bone marrow examination.

Measurable residual disease (MRD, also called "minimal residual disease") is defined as HCL infiltrates recognizable by immunohistochemical stains, but not by conventional stains. Depending on the criteria used, 13 to 53 percent of patients in apparent CR have evidence of MRD, which may or may not predict future relapse [66-69]. MRD has also been detected using polymerase chain reaction and flow cytometry [70-72].

The peripheral blood counts required for CR are slightly lower than normal because they account for the recovery period needed following exposure to purine analogs. The lymphocyte count, including lymphocyte subsets, may be reduced for a long time after exposure to purine analogs [40].

Patients with a partial response may remain asymptomatic for many years without further therapy. Alternatively, a second course of cladribine, an alternative purine analog, rituximab therapy, or combination therapy with rituximab plus a purine analog may be offered [19,42,73,74]. The extent of remaining MRD that may impact the potential for relapse must be balanced by the extent of therapy being used to achieve this end.

Those with stable or progressive disease need further therapy. Decreases in hematologic parameters may be due to disease progression or the myelosuppression of therapy. A decline in blood counts due to chemotherapy will recover with observation.

TREATMENT OF RESISTANT OR RELAPSED DISEASE

Resistant disease — The vast majority of patients treated with purine analogs will achieve a response, but up to 4 percent of patients have stable or progressive disease and up to 20 percent achieve only a partial remission (PR) [16,17,19,38]. For patients with HCL resistant to treatment with a purine analog, we suggest switching to an alternative purine analog (ie, pentostatin in those who have received cladribine, and vice versa) or off-label vemurafenib plus rituximab. (See 'BRAF inhibition (vemurafenib or dabrafenib)' below.)

Patients with HCL resistant to two or more therapies are candidates for moxetumomab pasudotox. Other options include vemurafenib, bendamustine plus rituximab, single-agent rituximab, splenectomy, or other investigational therapies. (See 'Moxetumomab pasudotox' below.)

Relapsed disease — Criteria for retreatment are the same as those used for initial treatment. Retreatment is not necessary simply for the reappearance of hairy cells in the peripheral blood or bone marrow by morphologic or immunophenotypic/immunohistochemical techniques. The decision to treat must weigh the potential toxicity of treatment. (See 'Indications for treatment' above.)

Our preferred therapy for patients with relapsed HCL depends in part on the length of response to initial therapy (algorithm 1):

For patients with a previous remission lasting >24 months, we suggest retreatment with the previously effective purine analog or alternative purine analog (ie, pentostatin in those who have received cladribine, and vice versa), each followed by rituximab. (See 'Purine analogs' above.)

For patients with an initial remission <24 months, we re-evaluate the accuracy of the original diagnosis. We do not retreat with the initial therapy. Options include:

Off-label vemurafenib plus rituximab. (See 'BRAF inhibition (vemurafenib or dabrafenib)' below.)

Moxetumomab pasudotox. (See 'Moxetumomab pasudotox' below.)

Alternative purine analog (ie, pentostatin in those who have received cladribine, and vice versa). (See 'Pentostatin' above.)

In addition, single-agent rituximab is a reasonable alternative for those relapsing <24 months after a purine analog alone. (See 'Rituximab' below.)

Patients are likely to experience serial relapses. Older therapeutic approaches (eg, interferon alfa, splenectomy) may still offer benefit in this setting, but a clinical trial would be preferred.

Retreatment with a second cycle of cladribine or pentostatin leads to a second complete remission (CR) in up to 70 percent of patients [16,17,21,23,37,38]. In one study, the probability of achieving a CR was not affected by whether the patient was retreated with the same purine analog (71 percent) or switched to the alternative one (68 percent) [17].

While overall response rates are 97 to 100 percent after second- and third-line treatment with the purine analogs, the rates of CR as well as the lengths of disease-free survival (DFS) become progressively shorter with each course of therapy. In one study, median DFS after an initial course of a purine analog was not reached at 14 years, and the median DFS after second- and third-line treatment with these agents was 7.5 and 4 years, respectively [17]. In our experience, retreatment with cladribine occasionally leads to long periods of myelosuppression and cytopenias.

Targeted therapies — At least three monoclonal antibodies, directed against CD22, CD20, or CD25, have been evaluated in the treatment of resistant or relapsed HCL. These agents appear to be highly active and well tolerated even in patients resistant to treatment with the purine analogs [75].

