Giuseppina Calvaruso

Hepatitis B virus reactivation and alemtuzumab therapy

Abstract:  Reactivation of hepatitis B virus infection in subjects receiving cytotoxic treatment for heamatological malignancies occurs in 21–53% of chronic HBsAg carriers and in an unknown number of HBsAg negative subjects harbouring occult HBV infection. Immunotherapy with alemtuzumab, a humanized monoclonal antibody against CD52 epitopes on lymphocytes cells produces deep immunosuppression. We describe two subjects with chronic lymphocytic leukaemia and occult HBV infection who developed a virological and biochemical flare of hepatitis B following immunotherapy with alemtuzumab. One of them developed full blown hepatitis with seroreversion from anti‐HBs to HBsAg after four weeks of alemtuzumab therapy. Lamivudine (100 mg die) achieved a complete clinical recovery and HBV‐DNA clearance from blood within 8 weeks. The second patient (HBsAg and HBV‐DNA seronegative, anti‐HBs and anti‐HBc positive before treatment) was kept under prophylaxis with lamivudine up to three months after alemtuzumab. Two months after withdrawal of lamivudine, clinical and laboratory features of acute hepatitis B developed. Lamivudine therapy was restarted and a prompt recovery was obtained with HBsAg and HBV‐DNA clearance.

Deoxycoformycin (pentostatin) in the treatment of splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes

Abstract:  Background: Splenic marginal zone lymphoma (SMZL) is an infrequent B‐cell neoplasm that pursues an indolent course. Signs and symptoms, mostly related to hypersplenism, are successfully managed by splenectomy. However, the therapy of patients who are not fit for a surgical procedure or who relapse after splenectomy, is still an unsettled issue. Patients and methods: We report a phase‐II study on 16 patients with SMZL, three therapy naïve and 13 pretreated, all showing systemic symptoms or progressive worsening of peripheral cytopenia, who were treated with pentostatin at a dose of 4 mg/m2 every other week for 6–10 wk. In relapsed patients, the median interval between diagnosis and treatment was 26 month (range: 8–49). Results: Overall, 68% of the patients showed a clinical response. Two out three patients, who received pentostatin as first line therapy, attained a complete response (CR). One CR and seven minor or good haematological responses were recorded in relapsed patients. Treatment toxicity, mostly haematological, proved manageable. With a median follow‐up of 35 month the median overall survival (OS) is 40 month and the median progression free survival (PFS) is 18 month. Conclusion: Our data show that pentostatin administered every other week has a good degree of activity in the treatment of SMZL and suggest that this schedule could be considered a possible therapeutic option for patients who are not fit for splenectomy or have relapsed.

Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients.

A multicenter randomized open-label long-term sequential deferiprone–deferoxamine (DFP-DFO) versus DFP alone trial (sequential DFP-DFO) performed in patients with thalassemia major (TM) was retrospectively reanalyzed to assess the variation in the left ventricular ejection fraction (LVEF) [1].

Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial

In patients with thalassemia intermedia (TI), such as beta‐TI, alpha‐thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta‐thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5‐year long‐term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P‐value = 0.035). The overall period of observation was 235.2 person‐years for the deferiprone patients compared with 214.3 person‐years for the deferoxamine patients. The results of the log‐rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P‐value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long‐term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated. Am. J. Hematol. 90:634–638, 2015.

Long-term treatment with deferiprone enhances left ventricular ejection function when compared to deferoxamine in patients with thalassemia major.

Transfusion and iron chelation treatment have significantly reduced morbidity and improved survival of patients with thalassemia major. However, cardiac disease continues to be the most common cause of death. We report the left-ventricular ejection fraction, determined by echocardiography, in one hundred sixty-eight patients with thalassemia major followed for at least 5years who received continuous monotherapy with deferoxamine (N=108) or deferiprone (N=60). The statistical analysis, using the generalized estimating equations model, indicated that the group treated with deferiprone had a significantly better left-ventricular ejection fraction than did those treated with deferoxamine (coefficient 0.97; 95% CI 0.37; 1.6, p=0.002). The heart may be particularly sensitive to iron-induced mitochondrial damage because of the large number of mitochondria and its low level of antioxidants. Deferiprone, because of its lower molecular weight, might cross into heart mitochondria more efficiently, improving their activity and, thereby, myocardial cell function. Our findings indicate that the long-term administration of deferiprone significantly enhances left-ventricular function over time in comparison with deferoxamine treatment. However, because of limitations related to the design of this study, these findings should be confirmed in a prospective, randomized clinical trial.

