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Low-toxicity regimen may be best approach for mixed phenotype acute leukemia
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Patients with mixed phenotype acute leukemia treated with a low-toxicity acute lymphoblastic leukemia therapy regimen achieved higher rates of complete remission and the potential for increased long-term survival, according to study results.
“This research provides key insights to help guide physicians treating patients walking in the door today,” Etan Orgel, MD, MS, physician in the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles, said in a press release. “It also highlights the critical need for a clinical trial to definitively determine the best therapy for mixed phenotype acute leukemia and help move treatment for this rare disease forward.”
Mixed phenotype acute leukemia (MPAL) is a rare disease that affects fewer than 5% of children and adults diagnosed with leukemia. Fewer than 50% of patients survive 5 years.
Although the disease contains characteristics of both acute lymphoblastic leukemia and acute myeloid leukemia, there is no clear consensus regarding the best treatment approach.
Orgel and colleagues assessed the association of treatment type — ALL, AML or hybrid regimens — on disease response and survival among 1,351 patients with sufficient treatment and outcome data included in 97 previously published studies.
Results showed patients treated with AML induction therapy appeared less likely than those treated with ALL regimens to achieve complete response (OR = 0.33; 95% CI, 0.18-0.58). Further analysis of those with patient-level data supported poorer efcacy for AML therapy (OR = 0.45; 95% CI, 0.27-0.77).
HemOnc Today spoke with Orgel about the study, why the less toxic ALL therapy may provide equal or greater efficacy, and whether this strategy should be adopted in practice.
Question: How has MPAL t raditionally been treated?
Answer: MPAL has been treated in many ways over the years. The problem is, because the disease is so rare and because it has features of different forms of leukemia, there has never been a clear answer as to the best treatment approach. Traditionally, physicians are faced with the choice to select therapy used to treat ALL or AML, or combinations of regimens used to treat both of those forms of the disease.
Q: Why have previous treatment strategies not been effective?
A: This is a challenging question, because the strategy itself may have been effective for some patients. The biggest problem is that we never tested this in a study or in an organized way, so we were never able to learn which approach is best for most patients. This same problem has been around for decades. We have been talking about the same questions and the same lack of answers for how to treat MPAL for a very long time.
Q: What prompted this study?
A: Although physicians published the success or failure of their different approaches to treat MPAL, these studies and reports were scattered across a large body of international literature. This made it difficult for physicians to find all available information to put together the best treatment option for their patient. We decided to take this step to help other physicians find all available information in one place.
Q: How did you conduct the study?
A: We synthesized all available data on MPAL treatments using formal guidelines for systematic reviews. We developed a search strategy that we implemented across multiple publication databases, pooled data from thousands of papers, screened all of them, and read in detail the hundreds of papers that were relevant. We then narrowed the papers down to those that contained the necessary information to help us answer our question: What is the best therapy for patients with MPAL?
Q: What did you find?
A: Regardless of what type of MPAL someone has, chemotherapy intended for patients with ALL was far better for starting treatment for MPAL than regimens designed for AML. Patients treated with ALL therapy were more likely to go into remission early. Remission was defined in the included studies as no morphologic evidence of leukemia in the bone marrow, blood, or body of these patients. We also wanted to look at survival based on the form of therapy patients initially received. Overall, patients who began with ALL therapy appeared more likely to survive than those who started treatment with AML therapy. However, among the few hundred patients for whom we had patient-level data, we did not see a survival difference between ALL or AML therapy. This difference between the larger review and the patient-level data was challenging to explain. But, from a clinical perspective, we could state that ALL and AML therapy were at least equally effective. This means we can provide a patient the less toxic and less intensive ALL chemotherapy and they are just as likely to survive as the patient who received the more intensive AML therapy. We also found that patients who underwent a hybrid therapy approach fared worse than those who received either treatmente alone.
Q: What are the clinical implications of the findings?
A: Regardless of what type of MPAL a patient has, ALL therapy is going to be sufficient to obtain a remission for most patients. This is very important because ALL therapy is less toxic and has fewer side effects.
Q: Why might the less toxic ALL therapy be more effective?
A: To clarify, we cannot necessarily say that ALL therapy is more effective than AML therapy overall. We only can say that it was more effective to place a patient into remission early. We do not fully know what happens afterward with each type of therapy, although the study suggests ALL therapy may be at least as effective as AML therapy. With leukemia therapy, the strongest and often most toxic treatment is not always the best. Some types of leukemia respond to prolonged but less intensive chemotherapy for years, whereas some types of leukemia require intense therapy to dive deep into the bone marrow and eradicate any early leukemia cells that are trying to grow. For very rare leukemia, such as MPAL, we simply never had enough information to see which treatment approach was best. Because of this, many physicians would opt to overtreat with the strongest chemotherapy possible based on the belief that it would be their best chance for cure, even though significant side effects were expected. Our study now shows this might not be necessary for most patients with MPAL. One of the key lessons we have learned over the years is that understanding what makes the leukemia tick can help determine which strategies will work best for certain patients and who will require other approaches with different chemotherapy or immunotherapies.
Q: What is next for research?
A: More research is definitely needed. It took an immense effort for us to pull all of this information together so we could learn these lessons. However, a lot more research is necessary because these findings need to be validated. Also, we know some patients will not respond to ALL therapy. We need to identify those patients and determine which therapy is best for them.
We had to rely on a lot of smaller, observational studies, each of which included a small number of patients. Despite looking at thousands of reports from all over the world, there has not been a single prospective randomized trial in MPAL. This identifies how much research is left for us to do. The next steps will be to develop a path toward larger clinical trials to definitively determine how best to treat patients with this rare disease. – by Jennifer Southall
Reference:
Maruffi M, et al. Leukemia. 2018;doi:10.1038/s41375-018-0058-4.
For more information:
Etan Orgel, MD, can be reached at Children’s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027; email: eorgel@chla.usc.edu.
Disclosure: Orgel reports an advisory board role with Jazz Pharmaceuticals.