Rituximab — The anti-CD20 antibody rituximab has been evaluated in patients with HCL. The use of single-agent rituximab has yielded mixed results in clinical trials. Toxicity in all of these trials has been minimal. The following is an overview of some of the studies that have evaluated this treatment approach. Rituximab consolidation after initial therapy is discussed separately. (See 'Cladribine plus rituximab' above.)

A phase II study of rituximab in 24 patients with relapsed disease after treatment with cladribine demonstrated overall response rates of 24 percent (three complete, three partial) [76].

A number of small studies have reported higher overall (64 to 100 percent) and complete (53 to 92 percent) responses, as well as overall molecular response rates as high as 70 percent [16,71,77-79].

A retrospective review evaluated pentostatin or cladribine combined concurrently or sequentially with rituximab as second-line therapy [80]. All eight patients responded to therapy with seven CRs. At a median follow-up of 29 months, only one patient had developed recurrent disease. The relative benefits of concurrent or sequential cladribine followed by rituximab will require further study.

A retrospective review of 15 patients with relapsed or refractory HCL treated with fludarabine plus rituximab reported disease response in all evaluable patients (13 patients) [81]. Three patients achieved measurable residual disease (MRD) negativity. After a median follow-up of 35 months, 14 patients remained progression-free, while one succumbed to complications of the disease. It is not clear that fludarabine provided additional benefit to the rituximab therapy.

A phase II trial evaluated five days of intravenous cladribine followed approximately one month later with eight weekly treatments of rituximab in 14 patients with relapsed HCL requiring treatment [7]. There were no severe (grade 3/4) events and all patients achieved a CR. No relapses or deaths had occurred after a median follow-up of 60 months.

Moxetumomab pasudotox — Initial trials of pseudomonas exotoxin-linked recombinant anti-CD22 antibodies, such as moxetumomab pasudotox, have shown high response rates in patients with previously treated HCL, but not in those with HCL-variant [82-88]. The incorporation of moxetumomab pasudotox into our treatment approach is discussed above and in the algorithm (algorithm 1). (See 'Relapsed disease' above and 'Resistant disease' above.)

A multicenter, open-label study evaluated moxetumomab pasudotox in 80 patients with relapsed or refractory HCL who had at least two prior systemic therapies, including at least one purine nucleoside analog [89]. Patients had received a median of three prior therapies and 75 percent had received rituximab. Moxetumomab pasudotox (0.04 mg/kg) was administered by intravenous infusion on days 1, 3, and 5 of each 28-day cycle. Treatment was continued for a maximum of six cycles and discontinued earlier in the event of a CR, disease progression, or unacceptable toxicity. The following outcomes were noted:

Responses were seen in 60 patients (75 percent) overall with 33 patients (41 percent) achieving a CR and 27 patients (34 percent) achieving MRD negativity. Of these, 24 patients (30 percent) maintained hematologic remission for more than 180 days. MRD negativity was associated with prolonged CR. None of the three patients with HCL-variant achieved CR.

Toxicities were mostly mild (grade 1 or 2) and included a cytokine release syndrome (fever, hypotension, myalgia or arthralgia), edema, gastrointestinal distress, transient hypoalbuminemia, and elevated aminotransferase levels. Severe toxicities were uncommon and reversible, but potentially life threatening, and included capillary leak syndrome (9 percent) and hemolytic uremia syndrome (8 percent). Three patients died with pneumonia, septic shock, and sepsis.

These results illustrate the efficacy of moxetumomab pasudotox in this heavily pretreated population and the complexity of administration. Long-term follow-up is needed to determine the durability of response and evaluate for long-term toxicity. Moxetumomab pasudotox is approved by the US Food and Drug Administration for adults with relapsed or refractory HCL who received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Administration is complicated and includes hydration, premedication for infusion-related reactions, and monitoring for renal toxicity, electrolyte abnormalities, capillary leak syndrome, and hemolytic uremic syndrome.

BRAF inhibition (vemurafenib or dabrafenib) — We reserve the off-label use of vemurafenib plus rituximab for patients with an unsatisfactory response to or progression within 24 months of initial treatment with a purine analog (algorithm 1). When used as single agents, BRAF inhibitors can induce partial, transient responses in HCL with BRAF mutations. The addition of rituximab to vemurafenib appears to result in faster, deeper responses with longer remissions, although further data are needed to confirm efficacy and clarify the optimal dosing and schedule. BRAF inhibitors are likely not effective in patients with the HCL-variant since such cases do not usually express the BRAF mutation.

