CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 15, 2024
Expiration: February 14, 2025
Case 2: An Older Patient With Newly Diagnosed CML and Multiple Comorbidities
For our next case, let’s consider a 68-year-old man with a history of hypertension, hyperlipidemia, and type 2 diabetes who is a heavy smoker. He had laboratory testing prior to a hernia surgery and it was discovered that his white blood cell concentration was 52,000 cells/mcL. A subsequent bone marrow biopsy determined that he had chronic-phase CML. For this older man with the indicated comorbidities and smoking history, I would recommend imatinib 400 mg daily as frontline therapy. Imatinib is generally well tolerated with no increased risk of cardiopulmonary disease (as seen with dasatinib) or cardiovascular disease and diabetes exacerbation (as seen with nilotinib). In older patients where normalization of survival is the endpoint, and not TFR, using imatinib was shown to result in similar long-term OS compared with second-generation TKIs. There is no need in this case to use more potent—and potentially more toxic—second-generation TKIs.
Individualizing Targeted Therapy in CML Patients With Specific History or Comorbidities
Although all the targeted therapies are generally safe, they have unique toxicity profiles that can help physicians and patients tailor the choice of the best first-line treatment for each individual. For example, patients with significant risk factors for arterial occlusive events such as coronary artery disease, cerebrovascular events, or peripheral artery disease may not be candidates for nilotinib or ponatinib, which are associated with an increased risk of cardiovascular events.6,7 For ponatinib, this risk can be minimized by using response-directed dose adjustments, but it should still be used with caution. Prophylactic use of aspirin and HMG-CoA reductase inhibitors (statins) could be considered in patients receiving long-term ponatinib therapy to decrease the risk of cardiovascular events. For nilotinib, HCPs could consider reducing the dose to 150 or 200 mg twice daily once patients achieve an MMR or deeper in an effort to decrease the risk of developing cardiovascular events. Bosutinib or imatinib are the preferred TKIs in patients with cardiovascular comorbidities due to their favorable cardiovascular safety profile and are recommended in this setting.
For patients with existing hepatic impairment, bosutinib is not the best choice as it is associated with the highest risk for liver dysfunction.4 Ponatinib also has liver toxicity concerns, but it is not used in the frontline setting.
A patient with a history of, or risk factors for, pulmonary arterial hypertension should avoid dasatinib, as it can cause this more frequently than any other TKI. Dasatinib is also not a preferred choice for patients at risk for hemorrhagic complications, as it has been associated with bleeding even in the absence of thrombocytopenia. Of course, all the TKIs can cause thrombocytopenia and thereby an increased risk for bleeding, but with dasatinib this may occur due to treatment-related platelet dysfunction. If a patient has risk features for developing pleural effusions (eg, lung disorders, uncontrolled hypertension) and is elderly, it may be prudent to avoid dasatinib, which is the TKI that has the highest risk of pleural effusion.5
Renal impairment, or at least a decrease in the glomerular filtration rate, is a risk with both imatinib and bosutinib. It is not clear that this represents kidney damage, but rather decreased reabsorption of creatinine. However, it may be prudent to avoid imatinib and bosutinib in patients who have some renal dysfunction.
For patients who have uncontrolled diabetes, nilotinib should be used with caution because it raises glucose levels, which makes managing diabetes more challenging.6
Patients who have a history of pancreatitis are at risk for treatment-related increases in lipase and amylase and, occasionally, clinical pancreatitis; they should be closely monitored if receiving frontline therapy with nilotinib. This is particularly true with ponatinib and asciminib, which are used in later-line therapy.7,8
HCPs need to become familiar with the AEs of each TKI and identify each patient’s comorbidities or risk factors to minimize the risks inherent in treatment.
Monitoring of TKI Therapy in an Older Patient
Let’s return to our 68-year-old patient with hypertension, hyperlipidemia, and type 2 diabetes who was diagnosed with CML and started imatinib 400 mg daily. He initiated routine recommended monitoring of response and achieved a BCR::ABL1 transcript of 0.3% at 12 months and 0.2% at 24 months. He never achieved a DMR of MR4 or MR4.5.
