John Apostolidis

Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Imatinib

Objective: Despite the high prevalence of headache and migraine in the general population, many people do not receive adequate medical attention and treatment. Case Summary: A 29-year-old woman was diagnosed with Bcr-abl+ acute lymphoblastic leukemia, and treatment was initiated with chemotherapy and imatinib 800 mg daily. Following imatinib initiation, a gradual decrease in serum sodium level was noticed. Prolonged aplasia and neutropenic fever prompted discontinuation of therapy for 4 weeks. Following the patients recovery, complete remission was achieved and monotherapy with imatinib 800 mg daily was restarted; however, hyponatremia recurred a few days later. The clinical findings and laboratory workup were compatible with the diagnosis of SIADH, which was attributed to high-dose imatinib. Fluid restriction and imatinib dosage reduction (to 600 mg/day) restored sodium levels. According to the Naranjo probability scale, this adverse reaction was probably associated with imatinib. Discussion: Imatinib emerged as the first tyrosine kinase inhibitor to enter everyday clinical practice for the treatment of Ph+ leukemias. Due to its molecular specificity, imatinib lacks the broad cytotoxicity of conventional chemotherapy. Inhibition of kinases in normal tissues accounts for many of imatinibs adverse reactions. To our knowledge, this is the first reported case of imatinib-induced SIADH. Conclusions: We recommend monitoring for SIADH if a patient receiving high-dose imatinib develops hyponatremia.

EBV-associated hemophagocytic syndrome†

Introduction Hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by fever, pancytopenia, organomegaly, multiorgan dysfunction, and hemophagocytosis by a large number of macrophages in bone marrow and other tissues [1]. Central to the pathophysiology is the impaired activity of NK and cytotoxic T lymphocytes resulting in uncontrolled immune activation, hypercytokinemia, and proliferation of macrophages. The diagnosis of HLH relies upon wellestablished criteria [2]. The syndrome has been described in familial conditions or as a secondary phenomenon to infections, malignancies, and collagen vascular diseases. HLH in the context of infection is best described in association with EpsteinBarr virus (EBV). EBV-associated HLH can occur either in primary infection or as a consequence of viral reactivation. EBV can also be the trigger in both familial and secondary cases. Although uncommon, hemophagocytic syndrome is a serious complication of EBV infection and can be fatal in many cases. Early recognition and prompt initiation of treatment are of great importance to reduce the high morbidity and mortality associated with this condition. The history and representative images from a case of EBV-associated hemophagocytic syndrome are described. The patient’s consent has been obtained. A 25-year-old woman was admitted with fever, pancytopenia, and hepatic dysfunction. Five weeks previously, she was diagnosed with infectious mononucleosis on the basis of pharyngitis, fever, and positive EBV antibodies. In the weeks after diagnosis, she continued to complain of intermittent fevers and sweating. Past medical and family history were unremarkable. Physical examination revealed temperature 388C, icteric sclera, and hepatosplenomegaly. Laboratory values included hemoglobin 8.1 g/dL, leucocytes 2,100 lL, neutrophils 720 lL, platelets 40,000 lL, bilirubin 7.4 mg/dL, ALT 135 U/L, LDH 1,080 U/L, triglycerides 459 mg/dL, and ferritin 6,070 ng/ mL. Peripheral blood film morphology was unremarkable. The direct and indirect antiglobulin test and screening for cold autoagglutinins gave negative results. The reticulocyte automated count and absolute value were 1.11% and 31,900 lL, respectively, indicating impaired production of red cells. Bone marrow aspiration showed numerous macrophages with striking phagocytosis of blood cells and marrow precursors (Images 1 and 2). EBV serologies indicated primary infection, and the EBV-PCR result was 18,000 copies/mL. Genetic testing for familial HLH was negative. The patient was treated with methylprednisolone and intravenous immunoglobulins and eventually recovered completely.

Is imatinib mesylate a promising drug in scleroderma due to extensive chronic graft-versus-host disease?

Clinical manifestations of extensive chronic graftversus-host disease (cGvHD), a serious and often deleterious complication following stem cell transplantation (SCT), resemble systemic sclerosis (SSc, scleroderma). The treatment of sclerodermatous cGvHD, which occurs in about 10% of allo-SCT patients, can prove difficult and futile [1]. Preliminary evidence suggests that oral imatinib mesylate (IM) may be beneficial for patients with severe and resistant to other treatments of scleroderma [2,3]. IM is a selective tyrosine kinase inhibitor interfering with both transforming growth factor-b (TGF-b) and platelet-derived growth factor (PDGF) signalling by blocking c-Abl and PDGF receptors, respectively [4–7]. These tyrosine kinases, and probably other molecular targets of IM such as c-Kit [8], are crucial for the induction of extracellular matrix proteins by profibrotic cytokines in vivo [5,6,9]. The concept behind the use of IM for fibrotic conditions is based on experimental data suggesting that TGF-b and PDGF play key roles in the overproduction of extracellular matrix. Regarding cGvHD pathogenesis, a particular role of TGF-b, which is produced from mononuclear cells late after SCT, has been proposed [10]. More interestingly, stimulatory auto-antibodies to the receptor of PDGF have been found in all tested patients with cGvHD but in none without cGvHD or healthy controls [11], further indicating a central role of these pathways in skin fibrosis. Notably, tyrosine kinase inhibitors abolished in vitro activation of skin fibroblasts mediated by these stimulatory auto-antibodies [12]. IM has an acceptable safety profile in large numbers of patients who have been treated for the approved indications. On the basis of the experimental evidence described above and our preliminary experience in patients with scleroderma [2], we decided to offer IM as in two patients with extensive cGvHD resistant to steroids and multiple treatments. IM was given as an antifibrotic treatment on a compassionate basis, after obtaining informed consent. GS, a 61-year-old male with advanced chronic lymphocytic leukemia in the context of autoimmune hemolytic anemia, underwent peripheral blood SCT from his HLA-identical brother, after lack of response in serial treatment with corticosteroids, chlorambucil, splenectomy, CHOPþrituximab and fludarabine. He was conditioned with total body irradiation (800 cGy) and fludarabine (90 mg/m). Cyclosporine (CSA) and mycophenolate mofetil (MMF) were used as GvHD prophylaxis. At 9 months post-transplant, he developed quiescent cGVHD, affecting the skin, liver, buccal mucosa

