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Azacitidine (Vidaza®) for the treatment of myelodysplastic syndromes

Source agency:

LBI -HTA

Date of Submission:

20/11/2009

Date of Printing:

10/03/2010

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

Azacitidine, Vidaza®

Technology - description:

Azacitidine (Vidaza ®), a new molecular entity, is a pyrimidine analogue with antineoplastic activity. Mechanisms of action include cytotoxicity on abnormal hematopoietic cells in the bone marrow and hypomethylation of DNA. Aberrantly methylated genes which are responsible for regulation of cell differentiation, death-pathways and cell-cycles, are believed to be re-expressed due to hypomethylation, leading to an uptake of cancer suppressing actitivities. Cytotoxic effects are exerted by incorporation and inhibition of DNA and RNA, resulting in an activation of DNA damage pathways.
The recommended treatment regimen consists of the subcutaneous injec-tion of 75mg/m² body surface area every day for 7 days, followed by three weeks without treatment (28-day treatment cycle). In case of local prob-lems at the injection site, intravenous treatment is also easily feasible. A full course of treatment should consist of a minimum of six cycles and should be continued as long as the patient continues to benefit or until disease progression is stopped.
Prior to every treatment cycle, laboratory blood tests (complete blood counts, liver function, serum creatinine) should be performed.

Company or developer:

Celgene Corporation

Reason for database entry:

major health impact expected

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Established

Licensing, reimbursement and other approval:

The European Medicines Agency (EMEA) granted market authorization for azacitidine in December 2008. Indications comprise the treatment of adults, if they are not eligible for bone marrow transplant and with:
- intermediate-2 and high risk MDS according to the IPSS,
- chronic myelomonocytic leukaemia (CMML) with 10% to 29% marrow blasts without myeloproliferative disorders,
- AML with 20% to 30% blasts (formerly known as refractory anaemia with excess blasts in transformation) and multi lineage dysplasia, according to the WHO classification.
For MDS orphan medicinal product designation was granted in February 2002 and for AML in November 2007.

The United States Food and Drug Administration (FDA) has granted market authorization for all MDS FAB subtypes in 2004.

Technology - type(s):

Drug

Technology - use(s):

Therapeutic

Patient Indication & Setting

Patient indications:

Azacitidine (Vidaza®) is indicated for the treatment of intermediate-2 and high risk MDS (according to International Prognostic Scoring System (IPSS)), chronic myelomonocytic leukemia and acute myeloid leukaemia in adults who are not eligible for haematopoietic stem-cell transplantation.

Disease description and associated mortality and morbidity:

Myelodysplastic syndromes (MDS) are caused by dysfunctions of the bone marrow and might develop de-novo or as a secondary MDS after chemotherapy or radiation therapy for other diseases. The inability of the bone marrow to produce mature blood cells results in cytopenia of one or more of the peripheral blood cells and in an increasing number of bone marrow blast cells – factors which relate directly to the prognosis. Symptoms include anaemia, repeated infections or bleeding. About one third of patients suffering from MDS progress to acute myeloid leukaemia (AML).
By reasons that MDS comprise a heterogeneous group of conditions differ-ent classification schemes, mainly based on the cellular morphology, are in use, such as the French-American-British Classification (FAB) or the World Health Organization’s (WHO) classification. To assess the individual risk, the IPSS discriminates four risk groups. Based on number of cytopenia, percentage of marrow blasts and karyotype different prognoses for survival and transformation to AML can be made for each risk-group.

According to the IPSS, individual prognosis depends on the risk-group with a median survival (without therapy) ranging from 0.4 years to 5.7 years. The research group which had developed the IPSS based their findings on 816 patients. Within this study population they found that 22% of MDS patients had an intermediate-2 risk and 7% had a high risk MDS.
The median age of diagnosis is about 70 to 75 years with 90% of patients aged over 60 years at the time of diagnosis. In individuals over 70 years the incidence rises to between 22 and 45 per 100,000 population per year.

Number of Patients:

No data is available on the overall incidence of MDS in Austria but estimates from other countries range from 3.3 to 5 per 100,000 people per year. Applied to an Austrian population of 8,355,000, an estimated 275 to 420 persons per year would be affected. Due to a constantly increasing elderly population stratum this number is likely to increase in the near future.

