Safety of azacitidine in patients with MDS

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Idoia Camarón Echeandia MPharm
Resident in Hospital Pharmacy
Breno Moreno de Gusmao MD
Haematologist
Carlos Martínez Martinez PharmD
Hospital Pharmacist and Head of
Pharmacy Service,
University Hospital of Araba-Txagorritxu,
Vitoria-Gasteiz,
Spain

Azacitidine is a demethylating agent recently introduced for patients with myelodysplastic syndromes (MDS). MDS are a diverse group of clonal haematopoietic stem cell disorders, characterised by dysplastic and ineffective haematopoiesis and peripheral cytopaenias that require frequent blood transfusions. MDS can transform to acute myeloid leukemia (AML).(1)

Incidence and presentation
Although the precise incidence of MDS is not known, it is estimated to be 3/100,000/year. This incidence increases among older people (approximately 20/100,000/year). Only 10-20% of patients with MDS are under the age of 60 years, as the median age at diagnosis is between 70 and 80 years.(2–4) In the USA, the incidence is approximately 3.4/100,000, with more than 10,000 diagnoses per year and approximately 60,000 people being affected.(5) Moreover, the overall incidence of MDS appears to be increasing.2 MDS are more common among men (incidence is approximately two-to-three times more frequent than in women).(4)
The clinical presentation of MDS is generally non-specific. However, initial findings of MDS can usually be attributed to the underlying cytopaenias. MDS can occur de novo (primary MDS) or following treatment with chemotherapy, radiation therapy or chemical injury (secondary MDS). Depending on the subtype of myelodysplasia, there is an approximately 50% risk of developing AML, which is often refractory to standard treatment.(6)

Treatment
Approximately half of the patients with MDS die within four years.(6) The only proven curative treatment may be intensive chemotherapy followed by allogeneic haematopoietic stem cell transplantation, which cannot be carried out in all patients (depending on age and general health condition). In those patients, best supportive care, comprising transfusions, growth factors and iron chelation therapy, is used most frequently. Otherwise, less intensive treatment strategies can be applied, including: non-intensive chemotherapy; treatment with immunomodulatory agents (thalidomide and lenalidomide); and treatment with immunosuppressive agents or new hypomethylating agents, such as azacitidine.(1,6)

Azacitidine
Azacitidine is a pyrimidine nucleoside analogue of cytidine. It exerts its antineoplasic effects by hypomethylation of DNA (DNA methyltransferase inhibitor) and direct cytotoxicity on abnormal haematopoietic cells in the bone marrow. Hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation, differentiation and death pathways can result in restoration of cancer-suppressing functions to cancer cells. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.(6,7)

Azacitidine was first approved by the US Food and Drug Administration (FDA) in 2004, and then in 2008 by the European Medicines Agency (EMA), through the centralised procedure, as an orphan drug. The ‘orphan designation’ means that a drug is used to treat life-threatening or chronically debilitating conditions that affect no more than five in 10,000 people in the EU, or are medicines which, for economic reasons, are unlikely to be developed without incentives. In this case, the calculated prevalence of MDS (including chronic myelomonocytic leukemia (CMML), which was classified as a type of MDS) is approximately 1.1–3 in 10,000 persons in the EU. In the indication for AML the calculated prevalence is approximately less than 2 in 10,000 persons in the EU.(6)

Azacitidine is indicated for treatment of all French–American–British (FBA) subtypes of MDS and CMML in the USA; and for treatment of intermediate-2 and high risk MDS (according to the International Prognostic Scoring System (IPSS)), of CMML with 10–29% marrow blasts without myeloproliferative disorder, and of AML with 20–30% blasts and multi-lineage dysplasia (according to World Health Organization Classification) in Europe.(6,7)

Dosing
In Europe, the recommended starting dose for the first treatment cycle is 75 mg/m2 injected subcutaneously daily for seven days every 28 days. The drug can be administered in an outpatient setting and is considered to be a low intensity form of therapy. The FDA also recommends the administration by intravenous infusion. The way of preparation depends on the administration route. For subcutaneous administration, each 100mg vial should be reconstituted aseptically with 4ml sterile water for injections and the suspension should not be filtered. For doses greater than 100mg, the dose should be equally divided into two syringes and injected into two separate sites. In cases of intravenous administration, each vial is reconstituted with 10ml sterile water for injection, obtaining a clear solution that is withdrawn into 50–100ml infusion bags of either 0.9% sodium chloride or lactated ringer solution. The administration should be carried out over a period of 10–40 minutes.(6,7)

Azacitidine improves peripheral blood values (reducing transfusion dependence), reduces the risk of transformation to AML, and improves quality of life, compared with conventional care regimens.(8)

By contrast, it seems to be well tolerated. The most common adverse reactions that appear during treatment with azacitidine, as described in different studies, are: myelosuppression, including leucopaenia; neutropaenia and thrombocytopaenia (71.4%); gastrointestinal events including nausea, vomiting, diarrhoea, constipation and anorexia (60.6%); pyrexia, fatigue and injection site reactions (77.1%). The highest rate of adverse reactions was reported during the first two cycles of therapy and decreased in subsequent cycles.(6)

Safety: authors’ experience
The authors evaluated the safety of azacitidine in patients with MDS. Post-marketing surveillance studies are important, because the less common adverse reactions, or the ones that are slower to develop in reality, are detected in these phases.

For the purpose of this retrospective observational study, we assessed all patients that had been treated with azacitidine between January 2009 and April 2010 from the electronic prescription program. Data on adverse reactions and reasons for hospital admissions were also collected from clinical histories.

