F L Dulley

Low mortality rates related to respiratory virus infections after bone marrow transplantation.

Summary:Respiratory viruses (RVs) frequently cause severe respiratory disease in bone marrrow transplant (BMT) recipients. To evaluate the frequency of RV, nasal washes were collected year-round from BMT recipients with symptoms of upper respiratory tract infection (URI). Direct immunofluorescence assay was performed for respiratory syncytial virus (RSV), influenza (Flu) A and B, adenovirus and parainfluenza (Paraflu) virus. Patients with RSV pneumonia or with upper RSV infection, but considered at high risk for developing RSV pneumonia received aerosolized ribavirin. Oseltamivir was given to patients with influenza. A total of 179 patients had 392 episodes of URI. In all, 68 (38%) tested positive: RSV was detected in 18 patients (26.4%), Flu B in 17 (25%), Flu A in 11 (16.2%) and Paraflu in 7 (10.3%). A total of 14 patients (20.6%) had multiple RV infections or coinfection. RSV pneumonia developed in 55.5% of the patients with RSV-URI. One of the 15 patients (6.6%) with RSV pneumonia died. Influenza pneumonia was diagnosed in three patients (7.3%). RSV and influenza infections peaked in fall–winter and winter–spring months, respectively. We observed decreased rates of influenza and parainfluenza pneumonia and low mortality because of RSV pneumonia. The role of antiviral interventions such as aerosolized ribavirin and new neuraminidase inhibitors remains to be defined in randomized trials.

Use of Oseltamivir to control influenza complications after bone marrow transplantation

Summary:Influenza infection can be severe in bone marrow transplant (BMT) recipients. Although yearly epidemics occur worldwide, and a higher risk of complication is expected in these patients, few studies have addressed the impact of the new neuraminidase inhibitors in the prognosis of influenza after BMT. Influenza A or B infections were found in 39 of the 66 patients (59%) showing a positive nasal wash by DFA. Influenza A was diagnosed in 18 patients and influenza B in 23 patients; two patients were infected by influenza A and B with 84- and 90-day intervals between episodes, respectively. Of the 41 episodes (61%) of influenza A or B, 25 infections occurred during the spring and summer months. Oseltamivir was introduced within 48u2009h of symptoms appearing. Only two patients (5.1%) developed influenza pneumonia, and no patient died of influenza. A total of 22 patients (56.4%) acquired influenza before day +180 when preventive vaccination strategies are precluded owing to poor immunogenicity of the vaccine during this period. Oseltamivir proved to be safe and appears to have played an important role in the outcome of influenza infection in this population. The therapeutic and/or prophylactic benefits of Oseltamivir in BMT recipients remain to be demonstrated in randomized, prospective trials.

The benefit of influenza vaccination after bone marrow transplantation

Summary:Influenza vaccine is recommended yearly for recipients after the sixth month of BMT. Although a higher risk of complications of influenza is expected to occur in BMT patients, no study has addressed the clinical efficacy of influenza vaccination in this setting. Focusing on the clinical benefits of influenza vaccination, we evaluated the risk factors for influenza infection in a cohort of 177 BMT recipients followed up for 1 year. Influenza was diagnosed in 39 patients. Multivariate analyses showed that seasonal exposure and more aggressive conditioning regimens were independently associated with increased risk for influenza. Influenza vaccination and steroid use showed a protective role. Of the 43 patients who had received BMT longer than 6 months, 19 were vaccinated (compliance rate= 44.2%) and vaccine efficacy was 80%. We conclude that influenza vaccination plays an important role in protecting BMT recipients against influenza and all efforts should be made to ensure good compliance with vaccination.

Early measles vaccination in bone marrow transplant recipients

Summary:Measles vaccination has been recommended after the second year following bone marrow transplant (BMT) in patients not receiving immunosuppressive drugs. During a measles outbreak, we vaccinated all patients after the first year of transplant, and conducted a prospective trial to evaluate safety, effectiveness and sustained immunity after early vaccination. Patients received attenuated virus vaccine between 9 and 18 months after BMT. A total of 51 patients were evaluated and 27 of them (52.9%) were receiving immunosuppressive drugs. Only mild adverse reactions were noted. Nine patients (17.6%) were susceptible (IgG⩽100u2009mIU/ml) at vaccination, and all seroconverted. In those immune at vaccination, a four-fold increase in measles IgG titers was found in one of 34 patients (2.9%) with specific IgG⩾200u2009mIU/ml compared to 14 of 17 (82.3%) with IgG<200u2009mIU/ml (P< 0.0001). Sustained immunity after 24 months was more likely to occur in patients with specific IgG levels⩽200 or ⩾500u2009mIU/mL (83.4 and 100%, respectively) in comparison to patients with 200<IgG<499u2009mIU/ml at vaccination (50% P=0.017). We conclude that even though early measles vaccination is safe, few patients are susceptible on day +365 and this strategy should be reserved for epidemic situations posing significant threat for the patients.

