Targeted Therapy Allows Patients to Live With CML

Developing Chronic Myeloid leukemia (CML) was once considered a death sentence. However, the introduction of targeted therapy transformed this cancer into a manageable, chronic condition. As of February 2022, CML accounted for about 15% of all adult leukemia cases, according to data from the National Comprehensive Cancer Network.¹ CML is a myeloproliferative disorder that originates in the stem cells and develops when a translocation involving chromosome 9 and chromosome 22 occurs. This translocation creates the Philadelphia (Ph) chromosome that results in fusion gene BCR-ABL.²

CML is characterized by an uncontrollable growth of myeloid cells at different stages. There are 3 stages patients may present: the chronic phase, accelerated phase, and blast phase or blast crisis.³ Each is characterized by the number of immature cells detected in the bone marrow and presence of cytogenetic or molecular abnormalities.⁴ When the chronic phase remains untreated, it will eventually progress to the more aggressive accelerated phase or blast phase. Patients who progress to an accelerated or blast phase are treated similarly to patients with acute leukemia.

Most patients presenting with CML are asymptomatic and a positive diagnosis is made after a routine laboratory evaluation. Some characteristics seen in the complete blood count may include leukocytosis paired with a left shift and myelocyte bulge, blasts equal to or less than 2%, basophilia, and eosinophilia.⁵ Other symptoms in patients with CML include fatigue, weight loss, malaise, left upper quadrant fullness or pain, and bleeding issues in rarer cases. These signs and symptoms are usually the result of anemia or splenomegaly.⁶

Prognostic Risk
CML prognosis has greatly improved since the development of tyrosine kinase inhibitors (TKIs). Prognosis has shown an association with several clinical characteristics. Many models have been developed to help determine the prognostic risk, including the Sokal index and the Hasford score.⁷

The Sokal index predicts survivalbased characteristics such as the patient’s age, spleen size on clinical examination, platelet count, and percentage of blasts in the peripheral blood. Depending on the Sokal score, patients are classified as having low-risk, intermediate-risk, or highrisk CML, which helps guide therapy selection. The Hasford score model includes similar variables but also accounts for the amount of eosinophils and basophils in the peripheral blood.^7,8

Treatment Goals
Current treatment goals vary based on the stage of CML. The overarching goal of therapy is eliminating Ph chromosomes in the bone marrow and achieving a major molecular response (MMR).

For chronic-phase CML, the treatment goals include maintaining hematologic, cytogenetic, and molecular remission; preventing progression to accelerated phase or blast crisis; and minimizing toxicity. The goal for patients with accelerated phase or blast crisis CML is to induce the disease into chronic phase.

Effectively assessing how patients respond to therapy can play a critical role in helping identify patients who are at high risk of disease progression or who may benefit from a change in therapy. The 3 types of responses to therapy are hematologic, cytogenetic, and molecular.^8,9

Targeted Therapy
In the past few decades there has been a huge shift from traditional chemotherapy medications, which affect organ systems, to more specifi targeted agents. The use of targeted agents provides a precise, more potent therapy with reduced toxicity.

First-line treatment of chronic-phase CML includes TKIs for BCR-ABL, such as imatinib (Gleevec; Novartis), dasatinib (Sprycel; Bristol Myers Squibb), nilotinib (Tasigna; Novartis), bosutinib (Bosulif; Pfizer), ponatinib (Iclusig; Takeda), and asciminib (Scemblix; Novartis), and the protein synthesis inhibitor omacetaxine (Synribo; Teva Pharmaceuticals).¹⁰ Studies have demonstrated superior rates of complete responses in TKIs, and they are positively transforming outcomes for patients who have received CML diagnoses.^10,11

Nevertheless, patients may develop resistance to TKIs. Resistance to imatinib led to the development of second-generation TKIs such as dasatinib, nilotinib, and bosutinib. These agents are more potent inhibitors of BCR-ABL than imatinib and exhibit significant activity against all resistant mutations except T315I. The second-generation TKIs have produced a faster, deeper response compared with imatinib, but do not provide any decrease in mortality.¹²

The third-generation TKI ponatinib was developed to help combat T315I, which is commonly known as the gatekeeper mutation. Ponatinib has demonstrated activity against T315I mutations and BCR-ABL mutations that are resistant or intolerant to other TKIs. The decision to use ponatinib must be determined after a risk-vs-benefit assessment because of potential toxicities.^13,14

Asciminib is an inhibitor that has multiple targets. It is a first-in-class BCR-ABL inhibitor specifically targeting the ABL myristoyl pocket. This agent shows activity against the T315I mutation and has the potential to overcome resistance to other approved TKIs.

In the ASCEMBL trial (NCT03106779),¹⁵ asciminib was compared to bosutinib and showed a superior efficacy with an improvement in the safety profile. In this randomized, open-label, phase 3 trial, 233 patients with chronic-phase CML previously treated with 2 or more TKIs were evaluated. After 24 weeks, the MMR rate was 25.5% vs 13.2% for asciminib and bosutinib, respectively^.15,16

Toxicity Management
The decision on a course of therapy for treating CML depends on the toxicity profile of the TKIs available. Treatment heavily relies on the monitoring of adverse effects (AEs) to enhance quality of life. Although most TKIs are generally well tolerated by patients when combined with adequate supportive care, the Table highlights the precautions, medication-specific AEs, and monitoring parameters to consider for each TKI.

