Dose Titration in a Patient with Myelodysplastic Syndromes

1
Dose Titration in a Patient with Myelodysplastic
Syndromes
2
Background

• The cornerstone of therapy in patients with
  myelodysplastic syndromes (MDS) is supportive
  care with blood transfusions
• With a median survival of 4060 months,
  International Prognostic Scoring System (IPSS)
  low-risk and intermediate-1-risk MDS patients
  live long enough to develop clinical consequences
  of iron overload

3
Background

• Complications of iron overload include heart
  failure/arrhythmias, liver disease, and diabetes
  mellitus
• Transfusion dependency has a significant impact
  on survival in MDS1
• A 30 greater risk of death was evident for
  every500 ng/mL increase in serum ferritin
  above1000 ng/mL1

1. Malcovati L, et al. J Clin Oncol.
2005237594-7603.
4
Patient Presentation

• 69-year-old female patient with IPSS Int-1-risk
  MDS presented with baseline serum ferritin level
  of 3214 ng/mL

5
Treatment History

• Patient has been transfusion-dependent for 2
  years, receiving 2 units of packed red blood
  cells per month
• She has had no prior chelation therapy

6
Question

• Should this patient be started on chelation
  therapy?
• A. No
• B. Yes, with deferiprone
• C. Yes, with deferasirox

7
Initiation of Chelation Therapy

• Iron chelation should be initiated when serum
  ferritin levels 1000 ng/mL
• The patients serum ferritin is considerably
  above that level and she is expected to live long
  enough to be at risk of clinical complications of
  iron overload
• Chelation therapy should be initiated

8
Choosing a Chelator

• Although deferasirox is approved for use in
  patients with MDS, deferiprone is not approved
  for this indication and thus is not an
  appropriate choice
• Therefore, treatment with deferasirox was
  initiated at 20 mg/kg/day
• Desferrioxamine, also approved for use in MDS,
  would be an acceptable alternative. However, the
  IV infusions required with desferrioxamine would
  place an unnecessary burden on an elderly patient

9
Question

• After 2 weeks, the patient began to experience
  moderately severe diarrhea. How should the
  diarrhea be managed?
• A. Supportive therapy with antidiarrheal
  medication and hydration only
• B. Supportive therapy as above, plus dose
  reduction
• C. Interruption of therapy until diarrhea
  resolves

10
Managing Deferasirox-Related DiarrheaMild to
Moderate

• The patient was given an antidiarrheal medication
  and adequate hydration was maintained
• Despite these measures, diarrhea episodes
  continued to occur
• Deferasirox dose was reduced to 10 mg/kg/day
• After 1 week, diarrhea episodes had fully
  resolved
• Deferasirox dose was gradually increased over the
  subsequent 2 weeks to 20 mg/kg/day in increments
  of 5 mg/kg/day
• With severe diarrhea, deferasirox should be
  interrupted, then reintroduced at 10 mg/kg/day
  and gradually escalated if diarrhea continues to
  be unmanageable on reintroduction, deferasirox
  should be discontinued

11
Response to TreatmentSerum Ferritin

• Following 6 months of treatment, patients serum
  ferritin levels remained essentially unchanged
  from baseline (3145 ng/mL)

12
Question

• What should the next step be?
• A. Switch to desferrioxamine
• B. Consider deferiprone
• C. Increase dosage of deferasirox

13
Dosage Titration

• Since inadequate dose titration may be the cause
  of suboptimal response, this possibility should
  be explored
• Deferasirox dose was increased to 30 mg/kg/day
• By month 9, serum ferritin levels had decreased
  to 2759 ng/mL and by month 12 they had been
  further reduced to 2504 ng/mL
• Patient is continuing to receive deferasirox 30
  mg/kg/day and steady decreases in serum ferritin
  levels have been observed
• No further adverse events have been noted

14
Deferasirox Therapy in MDS Induces Dose-Dependent
Changes in Iron Burden
In MDS patients, iron balance was achieved with
10 mg/kg/dand negative iron balance with 20 and
30 mg/kg/d
LIC liver iron concentration. Porter JB, et al.
Eur J Haematol. 200880168-176.
15
ConclusionsDiarrhea

• Mild diarrhea can be managed with supportive
  care, without the need for dosereduction/disconti
  nuation of treatment
• Depending on severity, moderate diarrhea may
  require temporary dose adjustment
• Once the diarrhea has resolved, deferasirox
  dosage can be gradually escalated from 10
  mg/kg/day in steps of 5 mg/kg/day until the
  target dose is reached

16
ConclusionsSerum Ferritin

• MDS patients receiving regular blood transfusions
  are at risk of developing chronic iron overload
  and may require chelation therapy
• According to current guidelines, chelation
  therapy should be initiated once serum ferritin
  levels 1000 ng/mL
• Deferasirox dose should be reviewed regularly
  at3- to 6-month intervals and adjusted according
  to trends in serum ferritin levels

Gattermann N. Leuk Res. 200731(Suppl 3)S10-S15.