Dasatinib or Imatinib: Final 5-Year Results From DASCERN Dr. Cortes ASH 2022
By Jorge Cortes, MD
What is the DASCERN clinical trial that treated patients chronic phase chronic myeloid leukemia?  The Dasatinib is a tyrosine kinase inhibitor where we refer to as a second generation tyrosine kinase inhibitors. It’s a very potent inhibitor of B or able but it is also inhibits other kinases. It inhibits, CT PGA receptor it also inhibits SARC and it is more potent than Imatinib treatment. For example, the first generation TKI, and it was actually initially developed as the as a treatment for patients who have develop resistance or intolerance to imagine. And it showed its efficacy in that context that was initial approval. We continue using it as a second line therapy for for patients with chronic phase CML (phase chronic myeloid leukemia) who have had resistance or intolerance to prior therapies.
But then it was also developed as a frontline therapy because in a frontline randomized study compared to I anatomy in patients with chronic myeloid leukemia without prior therapy. It was shown to give and improve the outcome measures with more responses, deeper responses, meaning more deep molecular responses, earlier responses, also more of the early molecular responses, fewer transformations, and so on.
So now it’s it’s indicated both for frontline therapy. In the chronic phase as well as in the second line therapy and beyond. So patients treated who have received prior therapy and it’s actually also approved for accelerated and blast phase. So it’s a very valuable tyrosine kinase inhibitor that we’ve used in many different settings of the treatment of chronic phase CML (Chronic Myeloid Leukemia). The the standard of care for chronic phase CML patients (chronic myeloid leukemia in chronic phase) is when they’re newly diagnosed or when a patient is newly diagnosed, we give them a tyrosine kinase inhibitor. And there are many choices. There are four drugs that are approved for frontline therapy imatinib, which is like the first generation.
Then three second generation TKIs, Dasatinib, Nilotinib, and Bosutinib which all have in separate randomized clinical trials against Imatinib, they all have shown benefit with with deeper responses, faster responses, and so on. So all of these are drugs that are approved for frontline therapy. We select them based on the patient (with chronic myeloid leukemia (CML) chronic phase) characteristics, the patient goals, the expected toxicity profile (adverse events) and comorbidities of the patients and all of these. And the treatment is continued. But increasingly we are aiming for treatment discontinuation. We know that a large majority of patients get to a complete cytogenetic response and even major molecular response, at least two thirds, to three fourths of the patients get to a major molecular response, which is very good. But we want to get them to a deeper molecular response, and MR4.5, and particularly with Imatinib, only about 30% of patients (with chronic myeloid leukemia) get to a deep molecule response. So that triggered the interest on this study to see what can we do for these patients.
And one of the early determinants is that response at 3 months, what we call that early molecular response. We know that those patients that don’t get to less than 10% transcripts at 3 months. They have not only a worse progression free survival and overall survival, but also a much lower probability of getting to a deep molecular response later on. So it’s what we call a suboptimal response or a warning. And but there’s never been a study, that looked at what to do for these patients with a suboptimal response. So many colleagues think that they, there should be a treatment change, but there’s, that’s never been clinical studies up until now. So that’s that part of the treatment is really not standardized. The recognition of the importance of achieving this response is well established. But what to do is not clearly established. But will in future studies.
What is the DASCERN Clinical Trial Design for Chronic Myeloid Leukemia?
The sign of this study based on the knowledge that these patients with CML, with their informed consent, that have more than 10% transcripts at 3 months have a worse outcome. Was then to select patients with chronic phase CML patients (diagnosed chronic myeloid leukemia) that have been receiving treatment with Imatinib at the standard dose and that have at the 3 month assessment more than 10% BCR-ABL. In the international scale at these 3 months. So recognizing that those patients have a poor outcome, then the study was randomized and it was randomized, a two to one fashion to either switch to the Dasatinib therapy at the dose of a 100 milligrams once daily, which is the standard dose or, to continue with Imatinib and they could continue with the same dose or dose escalation.
Because sometimes we do that that was at the discretion of the treating physician. But they would continue with with Imatinib and the primary endpoint was the achievement of a major molecular response at 12 months, what we are seeing. Is the 5 year follow up of this study in patients with CML (chronic myeloid leukemia) treated. The initial analysis, the 12 month (statistical) analysis was already presented and published. But it was important because of the clinical implications of these lack of early molecular response in long-term outcome. It was very important to assess what happens long term with these interventions. So this is what is being presented now.
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7 Key Takeaways of the DASCERN Trial
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DASCERN is an open-label (study), randomized, international, multicenter phase 2b trial of dasatinib versus imatinib in patients in the treatment group, with Philadelphia chromosome-positive (Ph+) CML-CP who have achieved complete hematologic response (CHR) but have BCR-ABL1 > 10% (IS) three months after beginning first-line treatment with imatinib 400 mg once daily (QD).
