Risk factor for death in hematopoietic stem cell transplantation: are biomarkers useful to foresee the prognosis in this population of patients?

BACKGROUND: The morbidity and mortality in hematopoietic stem cell transplantation (HSCT) occur due to infectious complications and constitute the major clinical problems in HSCT recipients. The role of the use of biomarkers in post-HSCT patients is still controversial. OBJECTIVES: To assess the serum values of biomarkers interleukin 6 (IL-6), procalcitonin (PCT) and C-reactive protein (CRP) and risk factors for post-HSCT death. PATIENTS AND METHODS: Prospective study conducted in patients submitted to HSCT at a university hospital. Biomarkers (IL-6, PCT and CRP) were assessed on the day afebrile neutropenia was detected, in the febrile event, 24 and 72 h after fever onset and 48 h or 5 days if fever persisted. Patients were compared as to the death outcome within 30 days from the HSCT. Variables with p < 0.15 were included in the multivariate analysis model (MVA) that were performed for all patients included in the study and separated for autologous and allogeneic HSCT patients. RESULTS: 296 patients with ages ranging between 15 and 70 years, neutropenic, submitted to HSCT, being 216 (73%) autologous and 80 (20%) allogeneic were assessed. One hundred and ninety (64.2%) patients presented fever after the transplantation and infection microbiologically controlled in 78 (26.4%). Twenty-three cases (7.8%) evolved to death. The risk factors associated with death in the bivariate analysis were age, allogeneic transplantation, unrelated transplantation, GVHD, bloodstream infection by Gram-negative, IL-6 >140 pg/mL and CRP ≥ 120 mg/L and the protective ones were lymphoma and hospital outpatient support. The independent variables in the MVA associated with death were allogeneic and unrelated transplantation, blood stream infection (BSI) by Gram-negative, LDH ≥ 390 UI/L, urea ≥ 25 mg/dL and CRP ≥ 120 mg/L for HSCT transplanted patients and BSI due to Gram-negative and CRP ≥ 120 mg/L for allogeneic HSCT, however, CRP ≥ 120 mg/L did not remain in the model when urea ≥ 25 mg/L was included. No independent risk factor was found for autologous patients. CONCLUSIONS: Out of the biomarkers assessed, only CRP ≥ 120 mg/L was independently associated with death. Other risk factors found were: type of transplantation (allogeneic and unrelated), bloodstream infection by Gram-negative, LDH ≥ 390 UI/L and urea ≥ 25 mg/dL. For allogeneic patients only CRP ≥ 120 mg/L and BSI due to Gram-negative were risk factors for death; however, CRP did not remain in the model when urea ≥ 25 mg/L was included.

An outbreak of respiratory syncytial virus infection in hematopoietic stem cell transplantation outpatients: good outcome without specific antiviral treatment.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of seasonal respiratory viral infection in hematopoietic stem cell transplantations (HSCT) patients. The efficacy of treatment, however, remains controversial. We describe an outbreak of 31 cases of RSV that occurred in an HSCT outpatient care unit in the fall season from March through May 2010, with a good outcome without any specific antiviral treatment. METHODS: During these 3 months, 222 nasal wash samples were tested and, of these, 31 outpatients were positive for RSV. In 2009, 99 samples had been tested and only 10 outpatients were positive for RSV in the same period. RESULTS: Seven (22.5%) patients had severe neutropenia (<500 cells/µL); severe lymphopenia (<200 cells/µL) was present in 13 (41.9%) patients, and 14 (45%) had received intravenous broad-spectrum antibiotics. Hospitalization was necessary only for 8 patients (25.8%); 20 had lower respiratory tract infection (64.5%). Only 1 patient died as a result of proven invasive aspergillosis. CONCLUSION: This report suggests that HSCT outpatients with no risk factors may not always require specific treatment for RSV.

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 DeltaNp63 and DeltaNp73 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 (p = 0.01). CONCLUSIONS: p63(+) high-intermediate and high risk DLBCL patients have a better DFS than negative cases.

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

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.

