Approach

Hairy cell leukaemia (HCL) is not curable. Treatment is aimed at alleviating symptoms and cytopenias; inducing long-lasting remission; and prolonging disease-free survival.

For the purpose of treatment, patients can be classified as asymptomatic or symptomatic.

Asymptomatic disease

Patients may be asymptomatic at presentation and have well-preserved blood counts for months or even years after confirmed diagnosis.[7][27]​​​​[33]​​​​​ For these patients, close observation is recommended until indications for treatment occur.[7][33][34]

Indications for treatment

Treatment should be initiated in patients with symptomatic disease (e.g., symptomatic splenomegaly or hepatomegaly; constitutional symptoms [excessive fatigue; unexplained weight loss >10% within prior 6 months]).​[33][34]​

Patients with declining hematologic parameters, recurring infections, or progressive lymphocytosis or lymphadenopathy may also require treatment.​[33][34]

Hematologic parameters indicating a need for treatment include at least one of the following: hemoglobin <11 g/dL; absolute neutrophil count <1000/microliter; or platelet count <100,000/microliter.​[33][34]

Initial treatment

A purine analog (cladribine or pentostatin) is standard first-line treatment for HCL.[7]​​[33][34]​​ Cladribine may be combined with rituximab (an anti-CD20 monoclonal antibody).

If patients are unsuitable for initial treatment with a purine analog (e.g., due to frailty, renal insufficiency, active infection), vemurafenib (a BRAF inhibitor) may be considered either alone or combined with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab).[27][34]​​[53]​​​

Cladribine and pentostatin have demonstrated high rates of complete response (>75%) and prolongation of disease-free survival in HCL.[54] Both agents are similarly effective, but they have not been compared in head-to-head randomized clinical trials.

Cladribine may be preferred over pentostatin because of its relative ease of administration, particularly when the subcutaneous route of administration is used.[7][42]

Combining rituximab with initial purine analog therapy (concurrently or after purine analog therapy) may help to achieve a complete response.[7][55][56]​ Concurrent use of cladribine plus rituximab as first-line treatment for HCL has been shown to improve minimal residual disease (MRD)-free complete response rate compared with cladribine with delayed use of rituximab.[56]

Initial treatment with vemurafenib alone or combined with rituximab has demonstrated rapid blood count recovery in patients with HCL.[57][58]

Initial treatment with vemurafenib combined with obinutuzumab has demonstrated high rates of complete response (90%) and MRD negativity (96%) in HCL.[59]

Adverse effects of purine analogs

Purine analogs are immunosuppressive and are associated with an increased risk of febrile neutropenia and infection (including reactivation or worsening of viral infections).[60]​ Pretreatment evaluation and infection control are required before initiating treatment with purine analogs.[7][33]​​​[34] See Supportive care below. 

There have been several confirmed cases of progressive multifocal encephalopathy (PML) in patients with hematologic conditions who were treated with cladribine.[61] PML should be considered in the differential diagnosis for patients with new or worsening neurologic signs or symptoms following treatment with cladribine. If PML is suspected, treatment with cladribine should be stopped immediately and patients should undergo specialist investigation.

Treatment response assessment and timing

Treatment response should be assessed with complete blood count (CBC), physical exam, and a bone marrow aspirate and trephine biopsy.[7][33]​​

Timing of bone marrow evaluation after purine analog therapy

The timing of bone marrow evaluation depends on the initial treatment regimen. If cladribine is used, bone marrow assessment should be deferred until 4-6 months after treatment.[7][33]​​[34][42]

If pentostatin is used, it should be performed after 8-9 courses or when CBC has normalized (although lymphopenia will persist).[7] If a complete response is achieved with pentostatin, then two or three further doses of pentostatin may be considered.[7][62]

Relapsed or refractory disease

Most HCL patients will respond to initial treatment, and some will achieve long-term remission lasting many years; however, many patients will relapse.[33][54] Relapse rate after initial purine analog therapy is approximately 50%.[54]

It is important to reassess the accuracy of the original diagnosis at relapse, or if there is incomplete hematologic recovery and no bone marrow response after initial treatment (i.e., refractory disease).[33]

Treatment for relapsed or refractory disease is guided by prior treatment, quality and duration of remission with prior treatment, and indications for treatment (e.g., symptoms).

