Angela Rago

Current trends in management of hepatitis B virus reactivation in the biologic therapy era

Hepatitis B virus (HBV) reactivation represents an emerging cause of liver disease in patients undergoing treatment with biologic agents. In particular, the risk of HBV reactivation is heightened by the use monoclonal antibodies, such as rituximab (anti-CD20) and alemtuzumab (anti-CD52) that cause profound and long-lasting immunosuppression. Emerging data indicate that HBV reactivation could also develop following the use of other biologic agents, such as tumor necrosis factor (TNF)-α inhibitors. When HBV reactivation is diagnosed, it is mandatory to suspend biologic treatment and start antiviral agents immediately. However, pre-emptive antiviral therapy prior to monoclonal antibody administration is crucial in preventing HBV reactivation and its clinical consequences. Several lines of evidence have shown that risk of HBV reactivation is greatly reduced by the identification of high-risk patients and the use of prophylactic antiviral therapy. In this article, we discuss current trends in the management of HBV reactivation in immunosuppressed patients receiving biologic therapy, such as rituximab, alemtuzumab and TNF-α antagonists.

Comorbidities and FLT3‐ITD abnormalities as independent prognostic indicators of survival in Elderly acute myeloid leukaemia patients

Elderly acute myeloid leukaemia (AML) patients have a dismal prognosis due to biological features of disease in itself and to presence of comorbidities. Aim of this study was to evaluate the prognostic impact of comorbidity prognostic score systems applied in our population of patients. as well as other clinical‐biological features. We retrospectively considered the outcome of 120 patients aged >65 years diagnosed as having AML between January 2001 and December 2005. Comorbidities were evaluated by using Charlson comorbidity index (CCI), Hematopoietic cell transplantation comorbidity index (HCTCI) and a score proposed by Dombret et al. in 2007. Median patient age was 67 years. Forty‐six patients were treated with intensive chemotherapy and 23 reached a complete remission. Seventy‐four patients received only supportive therapies or low‐dose chemotherapy. Multivariate analysis showed the effects of leukocytosis (p = 0.0013), antecedent Myelodysplastic syndrome (MDS) (p = 0.011), FLT3 abnormalities (p = 0.032), CCI (p = 0.0037) and Dombret et al. score (p = 0.045) as independent prognostic parameters for survival. Based on these variables we were able to stratify patients in low and high risk, with different median overall survival: patients were considered as low risk if they had none or only one of the above mentioned adverse factors for survival, with a median overall survival of 447 days. Patients with two or more adverse factors were categorized as high risk: this subgroup had a median overall survival of 227 days (p = 0.001). Comorbidities are independent factors that influence survival. Application of CCI and Dombret score may help to better identify patients at diagnosis who can benefit from intensive chemotherapy. Copyright

Prevalence of allo-immunization anti-HLA and anti-integrin αIIbβ3 in Glanzmann Thromboasthenia patients

Summary.  Platelet transfusions, main therapy of Glanzmann Thromboasthenia (GT), can induce an allo‐immunization against human leucocyte antigen and integrin αIIbβ3. We have investigated in our GT patients the rate of allo‐immunization and of refractoriness to platelet transfusions. From 1975 until December 2005, we have followed 17 GT patients: 14 type 1, 3 variant type; nine females, eight males; median age at diagnosis 9.8 years (range 1–44.5); median age at the time of the study 35.5 years (range 23.6–68.5). In our patients, 121 bleeding episodes occurred (24 severe, 37 moderate, and 60 mild). Ten major and 22 minor surgical procedures have been performed. Two spontaneous deliveries and three caesarian sections with five live births were performed; moreover, one late foetal loss occurred, and one voluntary abortion was performed. Sixteen of 17 patients have been transfused at least once in life with platelets and/or red blood cells (RBC). All transfused patients have been investigated for the presence of anti‐HLA and anti‐integrin αIIbβ3 allo‐antibodies. The positiveness of allo‐antibodies has been demonstrated in 4/16 transfused patients (25%): isolated for anti‐HLA in two; isolated for anti‐integrin αIIbβ3 in one; and combined in one. In spite of the presence of allo‐antibodies, platelet transfusions have always been effective and the haemostasis was not compromised.

Thrombosis and survival in essential thrombocythemia: a regional study of 1,144 patients.