Addition of low-dose busulfan to cyclophosphamide in aplastic anemia patients prior to allogeneic bone marrow transplantation to reduce rejection

Summary:Busulfan was added at the dose of 4u2009mg/kg to 200u2009mg/kg cyclophosphamide in 81 patients (3–53 years, median 24) with aplastic anemia to reduce graft rejection. Graft-versus-host disease (GVHD) prophylaxis comprised cyclosporine–methotrexate. The number of prior transfusions was 0–276 (median 26), and 48% had received prior immunosuppressive therapy. Two patients experienced primary graft failure, and 10 secondary rejection at 28–1001 days (median 317 days). The cumulative incidence of rejection was 22%; for heavily transfused patients (⩾50u2009U) it was 43% compared to 16% for the rest (P=0.06). Overall survival rate at 8 years was 56%; patients who received ⩽15 and >15 transfusions was 78 and 50%, respectively (P=0.01), whereas it was 67 and 28% for ⩽50 and >50 transfusions, respectively (P=0.002). In multivariate analysis, higher number of prior transfusions, shorter period of immunosuppression with cyclosporine and GVHD were associated with inferior survival; moreover, a higher risk of graft rejection were associated with a higher number of prior transfusions and a trend was observed for a shorter cyclosporine administration. Low-dose busulfan is feasible and may be helpful in patients exposed to <50 transfusions. However, rejection remains a significant problem, mainly in heavily transfused patients.

p63 Protein expression in high risk diffuse large B-cell lymphoma

Background: p63 gene is a p53 homologue that encodes proteins with transactivation, DNA-binding and tetramerisation domains. The isoforms TAp63 and TAp73 transactivate p53 target genes and induce apoptosis, whereas the isoforms ΔNp63 and ΔNp73 lack transactivation and might have dominant-negative effects in p53 family members. p63 is expressed in germinal centre lymphocytes and can be related to the development of the lymphoma, but the prognostic significance of its expression in the survival of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. Aims: To determine whether quantitative immunohistochemical (IHC) analysis of p63 protein expression correlates with CD10 antigen, Bcl-6 antigen and IRF4 antigen expression and to determine whether p63 is a surrogate predictor of overall survival in high–intermediate and high risk DLBCL populations. Methods: CD10, Bcl-6 and IRF4 expression were retrospectively evaluated by IHC in 73 samples of high–intermediate and high risk DLBCL and were used to divide the lymphomas into subgroups of germinal centre B-cell-like (GCB) and activate B-cell-like (ABC) DLBCL. Similarly, p63 expression was evaluated by IHC and the results were compared with subgroups of DLBCL origin and with the survival rates for these patients. Results: p63 was expressed in more than 50% of malignant cells in 11 patients and did not show correlation with subgroups of GCB-like DLBCL or ABC-like DLBCL, but p63(+) patients had better disease-free survival (DFS) than those who were negative (pu200a=u200a0.01). Conclusions: p63(+) high–intermediate and high risk DLBCL patients have a better DFS than negative cases.

Strongyloides stercoralis hyperinfection after allogeneic stem cell transplantation