Technology - specialities(s):

Oncology & radiotherapy, Haematology & blood products

Technology - setting(s):

Community and primary care, General hospital and ambulatory care, Specialist hospital

Setting - further information:

 

Impact

Alternative and/or complementary technology:

Other

Current Technology:

Treatment options for intermediate-2 and high-risk MDS patients comprise
- Supportive care: transfusion of red blood cells or platelets; antibi-otic therapy and prophylaxis to treat infections, and iron chelation.
- Low dose chemotherapy (ARA-C, hydroxyurea, low dose melphalan).
- Allogeneic hematopoietic stem cell transplantation (HSCT) is the single available curative treatment option and should be offered as first-line therapy to eligible patients. Due to an increasing risk of treatment-related mortality with increasing age, mainly younger patients are eligible. However, modern concepts such as the use of dose reduced conditioning “mini-allo tranplantation” have moved generally accepted age limits for allogeneic transplan-tation up to 70 years in selected patients.
- High-intensity chemotherapy for eligible patients lacking a stem cell donor or to reduce marrow blast counts.
- The use of haematopoietic growth factors (erythropoietin (off-label), granulocyte-colony stimulation factor).
- Decitabine, only as off-label use, either for patients who are not eligible for intensive therapy or as bridge to transplant if no donor is available.

Health Impact:

 

Diffusion:

 

Cost, infrastructure and economic consequences:

One vial of Vidaza® 100mg suspension for injection is approximately € 381 (manufacturer’s price). Therefore, one course of treatment (6 cycles) is expected to be around € 32,000 (assuming an average body surface area of 1.7m2 and therefore using 2 vials per day). These costs are alternatively to costs for other available treatment options for patients with intermediate-2 to high-risk MDS, such as allogeneic hematopoietic stem cell transplantation or high-intensity chemotherapy.

Ethical, social, legal, political and cultural impact:

 

Evidence & Policy

Clinical evidence and safety:

Phase III study:

Sponsor:
Celgene Corporation

Country:
Europe

Design:
Randomized, open label, active control

Participants characteristics:
358 pts (I 179 vs C 179), median age: 69 years (range: 38 – 88 years)

Treatments:
I(ntervention): azacitidine subcutaneous at 75mg/m² per day for 7 days every 28 days for at least 6 cycles;
treatment was continued until study completion (12 months after last patient was assigned) or discontinuation due to unacceptable toxicity, relapse, or disease progression
C(onventional care as control group):
- best supportive care
- low-dose cytarabine
- intensive chemotherapy (induction with cytarabine + daunorubicin/idarubicin or mitoxantrone)

In-/exclusion criteria:
Pts with higher-risk MDS - RAEB, RAEB-t or CMML (FAB Classification)
Exclusion of pts with therapy-related MDS, previous azacitidine treatment or planned allogeneic stem-cell transplantation

Follow-up:
Until death or study completion

Outcomes:
Primary: overall survival
Secondary: time to transformation to AML, haematological response, independence from red-blood-cell transfusions, infections requiring antimicrobials, occurrence of adverse effects

Key results:
(in comparison to conventional care group) Overall survival
at median follow-up of 21.1 months: I 24.5 months vs C 15 months (p=0.0001); HR =0.58 (95% CI 0.43 – 0.77);
at 2 years: I 50.8% vs 26.2% (p< 0.0001)
Median time to AML transformation:
I 17.8 months vs C 11.5 months; HR= 0.5 (95% CI 0.35 – 0.70; p< 0.0001)
Haematological response:
Any remission: I 29% vs C 12% (p=0.0001)
Complete remission: I 17% vs C 8% (p=0.015)
Partial remission: I 12% vs C 4% (p=0.0094)
Rate of infections treated with antimicrobials (per patient/year):
I 0.6 vs C 0.92; RR = 0.66 (95% CI 0.49 – 0.87; p=0.0032)

Adverse effects:
Deaths overall: I 46% vs C 63%, deaths during first 3 months I 11% vs C 9%
Neutropenia: I 91% vs C 76%, Thrombocytopenia: I 85% vs C 80%, Anaemia: I 57% vs C 68%
Other, non-haematological adverse effects: site reactions, nausea, vomiting, fatigue, diarrhoea with azacitidine

Commentary:
No significant difference between azacitidine and intensive chemotherapy group in all outcome measures, except lower rates of infections for azacitidine, possible explanation: small number of patients [1]

Further studies:

A phase II multicenter, randomized trial evaluated the impact of three different dosing regimens in a total of 151 patients [2]. The study population consisted mainly of patients with FAB lower-risk or RAEB. Hematologic improvement was observed in 44% to 56% of patients and transfusion independence was achieved in 50% to 64% patients. Within the six-cycle treatment phase adverse effects were neutropenia (38%), anaemia (29%), thrombocytopenia (25%) and leukopenia (18%). Non-haematological side-effects encompassed fatigue, nausea, erythema at the injection site and constipation. Out of three patients who died during treatment, one death is believed to have been treatment-related.

