Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020 Apr;34(4):966-984. doi: 10.1038/s41375-020-0776-2. Epub 2020 Mar 3. PMID: 32127639; PMCID: PMC7214240.
Definition, Etiology, Pathogenesis Top
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm involving clonal proliferation of a malignant multipotential hematopoietic stem cell. As a result of reciprocal translocation of the long arms of chromosomes 9 and 22, the Philadelphia (Ph) chromosome is formed, and the subsequent fusion of the BCR and ABL1 genes leads to the development of a new mutant BCR-ABL1 gene. This gene encodes the BCR-ABL1 fusion protein, which due to its constitutive tyrosine kinase activity causes an increased clonal proliferation of hematopoietic stem cells, inhibition of apoptosis, and impaired adhesion of leukemic cells to the bone marrow matrix.
Clinical Features And Natural History Top
Clinical manifestations include weight loss, constitutional symptoms, and manifestations of splenomegaly (left upper quadrant pain, early satiety). Rarely patients present with leukostasis (leukocytes >200-300×109/L) that alters microcirculation, manifesting as altered mental status, visual disturbances, headache, symptoms of hypoxemia, and priapism. In ~40% of patients CML is an incidental finding in a complete blood count (CBC) performed for other reasons.
The chronic phase of CML always progresses (sometimes rapidly) to blast crisis. The progression usually follows through an intermediate accelerated phase or less often it may be direct. In patients with blast crisis, peripheral blood or bone marrow blast counts increase to >20%, consistent with acute leukemia (in ~50% of patients CML transforms into myeloid leukemia; in ~30%, into lymphoblastic leukemia; in ~10%, into megakaryoblastic leukemia; and in the remaining cases blast crisis has features of myelofibrosis). The accelerated phase and blast crisis in CML are characterized by multiple cytogenetic abnormalities, resistance to treatment, and a poor prognosis.
1. CBC: White blood cell (WBC) counts are elevated in all patients with CML, with mature and immature granulocytes at all stages of development, thrombocytosis (in a third of patients), basophilia, and eosinophilia. Differential blood count reveals a left shift that may extend to blasts and includes promyelocytes, myelocytes, metamyelocytes, less frequently erythroblasts. Hemoglobin levels at diagnosis are typically normal.
2. Bone marrow examination: Required to confirm the chronic phase. Bone marrow aspiration and trephine biopsy reveal increased bone marrow cellularity with an elevated proportion of cells of neutrophilic (similar to that observed in peripheral blood) and megakaryopoietic lineages.
3. Cytogenetic and molecular studies of bone marrow (Ph chromosome) are performed both to establish diagnosis and exclude additional cytogenetic abnormalities.
4. Molecular studies of peripheral blood: These studies are used to confirm the diagnosis of CML (qualitative) and monitor response to therapy (quantitative).
At all stages the diagnosis is based on the presence of the Ph chromosome, documented using cytogenetic studies (karyotype or fluorescent in situ hybridization [FISH]), or the BCR-ABL1 gene, documented using molecular studies (reverse transcriptase–polymerase chain reaction [RT-PCR] of peripheral blood or bone marrow cells).
1. The World Health Organization (WHO) diagnostic criteria of accelerated phase (≥1 feature must be present):
1) 10% to 19% blasts in peripheral blood or bone marrow.
2) ≥20% of basophils in peripheral blood.
3) Sustained thrombocytopenia <100×109/L (unrelated to treatment).
4) Clonal cytogenetic evolution (emergent chromosomal aberrations) during treatment.
5) Progressive splenomegaly or leukocytosis not responding to treatment.
2. The WHO diagnostic criteria of blast crisis (≥1 feature must be present):
1) ≥20% blasts in peripheral blood or bone marrow.
2) Extramedullary blastic infiltrates (in organs other than spleen).
3) Large aggregates or clusters of blasts in bone marrow.
1. Conditions associated with elevated neutrophil counts:
1) Other myeloproliferative and myelodysplastic-myeloproliferative neoplasms.
3) Other neoplasms that produce granulocyte growth factors: Small cell lung cancer, ovarian cancer, melanoma, Hodgkin lymphoma.
4) Other conditions (WBC count, 30-40×109/L): Tissue necrosis, myocardial infarction, myositis, acute hemorrhage, glucocorticoid therapy.
5) Exogenous administration of granulocyte colony-stimulating factor or granulocyte and macrophage colony-stimulating factor.
2. Conditions associated with thrombocytosis:
1) Other myeloproliferative neoplasms (eg, essential thrombocythemia).
2) Reactive thrombocytosis: Infection, malignancy, chronic inflammatory disorders, tissue damage.
