1. Aristoteles A. N. Giagounidis, MD, PhD
The Role of Iron Chelation in High-Risk Myelodysplastic Syndromes Before Allogeneic Haematopoietic Stem Cell Transplant
Aristoteles A. N. Giagounidis, MD, PhD
Department of Haematology and Oncology St. Johannes Hospital Duisburg, Germany 1

2. Patient Presentation 59-year-old female
Diagnosis of myelodysplastic syndromes (MDS) 2 years prior as refractory cytopaenia with multilineage dysplasia
Now: refractory anaemia with excess blasts with 10%–20% blasts
Developed from low-risk MDS
High risk International Prognostic Scoring System >2
Cytogenetics: trisomy 21 clone
No comorbidities
Transfusion dependent, 4 units/month
Iron overload present
Ferritin 1890 ng/mL 2 2

3. Decision Point 1 What Is the Best Next Step?
a. Watch and wait
b. Demethylating agent alone
c. Chemotherapy alone
d. Chemotherapy followed by allo-HSCT

4. Decision Point 1 What Is the Best Next Step?
a. Watch and wait
INCORRECT: Not curative
b. Demethylating agent alone
INCORRECT: Not curative but potentially correct. Some could argue that trying a hypomethylating drug could be interesting. If the patient responds, she could still be scheduled for allo-HSCT.
c. Chemotherapy alone
d. Chemotherapy followed by allo-HSCT
CORRECT: Curative treatment required, and the patient has no comorbidities and is of a relatively young age

5. Factors Predictive of Successful Remission Induction in Patients with MDS
Younger age
Good performance score
No previous cytotoxic therapy
Short interval from diagnosis to treatment
RAEB/T >RAEB subtype
Presence of Auer rods
Normal karyotype
Low levels of multidrug resistance (MDR1) protein
Abbreviation: RAEB/T, refractory anaemia with excess blasts in transformation. Aul C, et al. Praxis (Bern 1994). 1999;88:

6. Complete Remission (%) Event-Free Survival (wk)
Results of Aggressive Chemotherapy in Patients with De Novo AML and High-Risk MDS (RAEB and RAEB/T)
Induction Protocol
Patients (n)
Complete Remission (%)
Event-Free Survival (wk)
Survival (wk)
Idarubicin + ara-Ca (IA)
322 77 63
Topotecan + ara-Ca (TA)
357 59 36 41
Fludarabine + ara-Ca (FA)
600 55 40 30
aAra-C doses: 1–2 g/m2/d, given by constant infusion in IA, and over 2–4 hours in TA and FA. Abbreviations: AML, acute myeloid leukemia; ara-C, cytosine arabinoside. Estey EH, et al. Blood. 2001;98: Graphic courtesy of Dr. Aristotles A.N. Giagounidis.

7. Allogeneic Stem Cell Transplant with HLA-Identical Siblingsa
MDS HLA-Identical Sibling and Standard Conditioning
Improvement Over Timeb
1.00
.80
> HR = 0.7
.60
Event-Free Survival
1997– HR = 0.7
.40
1993– HR = 0.9
.20
P <.01
< HR (1)
120
108 96 84 72 60 48 36 24 12
Months
aEuropean Organisation for Research and Treatment of Cancer (EORTC) transplantation group.
bCox model evaluated for good risk and age: 31–51 years. Abbreviations: HLA, human leucocyte antigen; HR, hazard ratio. With permission from Dr. Theo de Witte.

8. Allogeneic Stem Cell Transplant with HLA-Matched Unrelated Donors
MDS, MUD, and Standard Conditioning
Improvement Over Timea
1.00
.80
> HR = 0.6
.60
1997– HR = 0.7
Event-Free Survival
.40
1993– HR = 0.8
.20
P = .02
< HR (1)
120
108 96 84 72 60 48 36 24 12
Months
aEuropean Organisation for Research and Treatment of Cancer (EORTC) transplantation group. bCox model evaluated for good risk and age: 31–51 years. Abbreviation: MUD, matched unrelated donor. With permission from Dr. Theo de Witte.

9. AZA-001 Phase III Survival Study
Azacitidine (AZA) 75 mg/m2/d x 7d q28d (n = 179)
Stratify (FAB, IPSS)
Eligibility
RAEB, RAEB/T, CMML
10%–29% blasts
IPSS: INT-2/high risk
Conventional Care Regimen
1. BSC only (n = 105)
2. Low-dose ara-C (n = 49)
3. Standard chemotherapy (n = 25)
Primary endpoint: overall survival
Secondary endpoints: time to AML, RR, HI, TI, infection, safety
Abbreviations: ara-C, cytarabine; BSC, best supportive care; CMML, chronic myelomonocytic leukaemia; FAB, French-American-British; HI, haematologic improvement; RR, response rate; TI, transfusion independence. Fenaux P, et al. Lancet Oncol. 2009;10: With permission from Dr. Pierre Fenaux.

