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

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

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

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

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.

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;98:3575-3583. Graphic courtesy of Dr. Aristotles A.N. Giagounidis.

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) 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.

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) 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.

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.

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 = .0001. Abbreviations: CCR, conventional care regimen; ITT, intent to treat. Fenaux P, et al. Lancet Oncol. 2009;10:223-232.

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;10:223-232. With permission from Dr. Pierre Fenaux.

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) 21.1 11.5 9.6 0.58 .0045 AZA (n = 45) vs LDAC (n = 49) 24.5 15.3 9.2 0.36 .0006 AZA (n = 17) vs Std chemo (n = 25) 25.1 15.7 9.4 0.76 .51 Fenaux P, et al. Lancet Oncol. 2009;10:223-232. With permission from Dr. Pierre Fenaux.

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

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

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

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

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

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

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;109:4586-4588. 19

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

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