To identify prognostic factors affecting thrombosis‐free survival (TFS) and overall survival (OS), we report the experience of a Regional cooperative group in a real‐life cohort of 1,144 patients with essential thrombocythemia (ET) diagnosed from January 1979 to December 2010. There were 107 thrombotic events (9.4%) during follow‐up [60 (5.3%) arterial and 47 (4.1%) venous thromboses]. At univariate analysis, risk factors for a shorter TFS were: age >60 years (P < 0.0054, 95% CI 1.18–2.6), previous thrombosis (P < 0.0001, 95% CI 1.58–4.52) and the presence of at least one cardiovascular risk factor (P = 0.036, 95% CI 1.15–3.13). Patients with a previous thrombosis occurred ≥24 months before ET diagnosis had a shorter TFS compared to patients with a previous thrombosis occurred <24 months (P = 0.0029, 95% CI 1.5–6.1); furthermore, patients with previous thrombosis occurred <24 months did not show a shorter TFS compared with patients without previous thrombosis (P = 0.303, 95% CI 0.64–3.21). At multivariate analysis for TFS, only the occurrence of a previous thrombosis maintained its prognostic impact (P = 0.0004, 95% CI 1.48–3.79, RR 2.36). The 10‐year OS was 89.9% (95% CI 87.3–92.5): at multivariate analysis for OS, age >60 years (P < 0.0001), anemia (P < 0.0001), male gender (P = 0.0019), previous thromboses (P = 0.0344), and white blood cell >15 × 109/l (P = 0.0370) were independent risk factors. Previous thrombotic events in ET patients are crucial for TFS but their importance seems related not to the occurrence per se but mainly to the interval between the event and the diagnosis. Am. J. Hematol. 89:542–546, 2014.

Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms the mister hyde face of a safe drug

The current study was conducted to evaluate severe mucocutaneous toxicity during treatment with hydroxyurea (HU) in a large cohort of patients with Philadelphia chromosome‐negative myeloproliferative neoplasms (MPN).

Anti-CD20 Therapy Acts via FcγRIIIA to Diminish Responsiveness of Human Natural Killer Cells

Natural killer (NK) immune cells mediate antibody-dependent cellular cytotoxicity (ADCC) by aggregating FcγRIIIA/CD16, contributing significantly to the therapeutic effect of CD20 monoclonal antibodies (mAb). In this study, we show that CD16 ligation on primary human NK cells by the anti-CD20 mAb rituximab or ofatumumab stably impairs the spontaneous cytotoxic response attributable to cross-tolerance of several unrelated NK-activating receptors (including NKG2D, DNAM-1, NKp46, and 2B4). Similar effects were obtained from NK cells isolated from patients with chronic lymphocytic leukemia in an autologous setting. NK cells rendered hyporesponsive in this manner were deficient in the ability of these cross-tolerized receptors to phosphorylate effector signaling molecules critical for NK cytotoxicity, including SLP-76, PLCγ2, and Vav1. These effects were associated with long-lasting recruitment of the tyrosine phosphatase SHP-1 to the CD16 receptor complex. Notably, pharmacologic inhibition of SHP-1 with sodium stibogluconate counteracted CD20 mAb-induced NK hyporesponsiveness, unveiling an unrecognized role for CD16 as a bifunctional receptor capable of engendering long-lasting NK cell inhibitory signals. Our work defines a novel mechanism of immune exhaustion induced by CD20 mAb in human NK cells, with potentially negative implications in CD20 mAb-treated patients where NK cells are partly responsible for clinical efficacy.

Diagnostic and prognostic role of PET/CT in patients with chronic lymphocytic leukemia and progressive disease

In order to evaluate the predictive value of positron emission tomography–computed tomography (PET/CT) in discriminating the presence of a Richter’s syndrome (RS) or a second malignancy (SM), as well as to evaluate its prognostic value in patients with chronic lymphocytic leukemia (CLL), we retrospectively analyzed the data of 90 patients who, in the suspicion of a RS or a SM, underwent PET/CT followed by the biopsy of the involved tissue. The median maximum Standardized Uptake Value (SUVmax) in the presence of a CLL/small lymphocytic lymphoma, a diffuse large B-cell lymphoma (DLBCL), a Hodgkin lymphoma (HL), a SM were 3.5, 14.6, 7.0 and 6.3, respectively (P⩽0.0001). A SUVmax cutoff value ⩾5 showed a sensitivity, specificity, positive and negative predictive values of 88.2, 71.2, 51.3 and 94%, respectively, for the presence of a more aggressive disease (DLBCL, HL and SM). A SUVmax ⩾5 identified also a subset of treatment naive patients with an inferior progression-free survival (P=0.011) and overall survival (P=0.067). These findings suggest that PET/CT may helpfully integrate the biologically-based prognostic stratification of CLL. Prospective clinical trials including larger cohorts of patients are needed to conclusively define the role and prognostic impact of PET/CT in the routine management of CLL patients.

Antiviral treatment including entecavir plus tenofovir disoproxil fumarate for HBV reactivation following a rituximab-based regimen.

Entecavir and tenofovir disoproxil fumarate are potent and effective antiviral drugs that now represent recommended treatment options for chronic HBV infection. However, no or very limited clinical evidence is currently available on these drugs for the management of HBV reactivation in patients with haematological malignancies. Herein, we report a case of HBV reactivation in a patient with non-Hodgkins lymphoma following a rituximab-based regimen, and who was successfully treated with a combination antiviral treatment including entecavir and tenofovir disoproxil fumarate.

Arterial and venous thrombosis in patients with monoclonal gammopathy of undetermined significance: incidence and risk factors in a cohort of 1491 patients.

