Bone Marrow Transplantation (2010) 45, 1754–1755 & 2010 Macmillan Publishers Limited All rights reserved 0268-3369/10
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LETTER TO THE EDITOR
Prognostic impact of serum ferritin concentration on survival following reduced-intensity conditioned allogeneic haemopoietic SCT Bone Marrow Transplantation (2010) 45, 1754–1755; doi:10.1038/bmt.2010.36; published online 1 March 2010 The negative effect of elevated serum ferritin on overall survival (OS) following allo-SCT was first reported in fullintensity conditioning procedures;1–3 more recently, a similar effect was observed in reduced-intensity conditioned allo-SCTs.4–6 We report our retrospective assessment of the impact of pre-transplant serum ferritin on survival after reduced-intensity conditioned allo-SCT. Between 2005 and 2008, 64 patients referred to our centre went on to receive a reduced-intensity conditioned alloSCT. Of these, 47 had serum ferritin concentration levels measured. Indications for alloSCT were AML (CR1, n ¼ 5; other stages, n ¼ 12, ALL (CR1, n ¼ 2), myelodysplastic syndrome (RAEB: CR1, n ¼ 4; other stages, n ¼ 3; RARS, 1 (untreated)), CMML (n ¼ 1); CML (CP, n ¼ 4; AP, n ¼ 1), CLL (CR, n ¼ 1; PR, n ¼ 7; PD, n ¼ 1), advanced Hodgkin’s lymphoma (PR, n ¼ 5; CR, n ¼ 1), advanced nonHodgkin’s lymphoma (follicular lymphoma: CR3, n ¼ 2; PR, n ¼ 3; transformed marginal zone lymphoma: PR, n ¼ 1), advanced myeloma (CR, n ¼ 5; PR, n ¼ 1; refractory, n ¼ 1), myelofibrosis (n ¼ 1) and severe aplastic anaemia (n ¼ 2). Preparative regimens included fludarabine/cyclophosphamide (n ¼ 43, 42 with 2 Gy TBI), fludarabine/melphalan (n ¼ 10), fludarabine/BU (n ¼ 3, 2 with ATG), BEAM (n ¼ 3), FLAMSA (n ¼ 2), FLAG-I (n ¼ 1) and cyclophosphamide/ ATG (n ¼ 1). GVHD prophylaxis incorporated ciclosporin, mycophenolate mofetil and alemtuzumab (for volunteer unrelated donor transplants only; n ¼ 39). Supportive care included prophylactic aciclovir, itraconazole or liposomal amphotericin, cotrimoxazole and CMV monitoring by PCR, and pre-emptive treatment with ganciclovir or foscarnet. Three cohorts were defined by serum ferritin concentration before analysis: group I, ferritin level o1000 mg/l (n ¼ 18); group II, ferritin level 1000–2500 mg/l (n ¼ 21); group III, ferritin level 42500 mg/l (n ¼ 8). Median ages were 52, 53 and 49 years, respectively, and the distribution of matched sibling stem cell recipients was 7 (39%), 7 (33%) and 3 (38%). The distribution of AML in each group was 0 (0%), 9 (43%) and 4 (50%). The 2-year OS for group I was 75% (95% confidence interval: 56–100%), for group II 39% (19–81%) and for group III 0% (P ¼ 0.000026, as a continuous variable, by Cox proportional hazard modelling) (Figure 1). TRM at 1 year was 6% (1–22%) for group I, 25% (9–44%) for group II and 63% (23–86%) for group III (P ¼ 0.0082; Figure 2). Disease-related mortality at 1 year was 19% (5–42%), 23% (7–46%) and 25% (4–56%), respectively (P ¼ 0.7841).
