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

asymptomatic early stage (Binet A and B; Rai 0-II)

1st line – active surveillance

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ACUTE
|
asymptomatic early stage (Binet A and B; Rai 0-II)
1st line – 

active surveillance

Asymptomatic patients with early-stage CLL (Binet A and B; Rai 0-II [low-to-intermediate risk]) can be observed and closely monitored until symptoms (or other indications for treatment) develop.[2][33][52][53]​ 

Select patients with mild and stable disease-related cytopenia may continue to be observed (other causes of cytopenia should be excluded, e.g., autoimmune disorder).[33]

Routine physical exam and complete blood count with differential should be performed every month for 3 months, then every 3 months, to follow disease progression.[36][37]

advanced stage (Binet C; Rai III-IV) or with indications for treatment (e.g., symptoms)

1st line – targeted therapy or chemoimmunotherapy

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ACUTE
|
advanced stage (Binet C; Rai III-IV) or with indications for treatment (e.g., symptoms)
|
without del(17p) or TP53 mutation
1st line – 

targeted therapy or chemoimmunotherapy

Patients with advanced-stage CLL (Binet C; Rai III-IV [high risk]) or indications for treatment should be managed according to their genetic profile and performance status.[33][36]​​​​

Indications for immediate treatment include significant disease-related symptoms (including severe fatigue, drenching night sweats, unintentional weight loss, fever without infection); threatened end-organ function; progressive, symptomatic, or bulky disease (spleen >6 cm below costal margin; lymph nodes >10 cm); progressive lymphocytosis (increase of ≥50% over a 2-month period, or lymphocyte doubling time <6 months); progressive thrombocytopenia; progressive anemia; and corticosteroid-refractory autoimmune cytopenias (e.g., autoimmune hemolytic anemia, immune thrombocytopenic purpura).[2][33][36]​​

The following factors should be considered when determining the most appropriate first-line treatment: comorbidities (may be assessed using a comorbidity scoring system, e.g., Cumulative Illness Rating Scale [CIRS]), age, fitness, concomitant medications (anticoagulants, strong CYP3A inducers/inhibitors, proton-pump inhibitors), bulk of disease (by assessing absolute lymphocyte count, bulky lymphadenopathy), treatment toxicity profile, patient preference.[36][37][33]​​ 

First-line therapy for patients without del(17p) or TP53 mutation is continuous treatment with a covalent Bruton tyrosine kinase (BTK) inhibitor-based regimen (until disease progression or intolerance), or time-limited treatment with a B-cell lymphoma-2 protein (BCL2) inhibitor (venetoclax)-containing regimen.[33]

Recommended first-line covalent BTK inhibitor-based regimens include: acalabrutinib with or without obinutuzumab; zanubrutinib; or ibrutinib (an anti-CD20 monoclonal antibody [obinutuzumab or rituximab] may be combined with ibrutinib in certain circumstances).[33]

Recommended first-line BCL2 inhibitor-containing regimens include: venetoclax plus obinutuzumab; venetoclax plus acalabrutinib with or without obinutuzumab; or venetoclax plus ibrutinib.[33]

Time-limited treatment with chemoimmunotherapy or immunotherapy regimens may be considered for first-line therapy in certain circumstances.[33]

Patients with immunoglobulin heavy chain (IgHV)-mutated CLL without del(17p) or TP53 mutation (i.e., a favorable genetic profile) who are ages <65 years and without significant comorbidities can be treated with fludarabine plus cyclophosphamide plus rituximab (FCR).[33][46][47][48]​ Patients require close monitoring because FCR is associated with a high rate of infectious complications.[54]

Bendamustine plus an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) is an alternative to FCR for select patients with IgHV-mutated CLL (e.g., those ages ≥65 years who are not frail).[37][54][55][56]

Patients without del(17p) or TP53 mutation who are unsuitable for BTK inhibitors and BCL2 inhibitors, or who require rapid disease debulking, may be considered for treatment with the following regimens: bendamustine plus rituximab or obinutuzumab (not suitable for frail patients); obinutuzumab with or without chlorambucil (recommended only for patients ages ≥65 years or ages <65 years with significant comorbidities); or high-dose methylprednisolone plus rituximab or obinutuzumab.[33] 