Vemurafenib plus rituximab – A single center, phase 2 trial evaluated the combination of vemurafenib plus rituximab in 30 patients with relapsed or refractory HCL after a median of three prior therapies [90]. Two four-week induction cycles of vemurafenib plus rituximab were followed by four additional doses of rituximab consolidation. A CR was achieved in 26 patients (87 percent) and 17 had undetectable minimal residual disease. Among responders, 85 percent were relapse-free after a median follow-up of 34 months. Progression-free survival was 78 percent at 37 months for the larger population. Toxicities were mostly grade 1 or 2 and reflected those of the individual agents.

Vemurafenib or dabrafenib alone – Small prospective trials have evaluated vemurafenib and dabrafenib as single agents [91,92]. As an example, two phase 2 multicenter studies evaluated the efficacy of vemurafenib (960 mg twice daily) in patients with HCL relapsed after or refractory to treatment with purine analogs [91]:

In the Italian study of 28 patients, the overall response rate was 96 percent (35 percent complete) after a median of eight weeks of treatment. After a median follow-up of 23 months, those with a CR had median relapse-free and treatment-free survivals of 19 and 25 months, respectively. Partial responders had median relapse-free and treatment-free survival times of 6 and 18 months, respectively.

In the United States study, all 26 patients demonstrated a response (42 percent complete) after a median of 12 weeks. Rates of progression-free and overall survival at one year were 73 and 91 percent, respectively.

In a retrospective study of 27 patients treated with either vemurafenib or dabrafenib, 18 of 20 patients evaluable for response by bone marrow examination demonstrated a complete or partial response (6 CR and 12 PR) [93]. After discontinuation of the BRAF inhibitor, responses were not durable. The median time to next treatment was 12.1 months in the population overall, and 17.6 months in those who achieved CR without detectable minimal residual disease. The doses and durations of both BRAF inhibitors varied. The majority of patients had been previously treated.

Toxicities – Most toxicities with BRAF inhibitors are mild (grade 1 or 2), although dose reductions secondary to toxicity are common. The most common toxicities included rash, photosensitivity, arthralgias/arthritis, fever, and elevations in liver and pancreatic enzymes. Secondary cutaneous tumors developed in 14 percent, all of which were treated with excision. Squamous cell carcinomas and keratoacanthomas have also been reported. Rarely, vemurafenib has caused abnormal renal function [91]. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

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).

Many agents are under active investigation or in development. These include combinations of agents already used in HCL, agents approved for other diseases (eg, ibrutinib [94-96]) and other novel agents. Some of these are described in the sections above. (See 'Targeted therapies' above.)

As an example, a recombinant anti-CD25 antibody linked to a truncated form of pseudomonas exotoxin (LMB-2) has been used in phase I trials in patients with HCL who had experienced treatment failure with cladribine and interferon alfa [97,98]. Major responses were seen in these studies, with maximum reduction of malignant cells in the peripheral blood varying from 98 to 99.8 percent.

SECOND MALIGNANCIES — Patients should be encouraged to follow normal recommendations for cancer screening, including routine careful follow-up with a dermatologist.

There are conflicting data on the risk of second malignancies following therapy for HCL [59,99-106]. The range of findings can be illustrated by the following:

In a study of 117 patients with HCL, there were 44 second malignancies in 36 patients; the majority being nonhematologic [101]. Ninety percent confidence intervals for the relative risk of second malignancies varied widely, being 0.2 to 3.8 for splenectomy, 0.6 to 5.7 for purine analogs, 1.6 to 4.3 for interferon followed by purine analogs, and 1.6 to 8.4 for interferon alone.

In 358 patients with HCL treated with cladribine, second malignancies, only one of which was hematologic, were noted in 8 percent (observed-to-expected ratio [OER] 1.9; 95% CI 1.2-2.7) [23,24]. A similar OER for second malignancies of 1.5 for cladribine and 1.4 for pentostatin was noted in another series of more than 1300 patients [102]. These ratios are similar to those reported in HCL before the purine analog era [102].

The Italian Cooperative Group for the Study of Hairy Cell Leukemia observed a cumulative risk for development of a second malignancy of 14 percent at 15 years, similar to the expected rate (standard incidence ratio [SIR] of 1.01) [103]. However, the SIR for non-Hodgkin lymphoma was higher than expected, at 5.3. Use of interferon did not affect the incidence of second malignancies in this group.

Data on 3104 patients with HCL reported to 16 population-based registries in the SEER Program indicated a statistically increased incidence of second cancers compared with the general population (SIR 1.2; 95% CI 1.1-1.4), especially for Hodgkin lymphoma (SIR 6.6), non-Hodgkin lymphoma (SIR 5.0), and thyroid cancer (SIR 3.6) [104]. The cumulative probability of all second cancers was 32 percent at 25 years following the diagnosis of HCL. It was estimated that, among 1000 HCL patients, a total excess of 3.4 cancers might be observed per year (ie, 34/10,000).

