Clinical Practice Guidelines on Chronic Myeloid Leukemia (NCCN, 2020)

National Comprehensive Cancer Network

This is a quick summary of the guidelines without analysis or commentary. For more information, go directly to the guidelines by clicking the link in the reference.

October 30, 2020

In October 2020, the National Comprehensive Cancer Network (NCCN) released an updated version of its clinical practice guidelines on chronic myeloid leukemia (CML), including on diagnosis and workup, management of chronic-phase CML (CP-CML), and CML management during pregnancy and breastfeeding.[1]

Diagnosis and workup

A history and physical exam should make up the initial evaluation in chronic myeloid leukemia (CML), with the assessment including palpation of the spleen, a complete blood count with differential, a chemistry profile, and a hepatitis B panel. To confirm the diagnosis of CML, it is recommended that bone marrow aspirate and biopsy be performed for morphologic and cytogenetic evaluation and that the presence of quantifiable BCR-ABL1 mRNA transcripts at baseline be established through quantitative reverse transcription polymerase chain reaction (qPCR) assay.

At initial workup, detection of additional chromosomal abnormalities in Ph-positive cells (ACA/Ph+), also known as clonal cytogenetic evolution, should be determined through bone marrow cytogenetics. If bone marrow evaluation is not feasible, confirmation of a CML diagnosis can be achieved through fluorescence in situ hybridization (FISH) on a peripheral blood specimen, with dual probes for BCR and ABL1 genes.

Establishment of the presence of quantifiable BCR-ABL1 mRNA transcripts should be carried out at initial workup using qPCR assay.

Patients with ACA/Ph+ at diagnosis require careful observation for evidence of treatment failure.

In patients with no identifiable BCR-ABL1 mutations, consider next-generation sequencing (NGS) with a myeloid mutation panel

For patients diagnosed with chronic-phase CML (CP-CML), the risk score should be determined using the Sokal, Hasford (Euro), or European Treatment and Outcome Study long-term survival (ELTS) scoring systems prior to initiation of tyrosine kinase inhibitor (TKI) treatment.

Management of CP-CML

Risk score, toxicity profile, patient age, ability to tolerate therapy, and the presence of comorbid conditions should be used to select first-line TKI treatment (bosutinib, dasatinib, imatinib, or nilotinib) in CP-CML. It is no longer recommended that allogeneic hematopoietic cell transplantation (HCT) serve as a first-line treatment for patients with CP-CML.

Initial therapy with imatinib 800 mg is not recommended, as recent data have shown second-generation TKIs to have superior efficacy in newly diagnosed CP-CML. 

In patients with CP-CML across all risk scores, appropriate options for first-line TKI therapy include imatinib (400 mg daily) and second-generation TKIs (bosutinib [400 mg daily], dasatinib [100 mg once daily], nilotinib [300 mg twice daily]).

Transient interruptions of TKI therapy and dose modifications should be used in the management of cytopenias (anemia, neutropenia, thrombocytopenia).

For patients with grade 3-4 anemia, it is recommended that reticulocyte count, ferritin, iron saturation, vitamin B12, and folate be assessed and that nutritional deficiencies, if present, be corrected. In symptomatic patients, red blood cell transfusions are indicated.

Following initiation of TKI therapy, it is recommended that all patients be monitored with qPCR (international scale [IS]) every 3 months, including those in whom response milestones are met at 3, 6, and 12 months (≤10% BCR-ABL1 IS at 3 and 6 months, ≤1% BCR-ABL1 IS at 12 months, ≤0.1% BCR-ABL1 IS at >12 months). It is also recommended that after achievement of a complete cytogenetic response (CCyR; ≤1% BCR-ABL1 IS), molecular monitoring take place every 3 months for 2 years and every 3-6 months thereafter.

It is not currently recommended that patients undergo molecular monitoring of their response to TKI therapy more often than every 3 months.

Prevention of disease progression to accelerated-phase CML (AP-CML) or blast-phase CML (BP-CML) and achievement of either molecular response 2.0 (MR2.0; ≤1% BCR-ABL1 IS, which corresponds to CCyR) or major molecular response (MMR; ≤0.1% BCR-ABL1 IS) within 12 months after first-line TKI therapy are the most important goals of TKI treatment. Before drastic changes are made to the treatment strategy, especially in ambiguous situations, the clinical context must be used to interpret the achievement of response milestones.

In cases of TKI-resistant disease, characterized by greater than 10% BCR-ABL1 IS at 6 and 12 months, patients should be evaluated for allogeneic HCT (involving a discussion with a transplant specialist, which might include human leukocyte antigen [HLA] testing). Consideration should be given to alternate treatment options.

If cytogenetic or molecular responses are not achieved at 3, 6, or 12 months after second-line and subsequent TKI therapy, alternative therapies or allogeneic HCT should be considered, if the patient is deemed eligible.

It is recommended that patients with disease that is resistant to imatinib 400 mg daily be switched to an alternate TKI.

Patients whose disease is resistant to dasatinib, nilotinib, or bosutinib can be considered for changeover to an alternate TKI (other than imatinib) in the second-line setting.

Prior to the initiation of second-line TKI therapy, BCR-ABL1 kinase domain mutation analysis, evaluation of drug interactions, and compliance to treatment are recommended.

Caution must be exercised in the concomitant use of drugs that are metabolized by TKIs, and treatment outcome should be optimized by exploration of appropriate alternatives. Consider dose modification if coadministration is unavoidable.

It is believed that carefully selected, consenting patients (in early CP-CML) in whom a deep molecular response (DMR; ≥MR4.0) has been achieved and maintained for at least 2 years can, with close monitoring, discontinue TKI therapy.

CML management during pregnancy and breastfeeding

Due to the risk of fetal abnormalities, conception during active TKI treatment is strongly recommended against. Before a woman and her partner attempt pregnancy, inform them that there are no guidelines regarding how to best monitor CML during pregnancy or best treat progressive disease should it develop during pregnancy. Prior to the initiation of TKI therapy, discuss fertility preservation with all patients of childbearing age. It is recommended that patients be referred to a CML specialty center and consult with a high-risk obstetrician.

Despite limited experience, it is generally believed that men do not need to discontinue TKI therapy if a pregnancy is planned.

Due to the risk of miscarriage and fetal abnormalities during pregnancy, women should stop TKI therapy prior to natural conception, with the patient remaining off therapy over the pregnancy’s course.

If the BCR-ABL1 IS climbs above 1.0% during pregnancy, it is recommended that the patient be monitored monthly with qPCR and that treatment be initiated.

Following delivery, TKI treatment can be reinitiated. However, women should be advised against breastfeeding while on TKI therapy, as TKIs pass into human breast milk.

It is recommended that women who extend the treatment-free period for breastfeeding undergo close molecular monitoring. Breastfeeding should be terminated and TKI restarted upon confirmation that the patient has lost the MMR after treatment cessation.

For more information, please go to Chronic Myelogenous Leukemia (CML).

For more Clinical Practice Guidelines, please go to Guidelines.

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