A second-line regimen may be considered for patients without del(17p) or TP53 mutation who have disease progression or intolerance while receiving a first-line regimen.[33] 

Recommended second-line regimens following a first-line covalent BTK inhibitor-based regimen include: a BCL2 inhibitor-containing regimen (e.g., venetoclax plus obinutuzumab); pirtobrutinib (a noncovalent BTK inhibitor); or an alternative covalent BTK inhibitor (in the case of intolerance only).[33]

Recommended second-line regimens following a first-line BCL2 inhibitor-containing regimen include: a covalent BTK inhibitor (acalabrutinib, zanubrutinib, ibrutinib); or pirtobrutinib (in the case of progression with a first-line regimen containing a covalent BTK inhibitor).[33]

Recommended second-line regimens following a first-line chemoimmunotherapy or immunotherapy regimen include: a covalent BTK inhibitor (acalabrutinib, zanubrutinib, ibrutinib); or a BCL2 inhibitor-containing regimen (e.g., venetoclax plus obinutuzumab).[33]

Choice of third-line therapy for patients with disease progression or intolerance while on second-line therapy is contingent on previous treatment regimens. For example, pirtobrutinib may be considered after prior treatment with a covalent BTK inhibitor-based regimen and a BCL2 inhibitor-containing regimen.[33]

Targeted therapies and immunotherapies have unique adverse effect profiles.

Tumor lysis syndrome (TLS) has been reported in CLL patients treated with targeted therapies and immunotherapies, particularly venetoclax, obinutuzumab, rituximab, and chemoimmunotherapy regimens.[58][59][60][61]​ TLS is an oncologic emergency requiring immediate management. See Complications and Tumor lysis syndrome for further detail.

Ibrutinib is associated with an increased risk of hypertension, fatal and serious cardiac arrhythmias, and cardiac failure; patients with cardiac comorbidities may be at greater risk of these events.[62][63][64][65]​​​​​ Cardiac arrhythmias may occur with other BTK inhibitors (e.g., acalabrutinib, zanubrutinib), particularly in patients with cardiac risk factors. See Complications for further detail.

See local specialist protocol for dosing guidelines.

Primary options

acalabrutinib

OR

acalabrutinib

and

obinutuzumab

OR

zanubrutinib

OR

ibrutinib

OR

ibrutinib

and

obinutuzumab

OR

ibrutinib

and

rituximab

OR

venetoclax

and

obinutuzumab

OR

venetoclax

and

acalabrutinib

and

obinutuzumab

OR

venetoclax

and

acalabrutinib

OR

venetoclax

and

ibrutinib

OR

FCR

fludarabine

and

cyclophosphamide

and

rituximab

OR

bendamustine

and

rituximab

OR

bendamustine

and

obinutuzumab

OR

obinutuzumab

and

chlorambucil

OR

obinutuzumab

OR

methylprednisolone

and

obinutuzumab

OR

methylprednisolone

and

rituximab

Secondary options

pirtobrutinib

1st line – targeted therapy

Back
ACUTE
|
advanced stage (Binet C; Rai III-IV) or with indications for treatment (e.g., symptoms)
|
with del(17p) or TP53 mutation
1st line – 

targeted therapy

Patients with advanced-stage CLL (Binet C; Rai III-IV [high risk]) or indications for treatment should be managed according to their genetic profile and performance status.[33][36]​​​

Indications for immediate treatment include significant disease-related symptoms (including severe fatigue, drenching night sweats, unintentional weight loss, fever without infection); threatened end-organ function; progressive, symptomatic, or bulky disease (spleen >6 cm below costal margin; lymph nodes >10 cm); progressive lymphocytosis (increase of ≥50% over a 2-month period, or lymphocyte doubling time <6 months); progressive thrombocytopenia; progressive anemia; and corticosteroid-refractory autoimmune cytopenias (e.g., autoimmune hemolytic anemia, immune thrombocytopenic purpura).[2][33][36]​​ 

The following factors should be considered when determining the most appropriate first-line treatment: comorbidities (may be assessed using a comorbidity scoring system, e.g., Cumulative Illness Rating Scale [CIRS]), age, fitness, concomitant medications (anticoagulants, strong CYP3A inducers/inhibitors, proton-pump inhibitors), bulk of disease (by assessing absolute lymphocyte count, bulky lymphadenopathy), treatment toxicity profile, patient preference.[36][37][33] 

