21. Leukemia Treatment

• Chronic phase

  • TKIs: first-line and second-line treatment

  • Adjunctive medical treatment or hematopoietic stem cell transplantation (HSCT) may be considered if other treatments fail.

• Accelerated phase

  • Begin treatment with TKIs.

  • Consider systemic chemotherapy or HSCT, if the patient is eligible.

• Blast phase: Treatment is similar to that of acute leukemia.

  • Aggressive systemic chemotherapy in combination with a TKI

  • HSCT, if the patient is eligible

• Indication: all patients with CML, regardless of the phase

• Agents

  • First-generation TKIs (imatinib): indicated in low-risk CP-CML, patients with comorbidities, or older patients

  • Second-generation TKIs (e.g., dasatinib, nilotinib): usually indicated in AP-CML

  • Third-generation TKIs (e.g., ponatinib): especially effective in patients with additional mutations

• Mechanism of action

  • Selective inhibition of tyrosine kinase (e.g., by blocking its ATP binding site): inhibits tyrosine phosphorylation of downstream signaling proteins (no phosphate transfer from ATP to tyrosine residues)

  • Disruption of the BCR-ABL1 pathway: inhibits proliferation and induces apoptosis in BCR-ABL1-positive cells

• Special considerations

  • Second-generation and third-generation TKIs are more effective in patients with certain additional mutations than first-generation TKIs, but are also associated with more adverse events.

  • TKIs can interact with many common medications and herbal supplements (e.g., antacids, antidepressants, turmeric, green tea)

  • Teratogenic, therefore, they should not be used during pregnancy

• Adjunctive medical treatment

  • Hydroxyurea or IFN-α may be used to reduce leukocyte counts and control symptoms associated with extreme leukocytosis or thrombocytosis. [7]

• Systemic chemotherapy: indicated in BP-CML and certain cases of AP-CML

• Allogeneic HSCT: Should be considered in patients with TKI-resistant CML and certain patients in advanced phases (AP-CML or BP-CML)

• Indications for anticancer therapy: based on disease risk (Rai staging) and disease activity

  • Low-risk disease (Rai stage 0)

    • Expectant management

  • Intermediate risk disease (Rai stage I or II)

    • Consider expectant management if stable and asymptomatic.

    • Medical therapy: indicated for progressive or symptomatic disease (i.e., active disease)

  • High-risk disease (Rai stage III or IV): medical therapy

• Anticancer therapy may include:

  • Targeted therapy, e.g., ibrutinib, rituximab, alemtuzumab

  • Chemoimmunotherapy, e.g., FCR: fludarabine, cyclophosphamide, rituximab

  • Allogeneic HSCT: currently the only curative treatment option (not routinely performed)

The treatment of acute leukemia is decided by a hematologist-oncologist specialist depending on the specific subtype and results of molecular testing.

• Pretreatment: All patients should have prechemotherapy screening as part of preparation for cancer treatment.

• Chemotherapy

  • Systemic chemotherapy: The regimen of choice is based on individual patient and disease factors.

  • Intrathecal chemotherapy (commonly used): Consider adding for patients with or at high risk of CNS infiltration (e.g., all patients with ALL).

  • Targeted chemotherapy: Consider adding for leukemias with specific immunophenotype and genetic profiles, e.g., Philadelphia translocation.

• Adjunctive treatment, e.g., radiation therapy, immunotherapy, or stem cell transplantation (SCT): Consider based on individual evaluation.

• Supportive care: Provide holistic care to reduce symptoms and support patients and carers (see “Principles of cancer care”).

• Management of complications: initiate monitoring, prevention, and early aggressive treatment as needed for infection, bleeding, pancytopenia, and oncologic emergencies (see “Management of complications”).

• Alkylating agents: e.g., cyclophosphamide

• Anthracyclines: e.g., daunorubicin, doxorubicin

• Antimetabolites: e.g., cytarabine, methotrexate, 6-mercaptopurine

• Enzyme therapy: e.g., L-asparaginase

• Alkaloids: e.g., vincristine

• Glucocorticoids: e.g., prednisone, dexamethasone

• Anthracyclines (e.g., idarubicin, high-dose daunorubicin)

• Antimetabolites (e.g., cytarabine, methotrexate)

• Hypomethylating agents (e.g., azacitidine)

• Differentiation agents: to induce the maturation of immature malignant WBCs

  • ATRA (All-trans retinoic acid)

  • Arsenic trioxide

• Chemotherapy with anthracyclines (e.g., idarubicin)

In APL, the t(15;17) translocation and subsequent formation of the PML-RARA fusion gene can inhibit myeloblast differentiation under physiological levels of retinoic acid. High doses of ATRA (a vitamin A derivative) may induce myeloblast differentiation and promote remission.