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A complete cytogenetic response was determined according to established standards (CCyR = 0% Ph+ cells) based on the frequency of Ph+ cells in metaphase in bone marrow. MR4.5 was deemed to have 0.0032% BCR-ABL1 (IS).
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Patients could receive dasatinib or imatinib for up to 60 months after the last patient was randomized, or until disease progression, therapy failure, unacceptable toxicity (adverse event), withdrawal of consent, or trial termination.
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Except for the primary objective, all assessments included data analysis from a 24-month data cut (intention to treat analysis). All patients were followed every three months for the first 24 months, then every six months until month 60, and then annually thereafter.
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From September 12, 2012, to November 8, 2016, a total of 1126 patients were enrolled in the research; 260 patients with BCR-ABL1 > 10% were randomized (dasatinib, n = 174; imatinib, n = 86).
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Cochran-Mantel-Haenszel (CMH) test stratified by Sokal score (high, moderate, low, and unknown). And time between 3-month molecular analysis and randomization (=4 weeks vs. >4 weeks) is used to get the P-value.
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Adequate renal function is defined as serum creatinine less than three times the institution’s normal upper limit (ULN).
Inclusions and Exclusions of the DASCERN Clinical Trial?
The most significant inclusion was the fact that eligible patients should have been on Imatinib for 3 months and have BCR-ABL transcript levels greater than 3 and less than 10%. They should have been able to tolerate the Imatinib at 400 milligrams daily. And the standard, the need to have normal organ function signing form consents not be or become pregnant during the study. So a fairly standard inclusion criteria. It only included patients (with diagnosed chronic myeloid leukemia) in the chronic base.
Were There Any Statistically Significant Results?
The primary endpoint was the achievement of major molecular response at 12 months. And as I mentioned earlier this was statistically significant in favor of dasatinib. Much better. What we have now is that the, Is the five years follow up. And the the rate of major molecular response by five years, the cumulative rate of major molecular response was, again, significantly higher for the patients that switched to the Dasatinib compared to the patients that stayed on Imatinib there was significant differences, with multiple comparisons. Also the responses happen faster, and at all the time points we looked at the responses by 12 months and 24 months and 36 months of every annual increments. And they were all statistically significant. There was also the option to cross over to. From Imatinib to DA sat for patients who were not responding.
And for those patients who did, who stayed who on Imatinib the difference was even larger. So some of the achievement of major molecular response on an intention to treat analysis was due to the crossover. But also very important is that the one of. Issue that I mentioned earlier is aiming for these deep molecular responses. And so looking at both the MR4 and the MR4.5, both of these were also better with with the sat. MR four was statistically significant. The MR4.5 is a nice trend. It’s not statistically significant, although again, there was a crossover that that. It impacted the ability to see a statistically significant difference. What we did not see that being statistically significant is progression-free survival or overall.
Final Thoughts
This study shows that there is a potential benefit on switching patients from Dasatinib to Imatinib who do not have a, an early molecular response at three months. We need to be mindful of what we can accomplish and we cannot, what we cannot we certainly can. Improve the probability of achieving a deep molecular response, which is very valuable for some patients.
There is some trade off in terms of safety. We do have high risk factors of having a pleural effusion. This occurred in almost 20% of patients on the Dasatinib environment. It did not happen in patients who stayed on imatinib. We do not have a benefit in progression free survival and overall survival.
I don’t think that was expected to happen between the crossover design and the number of patients and all these things. But I think in aiming those for these deep molecular responses for selected patients, these could be an approach that could be considered in this context with the proper monitoring and the management of the patients.
Jorge Cortes, MD – About The Author, Credentials, and Affiliations
Dr. Jorge Cortes joins the Georgia Cancer Center after 23 years at the University of Texas MD Anderson Cancer Center, where he held various positions in the Department of Leukemia, Division of Cancer Medicine, such as Deputy Department Chair, Chair of the AML and CML Sections, Professor of Medicine, and Internist. Cortes also held the Jane and John Justin Distinguished Chair in Leukemia Research and was the Director of the Leukemia Fellowship Program. He was also the Deputy Division Head of the Cancer Network and the Chair of MD Anderson’s Executive IRB. Before completing his fellowship in Houston, TX, Cortes completed his undergraduate and graduate education in Mexico City. Over 230 grants and contracts for which he was the lead investigator have his name. He has produced approximately 1,000 peer-reviewed, original research articles and has received various other honors for his work in clinical oncology.
Reference
Nature – Dasatinib vs. imatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: the DASCERN randomized study. Nature, April 07, 2020