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Aristoteles A. N. Giagounidis, MD, PhD Department of Haematology and Oncology St. Johannes Hospital Duisburg, Germany

Aristoteles A. N. Giagounidis, MD, PhD Department of Haematology and Oncology St. Johannes Hospital Duisburg, Germany. The Role of Iron Chelation in High-Risk Myelodysplastic Syndromes Before Allogeneic Haematopoietic Stem Cell Transplant. Patient Presentation. 59-year-old female

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Aristoteles A. N. Giagounidis, MD, PhD Department of Haematology and Oncology St. Johannes Hospital Duisburg, Germany

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

  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

  3. Decision Point 1What Is the Best Next Step?

  4. Decision Point 1What Is the Best Next Step?

  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;88:431-438.

  6. Results of Aggressive Chemotherapy in Patients with De Novo AML and High-Risk MDS (RAEB and RAEB/T) 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;98:3575-3583. Graphic courtesy of Dr. Aristotles A.N. Giagounidis.

  7. 0 12 24 36 48 60 72 84 96 108 120 Allogeneic Stem Cell Transplant with HLA-Identical Siblingsa MDS HLA-Identical Sibling and Standard Conditioning Improvement Over Timeb 1.00 .80 >1999 HR = 0.7 .60 Event-Free Survival 1997–1999 HR = 0.7 .40 1993–1996 HR = 0.9 .20 P <.01 <1993 HR (1) 0 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. 0 12 24 36 48 60 72 84 96 108 120 Allogeneic Stem Cell Transplant with HLA-Matched Unrelated Donors MDS, MUD, and Standard Conditioning Improvement Over Timea 1.00 .80 >1999 HR = 0.6 .60 1997–1999 HR = 0.7 Event-Free Survival .40 1993–1996 HR = 0.8 .20 P = .02 < 1993 HR (1) 0 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;10:223-232. With permission from Dr. Pierre Fenaux.

  10. AZA CCR 60 50 40 30 20 10 AZA vs CCR–Overall SurvivalITT Population Median AZA cycles: 9Deaths: AZA = 82, CCR = 113 60 50.8 50 40 Months Percent 26.2 30 24.5 20 15.0 10 0 0 Median OverallSurvivala (m) Alive at Year 2 (%) aHR = 0.58 [95% CI, 0.43, 0.77] P = .0001.Abbreviations: CCR, conventional care regimen; ITT, intent to treat.Fenaux P, et al. Lancet Oncol. 2009;10:223-232.

  11. AZA vs CCR–Response Rate and Haematologic Improvementa 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;10:223-232. With permission from Dr. Pierre Fenaux.

  12. AZA vs CCR–Median OSa by Investigator Selection Fenaux P, et al. Lancet Oncol. 2009;10:223-232. 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

  14. Decision Point 2Which of the Following is the Best Preparation of this Patient for allo-HSCT?

  15. Decision Point 2Which of the Following is the Best Preparation of this Patient for allo-HSCT?

  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

  17. Decision Point 3What Is the Most Appropriate Target Ferritin Level?

  18. Decision Point 3What Is the Most Appropriate Target Ferritin Level?

  19. 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 Disease-Free Survival (%) Overall Survival (%) 60 60 40 40 P <.001 P <.001 20 20 0 0 0 1 2 3 4 5 6 7 8 0 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 60 Relapse (%) 40 40 P = .005 20 20 P = .7 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Years from Transplant Years from Transplant With permission from Armand P, et al. Blood. 2007;109:4586-4588.

  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

  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

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