Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

no indication(s) for treatment

1st line – observation

Back
ACUTE
|
no indication(s) for treatment
1st line – 

observation

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]​ 

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 haematological parameters, recurring infections, or progressive lymphocytosis or lymphadenopathy may also require treatment.[33][34]

Haematological parameters indicating a need for treatment include at least one of the following: haemoglobin <110 g/L (<11 g/dL); absolute neutrophil count <1000/microlitre; or platelet count <100,000/microlitre.[33][34] 

indication(s) for treatment present: without splenic rupture or massive splenomegaly or marked thrombocytopenia precluding chemotherapy

1st line – cladribine ± rituximab; or pentostatin

Back
ACUTE
|
indication(s) for treatment present: without splenic rupture or massive splenomegaly or marked thrombocytopenia precluding chemotherapy
1st line – 

cladribine ± rituximab; or pentostatin

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 haematological parameters, recurring infections, or progressive lymphocytosis or lymphadenopathy may also require treatment.[33][34]

Haematological parameters indicating a need for treatment include at least one of the following: haemoglobin <110 g/L (<11 g/dL); absolute neutrophil count <1000/microlitre; or platelet count <100,000/microlitre.[33][34] 

Treatment is aimed at alleviating symptoms and cytopenias, inducing long-lasting remission, and prolonging disease-free survival.

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

Cladribine and pentostatin have demonstrated high rates of complete response (>75%) and prolongation of disease-free survival in HCL.[55]​ Both agents are similarly effective but they have not been compared in head-to-head randomised 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 analogue therapy (concurrently or after purine analogue therapy) may help to achieve a complete response.[7][56][57] 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.[57]

Purine analogues are immunosuppressive and are associated with an increased risk of febrile neutropenia and infection (including reactivation or worsening of viral infections).[61]​ Pre-treatment evaluation and infection control are required before initiating treatment with purine analogues.[7][33][34] 

There have been several confirmed cases of progressive multifocal encephalopathy (PML) in patients with haematological conditions who were treated with cladribine.[62]​ PML should be considered in the differential diagnosis for patients with new or worsening neurological 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 should be assessed with full blood count (FBC), physical examination, and a bone marrow aspirate and trephine biopsy.[7][33]

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 FBC has normalised (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][63]​ 

See local specialist protocol for dosing guidelines.

Primary options

cladribine injection

OR

cladribine injection

and

rituximab

OR

pentostatin

Consider – supportive care

Back
ACUTE
|
indication(s) for treatment present: without splenic rupture or massive splenomegaly or marked thrombocytopenia precluding chemotherapy
Consider – 

supportive care

Additional treatment recommended for SOME patients in selected patient group

Supportive care measures should be considered during treatment.[7][83][85][86]

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 aciclovir to avoid pneumocystis infections and herpes reactivation, respectively.

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

2nd line – vemurafenib ± rituximab or obinutuzumab

Back
ACUTE
|
indication(s) for treatment present: without splenic rupture or massive splenomegaly or marked thrombocytopenia precluding chemotherapy
2nd line – 

vemurafenib ± rituximab or obinutuzumab

If patients are unsuitable for initial treatment with a purine analogue (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]​​​[54]

Initial treatment with vemurafenib alone or combined with rituximab has demonstrated rapid blood count recovery in patients with HCL.[58][59]

Initial treatment with vemurafenib combined with obinutuzumab has demonstrated high rates of complete response (90%) and minimal residual disease (MRD) negativity (96%) in HCL.[60]

See local specialist protocol for dosing guidelines.

Primary options

vemurafenib

OR

vemurafenib

and

rituximab

OR

vemurafenib

and

obinutuzumab

Consider – supportive care

Back
ACUTE
|
indication(s) for treatment present: without splenic rupture or massive splenomegaly or marked thrombocytopenia precluding chemotherapy
Consider – 

supportive care

Additional treatment recommended for SOME patients in selected patient group

Supportive care measures should be considered during treatment.[7][83][85][86]

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 aciclovir to avoid pneumocystis infections and herpes reactivation, respectively.

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

indication(s) for treatment present: with massive symptomatic splenomegaly or splenic rupture or marked thrombocytopenia precluding chemotherapy

1st line – splenectomy

Back
ACUTE
|
indication(s) for treatment present: with massive symptomatic splenomegaly or splenic rupture or marked thrombocytopenia precluding chemotherapy
1st line – 

splenectomy

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 haematological parameters, recurring infections, or progressive lymphocytosis or lymphadenopathy may also require treatment.[33][34] 

Haematological parameters indicating a need for treatment include at least one of the following: haemoglobin <110 g/L (<11 g/dL); absolute neutrophil count <1000/microlitre; or platelet count <100,000/microlitre.[33][34] 

Treatment is aimed at alleviating symptoms and cytopenias, inducing long-lasting remission, and prolonging disease-free survival.

