There can be a prolonged period of time between the initiation of azacitidine treatment and the clinical response. Before blood counts improve, patients may have a long period of pancytopenia. Clinicians must understand the side effects of treatment and be able to support patients through a period of prolonged cytopenias. Important data on supportive treatment of patients receiving azacitidine treatment were obtained from two studies, ie, CALGB 9221 and AZA-001.24
These data are summarized in . In both of these studies, most of the adverse events took place in the first two cycles of treatment before improvement in blood counts and tended to decrease in frequency during subsequent cycles. In subgroups of patients in both trials who completed 6 or more treatment cycles, a similar pattern of reduced frequencies of adverse events with each successive treatment was seen. Cytopenias were ubiquitous in both trials. In AZA-001 and CALGB 9221, more patients experience neutropenia, anemia, or thrombocytopenia during the first or two treatment cycles. Nadir for hematologic parameters occurred at a median of 15–16 days in CALGB 9221 and 14–15 days in AZA-001. Overall, in AZA-001 and CALGB 9221, 78% and 89% of patients, respectively, had anemia, thrombocytopenia, or neutropenia. Ten patients in AZA-001 and 19 patients on CALGB 9221 experienced fever with median durations of 5–7 days. Worsening of symptoms of fatigue was seen in patients in both trials, with median durations of 8 days on AZA-001 and 33 days on CALGB 9221. In AZA-001, the infection rates per patient year were not statistically different in the azacitidine group versus the conventional care group. Events associated with azacitidine administration included injection site reactions in 29% of AZA-001 patients and in 3.3% of patients on CALGB 9221. These involved erythema and discomfort, and were transient. Patients also reported gastrointestinal events. Constipation was the most frequently reported gastrointestinal event on AZA-001 (50.3%), and most occurrences were in the first two cycles of treatment and may have been exacerbated by antiemetic regimens. The median duration of constipation was 8 days in AZA-001 and 17 days in CALGB 9221. Nausea was the most frequently reported gastrointestinal event on CALGB 9221. Grade 3 and 4 gastrointestinal events were reported by less than 6% of patients in either study.
Symptomatic management of patients treated on azacitidine
Strategies used by both studies to manage anemia, thrombocytopenia, and neutropenia associated with azacitidine treatment included delay of the next treatment cycle, dose reduction, and blood product transfusions. In AZA-001, 86% of patients had no dose adjustments, with a median cycle length of 28 days. Twenty-nine percent of cytopenias were managed by drug dose delay and 9% by dose reduction. Anemia was managed with transfusion in 87% of cases and thrombocytopenia was managed by transfusion in 29% of cases. In 15% of cases, febrile neutropenia was managed with antibiotics. In cases of severe neutropenia and fever, a brief course of granulocyte colony-stimulating factor was added. In CALGB 9221, cytopenias resulted in dose interruptions and reductions in 23% and 11% of patients, respectively. The median duration of cycle length was 34.3 days.
In AZA-001, nausea, vomiting, constipation, and diarrhea were managed with antiemetics, laxatives, stool softeners, and antidiarrheals. Less than 12% of injection reactions were treated with corticosteroids or antihistamines. Little benefit was observed with the use of topical medications. In AZA-001, 99% of patients received concomitant medications. The most common were paracetamol, furosemide, ondansetron, allopurinol, and levofloxacin. The most common intravenous antibiotics used were vancomycin, piperacillin/tazobactam, and gentamicin. Thirteen percent of patients were treated with granulocyte colony-stimulating factor.
In CALGB 9221, the most common concomitant medications were antiemetics. Other medications used frequently included analgesics, systemic antibacterials, and systemic antihistamines. No patients were treated with granulocyte colony-stimulating factor because the medication was prohibited on the study.
Growth factor therapy with erythropoietin-stimulating agents and granulocyte-stimulating agents are used as primary treatment in low-grade MDS to improve cytopenias. To enhance efficacy and decrease the burden of transfusion during azacitidine treatment, there have been studies looking at the efficacy of combination therapy. Growth factors have been used in combination with azacitidine with some promising results. Itzykson et al retrospectively studied a cohort of 282 patients with high-risk MDS who received azacitidine in a compassionate program, including 32 patients who received concomitant erythropoiesis-stimulating agents. Forty-four percent of patients treated with azacitidine who received erythropoiesis-stimulating agents and 29% who did not receive this therapy achieved hematologic improvement in their anemia (P
= 0.07). Transfusion independence was achieved in 48% versus 20% and median overall survival was longer in the group treated with an erythropoiesis-stimulating agent (19.6 months versus 11.9 months, P
The results need to be confirmed in a prospective study of this combination. Azacitidine has also been used in conjunction with the thrombopoietin mimetic, romiplostim, in a Phase II study.41
Forty-five patients with low-risk and intermediate-risk MDS were stratified by baseline platelet counts and randomized to romiplostim at two dose levels versus placebo subcutaneously during the first four cycles of azacitidine treatment. The endpoint was incidence of clinically significant thrombocytopenic events. The numbers were too small to find significance in the clinical endpoints, but the data suggested that romiplostim may provide clinical benefit during azacitidine therapy. Patients in this study seemed to increase median platelet counts over time (3–4 months) and seemed to have a reduced need for platelet transfusion during azacitidine treatment. The combination of growth factors with azacitidine to reduce transfusion during treatment and improve outcome needs further investigation.