Elias Jabbour, MD

Elias Jabbour, MD

Meeting Insights

ASH 2017 Takeaways: CML

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Elias Jabbour, MD

Practice Community
Houston, Texas
Practice Niche
Associate Professor
Hospital and Institutional Affiliations
Department of Leukemia, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center

 

Question

Several studies were presented at the American Society of Hematology (ASH) Annual Meeting about tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML), including identifying criteria for discontinuation, disease outcomes, overall outcomes, and success after a second attempt at treatment-free remission. What are the key takeaways from these studies?

Answer

What we know so far is that stopping is feasible and it would not be a disaster. Essentially, we can stop therapy in patients who had a deep response for 3 years, if not longer, and who have been on TKIs for 6 years. That was the finding of one of the largest studies called Euro-Ski at the ASH meeting, with 3 years or more of deep molecular response in patients who have been on a TKI for 6 years or longer resulted in the best outcomes.

In the Euro-Ski study, patients with chronic-phase CML were eligible if they did not have a prior failure to any TKI and received treatment for at least 3 years, and were in deep molecular response for at least 1 year. Overall, 49% of patients had to restart their TKI because they were no longer in major molecular remission after discontinuation. Yet the duration of TKI treatment and deep molecular response duration was correlated with molecular recurrence and treatment-free survival. The best cutoff was determined to be 3.1 years for molecular response and 5.8 years for overall TKI treatment duration.

So, among all studies, the conclusion is stopping therapy is feasible, though it should be done in patients who have been on TKIs for at least 6 years and who have had a deep response for at least 3 years. That is the recommendation. There are data coming where we build on these findings to target the stem cell at an early stage, and one of the examples is being considered for the future is combining venetoclax and dasatinib, but there are no data yet available.

Question

Data were presented from the prospective CML-PAED-II trial, which evaluated first-line imatinib among pediatric patients with newly diagnosed CML. What are the key takeaways from these results?

Answer

There were data on dasatinib in the front-line that seemed to be quite reassuring, and which led to the approval of dasatinib in pediatric patients with acute lymphoblastic leukemia (ALL) in November 2017. In this phase 2 study, dasatinib plus EsPhALL chemotherapy was used among pediatric patients with Philadelphia chromosome-positive ALL, which resulted in a 3-year overall survival of 92%. The regimen was well-tolerated, with the most common toxicity being febrile neutropenia and infection. So, dasatinib seems to be coming more directly in that setting. The problem with that is that imatinib is generic and its prices are cheaper; therefore imatinib will remain a major frontline drug. There were data in adult patients with CML with a lower dose of dasatinib of 50 mg per day and it seems to be effective and safe; with half the dose, hopefully the price will be lower.

For pediatric CML, results of the CML-PAED-II prospective cohort study were also reassuring that frontline imatinib is effective. The 18-month event-free survival was 97%, and after 36 months of therapy, 86% of patients had a complete cytogenic response. At least 1 side effect occurred in 66% of patients, with the most common being anemia and neutropenia the most common grade 3/4 toxicity.

Question

Several studies about reduced dosing of TKIs, specifically nilotinib, dasatinib, and ponatinib, were presented. Does reduced dosing of these TKIs reduce the risk of adverse events while maintaining efficacy?

Answer

There are more and more data showing that a lower dose is as effective with a better safety profile. There was a study presented at ASH on nilotinib where they had initially been prescribed the full dose but then had interruptions, and those interruptions did not compromise outcome, and then the patients were prescribed 50 mg instead of 100 mg.

The observational NILO-RED study reduced the dose of nilotinib from BID to QD, usually due to adverse events or for the patient’s convenience. Most patients maintained their major molecular response after the dose reduction. The 1-year survival without unconfirmed major molecular response loss was 97%, and all of the patients who had achieved MR4 before their dose reduction maintained it. There were no cardiovascular events reported in this study.

There were also data for dose-reduced dasatinib that were presented at ASH. In this small study, patients in chronic phase CML received the reduced dose of 50 mg of dasatinib, rather than the full-dose of 100 mg. At 3 months, 93% of patients had a BCR/ABL PCR of less than 10%, and 51% achieved a major molecular response. There were no cases of pleural effusion at the time of the report.

I think we have more and more data that show that once you have a molecular response, you can dose reduce. Still, I think that should be done in the context of close monitoring.

Question

Radotinib is an emerging TKI that is being evaluated in the phase 3 RERISE trial. The 36-month follow-up was presented at ASH. What are the key takeaways about radotinib?

Answer

Radotinib is similar to nilotinib and it is not approved in the United States, and it is a Korean drug.

The phase 3 RERISE trial randomly assigned patients with newly diagnosed chronic phase CML to receive radotinib (300 mg or 400 mg BID) or imatinib. The 36-month update was presented at ASH, in which, overall radotinib resulted in higher rates of major molecular response, and this response was achieved more rapidly than with imatinib. In the trial, 75% of patients on radotinib achieved a major molecular response compared with 54% with imatinib. Overall survival and progression-free survival were similar between the groups. Fewer patients taking radotinib failed treatment compared with imatinib. Therefore, the results of the primary endpoints of the RERISE trial were similar to nilotinib compared with imatinib, so there is nothing really added here.

The drug has an adverse event signal like nilotinib, so one should be very careful. It is unlikely that it will become available in the US because it does not add to what we already have.