Treatment for late relapse (i.e., ≥2 years)

Patients with late relapse can be retreated with a purine analog (the same one used for initial treatment or a different one) in combination with rituximab.​[27][34]

Patients with late relapse who are retreated with the same purine analog used for initial treatment achieve a similar response to those who switch to a different purine analog.[63][64]

If patients with late relapse are unsuitable for purine analog therapy (e.g., due to frailty, renal insufficiency, active infection), treatment with vemurafenib (with or without rituximab) or rituximab alone may be considered.[34][65][66]​​​​[67]

Treatment for early relapse (i.e., <2 years) or refractory disease

Patients with early relapse or refractory disease and indications for treatment should be treated with a different regimen to the one used for initial treatment.[27][33][34]​​

The following treatments are recommended in this setting:[34][68][69][70][71][72][73]​​

  • Dabrafenib (a BRAF inhibitor) plus trametinib (if BRAF inhibitor-naive)

  • Vemurafenib with or without rituximab (if not used previously)

  • Peginterferon alfa-2a

  • An alternative purine analog with or without rituximab

  • Rituximab alone (if unsuitable for purine analog)

A clinical trial should be considered for all patients with early relapse or refractory disease, if available and eligible.[34]

Disease progression after treatment for relapsed or refractory disease

The following treatments are recommended if disease progression occurs after treatment for relapsed or refractory disease:[34][65][71][73][72][74]​​​[75][76]​​[77]​​​​​

  • Dabrafenib plus trametinib (if BRAF inhibitor-naive)

  • Vemurafenib with or without rituximab (if not used previously)

  • Bruton tyrosine kinase (BTK) inhibitor (ibrutinib or zanubrutinib)

  • Venetoclax (a BCL2 inhibitor) with or without rituximab (if unsuitable for a BRAF inhibitor)

A clinical trial should be considered for all patients with disease progression after treatment for relapsed or refractory disease, if available and eligible.[34]

Ibrutinib may increase the risk of cardiac events (including sudden fatal cardiac events) in patients with advanced age, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, or cardiac comorbidities. Clinical evaluation of cardiac history and function should be performed prior to initiating ibrutinib. The benefits and risks of initiating ibrutinib in patients with risk factors for cardiac events should be carefully assessed; alternative treatment may be considered. Patients should be carefully monitored for signs of deterioration of cardiac function and be clinically managed. Ibrutinib should be withheld for any new onset or worsening of grade 2 cardiac failure or grade 3 cardiac arrhythmias. Treatment may be resumed with dose modifications.[78]

Zanubrutinib may increase the risk of cardiac arrhythmias, but risk is lower than for ibrutinib.[79][80]​​​ The safety precautions described for ibrutinib should be considered for patients receiving zanubrutinib.[81]

Splenectomy

Splenectomy is not routinely used in patients with HCL, but may be considered in rare cases of massive splenomegaly, splenic rupture, or marked thrombocytopenia precluding chemotherapy (purine analog therapy).

Splenectomy increases leukocyte, erythrocyte, and platelet counts; although many patients require systemic therapy post-splenectomy because of progressive cytopenia.[63][64] The benefits of splenectomy may take time to become apparent; therefore, it is recommended to wait at least 6 months after splenectomy before considering systemic therapy (e.g., purine analog).[82] 

If splenectomy is considered, patients should be immunized against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis.[83]

Supportive care

The following supportive care measures should be considered during treatment:[7][82][84][85]

  • Antibiotics to manage febrile neutropenia and bacterial infections.

  • Granulocyte colony-stimulating factor (G-CSF; e.g., filgrastim) may be considered to manage neutropenia, but routine use is not recommended because meaningful improvements in health outcomes have not been shown with G-CSFs. See Febrile neutropenia.

  • Anti-infective prophylaxis with trimethoprim/sulfamethoxazole and acyclovir to avoid pneumocystis infections and herpes reactivation, respectively.

  • Transfusion (with irradiated blood products to avoid transfusion-associated graft-versus-host disease).

Minimal residual disease (MRD)

MRD monitoring is not currently recommended in routine clinical practice because its clinical significance is unclear.[86][87] Treated patients should be closely monitored to identify disease progression in a timely manner.

MRD is detected through examination of post-treatment bone marrow biopsies. Definitive evidence related to the presence of MRD as a predictor of relapse is lacking. The clinical value of eradication of MRD in patients who achieve complete remission by conventional criteria remains to be demonstrated.[88][89]

Consensus recommendations suggest that clinical trials in the relapse setting should incorporate MRD monitoring.[89]

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