Optimizing Outcomes With Azacitidine Treatment in Patients With MDS

Delays in treatment with azacitidine predicted lower survival rates in patients with myelodysplastic syndromes (MDS), independently of the International Prognostic Scoring System (IPSS) score or preexisting neutropenia, according to a study published in the British Journal of Haematology. Authors, led by Panagiotis T. Diamantopoulos, MD, PhD, from the National and Kapodistrian University of Athens, also found that outcomes were significantly worse when these delays occurred during the first two treatment cycles.

Azacitidine is approved at a standard dose of 75 mg/m2 per day for 7 consecutive days, but centers may choose to modify the regimen to use a shorter duration of therapy, Dr. Diamantopoulos and coauthors explained.

Using data from the Hellenic (Greek) National Registry of Myelodysplastic and Hypoplastic Syndromes, researchers sought to determine the effect of dose reductions and treatment delays on patient outcomes including response, duration of response, transformation to acute myeloid leukemia (AML), and overall survival (OS).

They retrospectively identified 897 patients with MDS from 28 centers who were treated with azacitidine. The analysis included information about the cumulative dose of azacitidine per cycle, dose reductions, and treatment delays per cycle. Only patients who were treated with ≥1 full treatment cycle were eligible for the response evaluation.

“[Azacitidine] treatment delays have a negative impact on patients’ prognosis, especially if they are imposed early or before the achievement of a response.”

—Panagiotis T. Diamantopoulos, MD, PhD

Most patients received the standard azacitidine 7-day regimen (n=762; 84.9%), while 89 (9.9%) received the same dose in a 5 days plus 2 days (5-2-2, omitting weekend treatments) schedule. The remaining 46 patients (5.1%) received several other variations of these regimens, such as only 5 days of therapy per cycle.

“No correlation between the used regimen and response to treatment was found, but patients to whom lower doses were offered (<525 mg/m2/cycle) had significantly lower OS than those offered higher doses (median = 9.5 vs. 23.9 months; p=0.0001),” the authors reported. “Interestingly, in the whole cohort, age was not a factor affecting prognosis.”

However, treatment delays were found to be independently associated with survival. Of the entire study population, 274 patients (30.5%) experienced treatment delay; of these, 150 patients (16.7%), experienced a delay within the first two cycles. The most common reason for azacitidine delays were infections (31.8%) and hematologic toxicity (including grade 4 neutropenia, anemia, thrombocytopenia, or pancytopenia; 43.1%). More than one-fifth of the delays were for nonmedical reasons, such as holidays or personal decision.

Delays during the first two cycles of azacitidine treatment were considered risk factors for OS, regardless of IPSS score or preexisting neutropenia (hazard ratios = 1.368 [p=0.033] and 1.42 [p=0.015], respectively).

Duration of delay also was linked to patient outcomes: Patients with delays longer than 7 days had significantly lower OS compared with those with shorter delays or no delay (median = 24.0 vs. 18.2 months; p=0.007).

In the group of patients who had a measurable response, delays were shorter among those who experienced a complete remission compared with those who achieved a partial remission and those who experienced only a hematologic improvement: 2.8 versus 3.3 versus 5.6 days per cycle.

Furthermore, among those whose disease responded to azacitidine, 16.6% later had a treatment delay, though these delays were not found to affect duration of response, time to AML transformation, or OS.

“This result can provide guidance about the avoidance of long delays during the first cycles of treatment,” the authors wrote, “but after achieving a response this strict strategy may be loosened.”

A total of 74 patients (8.2%) had an azacitidine dose reduction, which occurred more frequently in patients with treatment delays compared with patients without treatment delays (19.5% vs. 4.6%; p<0.0001). However, dose reductions did not have a prognostic impact on survival.

“Treatment delays have a negative impact on patients’ prognosis, especially if they are imposed early or before the achievement of a response [and] they lose their prognostic role after the achievement of best response,” the researchers concluded. “Moreover, neutropenia per se should not be a reason for treatment delays and the treating physician should be aware that even short-duration delays that are unnecessary may have a great impact on prognosis.”

Limitations of the study include its retrospective nature and lack of a uniform protocol for treating patients, which may have resulted in bias.

Study authors report relationships with Genesis Pharma, which sponsored this trial.

Reference

Diamantopoulos PT, Symeonidis A, Pappa V, et al. The effect of 5-azacytidine treatment delays and dose reductions on the prognosis of patients with myelodysplastic syndrome: how to optimize treatment results and outcomes. Br J Haematol. 2020 August 30. [Epub ahead of print]