Results of CHOP chemotherapy for diffuse large B-cell lymphoma

Patients with diffuse large B-cell lymphoma treated in a University Hospital were studied from 1990 to 2001. Two treatment regimens were used: ProMACE-CytaBOM and then, from November 1996 on, the CHOP regimen. Complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates were determined. Primary refractory patients and relapsed patients were also assessed. A total of 111 patients under 60 years of age were assessed and ranked according to the international prognostic index adjusted to age. Twenty (18 percent) of them were classified as low risk, 40 (36 percent) as intermediate risk, 33 (29.7 percent) as high intermediate risk, and 18 (16.3 percent) as high risk. Over a five-year period, OS and DFS rates were 71 and 59 percent, respectively, for all patients. For the same time period, OS and DFS rates were 72.8 and 61.3 percent, respectively, for 77 patients treated with CHOP chemotherapy and 71.3 and 60 percent for patients treated with the ProMACE-CytaBOM protocol. There was no significant difference in OS or DFS between the two groups. Eleven of 50 refractory and relapsed patients were consolidated with high doses of chemotherapy. Three received allogenic and 8 autologous bone marrow transplantation. For the latter, CR was 62.5 percent and mean OS was 41.1 months. The clinical behavior, CR, DFS, and OS of the present patients were similar to those reported in the literature. We conclude that both the CHOP and ProMACE-CytaBOM protocols can be used to treat diffuse large B-cell lymphoma patients, although the CHOP protocol is preferable because of its lower cost and lower toxicity.

Results of CHOP chemotherapy for diffuse large B-cell lymphoma.

Patients with diffuse large B-cell lymphoma treated in a University Hospital were studied from 1990 to 2001. Two treatment regimens were used: ProMACE-CytaBOM and then, from November 1996 on, the CHOP regimen. Complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates were determined. Primary refractory patients and relapsed patients were also assessed. A total of 111 patients under 60 years of age were assessed and ranked according to the international prognostic index adjusted to age. Twenty (18%) of them were classified as low risk, 40 (36%) as intermediate risk, 33 (29.7%) as high intermediate risk, and 18 (16.3%) as high risk. Over a five-year period, OS and DFS rates were 71 and 59%, respectively, for all patients. For the same time period, OS and DFS rates were 72.8 and 61.3%, respectively, for 77 patients treated with CHOP chemotherapy and 71.3 and 60% for patients treated with the ProMACE-CytaBOM protocol. There was no significant difference in OS or DFS between the two groups. Eleven of 50 refractory and relapsed patients were consolidated with high doses of chemotherapy. Three received allogenic and 8 autologous bone marrow transplantation. For the latter, CR was 62.5% and mean OS was 41.1 months. The clinical behavior, CR, DFS, and OS of the present patients were similar to those reported in the literature. We conclude that both the CHOP and ProMACE-CytaBOM protocols can be used to treat diffuse large B-cell lymphoma patients, although the CHOP protocol is preferable because of its lower cost and lower toxicity.

The benefit of influenza vaccination after bone marrow transplantation.

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.

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< or =100 mIU/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> or =200 mIU/ml compared to 14 of 17 (82.3%) with IgG<200 mIU/ml (P< 0.0001). Sustained immunity after 24 months was more likely to occur in patients with specific IgG levels< or =200 or > or =500 mIU/mL (83.4 and 100%, respectively) in comparison to patients with 200

Use of Oseltamivir to control influenza complications after bone marrow transplantation.

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 48 h 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.

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

Busulfan was added at the dose of 4 mg/kg to 200 mg/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 (>/=50 U) it was 43% compared to 16% for the rest (P=0.06). Overall survival rate at 8 years was 56%; patients who received 15 transfusions was 78 and 50%, respectively (P=0.01), whereas it was 67 and 28% for 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.

Effects of an exercise program on muscle performance in patients undergoing allogeneic bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) has been successfully used for the treatment of several hematological malignancies; however, it is associated with transplant-related toxicities such as functional impairment and muscle weakness. In order to analyze how an exercise program may influence muscle strength in patients undergoing BMT, we carried out a prospective study assessing patients from the pre-BMT phase to 16 weeks post-BMT. In all, 18 patients underwent three trials: (1) pre-BMT, (2) after marrow engraftment, and (3) 6 weeks after trial 2. After trial 2, the patients were randomized in a control group (CG) or treatment group (TG), which received a 6-week exercise program with active exercise, muscle stretching and treadmill walking. The results obtained in trial 1 showed similar values for CG and TG, as both groups had muscle strength lower than normal patterns based on data concerning age, sex and weight. In trial 2, CG and TG showed similarly decreased values. In trial 3, TG showed values higher than CG for all muscle groups tested. These results suggest that the exercise program was efficient in promoting an increase of muscle strength after allogeneic BMT.