Strongyloides hyperinfection is a potentially fatal syndrome associated with deficient cell-mediated immunity. However, despite the severe deficiency of cell-mediated immunity seen after hematopoietic stem cell transplantation (HSCT), this syndrome has rarely been reported, even in endemic areas such as South America. A 35-year-old man underwent a peripheral blood cell allograft from his HLA-identical sibling in October 2007 for ALL in third refractory relapse. The conditioning comprised oral busulfan (16mg/kg) and i.v. melphalan (140mg/m). GVHD prophylaxis comprised cyclosporine (3mg/kg/day). The CD34þ cell dose was 6.58 10 per kg. Prophylaxis consisted of fluconazole, acyclovir and cefepime. Engraftment was prompt, and the early post transplant course was uneventful. He was admitted 54 days after transplantation with abdominal pain, macroscopic hematuria with clots, dry cough and fever. He was on a low dose of prednisone. The chest X-ray revealed bilateral crackles. Hemoglobin was 10.6 g/100ml, the WBC count was 3.2 10/l (83% neutrophils, 12% lymphocytes, 5% monocytes and 0% eosinophils) and the platelet count was 25 10/l. Kidney function was normal. CMV antigenemia was detected. History showed that he had always lived in the Amazonian basin in Brazil, had consumed untreated or unfiltered water, had suffered insect bites and did not use protective footwear. The patient was treated with continuous bladder irrigation and broad-spectrum antibiotics, including ganciclovir. In the presence of computed tomography findings of probable invasive aspergillosis and diffuse bilateral infiltrates on the chest X-ray, liposomal amphotericin was started at the dose of 3mg/kg daily. Hemorrhagic cystitis was resolved with supportive treatment. The patient developed diarrhea, nausea, abdominal discomfort and anorexia, with cough and hemoptysis. Stool examinations showed Strongyloides stercoralis larvae on direct microscopy. He was treated with thiabendazole 25mg/kg for 7 days and sputum samples for detection of S. stercoralis were collected. Combination therapy with ivermectin (200mcg/kg/day) and thiabendazole (25mg/kg/day) for 7 days was initiated after the stool examinations continued to be persistently positive. The gram stain indicated the presence of multiple filariform larvae of S. stercoralis in the sputum. All subsequent stool examinations were negative, and the signs and symptoms disappeared after 3 days of treatment. The patient was discharged from hospital on day 75 after PBSC transplantation to continue the treatment in the outpatient clinic. The plan was to repeat antiparasitic treatment after 21 days. The low rates of strongyloidiasis after HSCT can be explained by routine screening for this parasite and the use of prophylactic treatment before transplantation. Examination of three or more stool samples has a sensitivity of 60–70% to detect S. stercoralis. In our hospital, three stool samples are examined before HSCT in all patients. Serology by ELISA can also be used to diagnose S. stercoralis. In a study of sera from 164 hematological patients tested for the presence of Ab to S. stercoralis, the Ab was detected in serum using ELISA. The sensitivity, specificity, and positive and negative predictive values were 68, 89, 48 and 95%, respectively. In endemic areas, the use of serology is controversial, and only a negative test is useful. A retrospective analysis showed that the overall rate of S. stercoralis infection was 1.0 per 10 000 new cancer cases in the United States. Most of the patients (88%) were US residents. Evidence of hyperinfection syndrome was observed in two HSCT recipients who developed fatal S. stercoralis hemorrhagic alveolitis despite receiving highdose thiabendazole and ivermectin therapy. One case of alveolar hemorrhage, post-HSCT, due to strongyloides hyperinfection was recently described. Therapy with parenteral ivermectin and thiabendazole was initiated, but the patient’s condition deteriorated and he died of respiratory failure and septic shock. There are two other reported cases of strongyloidiasis in autologous HSCT patients, one developing fatal hyperinfection after corticosteroids. They were both treated with albendazole and ivermectin. Our patient was not neutropenic, was on low doses of corticosteroids and had received cyclosporine, which has anti-helminth activity. Although there are no described cases of strongyloidosis hyperinfection while on cyclosporine, a recent report showed that three consecutive cadaveric kidney transplant recipients who were on tacrolimus died within 2 months from strongyloides hyperinfection. Two of the recipients had received their kidneys from a single cadaveric donor, wheras the third received it from a different donor. Both the donors came from areas endemic for strongyloidiasis. The best way to treat strongyloidiasis is unclear. Relapse is more frequent in immunocompromised patients, particularly with the use of corticosteroids. Combination therapy is frequently used to treat strongyloides hyperinfection Bone Marrow Transplantation (2009) 43, 741–742 & 2009 Macmillan Publishers Limited All rights reserved 0268-3369/09

Prognostic impact of diffuse large B-cell lymphoma subgroups in patients undergoing autologous SCT

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O transplante de medula óssea na leucemia mielóide aguda: análise de 80 pacientes transplantados no complexo do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

A total of 53 patients aged 18–60 years with high-intermediate or high-risk diffuse large B-cell lymphoma (DLBCL) were evaluated to analyze the impact of the cell of origin. Of 53 patients, 16 underwent autologous SCT (ASCT) in first remission and the rest received conventional chemotherapy. Immunohistochemistry was evaluated in 47 cases 17 were of germinal center (GC) origin and 30 were of non-GC origin. There was no survival difference between the two groups. Overall survival (OS) and disease-free survival (DFS) at 3 years were 93 and 83%, respectively, for the 14 patients who underwent ASCT. Their DFS was significantly better than that of patients who achieved CR but did not undergo ASCT. We conclude that ASCT is safe and improves the DFS of high-intermediate and high-risk DLBCL, regardless of the cell of origin. This observation should be confirmed in a larger study.

Liposomal daunorubicin and dexamethasone as a treatment for multiple myeloma: the DD Protocol

The patients records of eighty consecutive patients with acute myeloid leukemia (AML) submitted to allogeneic (allo BMT) and autologous (auto BMT) bone marrow transplantation (BMT) between 1989 and 2001 were assessed. Forty percent were alive in the end of the study; 37.9% of allogeneic patients and 45.4% of autologous. Factors such as gender, the French-American-British AML classification, induction treatment, number of infused cells and the conditioning regiment did not have any impact in survival. Patients with AML from M1 to M4, and who were consolidated with high doses of arabinoside had better a survival rate (p=0.0148). Patients in their first complete remission also had better survival both with allogeneic and autologous BMT, with respective survival rates of 52.6% and 69.2%. Acute graft-versus-host disease (GvHD) had an impact when it was compared the absence, grade I/II with III/IV giving a p-value of 0.0285. Infection was the most frequent cause of death in allogeneic BMT. In autologous BMT relapse was the principal cause of death. Toxicity related to the procedure occurred in 38.9% of patients who died in allogeneic BMT and 16.7% in autologous BMT. In univariant Cox analyses for prognostic factors, the disease status and acute GvHD were significant, but this significance was lost in the multiple variant analyses (p-value = 0.069).