Causes of death were: group I—relapse (n ¼ 3), infection (n ¼ 1); group II—relapse (n ¼ 5), infection (n ¼ 3), GVHD (n ¼ 2); and group III—relapse (n ¼ 3), GVHD (n ¼ 1), sinusoidal obstructive syndrome (n ¼ 1), heart failure (n ¼ 1), multi-organ failure (n ¼ 2). The possibility that the marked negative impact of elevated ferritin was a result of confounding variables was addressed by multivariable Cox regression analysis, incorporating age, donor type, diagnosis, pre-transplant ferritin and C-reactive protein levels at initial visit, with OS as the outcome of interest. Diagnostic groupings were AML/myelodysplastic syndrome (including CMML), chronic leukaemia (CML, CLL) and lymphoma (Hodgkin’s and non-Hodgkin’s lymphoma). Patients with ALL, myeloma, myelofibrosis or aplastic anaemia were not included in these diagnostic groupings. Data were used from the 17 patients without ferritin levels to improve the statistical power; there were no significant differences between those with and those without pre-transplant serum ferritin levels, in terms of age (P ¼ 0.9105 by t-test, treating age as a continuous variable), donor type (P ¼ 0.681 by Fisher’s exact test) and diagnosis (P ¼ 0.777 by Fisher’s exact test). In this model, only ferritin concentration was found to be significant (hazard ratio for groups ¼ 4.08 [95% confidence interval: 1.96–8.50], Po0.001). This result raises three issues regarding elevated serum ferritin levels before allo-SCT: its significance, the mechanism of impact upon OS and the appropriate clinical response. Serum ferritin is a proxy marker of body iron stores, but is also an acute-phase reactant and is released following hepatocellular damage. We found no significant association with contemporaneous serum C-reactive protein (correlation 0.0564, P ¼ 0.670) or albumin (0.1135, P ¼ 0.372); there was correlation with previous history of transfused red cell units (median 21, range 0–148; correlation 0.5505, P ¼ 0.001) and contemporaneous serum alanine transaminase (0.5363, Po0.001) and alkaline phosphatase (0.2705, P ¼ 0.031). There was no subsequent association with deranged liver function indices (alanine transaminase, alkaline phosphatase, albumin or bilirubin) at any timepoint after allo-SCT. Our data suggest that hyperferritinaemia reflected transfusional iron overload but not pre-existing inflammatory states; it affected OS and TRM, but not disease-related mortality. Small numbers precluded interpretation of trends in the cause of death. Tissue toxicity secondary to iron overload is possible given the cardiac, hepatic and endocrine impairment observed in haemochromatosis and hyper-transfused thalassaemia major.
Letter to the Editor
1755 100 2500 N=8 P=0.0003
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Measures include radiological assessment of cardiac and hepatic iron burden with T2* MRI and screening for genetic haemochromatosis. The role of pre- and/or peri-transplant iron chelation therapy should be addressed in clinical trials.
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Conflict of interest The authors declare no conflict of interest.
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R Oakes1, Nitin Sood1, R Pearce2, D Swirsky1, G Cook1 and M Gilleece1 1 Department of Haematology, St James Institute of Oncology, Leeds, UK and 2 British Society of Blood and Marrow Transplantation Registry, Derbyshire, UK E-mail:
[email protected]
Figure 1 Overall survival after RIC transplant by ferritin level.
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Figure 2 Non-relapse-related mortality after RIC transplant by ferritin level.
These observations of the significant negative impact of hyperferritinaemia on transplant outcome have led us to incorporate systematic evaluation of iron overload in patients with elevated serum ferritin pre-transplant.
1 Armand P, Kim HT, Cutler CS, Ho VT, Koreth J, Alyea EP et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007; 109: 4586–4588. 2 Mahindra A, Bolwell B, Sobecks R, Rybicki L, Pohlman B, Andresen S et al. Elevated pretransplant ferritin is associated with a lower incidence of chronic graft-versus-host disease and inferior survival after myeloablative allogeneic haematopoietic stem cell transplantation. Br J Haematol 2009; 146: 310–316. 3 Pullarkat V, Blanchard S, Tegtmeier B, Dagis A, Patane K, Ito J et al. Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2008; 42: 799–805. 4 Kim Y, Kim J, Cheong J, Song J, Min Y. Transfusionassociated iron overload as an adverse risk factor for transplantation outcome in patients undergoing reducedintensity stem cell transplantation for myeloid malignancies. Acta Haematol 2008; 120: 182–189. 5 Mahindra A, Sobecks R, Rybicki L, Pohlman B, Dean R, Andresen S et al. Elevated pretransplant serum ferritin is associated with inferior survival following nonmyeloablative allogeneic transplantation. Bone Marrow Transplant 2009; 44: 767–768. 6 Kataoka K, Nannya Y, Hangaishi A, Imai Y, Chiba S, Takahashi T et al. Influence of pretransplantation serum ferritin on nonrelapse mortality after myeloablative and nonmyeloablative allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2009; 15: 195–204.
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