Patient Characteristics Impact Effectiveness of TKIs in CML and AEs Experienced

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Dosing from pivotal phase 3 trials of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) is not optimal for real-world patients who experience different efficacy and adverse events (AEs).

While data in phase 3 clinical trials have shown the efficacy of tyrosine kinase inhibitors (TKIs) to treat chronic myeloid leukemia (CML), data in real-world patients (RWPs) is scarce. A new study in Annals of Pharmacotherapy found that 60% of RWPs would have been excluded from the pivotal phase 3 trials, and these patients require more precise dosing.

TKIs have revolutionized CML, turning what was a fatal malignancy into a chronic disease with reduced mortality. However, the patients in pivotal phase 3 clinical trials were often younger, healthier, and had fewer concomitant medications compared with RWPs.

“Although clinical trial data have suggested that patients with CML treated with TKIs may achieve a near-normal life expectancy, real-world registry studies have shown a 2-fold increased risk of death among patients with CML in the United States,” the authors explained.

As a result, there needs to be a better understanding of the effectiveness and tolerability of TKI in patients with CML who were not eligible for clinical trials. The authors conducted a single-center retrospective study to evaluate and describe the clinical and demographic factors associated with effectiveness and safety in RWPs with CML treated with TKIs.

The study was conducted at the University of North Carolina Medical Center. A total of 174 patients with CML were treated. All of the patients were evaluated for adverse event (AE) outcomes, but only 144 were evaluated for effectiveness outcomes.


The patients were stratified into 3 groups based on exclusion criteria in the pivotal phase 3 clinical trials:

  • Patients with 0 factors (n = 71, 40.8%)
  • Patients with 1 factor (n = 50, 28.7%)
  • Patients with ≥ 2 factors (n = 53, 30.5%)

The most common factor among the patients with 1 factor was uncontrolled hypertension (54.0%). Among the patients with ≥ 2 factors, the most common were uncontrolled hypertension (69.8%), past medical history (64.2%), and age > 70 years (54.7%).

Among the patients eligible for effectiveness evaluations, 72.2% had achieved major molecular response (MMR).

“However, the study failed to achieve its primary end point because no significant difference between patients with 0 factors versus 1 factor and 0 versus ≥ 2 factors were observed for MMR at 12 months, even when controlling for the effects of TKIs (P = 0.61 and P = 0.19, respectively),” the authors wrote.

Of the 37 patients (25.7%) who achieved MMR at 3 months, 22% had 0 factors, 12.8% had 1 factor and 41.3% had ≥ 2 factors. Even controlled for the TKI treatment effect, patients with ≥ 2 factors were still twice as likely to achieve early MMR.

After 1 month of treatment, 83.3% of patients achieved complete hematologic response (CHR). Patients with ≥ 2 factors were less likely to achieve CHR at 1 month: 71.7% vs 89.8%with 0 factors and 87.2% with 1 factor. These patients were still 20% less likely to achieve CHR after controlling for TKI treatment effect.

Among the full cohort of patients evaluated for AEs, the authors found:

  1. A total of 27.6% required a dose reduction.
  2. Among those who experienced a toxicity, 39.6% of patients with ≥ 2 factors, 18.0% with 1 factor, and 11.3% with 0 factors required a reduction by 6 months on TKI therapy.
  3. The median times to TKI-induced AE were 133 days for patients with 0 factors, 46 days for patients with 1 factor, and 34 days for patients with ≥ 2 factors.

“Although there was not an increased risk of AEs observed among RWPs with only 1 factor that would have precluded enrollment in a clinical trial, those with ≥ 2 factors experienced significantly more AE-induced dose reductions, and presented with AEs earlier, compared with those with 0 factors,” the authors wrote.

They noted that the small sample size was insufficient to comprehensively evaluate clinical outcomes with individual TKIs. In addition, the exclusion criteria across phase 3 trials varied slightly, so they had designed a composite list. Finally, long-term outcomes cannot be analyzed since they did not evaluate beyond 12 months after initiation of a TKI and only the first incidence of AEs was captured.

“This study supports the hypothesis that a ‘one size fits all’ TKI dosing regimen is not optimal for all patients,” they concluded. “Although effectiveness was similar between groups, RWPs were more intolerant of TKIs and required dose modifications.”


Szeto AH, Bucci T, Deal A, et al. Response to tyrosine kinase inhibitors in real-world patients with chronic myeloid leukemia. Ann Pharmacother. Published online September 18, 2021. doi:10.1177/10600280211044160