3) Iron deficiency.
4) Medications: Glucocorticoids, epinephrine, vincristine, tretinoin, methimazole.
1. Long-term treatment with tyrosine kinase inhibitors (TKIs):
1) Imatinib 400 mg orally once daily.
2) Dasatinib 100 mg orally once daily; this is effective in all patients with resistance to imatinib caused by BCR-ABL1 gene mutations except for T315I/A, F317L, and V299L mutations.
3) Nilotinib 300 mg orally bid; this is effective in all patients with resistance to imatinib caused by BCR-ABL1 gene mutations except for T315I, Y253H/F, E255V/K, and F359V mutations.
4) Bosutinib 400 mg orally once daily.
5) Ponatinib 45 mg orally once daily; this is effective in patients with the T315I mutation.
The first-line agents include imatinib, nilotinib, bosutinib, and dasatinib. In the case of imatinib resistance or intolerance, dasatinib, nilotinib (800 mg/d), or bosutinib may be used. Ponatinib is typically reserved for third-line treatment or for patients with the T315I mutation. No significant data in favor of any of these agents are available, except for the BCR-ABL1 mutations causing resistance to any one of them. The choice of the agent should be based on the availability, cost, toxicity profile, as well as the patient’s comorbidities and possible interactions with other administered drugs.
Criteria for response to treatment:
1) Complete hematologic response (CHR): WBC <10×109/L, no immature granulocytes on peripheral blood film, basophils <5%, platelet count <450×109/L, nonpalpable spleen. No CHR or presence of >95% Ph+ cells on cytogenetic examination following 3 months of TKI therapy is considered treatment failure.
2) Major hematologic response (MCyR) (≤35% of Ph+ cells on cytogenetic examination) and/or achieving ≤10% of BCR-ABL1 transcript on the International Scale (IS) in real-time quantitative polymerase chain reaction after 3 months of treatment is considered optimal.
3) Complete cytogenetic response (CCyR) (no Ph+ cells on cytogenetic examination) and/or <1% of BCR-ABL1 transcript on the IS after 6 months of treatment is optimal, 1% to 10% requires closer follow-up, and >10% warrants a change in therapy.
4) Major molecular response (MMR) (<0.1% of BCR-ABL1 transcript on the IS) 12 months from treatment initiation or anytime afterwards is optimal. Maintaining this level of response ensures progression-free survival.
2. Allogeneic hematopoietic stem cell transplant (HSCT) should be considered for patients in the chronic phase after failure of ≥2 TKIs and in patients with accelerated phase with a suboptimal response; it should be strongly considered for those with blast crisis.
3. Interferon alpha is used in pregnant women (monotherapy) and in patients with TKI treatment failure who are not eligible for allogeneic HSCT (in combination with cytarabine or another agent).
4. Hydroxyurea (INN hydroxycarbamide) is used as a short-term treatment to reduce WBC counts prior to confirming the diagnosis. It has no disease-modifying effect and no influence on survival.
5. Treatment of accelerated phase and blast crisis requires higher doses of TKIs. In patients with disease progression in the course of treatment, switch to another TKI (see above). Allogeneic HSCT should be considered, optimally after achieving a chronic phase. The only exception is TKI-naive patients with accelerated phase diagnosed de novo in whom the optimal response to TKI treatment has been achieved.
6. Treatment-free remission (TFR) is ongoing molecular remission in the absence of TKI therapy. Patients can only be considered for a trial of TFR if high-quality monitoring can be assured. Following ≥3 years of TKI therapy patients may attempt TFR if they have achieved a deep molecular response (BCR-ABL1 transcript ≤0.01% on the IS or deeper) and maintained it for ≥2 years. Patients attempting TFR must undergo molecular monitoring for relapse (>0.1% of BCR-ABL1 transcript on the IS) every 4 weeks for ≥6 months.
The response to TKI treatment is the most important prognostic factor. In patients treated with imatinib, 7-year rates of progression-free survival and survival free of accelerated phase/blast transformation are 81% and 93%, respectively. In patients undergoing allogeneic HSCT (from a related donor), the 3-year survival rate is reported as up to 76%.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to the selective nature of the observed cohort. Chronic Myeloid Leukemia (CML). National Marrow Donor Program/Be The Match. Accessed January 27, 2021. https://bethematchclinical.org/transplant-indications-and-outcomes/disease-specific-indications-and-outcomes/cml Various prognostic scores exist. At present the European LeukemiaNet recommends the use of the European Treatment and Outcome Study (EUTOS) long-term survival (ELTS) score at baseline to estimate survival risk.