P. Usardi

Autologous haematopoietic stem cell transplantation without CD34 + cell selection in refractory Crohn’s disease

Objectives: Autologous haematopoietic stem cell transplantation (HSCT) with CD34+ cell selection has recently been used in the treatment of refractory Crohn’s disease, showing good safety and promising efficacy. We investigated the safety and efficacy of HSCT with unselected peripheral blood stem cells (PBSCs) in moderate–severe refractory Crohn’s disease. Patients: Four patients (three male, one female; age range 26–45 years) with active moderate–severe Crohn’s disease (median Crohn’s Disease Activity Index (CDAI) 319, range 272–345), refractory or intolerant to multiple drugs including infliximab, were enrolled. Interventions: Unselected PBSCs were collected after mobilisation with cyclophosphamide (CTX) 1.5 g/m2 and granulocyte-colony stimulating factor (G-CSF) 10 μg/kg. The conditioning regimen included CTX 50 mg/kg on days −5 to −2 and rabbit anti-thymocyte globulin (ATG) 2.5 mg/kg on days −4 to −2. Main outcome measures: Primary endpoints were toxicity and clinical remission (CDAI<150) at 3 months. Secondary endpoints were clinical and endoscopic response at 3 months and toxicity, clinical and endoscopic remission at 12 months. Results: No improvement or slight deterioration was observed following mobilisation (median CDAI 339, range 258–404). At the third month, the primary endpoint of clinical remission was achieved in all patients, with a median CDAI of 91 (range 56–102), and complete endoscopic remission was achieved in 2/3 patients. After a median follow-up of 16.5 months, 3/4 patients maintained both clinical and endoscopic remission, despite withdrawal of all drugs, and complete fistula closure was observed in all affected patients. No deaths or life-threatening infection occurred. Unexpected adverse events included a perianal abscess after mobilisation in one patient, pleural and pericardial effusions in another and BK virus-related macrohaematuria in another, all rapidly resolved with conservative treatment. Conclusion: Autologous HSCT with unselected PBSC appears to be safe and can induce and maintain remission in previously refractory Crohn’s disease patients.

Prevalence of metabolic syndrome in long-term survivors of hematopoietic stem cell transplantation

Our purpose was to determine the prevalence and features of metabolic syndrome (MS) in a series of long-term hematopoietic stem cell transplantation (HSCT) survivors. We assessed the clinical, metabolic and endocrinological data, and plasma TNF, leptin, resistin and adiponectin levels relating to 85 HSCT recipients. MS was diagnosed on the basis of the National Cholesterol Education Program-Adult Treatment Panel III criteria. Its prevalence was compared with that observed in an Italian population, and its relationship with the clinical and laboratory parameters was assessed univariately and multivariately. Twenty-nine HSCT recipients had MS instead of the 12.8 expected (P<0.0001), with hypertriglyceridemia being the most common feature. Univariate analysis indicated that high insulin and leptin levels, low-adiponectin levels and hypogonadism were significantly related to a diagnosis of MS; multivariate analysis indicated plasma leptin, insulin resistance, age and hypogonadism. We conclude that HSCT recipients are at increased risk of a form of MS that has particular clinical features. Plasma leptin levels are independently related to MS, thus suggesting that leptin resistance may play a role as a pathogenetic clue, as in other conditions in which MS occurs as a secondary phenomenon. MS deserves consideration as a life-threatening complication in patients who are probably cured of their underlying disease.

Second malignancies in essential thrombocythemia (ET): a retrospective analysis of 331 patients with long-term follow-up from a single institution

Abstract Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by an indolent clinical course, with a median survival exceeding 20 years. A minority of patients undergo thrombohemorrhagic complications, which might be prevented by cytoreductive treatment in high risk categories. Alkylating agents (ALK) have been demonstrated to increase the risk of acute leukemia and myelodysplastic syndromes in patients with myeloproliferative disorders, whereas the potential oncogenicity of hydroxyurea (HU) remains a matter of debate. In this study, we retrospectively investigated long-term development of hematological and non-hematological second malignancies in 331 patients with ET, analyzing possible associations with chemotherapy treatments. Median follow-up was 108 months. Of the 194 patients who were treated with chemotherapy, 116 (60%) received only HU, 38 (19·5%) only ALK (busulfan or melphalan) and 40 (20·5%) ALK followed by HU. After a median time of 87 months from the diagnosis of ET, 43 patients developed a second malignancy, hematological in 15 and non-hematological in 28, for an overall cumulative incidence of 13%. According to the type of treatment, second malignancies were documented in 11·2% of patients treated with only HU, in 26·3% of patients who received only ALK, and in 25% of those treated with ALK followed by HU. Ten cases (7·3%) were recorded among the 137 patients who did not receive any treatment. Our analysis revealed a significant association between treatment with alkylating agents and an increased risk of developing second hematological malignancies, whereas no such association was detected with regard to treatment with hydroxyurea single agent in our ET population. In addition, different treatment strategies did not affect the risk of developing second solid cancers.

