Chronic Lymphocytic Leukemia: Drug Therapy

Therapeutic target

Prolongation of survival

Therapy recommendations

  • Chemotherapy (see below) is palliative (palliative therapy), therefore as late (“watch and wait” strategy) and as gentle as possible (treatment duration: over many years): a high lymphocyte count is not in itself an indication for therapy! Start of therapy: pronounced signs of bone marrow displacement or disease-related symptoms such as B-symptomatology (see “Symptoms – Complaints” below) or fatigue (tiredness or exhaustion):
    • Rapidly increasing bone marrow insufficiency
    • Corticoid-refractory autoimmune hemolytic anemia (anemia) or autoimmune thrombocytopenia (reduction in platelets (blood clots) due to autoantibodies)
    • Progressive lymphocytosis (> 50% increase within 2 months, lymphocyte doubling time shorter than 6 months from a lymphocyte count > 30 G/l)
    • Lymph node enlargement > 10 cm or rapid progression (progression of the disease).
    • Symptomatic or progressive splenomegaly (splenomegaly;> 6 cm extending below the costal arch).

    Notice:

    • If moderate but stable thrombocytopenia or anemia is present, it is possible to wait to initiate therapy even at Binet C stage.
    • In smoldering CLL (low activity, lymphocyte count < 30,000/μl, lymphocyte doubling time > 12 months), life expectancy is approximately normal, i.e., therapy is not indicated.
  • First-line therapy: unless there is a contraindication to antibody therapy, chemoimmunotherapy (combination of chemotherapy with anti-CD20 antibodies) is preferable to chemotherapy alone.
    • Patients without a 17p deletion/TP53 mutation should receive chemoimmunotherapy based on the administration of a CD20 antibody:
    • High-risk patients with 17p deletion/TP53 mutation: treatment in the setting of a clinical trial; if not possible → first-line Bruton tyrosine kinase (BTK) inhibitor ibrutinib Ibrutinib achieved better results than a standard of care of bendamustine and rituximab in a phase 3 trial: Overall survival rates between therapies did not differ; 2-year survival rates were 95% in the bendamustine plus rituximab group, 90% in the ibrutinib group, and 94% in the ibrutinib plus rituximab group
  • Second-line therapy
    • High-risk patients with 17p deletion: therapy with ibrutinib or idelalisib-based combination therapy (with rituximab or ofatumumab, respectively) or with venetoclax (applies regardless of whether 17p deletion and/or TP53 mutation is detected after early or after late disease relapse)
    • Early disease relapse without 17p deletion: early disease relapse or refractory disease without 17p deletion/TP53 mutation → therapy with ibrutinib or therapy with idelalisib-based combination therapy (with rituximab or ofatumumab, respectively)
    • Late relapse (>2 years after the end of chemoimmunotherapy) without 17p deletion: either repeat primary therapy or consideration of therapy with new agents, such as a kinase inhibitor
  • Indications for chemotherapy include the presence of any of the following criteria in addition to Binet stage C:
    • Occurrence or worsening of anemia (anemia) / thrombocytopenia (platelet deficiency).
    • Massive (>6 cm below the costal margin), progressive, or symptomatic splenomegaly (enlargement of the spleen)
    • Massive (> 10 cm in diameter), progressive or symptomatic lymphadenopathy (swelling of lymph nodes).
    • Progressive leukocytosis (lymphocyte doubling time < 6 months or 50% increase in 2 months starting from 30,000 lymphocytes/μl)
    • Autoimmune cytopenia refractory to standard therapy.
    • B symptoms (unwanted weight loss >10% in 6 months, fever of unknown cause longer than 2 weeks, night sweats longer than 1 month, severe fatique/tormenting form of fatigue).
  • If necessary, use of monoclonal antibodies (eg.B. Alemtuzumab) in B-cell type CLL (B-CLL), in patients for whom chemotherapy is not an option or who do not respond adequately to chemotherapy.
  • Relapse therapy/progression (progression of the disease).
    • Selection of therapy is based on the timing and presence of a del17p/TP53 mutation at the time of relapse
      • If no del17p/TP53 is present at that time: Repeat primary therapy possible if occurrence more than two years after end of chemoimmunotherapy or more than one year after end of chemotherapy.
    • Under a kinase inhibitor (such as ibrutinib or idelalisib) in the relapsed situation: therapy with the BCL-2 inhibitor venetoclax.
  • If necessary, in young patients with good general condition: high-dose therapy followed by allogeneic stem cell transplantation.
  • Wg. poor immune defense is often an antibiosis (antibiotic therapy) required, if necessary also supply of immunoglobulins.
  • See also under “Further therapy” (stem cell transplantation).

