Renato Fanin

Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia

Previous observational studies suggest that rituximab may be useful in the treatment of primary immune thrombocytopenia (ITP). This randomized trial investigated rituximab efficacy in previously untreated adult ITP patients with a platelet count of 20 x 10(9)/L or less. One hundred three patients were randomly assigned to receive 40 mg/d dexamethasone for 4 days with or without 375 mg/m(2) rituximab weekly for 4 weeks. Patients who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab. Sustained response (ie, platelet count > or = 50 x 10(9)/L at month 6 after treatment initiation), evaluable in 101 patients, was greater in patients treated with dexamethasone plus rituximab (n = 49) than in those treated with dexamethasone alone (n = 52; 63% vs 36%, P = .004, 95% confidence interval [95% CI], 0.079-0.455). Patients in the experimental arm showed increased incidences of grade 3 to 4 adverse events (10% vs 2%, P = .082, 95% CI, -0.010 to 0.175), but incidences of serious adverse events were similar in both arms (6% vs 2%, P = .284, 95% CI, -0.035 to 0.119). Dexamethasone plus rituximab was an effective salvage therapy in 56% of patients refractory to dexamethasone. The combination of dexamethasone and rituximab improved platelet counts compared with dexamethasone alone. Thus, combination therapy may represent an effective treatment option before splenectomy. This study is registered at http://clinicaltrials.gov as NCT00770562.

Lamivudine allows completion of chemotherapy in lymphoma patients with hepatitis B reactivation.

Reactivation of hepatitis B virus in patients receiving chemotherapy for non‐Hodgkins lymphoma (NHL) may give rise to hepatitis, hepatic failure and death, and prevent further chemotherapy. We report four patients with NHL in whom hepatitis flare‐up was observed after two (three patients) and six (one patient) cycles of chemotherapy. After spontaneous recovery, they were treated with Lamivudine (100u2003mg/day), which enabled completion of chemotherapy without further hepatitis B reactivation. In one patient, high‐dose chemotherapy and autologous stem cell transplantation was also performed. These data suggest a possible role for Lamivudine in preventing hepatitis B reactivation during chemotherapy administration to chronic carriers of the hepatitis B virus. Moreover, it enabled the completion of both standard and high‐dose chemotherapy in patients with previous hepatitis B reactivation.

Haematopoietic stem cell transplantation (HSCT) in a patient with Sjögren's syndrome and lung malt lymphoma cured lymphoma not the autoimmune disease

Haematopoietic stem cell transplantation (HSCT) has been used in an attempt to control autoimmune diseases that respond poorly to conventional treatment, or as a way of readjusting the immunological balance.1 As far as we know, only one case of primary Sjogrens (SS) has been reported,2 with an unfavourable outcome. Another patient received an allogeneic bone marrow transplant and also had an unfavourable outcome.3 We describe here a further patient with primary SS who underwent HSCT for a non-Hodgkins lymphoma affecting the lung (large cell, mucosa associated lymphoid tissue (MALT) lymphoma) and review the literature on the effects of HSCT on the autoimmune features and histopathological changes in primary SS.nn### Case reportnnA white woman, aged 42, developed recurrent parotid swelling and symptomatic sicca syndrome, with a Schirmers test I of 5 mm in the right eye and 4 mm in the left eye. Break up time was 6 s and sialometry was <1 ml.nnShe had periodic relapses of her parotid swelling. In August 1994 (aged 57) lung x rays …

mdr-1 GENE AMPLIFICATION IN ACUTE LYMPHOBLASTIC LEUKAEMIA PRIOR TO ANTILEUKAEMIC TREATMENT

Rovira. M.. Cervantes, F., Nomdeden. B. & Roman, C. (1990) Chronic neutrophilic leukaemia preceeding for seven years the development of multiple myeloma. Acta Haematologica. 83,94-95. Saglio, G.. Guerrasio. A.. Ross, C.. Zaccaria, A.. Tassinari, A.. Serra. A,. Rege-Cambrin. G.. Mama, U. & Gavosto. F. (1990) New type of kr/Abl junction in Philadelphia chromosome-positive chronic myelogenous leukemia. Blood. 76, 1819-1824. log.tj. 31, 300-301. Saglio, G., Ponzetto, C., Guerrasio. A.. Tassinari, A.. Zaccaria. A.. Testoni. P., Celso, B.. Rege Cambrin. G.. Serra. A.. Pegoraro. L.. Avanzi, G.C.. Attadia, V., Falda. M.. & Gavosto. F. (1988) Variability of the molecular defects corresponding to the presence of the Philadelphia chromosome in human hematologic malignancies. Blood. 72, 1203-1208. Yunis. 1.1. (1981)Newchromosome techniquein thestudy ofhuman neoplasia. Human Pathology. 12, 530-549.