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

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.

Different kinetics in anti-cytomegalovirus immunity reconstitution evaluated by lymphocyte proliferation and IFN-gamma production in allogeneic and autologous bone marrow transplantation.

Allogeneic bone marrow transplantation (ALLOBMT) is associated with an increased risk of cytomegalovirus (CMV) morbidity compared to autologous BMT (AUTOBMT). To investigate this, we evaluated AUTOBMT and ALLOBMT patients regarding anti-CMV immune reconstitution at 1 and 4 months after BMT and on the day after first CMV antigenemia detection. Intermittent ganciclovir preemptive therapy was prompted by antigenemia of >or=2 cells. One month after transplant, AUTOBMT recipients already displayed larger CD8+ T cell numbers than ALLOBMT recipients, but comparably small CD4+ T cell numbers. Most AUTOBMT patients had positive CMV antigen (CMV-Ag)-induced lymphoproliferation (86%) and IFN-gamma secretion (86%), whereas this was infrequently seen in ALLOBMT patients (20 and 10%, respectively). This early AUTOBMT immune reconstitution was associated with a lower frequency of CMV reactivation up to +4 months in AUTOBMT (21%) than ALLOBMT patients (91%). At +4 months, most ALLOBMT recipients had also recovered CMV-Ag immune responses. At first antigenemia detection, all 3 AUTOBMT recipients already displayed anti-CMV immune functions and 2 cleared the infection without therapy, whereas of the 10 ALLOBMT recipients only 1 had positive lymphoproliferation. In the latter group, none had IFN-gamma secretion or cleared the infection without therapy. Thus, differences in anti-CMV immune reconstitution may help to explain the contrasting rates of CMV morbidity between ALLOBMT and AUTOBMT patients.

Phialemonium curvatum infection after bone marrow transplantation.

We report a case of cutaneous infection caused by Phialemonium curvatum GAMS et COOKE, 1983, after bone marrow transplantation. The genus Phialemonium was created by GAMS & MCGINNIS in 1983 including three new species: Ph. obovatum, Ph. curvatum and Ph. dimorphosporum, and represents an intermediate genus between Acremonium and Phialophora. Nowadays, the genus Phialemonium is considered to be a pheoid fungus which may cause the eventual lesions observed in pheo- and hyalohyphomycosis. Species of this genus have been described as opportunistic agents in humans and animals, mainly as a result of immunosuppression. In the present case, the patient had multiple myeloma and received an allogenic bone marrow transplant from his HLA-compatible brother. Two months after transplantation, he developed purplish and painful nodular lesions on the right ankle. Some of these lesions drained spontaneously and apparently hyaline mycelial filaments were observed, whose culture was initially identified as Acremonium sp. Subsequent studies showed that the fungus was Phialemonium curvatum. The infection was treated with amphotericin B, followed by ketoconazole. The patient was submitted to surgical debridement followed by two skin grafts to repair the bloody area. The duration of the treatment was 4 months and secondary prophylaxis with ketoconazole alone was maintained for one additional month. No recurrence was observed after discontinuation of treatment. The authors comment on the pathogenicity of the genus Phialemonium.

Extended antigenemia surveillance and late cytomegalovirus infection after allogeneic BMT.

Late CMV disease remains a major concern in allogeneic BMT recipients. Few surveillance data are available on the occurrence of CMV infection and recurrences after day +100. We evaluated the occurrence of antigenemia (AG) recurrences until day +365 in 76 patients who received pre-emptive ganciclovir (GCV) therapy prompted by AG > or = 2 positive cells. Sixty-two episodes of AG recurrences were detected in 33 of the 52 patients who had positive AG. Survival analysis showed a 45.4% probability of AG recurrence on day +100, 64.8% on day +180 and 71.2% on day +365. The median time for AG recurrences was 113 (35 to 343) days. Thirty-five of the 62 episodes (56.4%) occurred after day +100. More than 70% of the patients responded to a 2-week course of GCV and no CMV disease was observed shortly after discontinuation of GCV. The Cox proportional model showed a significant effect of AG recurrences on patient's follow-up only when the patient developed chronic GVHD (P = 0.012). Extended surveillance favored early introduction of GCV and late CMV pneumonia occurred in only one of the 76 patients (1.3%). AG recurrences are frequent after day +100 and extended surveillance until day +365 is recommended for patients who develop chronic GvHD.