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Treatment Options for Recurrent or Refractory Chronic Lymphocytic Leukemia (CLL)

Source: Chronic Lymphocytic Leukemia Treatment (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 25, 2025 · Captured 2026-09-09.

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Context: Treatment of Recurrent or Refractory Chronic Lymphocytic Leukemia

The same regimens considered for first-line therapy for patients with CLL can be readministered in a sequential fashion. These regimens are described in more detail under first-line therapy. For more information, see the Treatment of Symptomatic or Progressive CLL section.

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Treatment of Symptomatic or Progressive CLL

Bruton tyrosine kinase (BTK) inhibitors (acalabrutinib, zanubrutinib, or ibrutinib).

Venetoclax with initial use of obinutuzumab or rituximab.

Bendamustine and rituximab (BR).

Fludarabine, cyclophosphamide, and rituximab (FCR).

BTK inhibitor (ibrutinib or acalabrutinib) plus venetoclax.

R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (only if Richter syndrome with histological progression is suspected clinically).

In the relapsed setting, venetoclax showed similar efficacy and safety even after previous therapy with ibrutinib or idelalisib (the phosphatidylinositol 3-kinase [PI3K] delta inhibitor).[1,2]

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Similarly, in a trial reported in abstract form, ibrutinib and acalabrutinib showed similar efficacy and safety after previous therapy with venetoclax.[3] Sequencing these novel agents showed efficacy in the relapsed/refractory setting.[4,5]

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Noncovalent BTK inhibitors →Chimeric antigen receptor (CAR) T-cell therapy →PI3K inhibitors →Lenalidomide (with or without rituximab) →Bone marrow or peripheral blood stem cell transplant →Ofatumumab →Involved-field radiation therapy →Alemtuzumab →

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Preserved source evidence · Not medical advice