Profiling of drug-metabolizing enzymes/transporters in CD33+ acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine, Cytarabine and Idarubicin

Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-Ozogamicin (GO) with Fludarabine–Cytarabine–Idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P=0.0006; OR=5.35, P=0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P=0.001; OR=0.09, P=0.003) and one on SLCO1B1 (OR=4.68, P=0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P=0.0009; OR=2.75, P=0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO–FLAI regimen.

Prognostic significance of the detection of tumour cells in peripheral blood stem cell collections in stage II and III breast cancer patients treated with high-dose therapy.

Summary:The purpose of this study was to evaluate the incidence and extent of tumour cell contamination in bone marrow specimens and stem cell collections from 34 breast cancer patients undergoing high-dose therapy as adjuvant treatment, and to determine the prognostic significance for the clinical outcome. Tumour cell contamination was evaluated by flow cytometry using a double-colour test and an anti- Pan cytokeratin (CK) antibody. Two out of 34 (6%) baseline bone marrow specimens, none of seven marrow harvests and nine out of 32 aphereses (28%) mobilised from seven out of 27 patients (26%) contained CK+ cells. Tumour contamination was more frequent in patients with 10 or more involved lymph nodes and in those who received a shorter course of adjuvant chemotherapy before mobilisation. At a median follow-up of 43 months, 24 patients are in complete remission, whereas 10 patients experienced recurrence. Out of the 10 patients who relapsed, five (50%) had CK+ peripheral blood stem cell (PBSC) collections, whereas disease recurrence was seen in only two out of 24 (8%) patients who received CK− products (P=0.02). Moreover, CK+ PBSC collections were associated with a significantly shorter event-free survival and overall survival. CK+ collection is an unfavourable prognostic factor for patients treated with high-dose therapy. Whether the negative impact on clinical outcome depends on reinfusion of tumour cells or whether it simply indicates a larger disease extension is still unclear.

Purging of chronic myelogenous leukemia cells by retrovirally expressed anti-bcr-abl ribozymes with specific cellular compartmentalization.

In patients with chronic myelogenous leukemia (CML), abnormal expansion of myeloid cells is maintained by expression of the p210bcr-abl fusion protein. Thus, this protein and its mRNA represent primary targets to inhibit proliferation of these cells. Here we describe the properties of a ribozyme against the bcr-abl mRNA, expressed as a fusion transcript with the human U1 small nuclear RNA or the adenovirus VA1 RNA and delivered to the cells through retroviral vectors. These fusion ribozymes are specifically localized in the nucleus or in the cytoplasm, respectively. Transduction of 32D-LG7 myeloid cells, whose growth is IL-3 independent thanks to deregulated bcr-abl expression, imposed strong negative selective pressure on cell growth and induced restoration of an IL-3–dependent phenotype. Although expressed at a level similar to that of the U1-fusion ribozyme, the cytoplasmic VA1 ribozyme was a more powerful inhibitor of p210bcr-abl gene expression. In cells transduced with the vector expressing this ribozyme, the levels of the bcr-abl transcript were reduced up to 104-fold, the p210bcr-abl protein became undetectable, and the cells underwent massive apoptosis when cultured in the absence of IL-3. Transduction of primary hematopoietic cells obtained from bone marrow of patients with CML resulted in remarkable reduction of bcr-abl mRNA levels, starting a few days after transduction. These results show the feasibility and efficacy of vector-expressed anti–bcr-abl ribozymes for purging of CML cells.

Autologous bone marrow transplantation in non-Hodgkin's lymphoma patients: effect of a brief course of G-CSF on harvest and recovery.

This study compares harvest and hematological recovery data of 100 lymphoma patients who underwent BM harvest either after a short course of G-CSF (16u2009μg/kg for 3 days) (nu2009=u200957) or in steady-state conditions (nu2009=u200943). G-CSF allowed the attainment of a significantly higher median number of total nucleated cellsu2009×u2009108/kg (4.4, range 1.4–17, vs 2.1, range 0.6–4.2; Pu2009<u20090.0001), mononuclear cellsu2009×u2009108/kg (0.55, range 0.20–1.4, vs 0.41, range 0.15–0.76, Pu2009<u20090.0001) and cfu-gm/ml (310, range 10–5500, vs 80, range 10–3800, Pu2009=u20090.008), with lower volumes of blood collected (17.5u2009ml/kg, range 8–31 vs 21.0, range 15–30, Pu2009=u20090.0001). Hematological recovery was faster in patients who received pre-treated BM (median time to PMN >0.5u2009×u2009109/l and to platelets >20u2009×u2009109/l was 12, range 10–14, and 13, range 10–18, days, respectively) than in those autotransplanted with steady-state BM (median time to PMN >0.5u2009×u2009109/l and to platelets >20u2009×u2009109/l 13, range 10–18 and 14, range 10–20 days, respectively, Pu2009=u20090.004 and Pu2009=u20090.01). Transfusional requirement was significantly different and patients of the G-CSF group needed shorter hospitalization (17 days, range 12–24, vs 20 days, range 14–32; Pu2009=u20090.02). These data suggest that treating patients with G-CSF before BM harvest improves the quality of the harvest and accelerates engraftment and hematological recovery.

