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Efficacy, safety must guide treatment sequencing decisions in chronic myeloid leukemia
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NEW YORK — The approval of multiple tyrosine kinase inhibitors for chronic myeloid leukemia has greatly expanded the therapeutic armamentarium but also created a complex treatment landscape, according to a presenter at Chemotherapy Foundation Symposium.
Decisions about how to sequence TKIs require careful consideration of several factors, Michael J. Mauro, MD, hematologist and leader of the myeloproliferative neoplasms program at Memorial Sloan Kettering Cancer Center, said during a presentation.
“When you think about sequencing, the key is to know your tools,” said Mauro, a HemOnc Today Editorial Board member. “You need to look not only at efficacy and the goals of therapy, but also toxicity.”
The FDA has approved four TKIs for use in the front-line setting: imatinib, nilotinib (Tasigna, Novartis), dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) and bosutinib (Bosulif, Pfizer). A fifth TKI, ponatinib (Iclusig, Takeda), is approved only for patients with T315I-mutated CML or in cases when other TKIs are not indicated.
These agents have key differences in terms of dosing, long-term safety, hematologic toxicity, nonhematologic toxicity and emerging toxicities, such as cardiovascular events.
“There also is still a little bit of mystery surrounding generic imatinib, and there has been a lot of coverage in the press about the cost of long-term maintenance therapy with CML,” Mauro said. “All of this also factors into sequencing.”
Mauro emphasized the “game plan to win” in CML must include several considerations, including determination of the optimal frontline TKI; assessing resistance, intolerance or both, and how that contributes to a decision to switch therapies; determining when ponatinib is appropriate; determining when treatment-free remission is OK to consider; and consideration of stem cell transplant and other alternatives.
National Comprehensive Cancer Network guidelines provide a great overview but don’t necessarily offer much clarity, Mauro said.
“They include a full spectrum of TKIs available for low-risk patients and even for high-risk patients based on level one evidence, so we don’t really get a lot of direction from the guidelines about which drug to use,” he said.
Results of comparative clinical trials offer some guidance for frontline sequencing.
The DASISION trial included 519 patients randomly assigned to dasatinib (n = 259) or imatinib (n = 260), with minimum follow-up of 5 years.
“It highlighted the benefit of second-generation TKIs,” Mauro said. “We have better gain of deep molecular remission, as well as major molecular response and improved early molecular response.”
The ENESTnd trial included 846 patients assigned to one of three regimens: nilotinib 300 mg twice daily (n = 282), nilotinib 400 mg twice daily (n = 281) or imatinib (n = 283).
Results showed higher rates of major molecular response and better early molecular remissions with both nilotinib regimens.
The randomized BFORE trial compared first-line bosutinib 400 mg (n = 268) with imatinib 400 mg (n = 268) in the frontline setting. Results showed improvements in molecular response with bosutinib at 12 months and 18 months.
Although researchers observed faster and deeper responses in those trials, they did not see a survival benefit.
Also, despite the efficacy improvements with newer agents, concerns remain about incidence of vascular-occlusive events.
“We need to understand the mechanism, we need to follow some of our trials longer and we need to do prospective studies,” Mauro said. “If you were at ASH last year and went to the CML session, you were probably interested to see a cardiologist was part of the session. That’s how important this is. We need to pay attention to our patients’ comorbidities and their vascular health.”
When resistance occurs, NCCN guidelines give direction about which mutations may warrant which TKI. However, mutations are present in a small percentage of cases and clinical response prediction is imprecise with the exception of select mutations, Mauro said.
A comparison of second-generation TKIs dasatinib, nilotinib and bosutinib in the second-line setting showed no dramatic differences in major or complete cytogenic response rates and only a small difference in PFS.
“A lot of decision-making in the second line of salvage depends on patients’ comorbidities, mutation status if it’s helpful, their prior drug exposure and your own intuition,” Mauro said.
Some clinicians struggle with the decision of whether to use ponatinib in the third-line setting instead of using a different second-generation TKI.
Available evidence favors ponatinib over “recycling” second-generation TKIs, and ponatinib response rates as third-line and fourth-line treatment for chronic phase CML suggested improved efficacy with earlier use, Mauro said.
However, ponatinib has a significant cardiovascular risk profile, Mauro said. Approximately 28% of patients experience arterial occlusive events, and 5% experience venous thromboembolic events.
Incidence has diminished over time, and research is ongoing to determine what the right dose of ponatinib might be to decrease toxicity, Mauro said.
“Response needs should temper toxicity concerns,” he added. “Consider ponatinib when a patient may really need it, as the benefit may clearly outweigh the risk.”
NCCN guidelines offer insights about treatment discontinuation and the monitoring required for patients in treatment-free remission.
“Treatment-free remission needs to follow a very specific recipe, and I urge you to follow the guidelines,” Mauro said.
He concluded by addressing the role and timing of allogeneic stem cell transplant for patients with CML.
“In chronic phase there are some patients who we still transplant early,” Mauro said. “For patients who have progressed to advanced phase, we clearly need to still think about transplant with curative potential and not miss an opportunity.” – by Mark Leiser
For more information:
Mauro MJ. Key sequencing considerations in CML treatment. Presented at: Chemotherapy Foundation Symposium; Nov. 7-9, 2018; New York.
Disclosure:
Mauro reports clinical trial research funding to his institution from Novartis, and consultant work with Bristol-Myers Squibb, Novartis, Pfizer and Takeda.