Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling.

Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P = .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.

Effectiveness and safety of combined iron-chelation therapy with deferoxamine and deferiprone.

INTRODUCTION: The purpose of our study was to evaluate the effectiveness and safety of combined therapy with deferoxamine (DFO) and deferiprone (DFP) in patients with beta-thalassemia major and increased serum ferritin. PATIENTS AND METHODS: Our study was performed in 36 patients with beta-thalassemia major. DFP was administered orally in a total daily dose of 60 mg/kg for 6 days per week and DFO was administered subcutaneously in a total daily dose of 40-50 mg/kg for 4-6 days per week. The efficacy of combined treatment was assessed by measurements of serum ferritin and 24-h urine iron excretion levels. RESULTS: Out of the 36 patients, 11 discontinued DFO after a mean of 4 months; however, 25 patients, who continued to receive the combined therapy showed a very satisfactory compliance. After a mean of 13.5 months, their mean serum ferritin levels reduced from 2637 + 1292 to 1580 + 1024 ng/ml (P = 0.002) and their mean urinary iron excretion elevated from 0.41 + 0.27 to 0.76 +0.49 mg/24h (P = 0.003). The observed side effects were gastrointestinal disorders,elevations in liver enzymes, mild neutropenia, joint symptoms, taste disorders, dizziness and fatigue. CONCLUSIONS: The results of this study show that combined iron-chelation therapy with DFO and DFP results in satisfactory reduction of serum ferritin with no significant toxicity.

Treatment of beta-thalassemia patients with recombinant human erythropoietin: effect on transfusion requirements and soluble adhesion molecules.

The most common single genetic disorder and a major public health issue in Greece and other Mediterranean countries is beta-thalassemia. Current therapeutic approaches for homozygous beta-thalassemia entail blood transfusions and iron chelation therapy with deferoxamine or deferiprone for preventing tissue hemosiderosis. Recently, much effort has focused on various inducers of fetal hemoglobin (HbF) such as recombinant human erythropoietin (rHuEPO), especially in beta-thalassemia intermedia. Ten adult patients, 5 with beta-thalassemia major and 5 with beta-thalassemia intermedia, received 150 IU/kg rHuEPO (epoetin-alpha) subcutaneously three times a week. Seven patients were transfused every 14-30 days and 3 with beta-thalassemia intermedia were only occasionally transfused. The minimum duration of treatment was 12 weeks in order to define if there was any response. Transfusion intervals were modified according to the rHuEPO response to maintain stable Hb values. Lower transfusion requirements were observed in 5 patients after rHuEPO treatment (p = 0.028). In the 3 non-transfused patients, Hb values increased, and the patients are still being treated and followed up for a period ranging from 14 weeks to 2 years. Two patients with thalassemia major discontinued treatment after 12 weeks, as they did not achieve any response regarding transfusion requirements or Hb values. Pretreatment serum transferrin receptor levels were higher than in controls (p < 0.001) and significantly increased following rHuEPO treatment (p = 0.027). Patients had higher serum endothelin-3, sICAM-1 and sE-selectin values before rHuEPO treatment compared to controls (p < 0.001, p < 0.001 and p = 0.016, respectively), but these values were not altered during treatment. HbF values presented a slight, non-significant increase. rHuEPO treatment has a beneficial effect in transfusion-dependent beta-thalassemia patients. Although a slight increase in HbF levels was observed, other possible mechanisms are probably involved. None of our patients experienced thrombotic complications and a rise in blood pressure.