For this patient, the goal of therapy is to have a BCR::ABL1 transcript level below 1% at 1 year and after, since this milestone is associated with normalization of survival. When TFR is not the goal, then TKI therapy should be maintained as long as it is being tolerated and the patient is maintaining a response (BCR::ABL1 transcript <1%). This patient should not change a TKI just to deepen his response.
Current CML Monitoring Recommendations
Monitoring of response to achieve key milestones is an essential element of quality care for patients. The National Comprehensive Cancer Network and other groups have designed clear guidance, but it must be referred to and followed at each time point.19 To obtain optimal outcomes with CML treatment, it is critical that patients be monitored according to current recommendations.
At diagnosis, a bone marrow aspiration should be performed with karyotype test to identify whether the patient may have additional chromosomal abnormalities, as well as fluorescence in situ hybridization (FISH) for BCR::ABL1 (rarely the translocation can be cryptic and not detected by conventional karyotype). A PCR analysis should also be conducted to ensure it can detect BCR::ABL1 transcripts; the occasional patient may have atypical BCR::ABL1 transcripts that are not identified by PCR, meaning the patient cannot be followed with PCR.
After therapy initiation, patients should be assessed every 3 months by both FISH and PCR, with a repeat bone marrow aspiration at 12 months after the start of therapy to evaluate the cytogenetic response and identify any additional chromosomal abnormalities.
Once the patient reaches a complete cytogenetic response (CCyR) or the equivalent (eg, ≤1% transcript levels), they can be monitored with PCR at 3- to 6-month intervals.
If BCR::ABL1 transcript levels increase, patients need more frequent monitoring. For example, although every 3 months tends to be sufficient, for a patient with a >1-log increase in BCR::ABL1 transcript levels, repeat monitoring should be done within a month to confirm whether it is a true loss of response (vs test variability). Physicians need to remember to not act based on a single measurement, as a technical issue with the assay could have caused the elevation in BCR::ABL1 transcript levels rather than a loss of response.
BCR::ABL1 mutation analyses are needed when there is clear evidence of resistance to therapy or a loss of response. They are not done at diagnosis, because it is very unlikely that the assay will identify any mutations at that time. Also, if a patient does not reach a molecular response, a mutation analysis is unlikely to find a mutation.
Typically, a change in therapy is recommended only if CCyR is lost or if the transcript levels go up more than 1%. Not achieving an MMR is typically not sufficient reason to change therapy.
Molecular Monitoring Techniques and Interlaboratory Standardization
It is important to understand some of the variabilities inherent to molecular monitoring. The gold standard is quantitative real-time PCR.21 Of importance, these tests only can quantify patient samples that have typical BCR::ABL1 transcripts, for example, B2A2, B3A2, E13A2, and E14A2, which include the majority of patients, but some patients have a different transcript that is not measurable by the standard assays. These results allow quantification of the oncogenic fusion gene BCR::ABL1 mRNA relative to the expected control genes. In the United States, most of the tests use ABL as the control, but other control genes can be used. Of importance, if ABL is the control gene and is expressed at very high levels, for example, at the time of diagnosis or early in the course of therapy, the level itself is not predictive. It is used as a control only to detect these transcripts at the time of diagnosis and rule out the possibility that the patient may have an atypical transcript.
Multiplex PCR can cover many other types of rearrangements, for example, the P190 rearrangement seen in acute lymphocytic leukemia, or an atypical transcript by identifying the BCR::ABL1 breakpoint. Multiplex PCR is not quantitative to the same extent, and not standardized, like the other tests.
Digital PCR is an investigational tool, but it is much more sensitive and is increasingly being used for patients who stop therapy.
There are many factors that affect the PCR test,22 including a coefficient variability that can be half a log or 1 log. There are even variabilities within the standardization, such as degradation of mRNA during transportation. In addition, continued standardization is not consistently done in all patients. HCPs need to be aware of current best practices, such as not testing more frequently than every 3 months.
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