Next Steps After TKIs for Patient With Chronic-Phase CML?

Here’s how readers responded to a You Make the Call question about the next steps after TKIs for patient with chronic-phase chronic myeloid leukemia.

Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.

Allogeneic hematopoietic cell transplantation (alloHCT).

Richard McGee, MD
True North Oncology Consulting
Edmonds, WA

I see two options for this patient: switch to another tyrosine kinase inhibitor (TKI; e.g., bosutinib) or perform autologous hematopoietic cell transplantation (AHCT), or alloHCT if a matched donor exists.

The choice obviously depends on the patient’s general health status, co-morbidities, and personal preference. Since the patient is still young, my preference would be transplant.

Samson Fung, MD
Fung Consulting
Munich, Germany

Stay on the same nilotinib dose.

Naftali Bechar, MD
Orlando, FL

Look for a mutation.

Fauzia Rana, MD, MBBS
UF Health Jacksonville
Jacksonville, FL

Sit tight and continue following on current regimen.

David Harrison, MD
UC Davis Comprehensive Cancer Center
Sacramento, CA

I would suggest the following steps:

  • Repeat the karyotype to detect additional chromosomal anomalies (e.g., complex translocation and hypo/hyperploidy)
  • Routine monitoring of complete blood count

Zeeshan Ansar Ahmed, MBBS, FCPS
Aga Khan University Hospitals Karachi
Karachi, Pakistan

Before making any further decisions clarify whether the patient has any concomitant pathology and conduct an analysis on the mutation, as the patient no longer has MMR.

In Russia, if there are no contraindications (there are no mutations or concomitant pathology), the patient can be transitioned to bosutinib 400-500 mg/day. If the optimal response to bosutinib is not achieved within one year, repeat the mutation studies, select the drug with optimal tolerability, and treat the patient for life.

Treatment with ponatinib at a dose of 30 mg/day (with further de-escalation to 15 mg/day after reaching the MMR) is not available in Russia.

Participation in the study of the drug ABL001 is highly desirable.

Anna Turkina, MD, Chelysheva Ekaterina, MD, PhD, and Oleg Shukhov, MD, PhD
National Research Center for Hematology
Moscow, Russia

Try ponatinib or, if available, bosutinib. Repeat mutation analysis.

Michael Pidcock, MBBS
Canberra Hospital
Canberra, Australia

Obtain mutation testing.

Namita Vinayek, MD
Springfield Clinic
Springfield, IL

Resume dasatinib.

Javid Gaziev, MD, PHD, DMSc
Mediterranean Institute of Hematology
Rome, Italy

Since no information about prognostic group and comorbidity was provided, we can consider these factors to be insignificant and can anticipate a long life expectancy of more than 20 years.

The patient started CML treatment with a standard dose of a second generation TKI and reached MMR in nine months, meaning that the patient had an optimal response to firstline TKI treatment according to European Leukemia Net (ELN) and National Comprehensive Cancer Network (NCCN) guidelines.

Six months after MMR, the BCR-ABL level surpassed the MMR level (0.1% on the International Scale [IS]), but MMR loss was not confirmed. There were no BCR-ABL mutations detected.

The molecular assessment is very sensitive and the allowable limit of variance is 1 log (10 times). For MMR loss validation, BCR-ABL should be more than 0.1% on the IS in two consecutive assessments and in one of these tests it should be higher than 1%.

The most frequent cause of MMR loss in CML treatment is patient non-compliance. Other common causes are concomitant drug interaction, BCR-ABL independent pathways (additional chromosome abnormalities) and individual TKI transport features.

Unfortunately, we do not have information about those factors in this patient.

The dasatinib dose was increased after BCR-ABL increased, but it did not have any significant effect.

Subsequently, the patient was switched to nilotinib 300 mg twice a day. Unfortunately, this dosage has not been tested as second-line therapy in large CML clinical trials. The BCR-ABL was stable on nilotinib treatment. The patient is compliant and has no significant adverse events.

A stable complete cytogenetic response that approximately corresponds with a BCR-ABL level below 1% leads to an overall survival similar to the general population, but the achievement of MMR could guarantee absence of progression. Guidelines set MMR as the optimal response and treatment goal. The TKI should be switched in the case of confirmed MMR loss, but there are no specific recommendations or evidence-based data for the management of unconfirmed MMR loss.

For this patient, I would recommend switching treatment to bosutinib 500 mg once a day.
An attractive option for a clinical trial is the combination treatment of nilotinib 400 mg twice a day with allosteric BCR-ABL inhibitor ABL001 (asciminib). This new experimental drug has a mechanism of action independent of the BCR-ABL kinase-activity site and could potentiate TKI activity.

Vasily Shuvaev, MD
Russian Research Institute of Hematology and Transfusiology
Saint Petersburg, Russia