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

Splenectomy increases leukocyte, erythrocyte, and platelet counts; although many patients require systemic therapy post-splenectomy because of progressive cytopenia.[64][65] 

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 analogue).[83]

If splenectomy is considered, patients should be immunised against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis.[84]

Plus – cladribine or pentostatin

Back
ACUTE
|
indication(s) for treatment present: with massive symptomatic splenomegaly or splenic rupture or marked thrombocytopenia precluding chemotherapy
|
with persistent symptoms post-splenectomy
Plus – 

cladribine or pentostatin

Treatment recommended for ALL patients in selected patient group

Splenectomy increases leukocyte, erythrocyte, and platelet counts; although many patients require systemic therapy post-splenectomy because of progressive cytopenia.[64][65] 

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 analogue).[83]

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

Purine analogues are immunosuppressive and are associated with an increased risk of febrile neutropenia and infection (including reactivation or worsening of viral infections).[61]​ Pre-treatment evaluation and infection control are required before initiating treatment with purine analogues.[7][33][34] 

There have been several confirmed cases of progressive multifocal encephalopathy (PML) in patients with haematological conditions who were treated with cladribine.[62]​ PML should be considered in the differential diagnosis for patients with new or worsening neurological 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 should be assessed with full blood count (FBC), physical examination, and a bone marrow aspirate and trephine biopsy.[7][33] 

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 FBC has normalised (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][63]​ 

Cladribine and pentostatin have demonstrated high rates of complete response (>75%) and prolongation of disease-free survival in HCL.[55]​ Both agents are similarly effective but they have not been compared in head-to-head randomised clinical trials.

See local specialist protocol for dosing guidelines.

Primary options

cladribine injection

OR

pentostatin

Consider – supportive care

Back
ACUTE
|
indication(s) for treatment present: with massive symptomatic splenomegaly or splenic rupture or marked thrombocytopenia precluding chemotherapy
|
with persistent symptoms post-splenectomy
Consider – 

supportive care

Additional treatment recommended for SOME patients in selected patient group

The following supportive care measures should be considered during treatment:[7][83][85][86]

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 aciclovir to avoid pneumocystis infections and herpes reactivation, respectively.

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

ONGOING

early relapse (<2 years) or refractory disease

1st line – clinical trial; or dabrafenib + trametinib (if BRAF inhibitor-naive); or vemurafenib ± rituximab (if not used previously); or peginterferon alfa-2a; or cladribine ± rituximab; or pentostatin ± rituximab; or rituximab alone

Back
ONGOING
|
early relapse (<2 years) or refractory disease
1st line – 

clinical trial; or dabrafenib + trametinib (if BRAF inhibitor-naive); or vemurafenib ± rituximab (if not used previously); or peginterferon alfa-2a; or cladribine ± rituximab; or pentostatin ± rituximab; or rituximab alone

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).

Patients with early relapse or refractory disease (i.e., incomplete haematological recovery and no bone marrow response after initial treatment) 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:

dabrafenib (a BRAF inhibitor) plus trametinib (if BRAF inhibitor-naive)

vemurafenib (a BRAF inhibitor) with or without rituximab (if not used previously)

peginterferon alfa-2a

an alternative purine analogue (cladribine or pentostatin) with or without rituximab; or

rituximab alone (if unsuitable for purine analogue).[34][66][69][70][71]​​[72][73][74]​​

Dabrafenib plus trametinib, or vemurafenib with or without rituximab, can be used if disease progression occurs after treatment for relapsed or refractory disease, if not used previously.[34][72][73][74][75][76]​ 

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

It is important to reassess the accuracy of the original diagnosis at relapse or if there is refractory disease.[33] 

Purine analogues are immunosuppressive and are associated with an increased risk of febrile neutropenia and infection (including reactivation or worsening of viral infections).[61]​ Pre-treatment evaluation and infection control are required before initiating treatment with purine analogues.[7][33][34] 

There have been several confirmed cases of progressive multifocal encephalopathy (PML) in patients with haematological conditions who were treated with cladribine.[62]​ PML should be considered in the differential diagnosis for patients with new or worsening neurological signs or symptoms following treatment with cladribine. If PML is suspected, treatment with cladribine should be stopped immediately and patients should undergo specialist investigation.

See local specialist protocol for dosing guidelines.

Primary options

dabrafenib

and

trametinib

OR

vemurafenib

OR

vemurafenib

and

rituximab

Secondary options

peginterferon alfa 2a

OR

cladribine injection

OR

cladribine injection

and

rituximab

OR

pentostatin

OR

pentostatin

and

rituximab

OR

rituximab

Consider – supportive care

Back
ONGOING
|
early relapse (<2 years) or refractory disease
Consider – 

supportive care

Additional treatment recommended for SOME patients in selected patient group

The following supportive care measures should be considered during treatment:[7][83][85][86]

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 aciclovir to avoid pneumocystis infections and herpes reactivation, respectively.

