Paper: Significant Impact of Iron Chelation After Allogeneic Hematopoetic Stem Cell Transplantation...

8/13/2019 Paper: Significant Impact of Iron Chelation After Allogeneic Hematopoetic Stem Cell Transplantation on Disease Re

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12/11/13, 8:12 Aaper: Signicant Impact Of Iron Chelation After Allogeneic Hematopoeansplantation On Disease Recurrence: Potential Anti-Leukemic Activity

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180 Significant Impact Of Iron Chelation After Allogeneic HematopoeticStem Cell Transplantation On Disease Recurrence: Potential Anti-LeukemicActivity

Program: Oral and Poster AbstractsType: OralSession: 102. Regulation of Iron Metabolism: Iron Regulation - Mechanisms and Therapeutic Implications

Monday, December 9, 2013: 8:15 AM353-355 (Ernest N. Morial Convention Center)

Mauricette Michallet, MD, PhD 1 , Mohamad Sobh, Pharm.M. 2* , Stephane Morisset, Stat. 2* , Helene Labussiere, MD 2* ,Marie Y. Detrait, MD 2 , Sophie Ducastelle, MD 2* , Fiorenza Barraco, MD 2* , Lila Gilis, MD 2* , Richard Cohen, Tech. 3* , Xavier Thomas, MD 2 , Franck E. Nicolini, MD, PhD 1,4,5 and Colette Chapuis-Cellier, MD 3*

1Centre Hospitalier Lyon Sud, Pierre Benite, France2Hematology department 1G, Centre Hospitalier Lyon Sud, Pierre Benite, France3Biochemistry department, Centre Hospitalier Lyon Sud, Pierre Benite, France4Centre de Recherche en Cancrologie de Lyon, Inserm U1052, Lyon, France5 Hematology department, Centre Hospitalier Lyon Sud, Pierre Bnite, France

Iron overload (IO), primarily related to multiple red blood cell transfusions, is a relatively common complication inallogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Elevated pre-transplant ferritin level, a surrogatemarker of iron overload, was demonstrated to be an important cause of mortality and morbidity in patients who haveundergone allo-HSCT. Excessive iron accumulation results in tissue damage and organ failure, mainly as a result of thegeneration of free radicals that cause oxidative damage and organ dysfunction. Iron chelators have been w idely usedleading to normalisation for ferritine level and lower IO-related complications. As iron has a fundamental role in cellsurvival affecting pathways involved in DNA synthesis, cell differentiation, and apoptosis, some studies evaluated the anti-proliferative activity of iron chelators in cancer and leukemia patients on disease recurrence. The objective of this studywas to determine at a first time the impact of serum f erritin level measured at time of allogeneic HSCT in adult patientswith hematological disorders on the different outcomes and t o investigate at a second time the role of iron chelation onrelapse incidence. We included 158 patients, 100 males and 58 females w ith a median age of 45 years (18-67) whounderwent allo-HSCT between 2002 and 2010. There were 83 acute myeloid leukemias, 10 chronic myeloid leukemias, 11myelodysplastic syndromes, 7 myeloproliferative disorders, 19 myelomas, 9 non-Hodgkin lymphomas, 6 Hodgkin diseases,5 aplastic anemias and 3 hemoglobinopathies. Sixty-seven (42%) patients were sex mismatched (F ! M:37; M ! F:30); forABO compatibility, 61% were compatible, 18% had minor incompatibility and 21% had major incompatibility. Concerningthe HSCT procedures, 60 patients (38%) received peripheral blood stem cell and 98 (62%) received bone marrow from 97(61%) HLA related donors [matched, n=76; mismatched, n= 21], and 61 (39%) HLA unrelated donors [matched, n=36;

mismatched, n=25] after myeloablative [n=64, (41%)] or red uced intensity conditioning [n=94, (59%)]. Attransplantation, 91 (58%) were in complete remission (CR) or chronic phase [CR1: n=61 (67%); ! CR2: n=30 (33%)].The median serum ferritin level at HSCT was 1327 microg./l ( 26-14136); 31(20%) patients had a level 26-500, 33 (21%)had a level 500-2500, and 94 (59%) >2500. There was no sig nificant correlation between the different ferritin levels,disease kind and status at HSCT. After transplantation, 23 pat ients received iron chelating agents after a serum ferritinlevel of 1000 microg/l and stopped when the level decreased below 1000. The cumulative incidence of acute GVHD ! II at3 months was 14% (11-16.5) with 10.5% (8-13) for grade III and 7% (5-9) for grade IV; the 1 year cumulative incidenceof limited and extensive chronic GVHD were 4% (2-6) and 12.4% (9-16) respectively. After a median follow-up of 18months (1-106), the 5 years OS probability was 65% for patients with ferritin level below 500 microg./l, 39% for levelbetween 500 and 2500 microg./l and 28% for level > 2500 micog./l, [Hazard ratio= 3.5 (1.5-8.1), p=0.002]; this wasexplained by a significant higher TRM in patients with level >2500 [Hazard ratio= 4.3 (1.02-18) , p=0.04]. Interestingly,we found in multivariate analysis that patients receiving iron chelators had significantly better OS [5 years OS= 59% vs.34% for non-chelated patients, Hazard ratio= 0.34 (0.15-0.76), p=0.008], (Figure 1a), and experienced less diseaserelapse [5 years relapse incidence= 18% vs. 41% for non-chelated patients, Hazard ratio= 0.22 (0.07-0.73), p=0.012],(Figure 1b). In conclusion, we confirmed the negative impact of iron overload on the outcomes allo-HSCT recipients. Moreimportantly, we demonstrated that iron chelators have a positive impact in reducing disease relapse by the possiblemechanism of iron deprivation in leukemic cells. This clinical observation needs to be confirmed by prospective randomizedtrials.
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Figure 1. a: Overall survival probability and b: relapse incidence in patients with or without iron chelation

Disclosures: Michallet: Novartis: Honoraria, Research Funding. Nicolini: Novartis: Consultancy, Honoraria, ResearchFunding.

See more of: 102. Regulation of Iron Metabolism: Iron Regulation - Mechanisms and Therapeutic ImplicationsSee more of: Oral and Poster Abstracts


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Paper: Significant Impact of Iron Chelation After Allogeneic Hematopoetic Stem Cell Transplantation...

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