Myelosuppression may occur because of TKIs targeting the c-KIT receptors, which are responsible for the development of normal blood cells, mast cells, and melanocytes. It is important to monitor complete blood counts weekly for the first 2 months, then every month after for most TKIs.¹⁷ The amount of occurrence varies according to the agents, with the greatest rates of grade 3 or 4 neutropenia seen with dasatinib. Other AEs that occur more frequently include fatigue, myalgia, nausea, and vomiting.¹⁸

Cardiovascular toxicity is another common drug class effect. This condition is typically reversible with the administration of systemic steroids and circulatory support. The cardiovascular status of patients should be routinely monitored when administering any TKI. Decreased left ventricular function is another class effect, occurring more in dasatinib and ponatinib compared with the other TKIs. Although the rates of this AE are rare, the longevity of treatment combined with an aging population increases the risk. For this reason, patients should be monitored regularly for the development of heart failure.

There is also the risk of QT prolongation. Ponatinib provides the least risk of QT prolongation and is equal to or less than the risk level from bosutinib for patients. Dasatinib provides a greater risk of QT prolongation than bosutinib, whereas nilotinib provides the highest risk of QT prolongation among the TKIs. To monitor this risk, evaluating levels of electrolytes such as calcium, potassium, and magnesium in patients is recommended. Additionally, it is recommended to not administer TKIs with medications like cytochrome P450 3A4 inhibitors or foods that can prolong QT.^17,18

Among the other AEs, fluid retention and edema are also observed in patients when using TKIs. Fluid retention can manifest as the cause of pleural effusion, presenting as a dry cough or shortness of breath. Treatment with a short course of steroids and diuretics can mitigate this AE. Dose reductions may help to diminish the risk as well.^17-22

Emerging Therapies

Newer TKIs may be more attractive because of their higher rates of efficacy and faster, deeper response compared with imatinib. With the ongoing concern for development of resistance, clinical trials are being conducted to investigate new treatment options. Some BCR-ABL inhibitors in clinical trials are radotinib and flumatinib.

Radotinib is a second-generation BCR-ABL TKI that has a profile similar to that of imatinib. It is approved as a first-line therapy option for patients with chronic-phase CML in Korea based on the results of the phase 3 RERISE study (NCT03722420).

In RERISE, 241 patients with newly diagnosed CML were evaluated. Patients who received radotinib demonstrated significantly faster, higher rates of MMR compared with imatinib at 86% vs 75%, respectively. Overall efficacy results were comparable to long-term results seen with other second-generation TKIs. Radotinib had a welltolerated safety profile and can be an appealing treatment option because of lower cost compared with other second-generation BCR-ABL TKIs.²³

Flumatinib is a BCR-ABL inhibitor that shows more potent activity compared with (NCT02204644) compared the efficacy and safety of flumatinib with that of imatinib in 394 patients with newly diagnosed CML. The study revealed that at 6 months, the rate of MMR was significantly higher in patients receiving flumatinib than in those receiving imatinib at 33.7% and 27.1%, respectively. These results demonstrated that MMR was achieved more quickly among patients receiving flumatinib. During the trial, flumatinib also demonstrated significantly lower rates of AEs such as edema, pain in extremities, rash, neutropenia, anemia, and hypophosphatemia. These results may suggest that flumatinib can be an alternative for patients with previously untreated chronic-phase CML.²⁴

Other novel agents that show promising results include olverembatinib (HQP1351) and vodobatinib (K0706). Both novel drugs are third-generation TKIs that can be used to treat patients with CML who are resistant to imatinib and second-generation TKI therapies. PF-114 is a fourth-generation TKI that is effective against both BCR-ABL and T315I mutation similarly to ponatinib with potentially reduced cardiotoxicity.²⁵

Treatment-Free Remission
A potential new goal of CML therapy is treatment-free remission because of the long-term survival outcomes seen with the use of TKIs. Treatmentfree remission is defined by the ability to maintain minimal residual disease that is undetectable or detectable at a stable low level after TKI discontinuation. Many individuals who have an optimal response can achieve life expectancy close to that of the general population.

Although treatment with TKIs is beneficial, they do come with prolonged use that can have an excessive cost and burden on patients. Recently, studies have shown that in a select group of patients with chronic-phase CML, TKIs can be safely discontinued. To be considered for TKI discontinuation, patients must meet strict criteria. Many studies are needed to safely make this an option for more patients in the future.^26,27

References

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About the Authors
Jameshia A. Below, PharmD, is an assistant professor of pharmacy practice in the School of Clinical Sciences at the University of Louisiana Monroe College of Pharmacy.

Alexis Horace, PharmD, BCACP, AAHIVP, is an associate professor of pharmacy in the School of Clinical Sciences at the University of Louisiana Monroe College of Pharmacy.