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Keywords:

  • myelodysplastic syndrome;
  • azacitidine;
  • chronic myelomonocytic leukaemia

Hypomethylation therapy with azacitidine improves the survival of patients with higher-risk myelodysplastic syndrome (MDS) in comparison to those receiving conventional supportive care or low-dose cytarabine (Fenaux et al, 2009). Following an appraisal of cost-effectiveness, the National Institute of Clinical Excellence (NICE) and Scottish Medicines Consortium (SMC) have approved azacitidine for use in patients with International Prognostic Scoring System (IPSS) intermediate-2 and high-risk MDS, and chronic myelomonocytic leukaemia (CMML) with a marrow blast percentage of 10–29%, not eligible for allogeneic stem cell transplantation. For the appraisal, numbers of patients likely to require azacitidine were estimated from available demographics, but an analysis based on actual prevalence was not performed. In addition, assessment of co-morbidity, a potential determinant of patient suitability for azacitidine (Breccia et al, 2012) was not included in the recommendations. Consequently, it is unclear whether the estimates provided by NICE/SMC can be used for budget allocation by health-care providers. Here, using the Tayside MDS Registry, we have investigated numbers of patients potentially eligible for azacitidine over a 12-year period in a catchment population of just over 400 000 people. Eligibility was assessed using a combination of (i) criteria stipulated by NICE/SMC (IPSS score and suitability for allogeneic stem cell transplantation), (ii). co-morbidity and (iii) predicted response to azacitidine.

The Tayside MDS Registry was established with approval from Tayside Medical Research Ethics and includes all adults attending National Health Service (NHS) Tayside with a diagnosis of MDS. A registry search identified 23 patients with intermediate-2 or high-risk MDS diagnosed between 2000 and 2012. One patient with CMML did not have proliferative disease, but had a marrow blast percentage of 14%. None of these patients was considered suitable for allogeneic stem cell transplantation or had received intensive chemotherapy. Thus, over 12 years, a total of 24 patients (median age 73·5 years, range 53–94) fulfilled the NICE/SMC criteria for a trial of azacitidine.

A further analysis of azacitidine suitability was undertaken in these 24 patients using additional criteria including co-morbidity. The preponderance of MDS in older people means that a proportion is likely to have significant co-morbidity that precludes drug therapy or is associated with reduced survival (Della Porta et al, 2011; Naqvi et al, 2011). Despite not being stipulated in NICE/SMC recommendations, co-morbidity status could therefore be used to identify patients most appropriate for azacitidine therapy (Breccia et al, 2012). We investigated co-morbidity in our patient cohort using the Adult Comorbidity Evaluation-27 (ACE-27) scale (Piccirillo et al, 2003) and identified three patients (12%) with severe co-morbidity; moderate co-morbidity was present in 11 (44%) patients. However, co-morbidity did not directly contribute to mortality, since all 21 patients who were dead at last follow-up had complications related to MDS/CMML, including infection, bleeding or leukaemic transformation. Nevertheless, in the absence of survival data from individuals without MDS/CMML adjusted for age and co-morbidity, the advantages of azacitidine in patients with severe co-morbidity are speculative and a trial of therapy may be inappropriate.

To identify patients most likely to benefit from azacitidine, we assessed the likelihood of response in our patient cohort using the prognostic scoring-system developed by Itzykson et al (2011). Amongst the 23 MDS patients, scores were low in one, intermediate in 17 and high in six. Patients with intermediate scores had an observed median survival of 24·5 months (range 1–47·3) compared to those with high scores (4·2 months, range 1·2–12·9, P = 0·02) suggesting the azacitidine-independent prognostic utility of the scoring-system. Of interest, in the study by Itzykson et al (2011), the median survival in patients with intermediate and high scores treated with azacitidine was 15 and 6·1 months respectively; however these outcomes cannot be compared to those in our cohort of untreated patients, given the differences in sample size, patient selection and disease heterogeneity. Whether our patients with high azacitidine prognostic scores would have experienced a modest survival benefit with azacitidine treatment is unclear, but the exclusion of these patients (two of whom also had severe co-morbidity) from a trial of therapy would have resulted in 18 of the 24 original patients being eligible for treatment.

Based on the exclusive use of NICE/SMC recommended criteria, we thus anticipate an average of 2 (0–4) newly diagnosed MDS/CMML patients to be eligible for azacitidine per year in areas with a similar population size to ours (Fig. 1). If the outcomes of patients receiving azacitidine were to remain unaltered, an average of three patients (range 1–6) would be expected to be on treatment annually; however, with the expected survival advantage (Fenaux et al, 2009), this number may be higher. In addition, an improvement in life-expectancy, coinciding with better supportive care (Dayyani et al, 2010) may increase the number of patients receiving azacitidine. However, in our cohort, survival of patients diagnosed between 2000–2006 (n = 13) and 2006–2012 (n = 10) was similar (= 0·47), despite more IPSS high-risk MDS being diagnosed between 2006–2012 (= 0·05), suggesting that any benefit of improved supportive care on the survival of high-risk MDS patients is likely to be evident only over a period of decades. The use of co-morbidity and azacitidine prognostic scores to optimize patient selection could enable an algorithmic approach to the management of higher-risk MDS and increase the clinical and cost-effectiveness of treatment, but these novel criteria require further evaluation along with predictive bio-makers of response (Follo et al, 2009). We suggest incorporating co-morbidity and azacitidine prognostic scores in the audit of outcomes in patients treated with azacitidine. In addition, the establishment of a centralized MDS bio-bank containing relevant laboratory and clinical data, with an associated tissue repository to enable correlative scientific studies, would help in validating clinical trial data in ‘real-life’ patients (Ozbalak et al, 2012).

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Figure 1. Numbers of newly diagnosed myelodysplastic syndrome/chronic myelomonocytic leukaemia patients (New) per annum fulfilling the National Institute of Clinical Excellence/Scottish Medicines Consortium criteria for azacitidine therapy in NHS Tayside between 2000–2012. On average, two new patients per year are likely to be eligible for a trial of treatment. The expected number of patients receiving treatment (On treatment) each year (average = three patients per year) has been calculated from the observed survival of individual patients, assuming patient outcomes were to remain unchanged with azacitidine therapy. However, given the expected survival benefit with azacitidine, this number is anticipated to be higher.

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Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. Declarations
  5. References

We are grateful to the Tayside Leukaemia Research Endowment Fund for supporting the Tayside MDS Registry.

Author contributions

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. Declarations
  5. References

ST and DTB – designed the study. SD, NK and AH – collected the data. ST and MJG – analysed the data. ST and DTB – wrote the paper.

Declarations

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. Declarations
  5. References

ST has participated in advisory board meetings for Celgene and is an advisor to the Scottish Medicines Consortium.

References

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. Declarations
  5. References
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