C. Üstün

Hepatitis B virus infection in allogeneic bone marrow transplantation

Fourty-four patients who underwent allogeneic bone marrow transplantation (alloBMT) were studied for hepatitis B virus (HBV)-related complications. The mean follow-up period was 15.3 months. Positivity for HBV surface antigen (HBsAg) was observed in 10 patients (22.7%) throughout the study. Four of the 10 patients were HBsAg carriers before alloBMT, while the remaining six became HBsAg(+) after alloBMT. During the follow-up period (from 6 months to 45 months), an elevation in serum ALT activity was observed in the four carriers when immunosuppression was reduced or withdrawn. All of the four HBsAg carriers developed hepatitis, but none of them died of liver failure due to HBV. Only one death due to GVHD and diabetic ketoacidosis was observed in this group. Two of the four carriers received marrow from anti-HBs positive donors and one of them cleared HBsAg from his serum via adoptive immunity 8 months after transplantation. The remaining six patients acquired HBV after alloBMT, but we were unable to demonstrate the source of HBV. Five of them had a moderate increase in serum ALT activity while the other patient had a normal ALT. Two patients seroconverted to anti-HBs spontaneously. Two patients died during the follow-up, one due to intracranial hemorrhage and the other due to GVHD and accompanying pulmonary infection. The rest of the study group (34 patients) remained HBsAg(−) throughout the study. Two of them had an HBsAg(+) donor, but neither developed HBV infection in their follow-up period. The acquisition rate of HBV infection was relatively low in recipients who were positive for anti-HBs compared to those who were negative for anti-HBs (8 vs 19%). Anti-HBs positivity remained for a longer period in recipients who received marrow from anti-HBs positive donors compared to those recipients who had anti-HBs negative donors (median 12 vs 3 months). We think that HBV is a frequent cause of liver dysfunction in alloBMT patients where HBV infection is endemic. Whether the disease is in the form of reactivation of HBsAg-positive recipients, or is acquired from unknown sources in recipients who never had contact with the virus, the course of the disease is not fatal. Silent serologic changes can be demonstrated if viral serologic markers are sought serially. Among them, the disappearance of serum anti-HBs may be important as it increases the risk of HBV contamination in recipients.

Autoimmune thrombocytopenia in a patient with small cell lung cancer developing after chemotherapy and resolving following autologous peripheral blood stem cell transplantation.

A 46-year-old white male with small cell lung cancer (SCLC) limited to the thorax developed autoimmune thrombocytopenic purpura (AITP), following a cyclophosphamide, paclitaxel and G-CSF-containing regimen for peripheral blood stem cell (PBSC) mobilization. AITP associated with small or non-small cell lung cancer has been reported. We considered that the AITP in this case may be a part of paraneoplastic syndrome, which is frequently seen in patients with SCLC. The patient received HDC and autologous PBSC transplantation (APBSCT) for SCLC and the AITP resolved following transplantation, thus supporting the concept of HDC + APBSCT for the treatment of autoimmune diseases.

Febrile neutropenia in allogeneic and autologous peripheral blood stem cell transplantation and conventional chemotherapy for malignancies.

The risk and outcome of infection in febrile neutropenic patients is mainly determined by the duration of neutropenia, the underlying disease or the treatment. This study was undertaken to compare infections and the outcome after conventional chemotherapy (CCT), allogeneic PBSC transplantation (alloPBSCT) or autologous PBSC transplantation (autoPBSCT), during the period of neutropenia, in a single center. A total of 145 patients (50 in CCT group, 50 in alloPBSCT and 45 in autoPBSCT) were evaluated. In the alloPBSCT group, 86% of the patients (43/50), in the autoPBSCT group 93% of the patients (42/45) and in the CCT group 92% (46/50) of the patients had at least one febrile episode during their neutropenic period (P > 0.05). Microbiologically and/or clinically documented infection rates were 50% (25/50), 42% (19/45) and 48% (24/50) respectively. Gram-positive pathogens, mostly coagulase-negative staphylococci were the most frequent cause of bacteremias in all groups. The frequency of CNS infections was significantly higher in the alloPBSCT and autoPBSCT groups compared to the CCT group (P < 0.008 and P < 0.04, respectively). Catheter infections were frequent in the pbsct groups and pulmonary infections were more frequent in the cct group (P < 0.05). The CCT group needed longer antibiotic usage compared to the alloPBSCT group (P < 0.006). The duration of neutropenia and the type of treatment given, does not affect the rate of febrile episodes, but affects the type of infections in febrile neutropenic patients. Bone Marrow Transplantation (2000) 26, 211–214.