10. Median Overall Survivala (m)
AZA vs CCR–Overall Survival ITT Population
AZA
CCR
Median AZA cycles: 9 Deaths: AZA = 82, CCR = 113 10 20 30 40 50 60 60
50.8 50 40
Months
26.2
Percent 30
24.5
15.0 20 10
Median Overall Survivala (m)
Alive at Year 2 (%)
aHR = 0.58 [95% CI, 0.43, 0.77] P = Abbreviations: CCR, conventional care regimen; ITT, intent to treat. Fenaux P, et al. Lancet Oncol. 2009;10:

11. AZA vs CCR–Response Rate and Haematologic Improvementa
CCR Arms
AZA n = 179 (%)
CCR n = 179 (%)
BSC n = 105 (%)
LDAC n = 49 (%)
Std CT n = 25 (%)
P-value AZA vs CCR
Remission (CR + PR) 29 12 5 40
.0001 CR 17 8 1 36
.02 PR 4
.009
IWG HI major + minor 49 31 25 28
<.0001
HI-E major 11 10 22
HI-P major 33 14 19 20
.0003
HI-N major 18 24
.87
aInternational Working Group (IWG) 2000 Criteria.
Abbreviations: CR, complete remission; E, erythroid; HI, haematologic improvement; LDAC, low-dose ara-C; N, neutrophil; P, platelet; PR, partial remission; Std CT, standard chemotherapy.
Fenaux P, et al. Lancet Oncol. 2009;10: With permission from Dr. Pierre Fenaux.

12. AZA vs CCR–Median OSa by Investigator Selection
Treatment
Median OS (mo)
Differences OS
Hazard Ratio
P-Value
AZA (n = 117) vs BSC (n = 105)
9.6
0.58
.0045
AZA (n = 45) vs LDAC (n = 49)
9.2
0.36
.0006
AZA (n = 17) vs Std chemo (n = 25)
9.4
0.76
.51
Fenaux P, et al. Lancet Oncol. 2009;10: With permission from Dr. Pierre Fenaux.

13. Case Continues Chemotherapy initiated
Idarubicin 12 mg/m2 days 1–3 and cytarabine 100 mg/m2 days 1–5
Bone marrow biopsy day 16 showed complete aplasia
Second induction course day 35
Idarubicin 12 mg/m2 days 1–3 and cytarabine 1000 mg/m2 days 1–5
Complete remission on day 62
No sibling donor
Search for matched unrelated donor started 13 13

14. Decision Point 2 Which of the Following is the Best Preparation of this Patient for allo-HSCT?
a. Maintenance chemotherapy
b. Iron chelation
c. Consolidation chemotherapy

15. Decision Point 2 Which of the Following is the Best Preparation of this Patient for allo-HSCT?
a. Maintenance chemotherapy
INCORRECT: Carries risk for severe infections and other complications; after 2 courses of chemotherapy, early progression is unlikely
b. Iron chelation
CORRECT: Emerging data suggest benefit
c. Consolidation chemotherapy

16. Case Continues Patient completed 2 courses of chemotherapy
Achieved complete response
After second course, patient started deferasirox
Deferasirox 20 mg/kg body weight
Ferritin 2600 ng/mL
Haemoglobin level reached normal levels 4 weeks after discharge following second induction course
Platelet counts and neutrophils also normalized within 2 weeks 16 16

17. Decision Point 3 What Is the Most Appropriate Target Ferritin Level?
a. <200 ng/mL
b. <2500 ng/mL
c. <1000 ng/mL

18. Decision Point 3 What Is the Most Appropriate Target Ferritin Level?
a. <200 ng/mL
INCORRECT: Within normal range
b. <2500 ng/mL
INCORRECT: Significant iron overload
c. <1000 ng/mL
CORRECT: Best level for prevention; risk/benefit ratio of deferasirox is best for treatment down to ferritin levels of 500–1000 ng/mL and this range has proved safe in allo-transplant

19. Disease-Free Survival (%) Treatment-Related Mortality (%)
Outcomes According to Pretransplant Serum Ferritin Level in MDS Patients Undergoing HSCT
Serum ferritin 1st–3rd quartile
Serum ferritin highest quartile
Serum ferritin 1st–3rd quartile
Serum ferritin highest quartile
100
100 80 80
Overall Survival (%)
Disease-Free Survival (%) 60 60 40 40
P <.001
P <.001 20 20 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8
Years from Transplant
Years from Transplant
Serum ferritin 1st–3rd quartile
Serum ferritin highest quartile
Serum ferritin 1st–3rd quartile
Serum ferritin highest quartile
100
100 80 80
Treatment-Related Mortality (%) 60
Relapse (%) 60 40 40
P = .005 20 20
P = .7 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8
Years from Transplant
Years from Transplant
With permission from Armand P, et al. Blood. 2007;109: 19

20. Case Continues
Ferritin level dropped to <1000 ng/mL within 3 months after starting chelation therapy
A matched unrelated donor was found
Chelation was stopped at the beginning of conditioning regimen for allo-HSCT
HLA-identical allo-HSCT was performed
3 months later, ferritin rose to 1785 ng/mL
Chelation restarted for 2 months
Thereafter, patient maintained on phlebotomies 20 20

21. Conclusion Iron chelation has a role in high-risk MDS
Meticulous planning is necessary as both pre- and posttransplant periods include a multitude of drugs that can interfere with iron chelation therapy
Pre- and posttransplant ferritin levels are linked to outcome in MDS
Ongoing trials are needed to further evaluate the use of iron chelation in high-risk MDS 21 21