Idiopathic Plasmacytic Lymphadenopathy with Polyclonal Gammopathy in a Patient of Western Origin

To THE EDITOR: Atypical lymphoproliferative disorders (ALD) entail a variety of entities characterized by indolent lymphadenopathy, organomegaly, and occasionally systemic symptoms. They usually represent a defective immune response to unknown stimuli and can clonally evolve to malignant transformation [1,3]. Kojima and colleagues [2] in a recent report, reviewed their experience with idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hypergammaglobulinemia, a rare ALD that has been described only in patients of Far East origin [2]. IPL is similar to but distinct from multicentric Castlemans disease, an entity seen in Western countries. In this letter we present a patient of Western origin who developed generalized lymphadenopathy, with clinical manifestations, serologic findings, and histopathological features in favor of the diagnosis of IPL. To our knowledge this is the first reported case of IPL in a patient of Western origin. A 35-year-old man was admitted to this department with a 4-month history of malaise and generalized lymphadenopathy. One year earlier, he had presented with significant hepatosplenomegaly and fever. At that time he underwent a splenectomy, which was not diagnostic. His medical antecedent was unremarkable and he had never received any medication. On admission, the patient was febrile.

Treatment of early clinically staged Hodgkin's disease with a combination of ABVD chemotherapy plus limited field radiotherapy.

Abstract The current management of early stage Hodgki ns disease (HD) is usually based on clinical staging, combined modality therapy and the use of less toxic chemotherapy regimens. This approach entails high cure rates, while ensures less long term toxicity with avoidance of laparotomy. The aim of this study was to assess the efficacy of a brief course of Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) chemotherapy followed by limited field radiotherapy (RT) in favorable clinical stage (CS) I and IIA HD. Forty patients, aged 17–68 (median 34) years, with favorable CS I and IIA HD, without bulky mediastinal disease, have been treated with 4–6 (median 4) cycles of ABVD plus limited field RT. Twenty seven (67%) patients received 4 cycles of chemotherapy, while 13 received 5–6 cycles. Thirty five (87%) patients received limited field RT with dose 24–36 Gy and five (13%) received extended field with 36–46 Gy. All patients responded completely to chemotherapy. One patient experienced a relapse two months after the end of therapy. All patients are alive; 39 in continuous complete remission. With a median follow-up period of 44 months (range 18–101) the actuarial overall and progress free survival was 100 and 97% at 5 years. We did not observe any case of secondary leukemia or solid tumor. Pulmonary toxicity was mild in cases of mediastinal irradiation. Considering the short follow-up time and the small number of patients, the combination of a brief course of ABVD plus regional RT is a very efficacious treatment of favorable CS I and IIA HD with mild toxicity. However, long term survival data are needed, which could give confident answers regarding the risk of late therapy related complications, particularly second malignancies.

Erythroblastic synartesis in a patient with small lymphocytic lymphoma

A 70-year-old patient was admitted with severe hypochromic microcytic anaemia with reticulocytopenia. The blood count showed a haemoglobin level of 49 g/l (MCV 73AE8 fl, MCH 22AE8 pg), white blood cell count of 6 · 10/l (normal differential) and platelet count of 440 · 10/l. The absolute reticulocyte count was 1AE5 · 10/l. The serum ferritin, vitamin B12 and folate levels were normal. A bone marrow aspiration and trephine biopsy were performed, including cytogenetic and flow cytometry analysis. The aspirate revealed striking erythroblastic hyperplasia and dyserythropoiesis with clusters of closely linked erythroid cells. At the intercellular junction of the erythroblasts, a clear non-basophilic zone was evident (Figs). The findings were diagnostic of erythroblastic synartesis. Furthermore, there were an increased number of lymphocytes in the marrow comprising 23% of nucleated cells. The trephine biopsy and flow cytometry confirmed the presence of a CD5+, CD19+, CD23+ low grade lymphoma (small lymphocytic lymphoma) infiltrating the marrow. Cytogenetic analysis was normal. Whole body computed tomography scans demonstrated intraabdominal lymphadenopathy and serum protein electrophoresis identified a monoclonal IgGj band (1AE5 g/l). Erythroblastic synartesis was first described in 1973 by Breton-Gorius et al in a patient with an acquired dyserythropoietic anaemia who died of haemochromatosis because of long-term transfusions. In that case, electron microscopy revealed junctions between erythroblasts formed by interdigitating cell processes. The new phenomenon was named ‘erythroblastic synartesis’, from the Greek words ‘rtm’ (with) and ‘ aqsgriV’ (link). This condition is a rare form of acquired autoimmune dyserythropoiesis that leads to ineffective erythropoiesis and accompanies lymphoproliferative and autoimmune disorders. Studies indicate that a monoclonal serum immunoglobulin (IgGj in our case) directed against an adhesive receptor of the erythroblast membrane is responsible for the dyserythropoiesis. Treatment of the underlying autoimmune or lymphoproliferative disease, as experienced with our patient, leads to correction of dyserythropoiesis and restoration of a normal haemoglobin level.