Active substances (main indication)

Cytostatic agents

Chemotherapy for CLL can be given with the following agents:

Monoclonal antibodies

Notice:

  • Before starting treatment with ibrutinib, patients should be screened for HBV infection.
  • If serology is positive, a liver disease expert should be consulted before starting treatment.
  • Patients with positive hepatitis B serology who require ibrutinib should be monitored/treated according to medical standards to prevent HBV reactivation.

Additional notes

  • B-cell type CLL (B-CLL), in patients in whom chemotherapy is not an option or who do not respond adequately to chemotherapy: Alemtuzumab (monoclonal antibody) for TP53 deficiency, in combination with cortisone.
  • For patients refractory to fludarabine and alemtuzumab, ofatumumab* is approved for first-line therapy in combination with chlorambucil or bendamustine of patients not suitable for fludarabine-based therapy.
    • Obinutuzumab (monoclonal antibody directed against CD20) – compared with chemotherapy alone, time to disease progression more than doubled; combination of obinutuzumab with chlorambucil is more effective than chlorambucil alone
  • Venetoclax: oral BCL-2 inhibitor to restore natural apoptosis processes in altered CLL cells. This is prevented by overexpression of BCL-2. Inhibition of apoptosis (programmed cell death) and dysregulation of proliferation are central elements in the pathogenesis (disease development) of chronic lymphocytic leukemia.Indications: Patients with relapsed or refractory CLL with evidence of a 17p deletion or TP53 mutation.
    • First-line therapy: patients with 17p deletion/TP53mutation who are ineligible for treatment with a B-cell receptor (BCR) pathway inhibitor
    • Second-line therapy: patients with 17p deletion/TP53 mutation after failure of a BCR inhibitor.
    • Third-line therapy: patients without 17p deletion/TP53 mutation after failure of chemoimmunotherapy and treatment with a BCR inhibitor.
  • In a phase II study, ibrutinib and venetoclax in combination frequently achieved complete remissions (temporary or permanent remission of disease symptoms) associated with elimination of tumor cells from the bone marrow; at 12 months, the proportion of patients in complete remission was 88%; in 61% of these patients, flow cytometry also showed no more leukemia cells in the bone marrow.
  • Some refractory patients with CLL of the B-cell type (B-cell ALL) are still helped by immunotherapy with their own genetically modified T lymphocytes (CAR T-cell therapy* * ; “CAR” = “Chimeric Antigen Receptor”): median PFS (Engl.progression-free survival; progression-free survival) was 12.3 months in patients with complete/partial remission, median overall survival was 12.4 months (comparison: ibrutinib: median 3 months).

* Ofatumumab has since received an extension of approval for non-pretreated chronic lymphocytic leukemia* * CAR T-cell therapy (“chimeric antigen receptor T cells”): patient’s own T cells are equipped with chimeric antigen receptors (“chimeric antigen receptor”, CAR) outside the body (ex vivo) at the genetic level, thus specifically targeting the cancer. These cells are then reinfused into the body. They then bind to the appropriate tumor features on the lymphoma cells, leading to a sustained immune response through the release of chemokines, cytokines and lytic molecules. Side effects: The release of the previously mentioned endogenous messenger substances (cytokine storm) may result in high fever and life-threatening organ damage; other possible side effects include tumor lysis syndrome (TLS; life-threatening metabolic derailment that can occur when a large number of tumor cells are suddenly destroyed) and neurotoxicity (property of a substance to have a damaging effect on nerve tissue). Allogeneic blood stem cell transplantation

For high-risk patients, allogeneic blood stem cell transplantation should also be discussed. Acute autoimmune hemolytic anemia or autoimmune thrombocytopenia (AITP).