Patients with del(17p) or TP53 mutations should be treated with targeted therapies (in a clinical trial where possible).[33][37]​​ 

Chemoimmunotherapy is not recommended in patients with del(17p) or TP53 mutation because it is associated with low response rates and poor progression-free survival.[33]

​First-line therapy is continuous treatment with a covalent Bruton tyrosine kinase (BTK) inhibitor-based regimen (until disease progression or intolerance), or time-limited treatment with a B-cell lymphoma-2 protein (BCL2) inhibitor (venetoclax)-containing regimen.[33] 

Recommended first-line covalent BTK inhibitor-based regimens include: acalabrutinib with or without obinutuzumab; zanubrutinib; or ibrutinib.[33] 

Recommended first-line BCL2 inhibitor-containing regimens include: venetoclax plus obinutuzumab; venetoclax plus acalabrutinib with or without obinutuzumab; venetoclax plus ibrutinib.[33] 

Alternative first-line regimens that may be useful in certain circumstances include high-dose methylprednisolone plus obinutuzumab or rituximab, or obinutuzumab alone.[33] 

Patients with del(17p) or TP53 mutation who have disease progression or intolerance while receiving a first-line regimen can switch to a different regimen for second-line therapy.[33] For example, patients with disease progression or intolerance while receiving a first-line covalent BTK inhibitor-based regimen can switch to a BCL2 inhibitor-containing regimen (e.g., venetoclax with or without obinutuzumab) or pirtobrutinib (a noncovalent BTK inhibitor).[33] 

Targeted therapies and immunotherapies have unique adverse effect profiles.

Tumor lysis syndrome (TLS) has been reported in CLL patients treated with targeted therapies and immunotherapies, particularly venetoclax, obinutuzumab, and rituximab.[58][59][60][61]​ TLS is an oncologic emergency requiring immediate management. See Complications and Tumor lysis syndrome for further detail.

Ibrutinib is associated with an increased risk of hypertension, fatal and serious cardiac arrhythmias, and cardiac failure; patients with cardiac comorbidities may be at greater risk of these events.[62][63][64][65]​​​​ Cardiac arrhythmias may occur with other BTK inhibitors (e.g., acalabrutinib, zanubrutinib), particularly in patients with cardiac risk factors. See Complications for further detail.

See local specialist protocol for dosing guidelines.

Primary options

acalabrutinib

OR

acalabrutinib

and

obinutuzumab

OR

zanubrutinib

OR

ibrutinib

OR

venetoclax

and

obinutuzumab

OR

venetoclax

and

acalabrutinib

and

obinutuzumab

OR

venetoclax

and

acalabrutinib

OR

venetoclax

and

ibrutinib

OR

methylprednisolone

and

obinutuzumab

OR

methylprednisolone

and

rituximab

OR

obinutuzumab

Secondary options

venetoclax

OR

pirtobrutinib

ONGOING

relapsed or refractory disease

1st line – retreatment with BCL2 inhibitor-containing regimen (for late relapse after initial BCL2 inhibitor therapy); or switch to an alternative systemic therapy; or consider allogeneic stem cell transplant

Back
ONGOING
|
relapsed or refractory disease
1st line – 

retreatment with BCL2 inhibitor-containing regimen (for late relapse after initial BCL2 inhibitor therapy); or switch to an alternative systemic therapy; or consider allogeneic stem cell transplant

Treatment selection is based on multiple factors, including: the patient's previous treatments and duration of remission (i.e., early vs. late relapse); indications for treatment; fitness (performance status); resistance to treatment (e.g., due to acquired genetic mutations); and patient preference.[33][37]​​[57]​​ 

Retreatment with a BCL2 inhibitor-containing regimen may be an option if relapse is late (i.e., disease remission lasting ≥36 months) after initial BCL2 inhibitor therapy.[33][37]​​[57]