Assessment of the frequency of additional cancers in patients with splenic marginal zone lymphoma

Abstract:  Objectives: Solid second primary cancers (SPC) have become an issue of extensive research. The purpose of the present study was to estimate the standardised incidence ratio (SIR) and the absolute excess risk (AER) of SPC in patients with splenic marginal zone lymphoma (SMZL).Methods: We investigated the incidence of additional cancers in 129 patients consecutively diagnosed with SMZL in three Italian haematological centres, asking the cooperating doctors for additional information on initial and subsequent therapies and on the onset and type of second cancers.Results: Twelve SPC were recorded (9.3%); the 3‐ and 5‐yr cumulative incidence rates were 5.5% and 18.3% respectively, with an SIR of 2.03 [95% confidence interval (CI): 1.05–3.56; P < 0.05; AER = 145.81]. Of 12 SPC observed, four were urinary tract neoplasms (SIR, 3.70; 95% CI: 1.01–9.48; P < 0.05; AER = 70.06), four were lung cancers (SIR, 9.16; 95% CI: 1.41–13.25; P < 0.05; AER = 85.50) and the other four were hepatic carcinoma, endometrial cancer, breast cancer and colorectal cancer. Conclusions: Our findings evidence a high frequency of additional cancers in patients with SMZL and suggest that the incidence rate of SPC is significantly different from that expected in the general population. The frequency of cases with urinary tract and lung malignancies in our series is higher than expected. Although confirmatory data are needed, it is our opinion that SMZL patients are at risk of second cancer and should be carefully investigated on diagnosis and monitored during the follow‐up.

Cerebrovascular events in sickle cell-beta thalassemia treated with hydroxyurea: A single center prospective survey in adult Italians

Stroke is a common cause of morbidity and mortality in sickle cell disease (SCD) and silent cerebral infarction is the most common form of neurologic injury. The frequency and risk factors for new silent cerebral infarction are incompletely understood. Moreover, no recommended treatment has been established. Although hydroxyurea (HU) is recommended for SCD, concerns remain regarding its role in the prevention of cerebrovascular events, including silent cerebral infarction. A single center population of 104 Italian patients with HbS‐ß thalassemia treated with HU has been followed for a mean of 11 years. Clinical evaluation and brain imaging by Magnetic Resonance Imaging were done before and during HU treatment. During follow‐up, the number of sickle cell crises (86%, 7.8 ± 6.9 vs. 1.2 ± 0.5 per year, P < 0.0001), hospitalizations (2.5 ± 2.9 vs. 0.3 ± 1.5 per year, P < 0.0001), and days in the hospital (22.4 ± 21.9 vs. 0.3±1.5 per year, P < 0.0001) decreased significantly and HbF increased from a mean of 8–20.8%. Cerebral infarcts occurred in 37.5% of patients. Among these, 6.7% had overt strokes, while 30% had new or progressive silent cerebral infarction. Stroke and silent cerebral infarction were not related to clinical hematologic or HbF response to HU. These findings suggest that in adults, HU treatment does not prevent new cerebrovascular events or the progression of existent silent cerebral infarcts in HbS‐β thalassemia. A major benefit of HU is the increase in HbF; the association of high HbF and reduced cerebrovascular disease has been weak. New treatment strategies should be developed for the prevention of sickle cerebrovascular disease. Am. J. Heamtol. 88:E261–E264, 2013.

Successful treatment of steroid resistant autoimmune thrombocytopenia associated with chronic lymphocytic leukemia with alemtuzumab.

To the Editor: Chronic lymphocytic leukemia (CLL) is frequently complicated by immune-mediated disorders (IMD) mainly directed against blood and bone marrow cells (1). IMDs are generally herald of active disease but can also represent the main clinical problem in CLL patients with low tumor burden (2). Alemtuzumab is a genetically engineered, humanized anti-CD52 monoclonal antibody. It may cause cell death by complement activation, antibody-dependent cellular cytotoxicity and apoptosis resulting in a profound and prolonged Tand B-lymphocyte depletion (3). Alemtuzumab has been demonstrated to be an effective therapy for patients with advanced CLL (4).Moreover, it was also shown to induce remission in patients with severe autoimmune cytopenias (5). In this paper we report a case of steroid-resistant autoimmune thrombocytopenia (AITP) in a patient with low tumor burden CLL successfully treated with alemtuzumab. A 53-yr-old woman was admitted to our department with diffuse purpura, leg bruises, and lymphocytosis. Physical examination showed nothing unusual except for the purpura and bruises. An abdominal echography documented a normal appearance of the liver and spleen. Complete blood cell count was as follows: Hb 13.4 g/dL, WBC 13.3 · 0/L, neutrophil 1.3 · 10/L, lymphocyte 10.7 · 10/L, and platelet (Plt) 22 · 10/L. Peripheral blood flow cytometry analysis showed a monoclonal B-cell population CD19+, CD5+, Sig CD20+, CD23+. Trephine biopsy revealed a normocellular marrow with 30% interstitial and nodular infiltration of small mature lymphocytes and a marked increase of megakaryocytes. Plt associated antibodies were also detected and the diagnosis of CLL associated with AITP was made. The patient was treated with oral prednisone 1 mg/kg/daily for 2 months without obtaining any improvement of the Plt count. At this time Alemtuzumab was started on a dose-escalating regimen of 3 mg s.c. on day 1, 10 mg s.c. on day 3, 30 mg s.c. on day 5, and then 30 mg s.c. three times a week for 11 weeks. Treatment produced a rapid clearance of neoplastic cells from the blood and bone marrow as well. Indeed, after 5 wks of therapy the trephine biopsy showed a normocellular bone marrow without any signs of residual disease. Platelet count, starting after the second week of therapy, steadily went up to reach a normal level after 12 wk. One year after the end of the therapy, both CLL and AITP are still in CR. Although the efficacy of antibody-mediated hematological disorders treatment with monoclonal antibodies is well known (6–8), this case report represents only the second published case of AITP successfully treated with Alemtuzumab (9). Another possible case, dealing with refractory CLL with massive bone marrow infiltration and severe anemia and thrombocytopenia has been recently reported (10). It has been suggested that the response to treatment of CLL-related IMDs relies on the clearance of the neoplastic clone that restore the perturbed cross-talk among B and T cell in the spleen (11). In this scenario alemtuzumab that target both B and T cells emerges as a well-fitted therapeutic option. This case report suggests that Alemtuzumab may be a good alternative for the treatment of CLLrelated IMDs not responding to conventional therapy, and encourages further clinical investigations. Eur J Haematol 2004: 73: 225–226 Printed in UK. All rights reserved Copyright Blackwell Munksgaard 2004

