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Decitabine especially effective in TP53–mutated AML, myelodysplastic syndrome
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Patients with acute myeloid leukemia or myelodysplastic syndrome who harbored TP53 mutations or other cytogenetic abnormalities associated with unfavorable risk experienced favorable clinical responses with decitabine, according to a prospective, uncontrolled trial published in The New England Journal of Medicine.
Further, patients demonstrated significant but incomplete mutation clearance.
“We started this study because we, like many other groups, had seen that a fraction of patients appear to benefit from decitabine, and we did not have good molecular markers that predicted which patients would respond to decitabine and which patients would not,” John S. Welch, MD, PhD, assistant professor in the department of medicine, oncology division, at Washington University School of Medicine, told HemOnc Today. “Response rates to decitabine in diverse clinical trials range between 20% and 35%. The response rates are a little higher with the newer 10-day regimens, but still are modest (between 40% and 64%). This means that some patients benefit, but many patients do not.
“We also wondered whether there might be subgroups of patients who would respond better to decitabine than they might to more aggressive chemotherapy (eg, a cytarabine-containing induction regimen),” Welch added.
Adults with AML who are older than 60 years or have karyotypes associated with unfavorable risk, have poor outcomes, with a median survival of approximately 1 year. Patients with AML and TP53 mutations tend to be older, and almost all have karyotypes associated with unfavorable risk. These patients have especially poor outcomes (median OS, 4 to 6 months) when they receive standard cytotoxic chemotherapy.
Welch and colleagues used enhanced exome sequencing and gene panel sequencing to determine whether the presence of specific mutations might correlate with a response or resistance to decitabine — a less aggressive form of chemotherapy first approved by the FDA in 2006 — and to characterize patterns of mutation clearance.
In the single-institution trial, 84 adults with AML or myelodysplastic syndrome received 20 mg/m2 decitabine every day for 10 consecutive days in monthly cycles. Fifty-nine patients received at least two monthly cycles of treatment.
The analysis also included an extension cohort of 32 patients who receive decitabine on different protocols (10 day or 5 day).
Welch and colleagues performed enhanced exome or gene-panel sequencing in 67 of the original 84 patients, as well as serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.
Median follow-up of the 19 patients who remained alive was 19 months.
Of the total 116 patients in the study, 46% had bone marrow blast clearance with less than 5% blasts — which indicated complete remission with incomplete count recovery or morphologic complete remission — and 13% had a complete remission. Researchers noted 12 patients withdrew from the protocol before a bone marrow biopsy could be performed at the end of the first cycle and could not be clinically evaluated for a response.
Response rates were higher among patients with an unfavorable-risk cytogenetic profile (67%) than among patients with an intermediate-risk or favorable-risk cytogenetic profile (34%; P < .001). Further, responses were higher among patients with TP53 mutations (100%) than those with wild-type TP53 (41%; P < .001).
“What was surprising was the high response rate we observed among patients with TP53 mutations,” Welch said. “When treated with cytotoxic chemotherapy, AML patients with TP53 mutations have one of the lowest response rates, yet in our cohort all the patients with TP53 mutations responded to decitabine.”
A total of 128 grade 3 to grade 5 adverse events occurred, which were predominantly associated with neutropenia and thrombocytopenia. Eight treatment-related deaths occurred due to infection (n = 6), acute kidney injury (n = 1) and cardiac arrest (n = 1).
Welch and colleagues noted that because bone marrow blast clearance usually precedes mutation clearance, decitabine may induce differentiation before eliminating leukemic cells, which could require months of therapy. They also noted responses are short-lived and remissions usually last less than a year, especially after discontinuation of therapy. The short durations of remission are due to incomplete clearance of leukemia cells bearing the pathogenetically relevant driver mutations.
“The next step will be to validate these results in larger cohorts,” Welch said. “We also will need to identify other consolidation approaches. Even in the patients with TP53 mutations who achieve complete remission, this response was durable, and relapse was very common. Stem cell transplantation has been the most aggressive consolidation approach for patients with AML and myelodysplastic syndrome, yet it has not been associated with long-term survival in TP53–mutated patients. We will need to determine whether stem cell transplantation after decitabine is more effective for TP53–mutated patients than it is following cytarabine-based induction.”
The study also demonstrated the utility of serial exome sequencing to track subclonal evolution in response to chemotherapy, Welch added.
“Using this approach, we observed differential sensitivity within a single patient: a subclone of cells could be resistant to decitabine, whereas the founding clone cells were sensitive,” he said. “The rules that determine subclonal resistance are not yet clear, but will be very important to delineate, as these appear intimately related to relapse and progression.” – by Chuck Gormley
For more information:
John S. Welch, MD, PhD , can be reached at Washington University School of Medicine, 660 S. Euclid Ave Box 8007, St. Louis, MO 63110; email: jwelch@wustl.edu.
Disclosure: Researchers reported no relevant financial disclosures.
Perspective
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Abimbola Farinde
The treatment of patients AML — particularly those who are aged 60 years or older — can be associated with poor outcomes and a median survival of about 1 year. This can even be more significant with the presence of TP53 mutations, which are associated with unfavorable risks.
The use of decitabine — an antimetabolite, antineoplastic agent — as a single agent is common when treating patients with myelodysplastic syndrome (MDS) and older adults with AML, but the observed response rates have been low.
Welch and colleagues sought to examine the clinical response to decitabine based on mutations that exist in specific patients. These participants included those with unfavorable-risk cytogenic profiles, favorable-risk cytogenic profiles and intermediate-risk cytogenic profiles.
The researchers determined that patients with AML and MDS who possessed unfavorable-risk cytogenic profiles, TP53 mutations or both were more likely to experience positive clinical responses after receiving a serial 10-day course of decitabine. However, these responses were not long-lasting, as the OS rates of these patients were comparable to those who had intermediate-risk cytogenic profiles.
The clinical implication of this finding is the potential for improved treatment outcomes for those diagnosed with AML and MDS. Historically, this diagnosis can be seen as a death sentence. This study gives promise of increased survival, even if it is not substantial. Further research is needed to extend the durability of these outcomes for patients and work to improve OS rates for patients who possess this type of unfavorable risk or mutation. Different patients with AML or MDS can achieve different responses to chemotherapy. This study was able to demonstrate that even patients with a TP53 mutation are able to achieve a response to decitabine, which can translate into an alternative strategy for treating patients in this high-risk group.
Disclosure: Farinde reports no relevant financial disclosures.
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