Chronic Myeloid Leukemia: Drug Therapy

Therapeutic targets

• Improvement of the symptomatology
• Remission (disappearance of disease symptoms).
• Prolongation of survival time
• Healing

Therapy recommendations

• Initiation of therapy before obtaining BCR-ABL status: hydroxyurea (40 mg/kg bw) if leukocyte count > 100,000/μl (avoidance of leukostasis/aggregation of leukocytes in blood vessels resulting in vascular occlusion).
• Prophylaxis of tumor lysis syndrome (TLS; life-threatening metabolic derailment that can occur when a large number of tumor cells are suddenly destroyed): Adjust urine pH to 6.4-6.8 with sodium bicarbonate (1-2 g/day p.o.) and uric acid clearance.
  • Xanthine oxidase inhibitor febuxostat (for intermediate TLS risk).
  • Rasburicase (for high TLS risk).
• Lifelong therapy in the chronic phase (< 15% blasts in blood or bone marrow) of chronic myeloid leukemia (CML) to prevent relapse and possible progression of the disease to the accelerated phase (see below) or blast crisis.Possibly a sales strategy in chronic biological leukemia. In a study of 190 participants who entered the treatment-free remission (TFR) phase, a majore molecular response (MMR) was maintained in 51.6%, and MR 4.5 (= decrease in BCR-ABL transcripts by 4.5 log levels from baseline (corresponding to 0.0032% by international scale)) in the majority. Nilotinib therapy (see below) was resumed in 86 patients. Resumption of therapy resulted in at least MMR again in 85 patients. Within 40 weeks of resumption of therapy, BCR-ABL load had returned to an MR 4.5 in nearly 89% (76/86).
• For first-line therapy, tyrosine kinase inhibitors (TKi; imatinib; in case of imatinib resistance, dasatinib, nilotinib); Note: risk of hepatitis B reactivation:
  • At 10.9 years after initiation of therapy with imatinib, 84.4 percent were still alive
  • Patients who achieved an optimal outcome (major molecular response with decrease in BCR-ABL levels <0.1%) at 18 months: Survival rates > 90%
  • After durable reduction of tumor burden by several log levels, controlled discontinuation of drugs is also possible (= therapy-free remission (TFR)).
• The combination of imatinib with pegylated IFN-α2a results in an increased deep molecular response. Maintenance therapy with IFN after TKI therapy results in good long-term remissions.
• For time-line therapy, interferons; possibly also hydroxyurea or cytosine arabinoside (hematologic and cytogenetic remission in 40-60%); bosutinib may be used in second-line therapy if pretreated with at least one other TKI and imatinib, dasatinib, and nilotinib are not considered appropriate therapeutic options. Side effects: Nausea, vomiting, rash, diarrhea (diarrhea).
• Ponatinib (third-generation TKI): therapy of choice in CML patients with T315I mutation and in cases when other TKIs are not indicated; side effects: vaso-occlusive disease, thrombotic events, pancreatitis (inflammation of the pancreas), severe rash;
• Asciminib: inhibits not in the tyrosine kinase domain but in that of the myristyl binding site: it slows down the BCR-ABL fusion protein resulting from a translocation between chromosomes 9 and 22 (“Philadelphia chromosome”); most patients achieved at least hematologic remission (normalization of blood count) (phase I study).
• Note: Regular follow-up (cytogenetic testing and molecular genetics) to assess remission status.
• Cure of CML only possible by allogeneic stem cell transplantation; patients who do not receive stem cell transplantation must be prepared for a lifetime of continuous medication
• See also under “Further therapy” (stem cell transplantation).

Note: Criteria for the accelerated phase are:

• 10-19% blasts in blood or bone marrow or.
• ≥ 20 % basophils in blood or bone marrow or
• Therapy-independent thrombocytopenia < 100,000/μl or
• Thrombocytosis (platelets (thrombocytes) in blood above normal range) > 1,000,000/μl, unresponsive to therapy or
• Additional clonal chromosomal “major route aberrations” of Ph+ cells (2nd Ph chromosome, trisomy 8, isochromosome 17q, trisomy 19, complex karyotype, aberrations of chromosomal segment 3q26.2) despite treatment; or
• Newly formed clonal evolution or
• Progressive splenomegaly (splenomegaly) and rising leukocytes that do not respond to therapy

Other indications

• If minimal residual disease (MRD) is below the detection threshold, the tyrosine kinase inhibitor imatinib can be tentatively discontinued without much risk.