Photo by Jen Smith
Jorge E. Cortes, MD
SAN DIEGO—Early results of the DASCERN trial indicate that patients with chronic myeloid leukemia (CML) in chronic phase who have a suboptimal response to imatinib as a first-line treatment benefit from switching to dasatinib at 3 months.
Twenty-nine percent of dasatinib-treated patients achieved a major molecular response (MMR) at 12 months, compared to 13% of patients who remained on imatinib (P=0.005).
Dasatinib-treated patients also attained MMR much faster than those on imatinib, at a median of 14 months, compared to 20 months for those treated with imatinib.
DASCERN is the first study, according to investigators, to explore the significance of an early switch for patients who have not achieved an early molecular response (EMR) with imatinib.
“[EMRs] are important because they correlate with the outcome of patients, certainly with progression-free survival and overall survival,” explained Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“[T]he possibility of changing to dasatinib appears, with these early results, to suggest that there may be a benefit to switching these patients to achieve better long-term outcomes. But also, those patients that have these early molecular responses have a better probability of achieving deep molecular responses that we desire for treatment-free remission.”
Dr. Cortes elaborated on the DASCERN data at the 2018 ASH Annual Meeting (abstract 788*).
Study design
DASCERN (NCT01593254) is a randomized, open-label, international, phase 2b trial in adult patients with chronic-phase CML who had achieved a complete hematologic response but still had more than 10% BCR-ABL1 transcripts at 3 months.
Patients were initially treated with imatinib at 400 mg daily, and 1,126 patients had a molecular assessment at 3 months.
Those who did not achieve an MMR (n=260) were randomized in a 2:1 fashion to 100 mg daily of dasatinib (n=174) or 400 mg daily or twice daily of imatinib (n=86).
If patients subsequently failed imatinib treatment by European LeukemiaNet standards, they could cross over to dasatinib.
“Importantly, there was a window of enrollment up to 8 weeks after the 3-month assessment, allowing for time to get response results and screen and enroll patients onto the study,” Dr. Cortes clarified.
Patients were also stratified according to Sokal risk score and time from molecular assessment to randomization.
Dr. Cortes noted that about 40% of patients were started on treatment within 4 weeks of the 3-month assessment. And another 58% were enrolled between 4 and 8 weeks from the 3-month assessment.
The primary endpoint is the achievement of MMR at 12 months from the first day of imatinib treatment; that is, at about 9 months from the start of the protocol treatment, in both trial arms.
Patient characteristics
Seventy-eight percent of patients were male, and 95% were younger than 65.
“This is a relatively younger patient population,” Dr. Cortes noted. “This has to do with the fact that this was an international study with a significant representation of patients that were from Asia (73%).”
The Asian patients were primarily from China, Dr. Cortes said, “and we know that, in some parts of the world, including Asia, patients seem to be younger.”
“This is also associated with a higher percentage of patients with high-risk Sokal scores, more than 20%,” he added. “That is different than what’s seen, for example, in the U.S. or in Europe.”
The prevalence of male patients, he said, broadly represents the distribution of patients in other parts of the world.
Patient disposition
Patients were followed for a median of 30 months.
Of the randomized patients—the intent-to-treat (ITT) population—143 (84%) in the dasatinib arm and 72 (84%) in the imatinib arm continued on treatment.
Study drug toxicity was the most common reason for discontinuing treatment and occurred in 9 patients (5%) in the dasatinib arm and 3 (4%) in the imatinib arm.
Nearly half the imatinib patients (n=42, 49%) crossed over to dasatinib at a median of 9 months.
The median duration of treatment was 22 months (range, 1 – 44) for patients on imatinib who did not cross over and 15 months (range, <1 – 38) for patients on dasatinib after crossing over from imatinib.
Response
In the ITT population, the rate of MMR at 12 months was 29% in the dasatinib arm and 13% in the imatinib arm (P=0.005).
The median time to MMR was significantly shorter for patients who received dasatinib compared with imatinib—14 months and 20 months, respectively (P=0.053).
“Over 60% of patients on the dasatinib arm achieved a major molecular response,” Dr. Cortes said. “This compares to about 55% of patients on the imatinib arm, even when you consider the crossover of a significant number of these patients.”
A few patients achieved a molecular response of a 4.5-log reduction in BCR-ABL1 transcripts (MR4.5).
“Of course, the follow-up is short, but we had twice as many patients [on dasatinib] at 12 months with MR4.5— 5% with dasatinib versus 2% with imatinib,” Dr. Cortes said.
Survival outcomes
Both overall and progression-free survival “look very good with both treatment approaches,” Dr. Cortes pointed out.
At a median follow-up of 30 months, the overall survival in the ITT population was 98.8% in each treatment arm.
Progression-free survival was 96.9% in the dasatinib arm and 97.6% in the imatinib arm.
“It is important to note that no patient in either treatment arm has transformed to accelerated or blast phase,” Dr. Cortes said.
Safety
Treatment was well tolerated with both agents, Dr. Cortes observed, with very few grade 3 adverse events (AEs) noted to date.
“The one that stands out here, and it’s only 2% of patients, is headache with dasatinib,” he said.
The headache did not lead to treatment discontinuation, and the patients were managed with dose adjustments.
The investigators observed no new safety signals with either drug.
Treatment-emergent AEs of any grade occurring in 15% or fewer dasatinib- or imatinib-treated patients, respectively, in the ITT population included headache (15%, 9%), diarrhea (9%, 8%), nausea (9%, 8%), eyelid edema (1%, 9%), hypocalcemia (1%, 7%), and muscle spasms (1%, 8%).
Patients who crossed over to dasatinib had similar rates of AEs to those documented for imatinib.
“They are typical for what we know of both of these tyrosine kinase inhibitors,” Dr. Cortes stated.
Investigators observed pleural effusion in 9 (5%) patients on dasatinib, and only one grade 3. That patient discontinued therapy due to the AE.
Of the patients who were on imatinib and crossed over to dasatinib, 3 (7%) experienced pleural effusion, most of them grade 1 or 2. One patient with grade 4 discontinued therapy with dasatinib due to the AE.
“Hematologic toxicity has been mild,” Dr. Cortes said, and in keeping with the known toxicities of dasatinib and imatinib.
Grade 3/4 treatment-emergent AEs in the dasatinib and imatinib arms, respectively, in the ITT population included anemia (5%, 4%), neutropenia (11%, 16%), thrombocytopenia (11%, 11%), and leukopenia (1%, 1%).
Patients who crossed over to dasatinib experienced more of these AEs than patients who did not cross over, Dr. Cortes clarified, but they are still within the expected range with these agents.
“We acknowledge the results are early and we need to continue following for both safety and efficacy, as it will be important to see if those rates of MR4.5 continue to increase with the same difference in favor of dasatinib that we are starting to see very early on,” Dr. Cortes said.
He disclosed serving as a consultant for Pfizer, Daiichi Sankyo, Astellas Pharma, Novartis, and Bristol-Myers Squibb, and he received research funding from Pfizer, Daiichi Sankyo, Arog Pharmaceuticals, Astellas Pharma, Novartis, and Bristol-Myers Squibb.
The study was supported by Bristol-Myers Squibb.
*Data in the abstract differ from the presentation.