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

2nd line – clinical trial; or ibrutinib; or zanubrutinib; or venetoclax ± rituximab

Back
ONGOING
|
early relapse (<2 years) or refractory disease
2nd line – 

clinical trial; or ibrutinib; or zanubrutinib; or venetoclax ± rituximab

The following treatments are recommended if disease progression occurs after treatment for relapsed or refractory disease: Bruton tyrosine kinase (BTK) inhibitor (ibrutinib or zanubrutinib); or venetoclax (a BCL2 inhibitor) with or without rituximab (if unsuitable for a BRAF inhibitor).[34][66][77][78]

A clinical trial should be considered for all patients with disease progression after treatment for relaped 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.[79]

Zanubrutinib may increase the risk of cardiac arrhythmias, but risk is lower than for ibrutinib.[80][81] The safety precautions described for ibrutinib should be considered for patients receiving zanubrutinib.[82]

See local specialist protocol for dosing guidelines.

Primary options

ibrutinib

OR

zanubrutinib

OR

venetoclax

OR

venetoclax

and

rituximab

Consider – supportive care

Back
ONGOING
|
early relapse (<2 years) or refractory disease
Consider – 

supportive care

Additional treatment recommended for SOME patients in selected patient group

The following supportive care measures should be considered during treatment:[7][83][85][86]

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 aciclovir to avoid pneumocystis infections and herpes reactivation, respectively.

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

late relapse (≥2 years)

1st line – cladribine + rituximab; or pentostatin + rituximab; or vemurafenib ± rituximab; or rituximab alone

Back
ONGOING
|
late relapse (≥2 years)
1st line – 

cladribine + rituximab; or pentostatin + rituximab; or vemurafenib ± rituximab; or rituximab alone

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

Patients with late relapse can be retreated with a purine analogue (cladribine or pentostatin) in combination with rituximab.[27][34] The same purine analogue used for initial treatment or a different one can be used in this setting.

Patients with late relapse who are retreated with the same purine analogue used for initial treatment achieve a similar response to those who switch to a different purine analogue.[64][65] 

If patients with late relapse are unsuitable for purine analogue therapy (e.g., due to frailty, renal insufficiency, active infection), treatment with vemurafenib (a BRAF inhibitor) with or without rituximab, or rituximab alone may be considered.[34][66][67][68]​​

Vemurafenib with or without rituximab can be used if disease progression occurs after treatment for relapsed or refractory disease, if not used previously.[34][72][73][75][76] 

It is important to reassess the accuracy of the original diagnosis at relapse.[33]

Purine analogues are immunosuppressive and are associated with an increased risk of febrile neutropenia and infection (including reactivation or worsening of viral infections).[61]​ Pre-treatment evaluation and infection control are required before initiating treatment with purine analogues.[7][33][34] 

There have been several confirmed cases of progressive multifocal encephalopathy (PML) in patients with haematological conditions who were treated with cladribine.[62] PML should be considered in the differential diagnosis for patients with new or worsening neurological signs or symptoms following treatment with cladribine. If PML is suspected, treatment with cladribine should be stopped immediately and patients should undergo specialist investigation.

See local specialist protocol for dosing guidelines.

Primary options

cladribine injection

and

rituximab

OR

pentostatin

and

rituximab

Secondary options

vemurafenib

OR

vemurafenib

and

rituximab

OR

rituximab

Consider – supportive care

Back
ONGOING
|
late relapse (≥2 years)
Consider – 

supportive care

Additional treatment recommended for SOME patients in selected patient group

The following supportive care measures should be considered during treatment:[7][83][85][86]

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 aciclovir to avoid pneumocystis infections and herpes reactivation, respectively.

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

2nd line – clinical trial; dabrafenib + trametinib (if BRAF inhibitor-naive); or ibrutinib; or zanubrutinib; or venetoclax ± rituximab

Back
ONGOING
|
late relapse (≥2 years)
2nd line – 

clinical trial; dabrafenib + trametinib (if BRAF inhibitor-naive); or ibrutinib; or zanubrutinib; or venetoclax ± rituximab

The following treatments are recommended if disease progression occurs after treatment for relapsed or refractory disease:

dabrafenib (a BRAF inhibitor) plus trametinib (if BRAF inhibitor-naive);

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

venetoclax (a BCL2 inhibitor) with or without rituximab (if unsuitable for a BRAF inhibitor).[34][66][74][77][78]​​​

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.[79] 

Zanubrutinib may increase the risk of cardiac arrhythmias, but risk is lower than for ibrutinib.[80][81] The safety precautions described for ibrutinib should be considered for patients receiving zanubrutinib.[82]

See local specialist protocol for dosing guidelines.

Primary options

dabrafenib

and

trametinib

OR

ibrutinib

OR

zanubrutinib

OR

venetoclax

OR

venetoclax

and

rituximab

Consider – supportive care

Back
ONGOING
|
late relapse (≥2 years)
Consider – 

supportive care

Additional treatment recommended for SOME patients in selected patient group

The following supportive care measures should be considered during treatment:[7][83][85][86] 

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 aciclovir to avoid pneumocystis infections and herpes reactivation, respectively.

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

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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