Clinical effectiveness of decitabine in severe sickle cell disease

The haemolytic anaemia in sickle cell disease (SCD) may be exacerbated acutely and chronically by aplastic crises, splenic or hepatic sequestration, folate or iron deficiency, erythropoietin deficiency, bone marrow scarring, delayed haemolytic transfusion reactions, autoimmune haemolysis or hyper-haemolysis of unknown aetiology. Progressive and acute anaemia exacerbations can be life-threatening and standard management options, such as transfusion, hydroxycarbamide and erythropoietin therapy may fail to rescue patients from clinical decline and early death. The DNA hypomethylating agent 5-aza-2’-deoxycytidine (decitabine) has been studied as a potential disease modifying agent for SCD. In phase I/II studies, decitabine produced clinically significant increases in total and fetal haemoglobin (HbF) and improvements in a range of surrogate clinical end-points (Koshy et al, 2000; DeSimone et al, 2002; Saunthararajah et al, 2003). However, relatively short-term drug administration limited the ability to measure definitive clinical improvement. We describe the outcomes of decitabine treatment for four patients with deteriorating clinical courses and severe illness despite maximized standard of care. The severe clinical status and trends prior to decitabine initiation and the duration of follow-up enabled persuasive documentation of clinical improvement. Decitabine is approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome. Therefore, decitabine administration in SCD is ‘off-label’. The off-label prescription was to provide direct benefit to these patients and not for research. Decitabine was considered because of clinical deterioration and life-threatening complications despite hydroxycarbamide therapy, erythropoietin for relative reticulocytopenia (haemoglobin <90 g/l, reticulocytes ≤250 × 109/l), decreased availability and increased transfusion risks from ≥5 red blood cell (RBC) allo-antibodies and autoantibodies, and ineligibility for available protocol therapy. The rationale for decitabine use and its potential risks were discussed with patients and family members with appropriate documentation in the medical chart. Females of child-bearing age were extensively counseled regarding the need for contraception and underwent pregnancy tests every 4 weeks. The retrospective review of patient data was approved by the University of Illinois at Chicago (UIC) Institutional Review Board. The initial decitabine dose was 0·2 mg/kg subcutaneously once (patients 3, 4) or twice (patients 1, 2) a week. In patients 2, 3 and 4, decitabine was added to stable erythropoietin or darbopoietin doses that had been administered for >6 months. Decitabine dose reductions were triggered by a platelet count >800 × 109/l (patients 1, 2) or a neutrophil count <2 × 109/l (patient 3) (Fig S1). The initial dose reduction was to 1x/week or, if already on a 1x/week regimen, by 0·05 mg/kg. Haemoglobin responses were maintained on the reduced doses. Decitabine increased total haemoglobin in all patients. Haemoglobin increases were rapid, with >15 g/l haemoglobin increases (that were clinically not from transfusion) noted within 2–4 weeks. Maximum haemoglobin increases were 35–50 g/l, achieved within 8 weeks (Fig 1). In patient 3, haemoglobin increased without a concurrent increase in HbF (Fig 1). In this patient, haemoglobin levels of >100 g/l on the decitabine/darbopoietin combination prompted attempts at single agent therapy, exarcebating anaemia and triggering recurrent heart failure (response needed the combination) (Fig 1). Generally, reticulocyte counts increased during the first 2–8 weeks of therapy. Reticulocyte trends reversed after haemoglobin levels >90 g/l, presumably because of negative feed-back on endogenous erythropoietin production. This was most obvious in patient 1, who was not receiving exogenous erythropoietin. HbF%, total haemoglobin (Hb) and absolute reticulocyte count (Abs Retics) changes before and during decitabine therapy. The large open rectangles indicate periods of decitabine administration (patient 1) or periods of combined erythropoietin/decitabine administration (patients 2, 3, 4). Patients 2, 3 and 4 were on stable doses of erythropoietin or darbopoietin for at least 6 months prior to the addition of decitabine to their medication regimen. Red arrows indicate packed red blood cell transfusions. Timings of laboratory measurements were clinically determined. The gap in therapy for patient 2 was produced by infrequent compliance as an out-patient. The gaps in therapy for patient 3 were produced