Twelve patients had received azacitidine during this period (ten men and two women), with an average age of 74 years (range 52–84). Azacitidine was used in a daily regimen of 75mg/m2 for five, six or seven days repeated every 28 days (seven days dose regimen in one patient, six days dose regimen in eight patients and five days in three patients). Patients received a median of 3.3 cycles (range 1–10 cycles). Patients were premedicated to prevent nausea and vomiting with 8mg oral ondansetron when administration of azacitidine was subcutaneous, and with 1mg intravenous granisetron when administration of azacitidine was also intravenously.
In Europe azacitidine is only approved for subcutaneous use but the FDA approves both subcutaneous and intravenous routes. Seven of the 12 patients received azacitidine intravenously, three subcutaneously, and two patients began with subcutaneous administration and changed to the intravenous route to prevent from haematoma resulting from thrombocytopaenia (Table 1). As mentioned previously, thrombocytopaenia is characteristic of MDS as it also affects platelet lineage. The estimated prevalence of thrombocytopenia in MDS, defined as a platelet count of <100,000/microlitre, ranges from 40% to 65%.9
Patients who received azacitidine in different conditions than those approved by the EMA were required to give informed consent.

Adverse events
The most frequent adverse event in patients receiving azacitidine subcutaneously was injection site reactions. Four out of five patients registered this kind of adverse reaction: haematoma in four patients; blushing in three patients; pain in two; and inflammation and induration in two patients.

Another way to detect adverse events is from hospital admissions, in which more serious adverse events can be detected. Ten out of twelve patients were in hospital at least once during this period. There were 20 admissions, as one patient had four admissions, two patients had three, three patients had two and four patients were admitted only once. The average number of hospitalisations per patient was 1.7 (range 0–4). The reasons for the hospitalisations were diverse and in some cases there were more than one: febrile neutropenia (five cases), anaemia (four cases), respiratory infection (three cases), fever (three cases), thrombocytopaenia (two cases), pancytopaenia (one case), hypotension (one case), epistaxis (one case), local skin infection (one case), septic shock (one case) and hypocalcaemia with paralytic ileus (one case). Two of the 20 admissions were for reasons unrelated to their pathology (diverticulitis and traumatism).

Six patients died during hospitalisations: two patients diagnosed with febrile neutropaenia; two patients with anaemia and fever; and the two patients whose admissions were for reasons unrelated to MDS (one patient with diverticulitis and the other one with traumatism) (Figure 1). Most of these complications occurred before the third cycle (12 of 18 possible adverse events), which is consistent with what is described in the literature (most of the adverse events arise during the first two cycles of treatment).

Hypotension was also evaluated owing to the subjective impression of the clinicians of its high frequency. Blood pressure measurements are recommended before and after chemotherapy is administered in an outpatient setting in our hospital. We considered hypotension when blood pressure levels were below 90/60mmHg, or when baseline levels decreased more than 20mmHg after azacitidine administration. We had blood pressure data for eight patients, six of whom presented with hypotension that required fluid therapy. Two cycles had to be delayed owing to hypotension. Four of these six patients had antihypertensive treatment. No differences in the incidence of hypotension were observed between administration routes.

Conclusions
The most frequently observed adverse events with azacitidine, other than injection site reactions, are febrile neutropaenia, anaemia and infections. These adverse reactions overlap with the complications of the disease itself, so it is difficult to assess if they are therapy-related or part of the natural course of the disease. Furthermore, these symptoms can be exacerbated by the treatment of MDS. The number of patients affected by these adverse reactions is consistent with the rates described in the assessment report.

Nevertheless, many of the complications seen in our patients could be a result of the advanced state of the MDS, which had already transformed to AML in five of the 12 patients.
With regard to hypotension, it is a predictable common adverse event that can be managed easily, especially in patients already taking antihypertensive drugs. In these patients, antihypertensive drugs can be discontinued temporarily during azacitidine administration. Dizziness and discomfort caused by hypotension can be avoided and delays in treatment prevented.

The method of preparation is different, depending on the administration route; sometimes vials had to be discarded and this frequently occurred when patients with different treatment schedules coincided on the same day. To avoid this wastage, we scheduled appointments for those patients receiving azacitidine subcutaneously during one week, and appointments for patients receiving intravenous administration on another. This way of organising patients also provides more security.

Further studies would be necessary to determine frequency and severity of adverse reactions and, in the case of hypotension, if antihypertensive treatment should be discontinued temporarily in these patients.

References

1. Musto P et al. Azacitidine for the treatment of lower risk myelodysplastic syndromes. A retrospective study of 74 patients enrolled in an Italian named patient program. Cancer 2010:1485–94.
2. Kouides PA, Bennett JM. Understanding the myelodysplastic syndromes. The Oncologist 1997;2:389–401.
3. Doll DC, Landaw SA. Clinical manifestations and diagnosis of the myelodysplastic syndromes. Version 19.3. January 2012. www.uptodate.com.
4. Nguyen PL. The myelodysplastic syndromes. Hematol Oncol Clin N Am 2009;23:675–91.
5. Sekeres MA. Epidemiology, natural history, and practice patterns of patients with myelodysplastic syndromes in 2010. J Natl Compr Canc Netw 2011;9(1):57–63.
6. Assessment Report for Vidaza. European Medicines Agency. Evaluation of Medicines for Human Use.
7. FDA Center for Drug Evaluation and Research. Drug information. Vidaza.
8. Götze K et al. Azacitidine for treatment of patients with myelodysplastic syndromes (MDS): practical recommendations of the German MDS Study Group. Ann Hematol 2010;89:841–50.
9. Kantarjian H et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007;109:1705–14.