Dramatic erythroid response to low‐dose thalidomide in two patients with transfusion independent thalassemia and severe post‐transfusional alloimmune hemolysis
Authors: Claudio Fozza, Simonetta Pardini, Domenica Barbara Giannico, Clara Targhetta, Anna Angela Di Tucci, Paolo Dessalvi, Emanuele Angelucci, Fausto Dore
Journal: American Journal of Hematology (2015)

Fetal hemoglobin inducers are a promising therapeutic strategy for patients with beta thalassemia major and other hemoglobinopathies. Hydroxyurea and histone deacetylase inhibitors improve the α/β chain imbalance typical of these diseases 1. Immunomodulator compounds such as pomalidomide and lenalidomide slow erythroid maturation, increase the proliferation of immature erythroid cells, and modulate hemoglobin transcription, thus resulting in a strong induction of fetal Hb 2. Use of thalidomide in patients with transfusion dependent thalassemia (TDT) is anecdotal 3, 4, but no data are available for patients with non-transfusion dependent thalassemia (NTDT). We report here two cases in which thalidomide was used as erythroid stimulating agent for NTDT. Case 1: A 48-year-old woman had been diagnosed with NTDT at the age of 6 years. Direct sequencing revealed: (a) an heterozygous state for the β039 and β06 mutations, with a ATG–>ACG heterozygous point mutation involving the initiation codon of the α2 gene; (b) a homozygous state for the polymorphism Gγ-158 C–>T, which is associated with an increase in fetal hemoglobin synthesis 5; (c) absence of the known single point mutations in the gamma-globin promoter, associated with hereditary persistence of fetal haemoglobin (HPFH). Splenectomy was performed in 2002 at the age of 32. In May 2012 at the age of 42 years she required chronic transfusion treatment and received 2 packed red blood cell (PRBC) units roughly every 2 weeks until December 2012, when severe post-transfusional alloimmune hemolytic anaemia ensued (Figure 1). She was firstly treated with high dose steroids plus azatioprine 100 mg and then since November 2013 with rituximab 375 mg/m2 up to eight cycles. This approach was unsuccessful with Hb levels fluctuating between 6 and 8 g/dL. In April 2014, while her Hb was 7.35 g/dL (HbF 96%) on azatioprine 50 mg daily and her indirect Coombs test was still positive with an anti-Jkb titer of 1:8, she was started on thalidomide 50 mg/100 mg on alternate days. Quite strikingly her Hb level rose up to 9.99 g/dL within the first month and then to 10.7 g/dL in the second one, notwithstanding a dose reduction for thalidomide to 50 mg daily. After 4 months of treatment and a further dose reduction to 50 mg every other day, thalidomide was stopped with a Hb of 10 g/dL. Within one month Hb dropped to 8.75 g/dL but, after restarting thalidomide at a dose of 50 mg 5 days a week, a further response was achieved within one month. Ten months after starting thalidomide the patient is still responding with Hb above 10 g/dL. Case 2: A patient with homozygosity for the β039 mutation, and for α-thalassemia, received her first transfusion at the age of 13 years and was splenectomized at the age of 28 years. At the age of 48 she developed a recurrent post-transfusional alloimmune hemolytic anaemia. In February 2011, at age 56, with an overall transfusional burden of 10 PRBC units she presented with a Hb of 2.6 g/dL (HbF 98%). All the hemolytic indexes as well as both direct and indirect Coombs test were highly positive (anti -IgG, C3b, C3d). After an unsuccessful first line treatment with high doses steroid, she was started on thalidomide 50 mg/100 mg on alternate days together with mycophenolate mofetil 500 mg/day and high dose poly-specific IV Ig (5 cycles with 20 g for 5 days up to day +115 of thalidomide therapy). With this treatment her Hb level rose to 3.3 g/dL within the first month and to 6.5 g/dL in the second one. Mycophenolate mofetil was tapered and stopped at day +105 and she maintained a stable Hb level of 8–9 g/dL thereafter. The thalidomide dose was slowly tapered to the current one of 50 mg every other day. After 4 years of continuous treatment with thalidomide her Hb remains above 8 g/dL (HbF = 98%), with no detectable thalidomide-related side effects These two cases highlight a possible beneficial role of thalidomide in NTDT: since baseline Hb in these two patient was almost completely represented by HbF, it is not possible to determine the role of Hb F induction vs. immunomodulatory effects. The failure of various immunomodulatory approaches suggests a prominent role for the former mechanism. Epigenetic mechanisms have been hypothesized to promote a sustained fetal hemoglobin production even in thalassemic patients not engrafting after bone marrow transplantation 6. Such epigenetic modifications, which have been advocated to explain the efficacy of thalidomide as a HbF inducer at least in vitro 7, would deserve to be specifically explored in thalassemic patients. Hemoglobin values (black line) from the time the patient became transfusion dependent and during rituximab and thalidomide therapy. CF wrote the paper; SP, DBG, CT, AAD, PS, EA and FD were involved in the patient management, provided fundamental intellectual feed-back and reviewed the manuscript. Claudio Fozza,1* Simonetta Pardini,1 Domenica Barbara Giannico,1 Clara Targhetta,2 Anna Angela Di Tucci,2 Paolo Dessalvi,2 Emanuele Angelucci,2 and Fausto Dore1 1Dipartimento Di Scienze Biomediche, Università Di Sassari, 07100 Sassari, Italy; 2UO Ematologia E Centro Trapianti Ospedale Oncologico Di Riferimento Regionale "Armando Businco, Cagliari, Italy