Chronic Myeloid Leukemia: Evaluation and Diagnosis

Monitoring Response to Therapy

Case Continued

Fluorescent in-situ hybridization using a peripheral blood sample to detect the BCR-ABL gene rearrangement is performed and is positive in 87% of cells. Bone marrow biopsy and aspiration show a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics are 46,XX,t(9;22)(q34;q11.2).²⁰ RQ-PCR assay performed to measure BCR-ABL1 transcripts in the peripheral blood shows a value of 98% IS. The patient is ultimately given a diagnosis of CP-CML. Her Sokal risk score is 1.42, making her disease high risk.

• How is response to TKI therapy measured and monitored?

After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, the successful management of a CML patient relies on close monitoring and follow-up to ensure patients are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses. A complete hematologic response (CHR) implies complete normalization of peripheral blood counts (with the exception of TKI-induced cytopenias) and resolution of any palpable splenomegaly. The majority of patients will achieve a CHR within 4 to 6 weeks after initiating CML-directed therapy.²¹

Cytogenetic Response

Cytogenetic responses are defined by the decrease in the number of Ph chromosome–positive metaphases when assessed on bone marrow cytogenetics. A partial cytogenetic response (PCyR) is defined as having 1% to 35% Ph-positive metaphases, a major cytogenetic response (MCyR) as having 0% to 35% Ph-positive metaphases, and a CCyR implies that no Ph-positive metaphases are identified on bone marrow cytogenetics. An ideal response is the achievement of PCyR after 3 months on a TKI and a CCyR after 12 months on a TKI.²²

Molecular Response

Once a patient has achieved a CCyR, monitoring their response to therapy can only be done using RQ-PCR to measure BCR-ABL1 transcripts in the peripheral blood. The NCCN and the ELN recommend monitoring RQ-PCR from the peripheral blood every 3 months in order to assess response to TKIs.^19,23 As noted, the International Scale (IS) has become the gold standard reporting system for all BCR-ABL1 transcript levels in the majority of laboratories worldwide.^14,24 Molecular responses are based on a log-reduction in BCR-ABL1 transcripts from a standardized baseline. Many molecular responses can be correlated with cytogenetic responses such that if reliable RQ-PCR testing is available, monitoring can be done using only peripheral blood RQ-PCR rather than repeat bone marrow biopsies. For example, an early molecular response (EMR) is defined as a RQ-PCR value of ≤ 10% IS, which is approximately equivalent to a PCyR.²⁵ A value of 1% IS is approximately equivalent to CCyR. A major molecular response (MMR) is a ≥ 3-log reduction in BCR-ABL1 transcripts from baseline and is a value of ≤ 0.1% IS. Deeper levels of molecular response are best described by the log-reduction in BCR-ABL1 transcripts, with a 4-log reduction denoted as MR4.0, a 4.5-log reduction as MR4.5, and so forth. Complete molecular response (CMR) is defined by the level of sensitivity of the RQ-PCR assay being used.¹⁴

The definition of relapsed disease in CML is dependent on the type of response the patient had previously achieved. Relapse could be the loss of a hematologic or cytogenetic response, but fluctuations in BCR-ABL1 transcripts on routine RQ-PCR do not necessarily indicate relapsed CML. A 1-log increase in the level of BCR-ABL1 transcripts with a concurrent loss of MMR should prompt a bone marrow biopsy in order to assess for the loss of CCyR, and thus a cytogenetic relapse; however, this loss of MMR does not define relapse in and of itself. In the setting of relapsed disease, testing should be done to look for possible ABL kinase domain mutations, and alternate therapy should be selected.¹⁹