Caspofungin treatment of Pneumocystis pneumonia during conditioning for bone marrow transplantation

Pneumocystis pneumonia (PCP) is a well-known compli-cation in AIDS patients, but it is also frequently diagnosedin hemato-oncological patients [1]. High-dose cotrimoxa-zole is the first-line treatment for PCP, but some patientsshow contraindications and drug resistance may appear[2]. Since Pneumocystis jirovecii cannot be cultivated invitro, mutations in the genes involved in folate metabo-lism have been investigated as a possible expression ofcotrimoxazole resistance [3], but the search for a clinicalcorrelate has so far led to equivocal results [4]. There issome doubt as to what may be the best alternative tocotrimoxazole in the treatment of PCP [5]. The presentreport refers to the use of caspofungin to treat a patientwith PCP undergoing bone marrow transplantation (BMT)in whom cotrimoxazole had to be discontinued because ofits myelotoxicity.A 45-year-old male patient with T-lymphoblastic leu-kemia in second complete remission was scheduled to re-ceive an allogeneic BMT from an unrelated HLA-matcheddonor in October 2004. In September, he was admitted tohospital because of acute respiratory failure. Subsequentexamination of bronchoalveolar lavage (BAL) led to thediagnosis of PCP, and a computed tomography (CT) scanshowed diffuse, bilateral, interstitial disease with “groundglass”parenchymaandthickeningoftheinterlobularsepta.Molecular, cultural and cytological investigations of theBAL failed to identify any other pathogen. Transbronchialbiopsy was not performed. High-dose cotrimoxazole wasstarted in combination with methylprednisolone. A bonemarrow aspirate revealed signs of an initial leukemic re-lapse that was treated with weekly vincristine and dailyoral 6-mercaptopurine, which led to a stable bone marrowblast count and the maintenance of normal peripheralhematometry.During cotrimoxazole treatment, the CT findings im-proved significantly but did not normalize, and the drugwas discontinued after 2 weeks because of patient refusal.On 7 October, the patient was discharged for personalreasons, and he continued taking oral cotrimoxazole at adaily dose of 3,840 mg. Two weeks later, a further CTscanshowed persistence of significant lung infiltrates.On 11 November, when the patient was admitted toundergoBMT,apositronemission tomography(PET)scanrevealed the presence of diffuse, active, alveolar disease(Fig. 1) and high-dose intravenous cotrimoxazole wasresumed. On 22 November, standard-dose caspofungin(70mgonthefirstday,followedby50mg/day)wasadded,and a conditioning regimen was started including thio-tepa (15 mg/kg divided into three equal doses on days −8and−7),andcyclophosphamide(50mg/kg/dayondays−4,−3 and −2). A bone marrow aspirate showed a raised butstable blast count. On 29 November, the CT findings wereunchanged, and cotrimoxazole was discontinued. On 30November, BMT was performed, with standard-dose cy-closporine-Aandmethotrexatebeingadministeredasgraft-versus-host disease prophylaxis. During pancytopenia,mixed Enterobacter/coagulase-negative Staphylococcusbacteremia was observed. Polymorphonuclear recoverywasachievedonpost-BMTday25,andplateletrecoveryonday 34, after being delayed by mild microangiopathichemolytic anemia responsive to defibrotide therapy. On22 December, a CT scan showed complete resolution ofthe lung infiltrates. On 5 January, caspofungin was dis-continued and a bone marrow aspirate showed completeremission and full donor chimerism. On 12 January thepatient was discharged. One month later, the leukemiarelapsed; a CTscan did not show any lung infiltrates.A diagnosis of PCP is frequently established in BMTrecipients,inwhomimmunodepressionmayplayaprimaryrole, and also in hematological patients receiving che-motherapy alone [1]. In such cases, cotrimoxazole mayinterfere with the possibility of delivering the subsequent

Retrospective evaluation of amphotericin B deoxycholate toxicity in a single centre series of haematopoietic stem cell transplantation recipients

events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther 2005; 10: 489–98. 4. Isentress SPC (date of revision September 2008). electronic Medicines Compendium (eMC). http://emc.medicines.org.uk (13 October 2008, date last accessed). 5. Moreno A, Barcena R, Quereda C et al. Safe use of raltegravir and sirolimus in an HIV-infected patient with renal impairment after orthotopic liver transplantation. AIDS 2008; 22: 547–8.