by attempts to discontinue decitabine then darbopoietin when haemoglobin levels exceeded 100 g/l. The clinical status of the patients for 12 months before decitabine and during decitabine therapy is summarized in Table I. At the time of this report, all patients were on continued therapy. Decitabine is a nucleoside analogue, and like hydroxycarbamide, it can exert cytotoxic or cytostatic effects. However, if given at low doses, decitabine hypomethylates cellular DNA without cytotoxicity (Chabot & Momparler, 1986; Saunthararajah et al, 2003; Milhem et al, 2004). A well-described consequence of this action is HbF upregulation, and consequently a decrease in SCD haemolysis (Koshy et al, 2000; DeSimone et al, 2002; Saunthararajah et al, 2003). Another important consequence is shifts in patterns of differentiation. In-vitro and in-vivo, haematopoietic stem-cells exposed to decitabine undergo a shift in commitment to favour megakaryocyte-erythroid progenitor production over granulocyte-monocytes (Visvader & Adams, 1993; Saunthararajah et al, 2003; Milhem et al, 2004). Erythropoietin is required for red cell precursor survival (Koury & Bondurant, 1990), therefore increased megakaryocyte-erythroid progenitor commitment by decitabine probably requires erythropoietin for translation into increased reticulocytes and haemoglobin. These considerations explain the HbF-independent, but erythropoietin-dependent, increase in haemoglobin in patient 3. Although vaso-occlusion is a major cause of morbidity in SCD, severe anaemia per se can also determine outcomes, especially in patients with cardiac decompensation. Therefore, both increased erythropoiesis and decreased haemolysis are likely to contribute to the clinical benefit observed with decitabine treatment. Although this is an off-label, non-protocol experience, it is suggestive of clinical effectiveness for the following reasons: all patients had severe acute illness on a background of chronic deterioration and progressive anaemia over the preceding years or months; the follow-up period, ranging from 4–12 months, enabled the documentation of durable clinical improvement that contrasted convincingly with clinical status and trends in the preceding months; although three of the four patients were on concurrent erythropoietin, it had been administered at stable doses for more than 6 months with progressive anaemia and recurrent severe anaemia exarcebations; although two of the four patients received transfusions during decitabine therapy, these do not explain the durable increases in haemoglobin and eventual transfusion independence. Decreased survival and great morbidity has warranted the standard use of hydroxycarbamide in symptomatic SCD patients, although hydroxycarbamide has potential genotoxic and teratogenic effects and could have transient effects on fertility. Similarly, stem cell transplantation after cytotoxic conditioning, with its attendant risks of treatment-related mortality, is used for this non-malignant disease. Decitabine shares potential toxicities with hydroxycarbamide, but holds promise of greater effectiveness, with the likelihood of greater and more rapid HbF and haemoglobin increases in individual patients, and a likelihood that most treated patients will demonstrate these responses [17 of 17 SCD patients treated with decitabine at UIC (13 on protocol, 4 off-label) have had significant haemoglobin responses]. This report is no substitute for the phase III studies that are required to definitively demonstrate the effectiveness of decitabine for the chronic disease modification of SCD. However, the severe and complicated clinical circumstance described here is not typically represented in clinical trials. Therefore, this description can complement the necessary studies and prompt and inform their conduct. Fig S1. Platelet, absolute neutrophil and LDH changes before and during decitabine therapy. The large open rectangles indicate periods of decitabine administration (Patient 1) or periods of combined erythropoietin/decitabine administration (Patient 2, 3, 4). Red arrows indicate packed red blood cell transfusions. Timings of laboratory measurements were clinically determined. The gap in therapy for Patient 2 was produced by infrequent compliance as an out-patient. The gaps in therapy for Patient 3 were produced by attempts to discontinue decitabine then darbopoietin when haemoglobin levels exceeded 100 g/l. Please note: Blackwell Publishing are not responsible for the content or functionality of any supplementary materials supplied by the authors. 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