Another publication [3] reanalysed data of three trials, one randomized controlled trial where patients were allowed to cross-over after 4 months and two trials with only one arm. Of a total of 309 patients, 286 had been treated with azacitidine and out of those 48 had received the drug intravenously. Across all azacitidine arms a treatment response (defined as complete/partial remission or haematological improvements) was observed in 40% to 47% of patients. A subgroup analysis of AML patients who had been participating in the randomized controlled trial showed a median survival time of 19.3 months in the intervention group compared to 12.9 months in the control group. Improvements in platelet and red blood cell transfusion were more often achieved in the active treatment arm. Adverse effects, including haematologic and non-haematologic effects were seen more frequently in the control group than in the intervention group.

Economic evaluation:

 

Ongoing research:

Three further phase III trials are currently enrolling patients:

NCT00454480: will assess different chemotherapy regimens (including azacitidine) with combinations of monoclonal antibodies for the treatment of MDS and AML. First results can be expected in August 2012.
NCT00887068: will evaluate the use of azacitidine after allogeneic trans-plantation and is scheduled until April 2014.
NCT00422890: azacitidine for the treatment of the haematological relapse in patients suffering from AML or MDS with falling CD34-chimerism after haematopoietic stem cell transplantation. Primary completion date is expected to be January 2010.
Additionally, plenty of phase I and phase II trials are ongoing or recruiting patients. Research areas include azacitidine for patients with low-risk MDS, in combination with other treatment options for the management of MDS/AML or azacitidine prior to stem-cell transplantation in high-risk MDS and fullblown AML.

Ongoing or planned HTA:

 

Web link:

http://eprints.hta.lbg.ac.at/852/

References and sources:

1. Fenaux, P., et al., Efficacy of azacitidine compared with that of conven-tional care regimens in the treatment of higher-risk myelodysplastic syn-dromes: a randomised, open-label, phase III study. Lancet Oncol, 2009. 10(3): p. 223-32.
2. Lyons, R.M., et al., Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol, 2009. 27(11): p. 1850-6.
3. Silverman, L.R., et al., Further analysis of trials with azacitidine in pa-tients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol, 2006. 24(24): p. 3895-903.

Notes:

Based on the promising results of mainly one phase III study which demonstrated increased survival rates for intermediate-2 to high-risk MDS patients in comparison to three other forms of treatment, European Union-wide market authorization was granted by EMEA in December 2008.
So far, treatment options for higher-risk MDS patients included therapies such as high-intensity chemotherapy and allogeneic HSCT. However, eligibility for these treatment regimens depends on age, co-morbidities and clinical performance, hence only a limited number of patients are suitable. Thus, azacitidine provides a valuable treatment option for these difficult to treat MDS patients and has consequently found its way into daily clinical practice in Austria. Nevertheless, data assessing azacitidine under real-life conditions are missing, emphasizing the need for pragmatic trials conducted by independent institutions and comparing azacitidine to, for example, conventional chemotherapy regimens.
Although decitabine, an azacitidine congener, can theoretically be used off-label for the treatment of MDS patients, data from randomized phase III trials reporting survival benefit for individuals treated with this drug are still missing.
Most commonly reported side-effects of azacitidine are haematologic reac-tions occurring during the first two treatment cycles. Treatment options and preventive measures include monitoring of complete blood count, prophylactic antibiotics, delay of azacitidine administration or red-blood-cell transfusions.
As subcutaneous administration provides an easy way of treatment delivery, self-administering at home is feasible. Additionally, a phase I trial is recruiting participants to assess the oral application of this drug which might facilitate its application even further.

It is likely that azacitidine will be used more frequently in the near future: the FDA has approved the drug for all FAB-subtypes, the National Comprehensive Cancer Network has incorporated azacitidine into its clinical practice guidelines for low-risk MDS patients as well as for patients who relapse after stem-cell transplant and more studies to assess its value prior to/ after transplantation are under way. Therefore, off-label use in Austria is already going on.

The economic consequences are unclear. On the one hand, by reasons that treatment should be continued as long as patients experience benefit or the disease does not progress and combined with the potential of a more widespread use for broader indications (e.g. low risk MDS, stem-cell trans-plant, AML in the elderly), costs might be considerable. On the other hand, increased transfusion independence and the self-administration at home could lead to a reduced use of in-patient services and therefore to cost savings. If the costs have to be borne mainly by hospital providers or will occur in the out-patient sector will depend on the presence of oncologists in own practices – a condition practically absent in Austria.