Selecting A TKI for Chronic Myeloid Leukemia

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TKI selection in the first line is based on risk score and TKI toxicity profile as well as the patient’s age, ability to tolerate therapy, and comorbid conditions.
TKI selection in the first line is based on risk score and TKI toxicity profile as well as the patient’s age, ability to tolerate therapy, and comorbid conditions.

Of the estimated 8950 people who will be diagnosed with chronic myeloid leukemia (CML) in the United States in 2017, the majority will present in the chronic phase (CP). If left untreated, CML-CP will progress to advanced phase — accelerated (AP) or blast (BP) — in 3 to 5 years.1

The primary treatment for newly diagnosed CML-CP is a tyrosine kinase inhibitor (TKI), including the first-generation TKI, imatinib, and second-generation TKIs, dasatinib and nilotinib. TKI selection in the first line is based on risk score and TKI toxicity profile as well as the patient's age, ability to tolerate therapy, and comorbid conditions.

Generic imatinib, where the price can be 25% to 30% of the patented agent, “should be front-line for all newly diagnosed patients,” Hagop M. Kantarjian, MD, professor and chairman of the department of leukemia and Samsung Distinguished University Chair in Cancer Medicine at the MD Anderson Cancer Center in Houston, Texas, said in an e-mail interview with Cancer Therapy Advisor. If the patient has high-risk CML or is very young, clinicians may consider selecting “dasatinib or nilotinib to have higher chance of achieving durable complete molecular response,” he added.

Guidelines recommend imatinib for patients with a low-risk score, and dasatinib and nilotinib for those with intermediate- or high-risk scores. In patients with a low-risk score, dasatinib may be preferred for patients with a history of arrhythmias, heart disease, pancreatitis, or hyperglycemia, while nilotinib may be chosen for those with a history of lung disease or at risk for pleural effusion.2

One study showed that responses to second-line dasatinib and imatinib are durable, though after failing imatinib, patients with side effects may need to be treated with more than 1 second-generation TKI “to achieve an optimal outcome.”3

To aid clinicians in treatment selection, the National Comprehensive Cancer Network (NCCN) introduced NCCN Evidence Blocks for systemic therapies in 2016, with the end of 2017 as the target date for completing its entire library.

Using published data and clinical experience, NCCN Guidelines panel members score the 5 “key components of value that provide important information about specific recommendations contained within the NCCN Clinical Practice Guidelines in Oncology” — efficacy of regimen/agent, safety of regimen/agent, quality of evidence, consistency of evidence, and affordability of regimen/agent—on a scale from 1 (least favorable) to 5 (most favorable).4

The final scores are used to build a 5 by 5 table that can be used to “scan a group of potentially appropriate interventions and make treatment recommendations based on what is most important to the patient.”4

When a TKI is indicated for a patient with CML, clinicians can use the NCCN Evidence Blocks to weigh available agents for the first-, second-, and third-line treatment of CML-CP, for advanced phase CML, and by BCR-ABL mutation (see Table).

Evidence Blocks are also available for treating patients with relapse or failure to achieve complete cytogenetic response following allogeneic hematopoietic cell transplantation.

Table. TKI Treatments for CML5-10

TKI
(year approved)

First-line Treatment for CML-CP
Low- , Intermediate-, and High-risk

Second-line Treatment for CML-CP

Third-line Treatment for CML-CP

Treatment for
Advanced Phase

BCR-ABL1 Mutation

CML-AP

CML-BP

Bosutinib

(2012)

 

X

X

X

X

E255K/V

F317L/V/I/C

F359V/C/I

T315A

Y253H

Dasatinib

(2006)

X

X

X

X

X

Y253H

E255K/V

F359V/C/I

Imatinib

(2001)

X

 

 

X

X

 

Nilotinib

(2007)

X

X

X

X

X

F317L/V/I/C

T315A

V299L

Ponatinib

(2012)

 

 

X

X

X

T315I

*All TKIs administered with steroids

Dr Kantarjian believes that these evidence blocks are useful, for example, in selecting one agent over another based on cost: the “price of TKIs is very relevant when 2 treatments are equal,” he wrote.

In the case when the evidence blocks are equal, such as second-line bosutinib and nilotinib after first-line dasatinib, the clinician would weigh prior TKIs, mutations, and patient comorbidities, he added.

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