Monoclonal gammopathy of undetermined significance (MGUS) has been associated with an increased risk of thrombosis. We carried out a retrospective multicentre cohort study on 1491 patients with MGUS. In 49 patients (3·3%) MGUS was diagnosed after a thrombotic event. Follow‐up details for a period of at least 12 months after diagnosis of MGUS were obtained in 1238 patients who had no recent history of thrombosis (<2 years) prior to diagnosis, for a total of 7334 years. During the follow‐up, 33 of 1238 patients (2·7%) experienced thrombosis, with an incidence of 2·5 arterial events and 1·9 venous events per 1000 patient‐years. Multivariate analysis showed increased risks of arterial thrombosis in patients with cardiovascular risk factors [hazard ratio (HR) 4·92, 95%confidence interval (CI) 1·42–17·04], and of venous thrombosis in patients with a serum monoclonal (M)‐protein level >16 g/l at diagnosis (HR 3·08, 95%CI 1·01–9·36). No thrombosis was recorded in patients who developed multiple myeloma (n = 50) or other neoplastic diseases (n = 21). The incidence of arterial or venous thrombosis in patients with MGUS did not increase relative to that reported in the general population for similarly aged members. Finally, the risk of venous thrombosis did increase when the M‐protein concentration exceeded >16 g/l.

Efficacy of rituximab treatment in postpartum acquired haemophilia A

Acquired haemophilia A is a rare but often severe bleeding disorder caused by the development of autoantibodies directed against coagulation factor VIII (FVIII:C). An estimated incidence of 0.2–1 per million persons has been reported. This disorder may be associated with pregnancy, malignancies and autoimmune disorders; in most cases, no cause can be identified [1]. The mortality rate is very high, varying from 8% to 22%, usually because of fatal haemorrhages [2]. Postpartum FVIII inhibitors constitute 7–21% of all cases of acquired haemophilia A [1]. Although up to 36% of patients who do not receive immunosuppressive therapy experience a spontaneous remission of their auto-antibodies, this occurrence is unpredictable and patients remain at great risk of fatal bleeding as long as the antibodies persist [3]. Thus inhibitor eradication is advisable. Treatments for inhibitor eradication include immunosuppression with corticosteroids, high-dose immunoglobulin, cyclophosphamide, cyclosporine and other cytotoxic drugs. Recent reports suggest a role for rituximab, a chimeric anti-CD20 monoclonal antibody, for the treatment of patients with acquired FVIII inhibitors [3,4]. Here, we report a successful treatment with rituximab of a postpartum acquired anti-FVIII inhibitor resistant to other immunosuppressive therapies. A 25-year-old primipara woman with a previous diagnosis of postpartum acquired haemophilia A occurred 2 weeks after delivery, came to our Institution in December 2002, just 11 months after diagnosis, because not responsive to conventional prednisone treatment (initial dose 1 mg kg day) and presenting severe bleeding tendency. On admission, the activated partial thromboplastin time (APTT) ratio was 2.59; FVIII:C <1%; inhibitor titre 621 Bethesda Units (BU) mL. The antibody was directed against a single FVIII epitope (A2 domain). Lymphoproliferative disorders and other autoimmune diseases were excluded. The patient was treated with high-dose dexamethasone (40 mg day for 4 days, then tapered to a maintenance dose) and high-dose immunoglobulin (1 g kg for two consecutive days for four cycles, every 14 days) up to March 2003, without clinical improvement, but with a slight decrease in the inhibitor titre (400 BU mL). In April 2003, she began treatment with cyclophosphamide (100 mg day orally) continued for 2 months and stopped because of no response (June 2003: inhibitor titre 717 BU mL). Muscle haematomas in the arms and legs were the most frequent haemorrhagic symptoms. During these events, the patient was treated with recombinant activated FVII (rFVIIa) at a dosage of 90 lg kg every 3–4 h until resolution. Since July 2003, after dexamethasone stopping, the patient has remained on treatment with low-dose prednisone (0.25 mg kg day) for 1 year; during this period she presented mild bleeding symptoms, although the inhibitor titre was persistently high. In July 2004, a sudden abdominal shedding of blood was diagnosed. To control the severe anaemia (haemoglobin 6.5 g dL), treatment with rFVIIa, 90 lg kg every 3 h (for a total of 53 doses) was performed and four red blood cells filtered and washed units were transfused. A concomitant laparoscopy was carried out, and an haemorrhagic corpus luteum was found and intraoperatively coagulated. Recombinant FVIIa was effective to treat the event and in the prophylaxis of the minor surgery performed. Because of the above severe haemorrhagic event, in August 2004 we decided to begin an alternative therapy with rituximab at the dosage of Correspondence: Maria Gabriella Mazzucconi, MD, Department of Cellular Biotechnology and Haematology, University La Sapienza, Via Benevento 6, 00161 Rome, Italy. Tel.: +39 0 685 7951; fax: +39 064 424 1984; e-mail: mazzucconi@bce.uniroma1.it