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

Venocclusive disease of the liver after chemoradiotherapy and autologous bone marrow transplantation.

We determined the incidence of venocclusive disease of the liver (VOD) in 96 recipients of autologous bone marrow transplants (BMT) to be 9.4%, a figure less than that reported for allogeneic transplantation. The development of VOD was compared in a cohort of 21 autologous BMT recipients and in 56 randomly chosen, comparably conditioned, concurrent allogeneic BMT recipients. One of these 21 (4.8%) autologous recipients developed VOD, versus 14 of 56 (25%) allogeneic recipients (P less than 0.05). Logistic regression analysis confirmed pretransplant hepatocellular dysfunction as a risk factor for VOD, and suggested that the use of methotrexate and/or cyclosporine contributes to the development of VOD after chemoradiation therapy. However, a graft-versus-host reaction cannot be excluded as a cause of the higher incidence of VOD in allogeneic recipients.

Bone marrow transplantation in Brazil.

The first program of bone marrow transplantation in Latin America was started 5 years ago at the Federal University Hospital, Curitiba, Paraná. The results of 62 patients who underwent bone marrow transplantation are presented and discussed.

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.

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.

Clinical features and successful recovery from disseminated nocardiosis after BMT.

Nocardiosis has rarely been described after BMT. When the doses of immunosuppressive therapy were tapered, a 46-year-old BMT recipient developed chronic graft-versus-host disease (GVHD) and immunosuppresive drugs were increased. Sixteen days later the patient developed nocardiosis diagnosed by lung biopsy. Trimethoprim/sulfamethoxazole (TMP/SMZ) was initiated but the doses were reduced because of rising creatinine levels. Skin and cerebral dissemination of nocardiosis was observed and TMP/SMZ doses were increased. After 4 months, the brain lesion was unaltered despite resolution of pulmonary lesions. Clinical improvement was observed after drainage of the brain abscess.

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.

CMV pneumonia in allogeneic BMT recipients undergoing early treatment of pre-emptive ganciclovir therapy.

The incidence, treatment and outcome of CMV interstitial pneumonia (CMV-IP) were reviewed in 139 consecutive allogeneic BMT patients undergoing extended CMV antigenemia surveillance and two different ganciclovir (GCV) strategies to control CMV infection. Nineteen cases of CMV-IP were reviewed, 16 of 63 patients (25.4%) who received early GCV treatment (ET) and three of 76 patients (3.9%) who received preemptive (PE) GCV therapy. In the ET group, the median time for occurrence of CMV-IP was 55 (range 36 to 311) days. Two patients had three episodes of CMV-IP recurrences after day +100. CMV-IP-related death occurred in two patients (15.4%). In the PE group, 41 patients received pre-emptive GCV therapy prompted by the appearance of positive antigenemia > or =2 cells. The median time for the occurrence of CMV-IP was 92 (range 48 to 197) days. Response to therapy was observed when GCV was introduced within 6 days of antigenemia positivity. The use of IVIg in association with GCV did not play a major role in response to therapy. The median time for occurrence of CMV-IP was delayed during PE strategy and the cost-effectiveness of CMV surveillance after day +100 should be investigated in this population.

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.

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.

Scedosporium apiospermum sinusitis after bone marrow transplantation: report of a case.

A forty-year-old man underwent an allogeneic BMT from his HLA identical sister. GvHD prophylaxis was done with cyclosporine (CyA), methotrexate and prednisone (PDN). On day +90 extensive GvHD was noted and higher doses of immunosuppressive drugs alternating CyA with PDN were initiated. Patient's follow-up was complicated by intermittent episodes of leukopenia and monthly episodes of sinusitis or pneumonia. One year after BMT, the patient developed hoarseness and nasal voice. No etiologic agent could be identified on a biopsy sample of the vocal chord. Upon tapering the doses of immunosuppressive drugs, the patient had worsening of chronic GvHD and was reintroduced on high doses of cyclosporine alternating with prednisone on day +550. Three months later, GvHD remained out of control and the patient was started on azathioprine. On day +700, hoarseness and nasal voice recurred. Another biopsy of the left vocal chord failed to demonstrate infection. Episodes of sinusitis became more frequent and azathioprine was withheld 3 months after it was started. One month later, the patient had bloody nasal discharge and surgical drainage of maxillary sinuses was performed. Histopathology showed hyphae and cultures grew Scedosporium apiospermum. Itraconazole 800 mg/day was initiated. The patient developed progressive respiratory failure and died 15 days later.

Cytomegalovirus and other herpesviruses infections in heart and bone marrow transplant recipients.

From January 1988 to January 1989 all the heart transplant and bone marrow recipients at the Instituto do Coração of the Hospital das Clínicas of the University of São Paulo Medical School were studied for the incidence and morbidity associated with herpesviruses infections after transplantation. Five bone marrow and 5 heart transplant recipients were followed for a mean of 4.2 months post-transplantation. All the patients were seropositive for cytomegalovirus (CMV) before admission and 80% experienced one or more recurrences during the observation period. Of the 12 episodes of CMV infection, that were identified in this study, 83% were accompanied by clinical or laboratory abnormalities. However, there was only one case of severe disease. The overall incidence of infection for herpes simplex (HSV) was 50%. Although most of HSV reactivations were oral or genital, one case of HSV hepatitis occurred. One of the 6 episodes of HSV infections that were treated with acyclovir showed an unsatisfactory response and was successfully managed with ganciclovir. All the individuals had anti-varicella zoster virus antibodies, but none of them developed infection. The study emphasizes the importance of active diagnostic surveillance of herpesvirus infections in transplant patients. Both CMV and HSV reactivations showed high incidence and important morbidity and thus, deserve prophylactic therapy.

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.

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.