The following treatment options can be considered for patients with relapsed or refractory disease after prior therapy with BTK inhibitor and BCL2 inhibitor regimens (if not previously used): lisocabtagene maraleucel (CD19-directed chimeric antigen receptor [CAR] T-cell therapy); pirtobrutinib (noncovalent BTK inhibitor); phosphoinositide 3-kinase (PI3K) inhibitor-based regimens (e.g., duvelisib; idelalisib with or without rituximab); high-dose methylprednisolone plus obinutuzumab or rituximab; lenalidomide (an immunomodulatory drug) with or without rituximab; fludarabine plus cyclophosphamide plus rituximab (FCR), for patients without del(17p) or TP53 mutation who are aged <65 years without significant comorbidities; bendamustine plus rituximab, for patients without del(17p) or TP53 mutation (not suitable for frail patients); obinutuzumab, for patients without del(17p) or TP53 mutation; alemtuzumab with or without rituximab, for patients with del(17p) or TP53 mutation; allogeneic stem cell transplant, may be considered for patients without significant comorbidities (the hematopoietic cell transplant-comorbidity index [HCT-CI] can be used to assess health status and to predict mortality risk after transplant).

All patients with relapsed or refractory disease should be considered for treatment in a clinical trial wherever possible due to the continually evolving treatment options in this setting.[2][33][37]​​​​​

Targeted therapies and immunotherapies have unique adverse effect profiles.

Tumor lysis syndrome (TLS) has been reported in CLL patients treated with targeted therapies and immunotherapies, particularly venetoclax, obinutuzumab, rituximab, lenalidomide, and chemoimmunotherapy regimens.[58][59]​​[60][61]​ TLS is an oncologic emergency requiring immediate management. See Complications and Tumor lysis syndrome for further detail.

Ibrutinib is associated with an increased risk of hypertension, fatal and serious cardiac arrhythmias, and cardiac failure; patients with cardiac comorbidities may be at greater risk of these events.[62][63][64][65]​ Cardiac arrhythmias may occur with other BTK inhibitors (e.g., acalabrutinib, zanubrutinib), particularly in patients with cardiac risk factors. See Complications for further detail.

Lisocabtagene maraleucel is associated with cytokine release syndrome (CRS), neurologic toxicity (including immune effector cell-associated neurotoxicity syndrome [ICANS]), and T-cell malignancies.[66][67] In the US, lisocabtagene maraleucel is available only through a Risk Evaluation and Mitigation Strategy (REMS) program.

PI3K inhibitors are associated with fatal or serious toxicities including hepatotoxicity, severe diarrhea or colitis, pneumonitis, infections, and intestinal perforation. The Food and Drug Administration (FDA) has issued a safety warning for duvelisib following results from a phase 3 trial that showed a possible increased risk of death and serious adverse effects (including infections, diarrhea, colitis, pneumonitis, cutaneous reactions, and high liver enzyme levels in the blood) with duvelisib compared with ofatumumab.[68][69]​ The FDA is continuing to evaluate the safety of duvelisib in patients with relapsed or refractory CLL (or SLL), and advises healthcare professionals to review patients' progress on duvelisib and to discuss with patients the risks and benefits of continuing duvelisib in the context of other available treatments.[68] Monitor patients closely during PI3K inhibitor treatment. 

Lenalidomide is associated with tumor flare reaction (typically presenting as sudden onset of painful and tender enlargement of lymph nodes), venous thromboembolism, and TLS.[61][70][71]​​

See Complications for further detail on treatment-related toxicities.

See local specialist protocol for dosing guidelines.

Primary options

With or without del(17p)/TP53 mutation

lisocabtagene maraleucel

OR

With or without del(17p)/TP53 mutation

pirtobrutinib

OR

With or without del(17p)/TP53 mutation

duvelisib

OR

With or without del(17p)/TP53 mutation

idelalisib

OR

With or without del(17p)/TP53 mutation

idelalisib

and

rituximab

OR

With or without del(17p)/TP53 mutation

methylprednisolone

and

obinutuzumab

OR

With or without del(17p)/TP53 mutation

methylprednisolone

and

rituximab

OR

With or without del(17p)/TP53 mutation

lenalidomide

OR

With or without del(17p)/TP53 mutation

lenalidomide

and

rituximab

OR

Without del(17p)/TP53 mutation

fludarabine

and

cyclophosphamide

and

rituximab

OR

Without del(17p)/TP53 mutation

bendamustine

and

rituximab

OR

Without del(17p)/TP53 mutation

obinutuzumab

OR

With del(17p)/TP53 mutation

alemtuzumab

OR

With del(17p)/TP53 mutation

alemtuzumab

and

rituximab

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Choose a patient group to see our recommendations

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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