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Early MMR With TKI Therapy Not Necessary to Normalize Survival in Patients Over 60 With CML

March 8, 2023

April 2023

Khylia Marshall

Khylia Marshall is a freelance journalist based in Tucson, Arizona. 

Achieving a major molecular response (MMR) within the first two years of initiating tyrosine kinase inhibitor (TKI) therapy has been associated with higher chances of deep and durable molecular responses and treatment-free remission in patients with chronic myeloid leukemia (CML), as indicated by the European LeukemiaNet (ELN) recommendations and the National Comprehensive Cancer Network guidelines. However, according to a retrospective study conducted by Hagop Kantarjian, MD, of the University of Texas, and colleagues, patients with CML who do not achieve an MMR, or even a complete cytogenetic response (CCyR), at two years after initiating TKI therapy still have good long-term overall survival (OS), especially patients over 60. Study findings were published in the American Journal of Hematology.

The study included 131 patients with CML who were treated at the University of Texas MD Anderson Cancer Center between 2003 and 2020 and did not achieve an MMR within two years of initiating TKI therapy. Although no patients achieved an MMR, 46 patients (35%) achieved a CCyR, 29 patients (22%) achieved a major cytogenetic response (MCyR), and 56 patients (43%) had a minor or no cytogenetic response.

Researchers observed rates of progression-free survival (PFS), OS, CML-related OS (CML-OS), and change of TKI from frontline treatment.

Of the total study group, the 10-year OS was 76% and the 10-year CML-OS was 88%. Researchers noted similar PFS between patients who achieved a CCyR and those who achieved a MCyR (80% vs. 88%; p=0.2). Similarly, there was an insignificant difference between those who achieved a CCyR and those who achieved an MCyR in OS (84% vs. 88%; p=0.4) and CML-OS (95% for both; p=0.9). In contrast, those who achieved a minor or no cytogenetic response two years after initiating TKI therapy demonstrated inferior PFS (61%), OS (64%), and CML-OS (80%).

These findings indicate “you don’t have to be in a deep molecular response to normalize survival,” Dr. Kantarjian said. “All you have to do is achieve better than a partial cytogenetic response.”

Moreover, of the patients studied who were 60 years and older (n=24, 18%), only nine achieved a CCyR after two years of TKI therapy (38%). While the 10-year OS of these patients was 55%, the 10-year CML-OS was 100%, and only one patient had progression to the accelerated phase. Therefore, the study’s findings challenge the “ELN’s recommendation that patients who do not achieve a CCyR at one year or beyond are failures. They are not failures. They are suboptimal responses,” Dr. Kantarjian said.

“What has happened in the community practice is there has been a tendency to continue changing the TKI even in patients who were in a [CCyR]” to achieve an MMR, Dr. Kantarjian said.

Instead, he added, oncologists should not “panic ... or immediately decide to change TKIs, particularly if the change is to a TKI that’s toxic, either clinically or financially,” and particularly in patients “over the age of 60 whose treatment tolerance and survival are confounded by comorbidities unrelated to CML.”

While researchers noted the retrospective nature and size of the study as limitations, they mentioned “large databases where investigators could analyze their BCRs [breakpoint cluster regions] and see if they reproduce our findings, and therefore make stronger recommendations,” Dr. Kantarjian said.

While oncologists and patients often opt for more expensive or toxic treatments in the pursuit of an MMR, researchers said, “the risk of treatment toxicity [from changing TKIs or increasing the dose of TKIs] outweighs the benefit of achieving responses deeper than CCyR, especially in the older population.”

Any conflicts of interest declared by the authors can be found in the original article.

Khylia Marshall is a freelance journalist based in Tucson, Arizona.

Reference

Bidikian A, Jabbour E, Issa GC, Short NJ, Sasaki K, Kantarjian H. Chronic myeloid leukemia without major molecular response after 2 years of treatment with tyrosine kinase inhibitor [published online ahead of print, 2023 Jan 6]. Am J Hematol. doi: 10.1002/ajh.26836.

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