PROGNOSIS — Without treatment, the median survival is approximately four years [107]. While treatment is not curative, survival rates with modern therapy are only slightly lower than the general population.

The prognosis of patients with HCL was evaluated in an analysis of the Surveillance Epidemiology and End Results (SEER) database that included over 3300 patients diagnosed with HCL between 1973 and 2008 [108]. Over this time period, the age-adjusted risk of death decreased by 85 percent, with the greatest improvement seen in younger patients who have survival rates only slightly lower than the general population. Older age and African American ethnicity were independent predictors of higher mortality.

In an attempt to address the issue of quality of life in patients, a questionnaire was sent to individuals with a prior diagnosis of HCL who had been treated by this author [109]. There was a 61 percent response rate, with the following observations:

Lifestyle changes were noted by 40 to 60 percent of respondents (eg, more frequent exercise, healthier diets, a greater appreciation of life, loved ones, and physical health).

More than 60 percent paid for some aspect of medical care in spite of having health insurance coverage at the time of diagnosis.

Twelve percent could not obtain health insurance following treatment.

Ten of 13 subjects had difficulty obtaining a life insurance policy or were denied coverage.

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

ADDITIONAL INFORMATION — The Hairy Cell Leukemia Research Foundation is a non-profit, all volunteer, patient-run organization whose primary goal is to provide support and information concerning this disease and its treatment. Information about this foundation can be found at: www.hairycellleukemia.org [110].

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: Hairy cell leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topics (see "Patient education: Hairy cell leukemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

Observation for asymptomatic patients – Many patients with hairy cell leukemia (HCL) are asymptomatic and can be observed for months and occasionally years after the diagnosis is established before requiring treatment. There is no clear advantage to early therapy. As the goal of treatment is alleviation of symptoms and cytopenias, we believe that asymptomatic patients with HCL should not be treated. There is a theoretic risk of infection in such patients, occasionally with opportunistic organisms. (See 'Asymptomatic patients' above.)

Indications for treatment (see 'Indications for treatment' above)

Significant cytopenias; typical peripheral blood counts that warrant treatment include an absolute neutrophil count <1000/microL with repeated infections, symptomatic anemia with a hemoglobin concentration <11.0 g/dL, or bleeding due to a platelet count <100,000/microL

Symptomatic splenomegaly (common) or adenopathy (uncommon)

Constitutional symptoms (eg, fever, night sweats, fatigue, weight loss)

Initial treatment – For most patients, we recommend a purine-analog-based therapy as first-line therapy (algorithm 1) (Grade 1A). Because of ease of administration and shorter treatment duration, we prefer cladribine over pentostatin.

Starting four to six weeks after initial treatment with cladribine, we offer four weekly doses of rituximab consolidation. (See 'Choice of purine analog' above.)

Patients with an active infection are treated with antimicrobials in an attempt to control the infection prior to starting a purine analog. If it is not possible to control the infection and there is need for immediate treatment, alternative therapies or dosing not associated with myelosuppression (eg, low dose pentostatin, off-label vemurafenib) may be offered until the infection is controlled. (See 'Infections' above.)

Purine analogs must be used with caution in patients with renal impairment.

For the rare patients who do not respond to initial therapy with a purine analog, we suggest switching to an alternative purine analog or off-label vemurafenib plus rituximab (Grade 2C). (See 'Resistant disease' above.)

Management at relapse – The preferred therapy for patients with relapsed HCL depends in part on the length of response to initial therapy (algorithm 1):

For patients with a previous remission lasting ≥24 months, we suggest treatment with a purine analog followed by rituximab rather than a purine analog alone (Grade 2C). Cladribine and pentostatin are equally effective in this setting, leading to a second complete remission in approximately 70 percent of patients and a third complete remission in approximately 50 percent. (See 'Purine analogs' above.)

For patients with an initial remission <24 months, we re-evaluate the accuracy of the original diagnosis. We do not retreat with the initial therapy. Instead, we offer one of the following:

-Off-label vemurafenib plus rituximab. (See 'BRAF inhibition (vemurafenib or dabrafenib)' above.)

-Moxetumomab pasudotox. (See 'Moxetumomab pasudotox' above.)

-Alternative purine analog (ie, pentostatin in those who have received cladribine, and vice versa). (See 'Pentostatin' above.)

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Topic 4535 Version 44.0

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