Aerobic bacterial and fungal infections in peripheral blood stem cell transplants

Allogeneic and autologous peripheral blood stem cell transplants are frequently complicated by infections. This study was performed to evaluate early and late infections in 74 patients who underwent peripheral blood stem cell transplantation (PBSCT). Fifty-eight patients received allogeneic and 16 autologous PBSCT. All patients received fluconazole, ciprofloxacin and acyclovir prophylaxis. 93.1% of alloPBSCT patients and 87.5% of autoPBSCT patients developed fever. Febrile episodes were commonly seen in the week of transplantation (66%). There was a median of 3 days with fever in alloPBSCT, and 2 days in autoPBSCT. Period of neutropenia was 15 days for AlloPBSCT and 12 days for AutoPBSCT. The microbiological identification rate was 47% (32/68). Gram-positive infections dominated the early period (50%) and Gram-negative bacterial infections dominated the late period (50%). All our patients had Hickman-type catheters and 26 infections involving catheters were seen. Sixteen occurred in the early, and 10 in the late period. Ten of 14 (71.4%) late bacterial infections were catheter-related. The dominance of Gram-positive infections and high rates of methicillin resistance warranted the use of vancomycin extensively. Surveillance cultures were found to be useful in selected patients. Although slime factor is an important virulence factor, there was no difference between slime factor positive and negative coagulase-negative staphylococci isolated during infections. In conclusion, febrile episodes are the most frequent complication of PBSCT and Gram-positive microorganisms remain the main pathogen in these patients because of catheter use, mucositis and ciprofloxacin prophylaxis. Methicillin resistance is increasing and glycopeptides remain the only choice for treating such infections. Although the infection rate is high, measures taken to prevent and treat infections result in very low rates of mortality from infection in PBSCT patients. Bone Marrow Transplantation (2001) 27, 201–205.

Hepatitis B virus vaccination of recipients and donors of allogeneic peripheral blood stem cell transplantation

Abstract: Background: The aim of this study was to determine the role of hepatitis B virus (HBV) vaccination as defined by the seroconversion to hepatitis B surface antibody (anti‐HBs) positivity in peripheral blood stem cell transplants.

Recombinant human granulocyte colony-stimulating factor (rh-G-CSF) may accelerate hematopoietic recovery after HLA-identical sibling allogeneic peripheral blood stem cell transplantation.

We studied the effects of recombinant human granulocyte colony-stimulating factor (G-CSF) on hematopoietic recovery and clinical outcome in patients undergoing allogeneic peripheral blood stem cell (PBSC) transplantation. Fifty-six patients with hematological malignancies who underwent allogeneic PBSC transplantation between 1995 and 1998 were entered into this study. Twenty-eight patients who received daily G-CSF from day +1 after allogeneic PBSC transplantation until the absolute neutrophil count (ANC) reached >0.5 × 109/l for 3 consecutive days were compared with 28 patients (control group) who did not receive G-CSF in a non-randomized manner. The study group and the control group were comparable with respect to baseline patient and transplantation characteristics. Median times to ANC of >0.5 × 109/l and 1 × 109/l with or without G-CSF were 12 days (range 8–21), 13 days (10–32) (P = 0.04) and 13 days (9–21), 15 days (11–44) (P = 0.02), respectively. Median times to reach a platelet count of >20 × 109/l with and without G-CSF were 11 days (0–20) and 13 days (9–26), respectively (P = 0.03). The incidence of febrile episodes was significantly lower with G-CSF, 75% vs 100% (P = 0.008). Patients receiving G-CSF had less grade III–IV mucositis than those who did not receive G-CSF (P = 0.01). There was also no increase in the incidence and severity of acute GVHD in patients using G-CSF (P = 0.22). Although the number of relapsing patients was greater in the G-CSF group (seven vs three patients), this was not statistically significant (P = 0.24). Disease-free and overall survival rates did not differ between the two groups (P = 0.58 and 0.53, respectively). The administration of G-CSF after allogeneic PBSC transplantation provided faster neutrophil and platelet engraftment associated with less severe mucositis and less febrile episodes. Bone Marrow Transplantation (2001) 27, 499–505.

Acquired ichthyosis associated with chronic graft-versus-host disease following allogeneic peripheral blood stem cell transplantation in a patient with chronic myelogenous leukemia

Acquired ichthyosis (AI) has rarely been described following bone marrow transplantation (BMT). We report a 29-year-old male, who underwent allogeneic peripheral blood stem cell transplantation (alloPBSCT) for chronic myelogenous leukemia, and who developed AI associated with chronic graft-versus-host disease (cGVHD). Both of these disorders were treated successfully with cyclosporin A. We conclude that AI may be related to an autoimmune process on the basis of cGVHD, and dermathopathologic evaluation must be performed in patients with skin changes suggesting AI following allogeneic bone marrow transplantation.