Paraneoplastic cerebellar degeneration associated with anti-neuronal anti-Tr antibodies in a patient with Hodgkin's disease

Paraneoplastic syndromes often occur during the course of the underlying disease, but sometimes may be the first sign of an occult cancer. Several paraneoplastic neurologic syndromes have been linked to the production of antibodies against a neuronal antigen, including Lambert – Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration (PCD), paraneoplastic sensory neuropathy, opsoclonusmyoclonus, autonomic dysfuction, paraneoplastic encephalomyelitis, dermatomyositis, limbic encephalopathy and subacute motor neuropathy. PCD is a paraneoplastic disorder of the central nervous system (CNS) in which cerebellar dysfunction is associated with identifiable or occult cancer without direct involvement of the CNS by the neoplasm. Patients with PCD present with a subacute cerebellar syndrome progressive over weeks to months, characterized by truncal and appendicular progressive ataxia, vertigo, dysarthria and nystagmus. PCD can complicate ovarian, breast and lung cancer or Hodgkin’s lymphoma (Hodgkin’s disease; HD) [1 – 4]. Histologically, this severe paraneoplastic dysfunction is characterized by a cerebellar atrophy, with an extensive loss of Purkinje cells, sometimes with a decreased number of granular cells and sometimes with meningeal and deep cerebellar nuclear inflammatory infiltrates [1,5]. Immunologic studies show that PCD is probably caused by an immune response against a tumoral antigen that cross-reacts with cerebellar epitopes, and the first evidence that PCD might be an autoimmune disease was reported in 1976 by Trotter et al. [6]. Several auto-antibodies have been described, but the most common, first called anti-Purkinje cell antibody, is directed against a 34-kDa protein [7]. Graus et al. [7] have recently identifed a new anti-neural antibody, anti-Tr, that appears to be specific for HDassociated PCD; this antibody has a characteristic dotted staining pattern, suggestive of immunoreactivity for cytoplasm and dendrites of Purkinje cells [7,8]. We report the case of a patient who developed a severe cerebellar disfunction, before relapse of HD, with evidence of anti-Tr antibodies in the serum and cerebrospinal fluid (CSF). In September 1995 a 17-year-old woman was diagnosed with nodular sclerosis HD stages II A by biopsy of supraclavicular lymph node. The patient was treated with mantle irradiation (36 Gy) and a boost of 45 Gy to the supraclavicular and mediastinal lymph nodes. In February 1996, a total body computed tomography (CT) scan showed complete remission of HD. At the end of August 1996, she suddenly presented with vertigo, nausea, and dysarthria. On neurologic examination, she was found to have a left cerebellar syndrome with horizontal nystagmus, severe dysarthria, dysmethria and ataxia; there were no pyramidal signs. Sensation and cranial nerve functions were normal. Three days after the onset of symptoms she developed a complete cerebellar syndrome and, 1 week later, she presented with hyper-reflexia in the four limbs. Physical examination showed no peripheral lymphadenopathy nor hepatosplenomegaly; all

The Role of Rituximab in the Therapy of Mixed Cryoglobulinemia

The chimeric monoclonal antibody (IgG1/κ) rituximab (RTX) is directed against the CD20 antigen, expressed on the surface of normal (from pre-B to mature B lymphocytes) and malignant B lymphocytes. Since mixed cryoglobulinemia is sustained by a low-grade B lymphoproliferation exhibiting autoimmune features, there is a strong rationale for using RTX in the treatment of this disorder. Almost all clinical manifestations of mixed cryoglobulinemia may benefit from RTX treatment, and the antibody is generally well tolerated and safe. Caution should be exerted in patients with high cryoglobulin levels or hyperviscosity at baseline, because of possible flare syndrome. Although RTX can lead to an increase of HCV viremia, hepatitis re-activation is rarely observed. Prospective comparative trials are warranted in order to better evaluate the therapeutic impact of RTX and to define the best treatment approach.