Response-guided ABVD chemotherapy plus involved-field radiation therapy for intermediate-stage Hodgkin lymphoma in the pre-positron emission tomography era: a Gruppo Italiano Studio Linfomi (GISL) prospective trial.

PURPOSE In the pre-positron emission tomography era, the Gruppo Italiano Studio Linfomi (GISL) investigated the feasibility and efficacy of a treatment based on a response-tailored number of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) courses in 218 intermediate-stage Hodgkin lymphoma patients. PATIENTS AND METHODS Patients with stage I/II showing at least one adverse prognostic factor and stage IIIA without adverse prognostic factors were recruited. Treatment included a first step of 3 ABVD courses, followed by an early-restaging. Patients in CR/CRu received 1 additional ABVD cycle, patients in PR received 3 more ABVD, and nonresponder patients went off study. Involved-field radiation therapy (RT) was recommended on chemotherapy completion. RESULTS The median age was 30 years (range, 15-68 years) and 131 patients (61%) were female. Seven percent of patients were in stage I, 78% in stage II, and 15% in stage III; B-symptoms, bulky tumor and erythrocyte sedimentation rate > 30 were recorded in 20%, 26%, and 43% of cases, respectively. The CR/CRu rate was 62% at early restaging, 72% at the end of chemotherapy, and 95% following RT. With a median follow-up of 74 months (range, 6-193 months), 7-year overall survival, relapse-free survival, and freedom from treatment failure were 91.8% (95% CI, 86%-95.5%), 89.2% (95% CI, 82.8%-93.3%), and 81.8% (95% CI, 75.2%-86.7%), respectively. Patients in CR/CRu on early restaging, receiving 4 ABVD, had an excellent outcome with 7-year RFS and cause-specific survival similar to those of the late responders treated with 6 ABVD (RFS, 87.5% vs. 90.5% and CSS, 96.6% vs. 92.7%, respectively). CONCLUSION The response-guided ABVD program we report, based on standard clinical staging procedures, proved to be feasible and safe in patients with intermediate-stage Hodgkin lymphoma.

The era of comparable life expectancy between thalassaemia major and intermedia: Is it time to revisit the major-intermedia dichotomy?

In the last few decades, the life expectancy of regularly transfused β‐thalassaemia major (TM) patients has dramatically improved following the introduction of safe transfusion practices, iron chelation therapy, aggressive treatment of infections and improved management of cardiac complications. How such changes, especially those attributed to the introduction of iron chelation therapy, improved the survival of TM patients to approach those with β‐thalassaemia intermedia (TI) remains unknown. Three hundred and seventy‐nine patients with TM (n = 284, dead 40) and TI (n = 95, dead 13) were followed retrospectively since birth until 30 June 2015 or death. Kaplan‐Meir curves showed statistically significant differences in TM and TI survival (P < 0·0001) before the introduction of iron chelation in 1965, which were no longer apparent after that date (P = 0·086), reducing the Hazard Ratio of death in TM compared to TI from 6·8 [95% confidence interval (CI) 2·6–17·5] before 1965 to 2·8 (95% CI 0·8–9·2). These findings suggest that, in the era of iron chelation therapy and improved survival for TM, the major‐intermedia dichotomy needs to be revisited alongside future directions in general management and prevention for both conditions.