patient care perspectives
Higher-Risk MDS and AML: Need for Treatment Without Intensive Chemotherapy
The US Food and Drug Administration approval of lower-intensity treatments, including hypomethylating agents (HMAs) and targeted and/or immunomodulatory therapies, has led to the availability of effective treatment options with modest toxicity for patients who are not candidates for intensive chemotherapy. Further, a number of promising research protocols have been completed or are just starting, in both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
Professor and Dr. Kenneth B. McCredie Chair in Clinical Leukemia Research
“Therapy should be individualized because not all older patients have the same prognosis. We look at performance status and their molecular and cytogenetic profiles, and we consider their comorbidities, which may be severe in some cases. Then, we tailor our treatment recommendations accordingly.”
There are many patients with high-risk MDS or AML who are not candidates for treatment with high-intensity chemotherapy and will require an alternative treatment approach. Factors including age, cardiovascular comorbidities, renal function, bone marrow status, and molecular profile may guide treatment decisions in this patient population. With respect to comorbidities, it is interesting that they frequently seem to be related to the disease itself. The treatment approach for older individuals with AML that is favored by clinicians and has become the standard of care is low-intensity chemotherapy with an HMA. Data have shown that this lower-intensity approach provides similar—if not better—survival outcomes with less toxicity compared with higher-intensity chemotherapy. While we have favored this approach for many years, the combination of an HMA with venetoclax, a BCL-2 inhibitor, has improved overall survival and is now considered the standard of care in older individuals with AML who are not candidates for intensive chemotherapy. Based on these outcomes in AML, there is interest in using this approach for high-risk MDS; however, it is also important to note the heterogeneity of MDS and the need to better understand the different molecular subsets in that regard.
For patients with core binding factor AML or NPM1 mutations, even those who are older, some types of intensive therapy may be curative. So, therapy should be individualized because not all older patients have the same prognosis. We look at performance status and their molecular and cytogenetic profiles, and we consider their comorbidities, which may be severe in some cases. Then, we tailor our treatment recommendations accordingly.
We are beginning to see a transformation in the types of therapies available for patients with high-risk MDS or AML. While the traditional way of treating AML is by combining cytarabine with an anthracycline, also known as 7+3 therapy, this intensive treatment approach is generally limited to younger patients. There is now a liposomal formulation of cytarabine and daunorubicin available, known as CPX-351. This may be an option for some older individuals with high-risk features; however, with any intensive chemotherapy regimen, there is still a concern for severe toxicity. Intensive chemotherapy regimens may suppress the bone marrow in susceptible patients, putting them at significant risk for infections or sepsis. Unfortunately, some individuals may be unable to recover from this degree of bone marrow suppression. Since lower-intensity treatments, including HMAs and targeted and/or immunomodulatory therapies, are effective treatment options with modest toxicity, I tend to use this regimen in older patients with high-risk features frequently. With the approval of targeted therapies over the last few years, we have seen an improvement in response rates and overall survival, and more patients are proceeding to hematopoietic stem cell transplantation.
On the research front, there are a number of exciting protocols that have been completed and some that are just being started, in both MDS and AML. For instance, the combination of the TIM-3 inhibitor MBG453 with decitabine is being explored in clinical trials of high-risk MDS and AML. Additionally, there is an AML protocol underway that combines MBG453, venetoclax, and azacitidine. Other trials include agents to inhibit the degradation of TP53 (eg, HDM201 in TP53 wild-type AML) or agents to reactivate mutant p53 (eg, APR-246 in TP53-mutated disease).
Borate U, Esteve J, Porkka K, et al. Phase 1b study of the anti-TIM-3 antibody MBG453 in combination with decitabine in patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Blood. 2019;134(suppl 1):570. doi:10.1182/blood-2019-128178
ClinicalTrials.gov. APR-246 in combination with venetoclax and azacitidine in TP53-mutant myeloid malignancies. Accessed October 21, 2020. https://clinicaltrials.gov/ct2/show/NCT04214860
ClinicalTrials.gov. A study of MBG453 in combination with azacitidine and venetoclax in AML patients unfit for chemotherapy (STIMULUS-AML1). Accessed October 21, 2020. https://clinicaltrials.gov/ct2/show/NCT04150029
ClinicalTrials.gov. HDM201 in combination with MBG453 or venetoclax in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Accessed October 21, 2020. https://clinicaltrials.gov/ct2/show/NCT03940352
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