A phase I dose escalation study of high-dose thiotepa, melphalan and carboplatin (TMCb) followed by autologous peripheral blood stem cell transplantation (PBSCT) in patients with solid tumors and hematologic malignancies.

The purpose of this study was to determine the maximum tolerated dose of carboplatin administered with 500 mg/m2 thiotepa and 100 mg/m2melphalan followed by autologous peripheral blood stem cell (PBSC) infusion in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose thiotepa (500 mg/m2, melphalan (100 mg/m2) and escalating doses of carboplatin 900–1500 mg/m2) followed by infusion of cryopreserved autologous PBSCs. The maximum tolerated doses were determined to be 500 mg/m2 thiotepa, 100 mg/m2 melphalan and 1350 mg/m2 carboplatin. Two consecutive patients receiving 1500 mg/m2 carboplatin experienced grade 3 mucositis and colitis. Ten patients were enrolled at the maximum tolerated dose and none had grade 3–4 regimen-related toxicity and mortality. All patients at this level experienced grade 1–2 mucositis, 90% grade 1–2 gastrointestinal toxicity, 30% grade 1–2 cardiac and renal toxicity, and 10% experienced grade 1 hepatic toxicity. The median time to achieve a granulocyte count of 0.5 × 109/l was 9 days (range 7–12 days) and platelet count of 20 × 109/l was 10 days (range 7–15 days). Of eight patients with stage IV refractory breast cancer, even were evaluable for response, one patient on day 75 will be evaluated soon. Five of seven (71.5%) evaluable patients achieved a complete remission (CR) and two had no response. Of seven patients with non-Hodgkins lymphoma (n = 4) or Hodgkins disease (n = 3), five achieved a CR (71.5%). Thiotepa, melphalan and carboplatin can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy-sensitive malignancies are warranted. Bone Marrow Transplantation (2000) 25 , 697–703.

In vivo use of all-trans retinoic acid prior to induction chemotherapy improves complete remission rate and increases rhodamine 123 uptake in patients with de novo acute myeloid leukemia.

All-trans retinoic acid (ATRA) is used in the treatment of acute promyelocytic leukemia. Because ATRA has effects (increase in apoptosis, suppression of bcl-2), it has also been used for the treatment of other French-American-British (FAB) subtypes of acute myelogenous leukemia (AML). To find out the in vivo and in vitro effects of ATRA in AML, we analyzed 37 patients with de novo AML. Twenty-seven patients received ATRA before remission-induction (RI) treatment (ATRA group). Results were compared to a control group (10 patients) that received induction without ATRA during the same time period. Bone marrow or peripheral blood samples were collected from all patients on d 0 and 4. The immunphenotype, myeloperoxidase (MPO), reaction and the efflux uptake of rhodamine 123 (Rh123) were analyzed on myeloblasts in these samples. In the myeloblasts from patients treated with ATRA, the uptake of Rh123 was increased significantly (p=0.026) from d 0 to d 4, and all other parameters remained unaltered. ATRA administration increased the complete remission (CR) rate (88%, 22/25 vs 55%, 5/9) significantly (p=0.042). Logistic regression analysis revealed that ATRA administration was the important factor in CR, among other potential factors including age, white blood count, bcl-2 expression, and the uptake and efflux of Rh123 (p=0.05). Estimated disease-free survival and overall survival were similar between these two groups (43% vs 37.5% and 51.2% vs 37.5%, respectively). In conclusion, ATRA treatment prior to RI treatment may improve the CR rate in patients with de novo AML, which seems to be related to its beneficial effect on multidrug resistance.

Febrile neutropenia in a bone marrow transplantation unit

In our clinic, between May 1988 and December 1994, 117 bone marrow transplants (78 allogenic BMT (alloBMT), 26 autologous BMT (autoBMT), 13 autologous peripheral stem cell transplant (autoPSCT). Eighty-six (73.5%) febrile neutropenic episodes (FNEs) were encountered (64 alloBMTs, 15 autoBMTs, 7 autoPSCTs). There were 28 (32.5%) microbiologically documented infections, 18 (20.9%) clinically documented infections and 40 (46.5%) FUO. Gram-positive microorganisms were the most frequently isolated agents (57.1%) and Staphylococcus spp. were the main pathogens to cause bacteremia (%54.1). Enterobacter spp. were the most common (75%) in urinary tract infections, FNEs were most frequently (82%, 64 78 ) encountered in AlloBMT patients. No significant difference in the number of FNEs was found between autoBMT and autoPSCT groups (P < 0.05). Overall response rate to empirical antibiotherapy was 87.2% (75 86 ) and the success of treatment disclosed no difference in relation to transplant type and definition of infection (P > 0.05). Seven (6%) patients suffered from catheter infections and eight (7%) from Candida esophagitis.