Aggressive multiple sclerosis: a single-centre, real-world treatment experience with autologous haematopoietic stem cell transplantation and alemtuzumab.

BACKGROUND AND PURPOSE: The best therapeutic approach for aggressive relapsing-remitting multiple sclerosis remains unknown. The objective was to compare the efficacy and safety of autologous haematopoietic stem cell transplantation (aHSCT) and alemtuzumab in aggressive relapsing-remitting multiple sclerosis. METHODS: The time to first relapse, time to confirmed disability worsening, time to first evidence of magnetic resonance imaging (MRI) activity and time to first evidence of disease activity were compared between the two treatment groups. Secondary outcomes included the 12, 24 and 36 month annualized relapse rate (ARR) and the 6-month confirmed Expanded Disability Status Scale (EDSS) changes at months 12 and 24. RESULTS: Fifty-seven patients treated with aHSCT (n = 25) or alemtuzumab (n = 32) were included. At baseline, aHSCT patients had a higher EDSS (median score 6 vs. 3; P < 0.001), higher ARR (mean ARR 3.2 vs. 1.7; P = 0.001) and a higher number of baseline T1 gadolinium-enhancing lesions on MRI (mean number 15.5 vs. 1.6; P < 0.001). NEDA-3 (no evidence of disease activity) status was more frequently achieved in aHSCT-treated patients than in alemtuzumab-treated patients [75% vs. 56% of patients at the end of the observation period; hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.08-0.84; P = 0.023]. aHSCT significantly reduced the risk of relapse (relapse-free survival 84% vs. 69%; HR 0.13, 95% CI 0.02-0.63; P = 0.012) and MRI activity (MRI-activity-free survival 85% vs. 59%; HR 0.13, 95% CI 0.03-0.59; P = 0.009). The ARR at 36 months was significantly lower in the aHSCT group (0.05 vs. 0.35, P = 0.02). A significant effect of aHSCT in promoting EDSS improvement compared with alemtuzumab was noted (P = 0.035). CONCLUSIONS: Alemtuzumab and aHSCT are effective treatment choices for aggressive multiple sclerosis. aHSCT seems to be superior to alemtuzumab in inducing complete disease control and in promoting short-term disability improvement.

Serial monitoring of isavuconazole blood levels during prolonged antifungal therapy.

BACKGROUND: Isavuconazole is the newest triazole antifungal approved for the treatment of invasive aspergillosis (IA) and invasive mucormycosis in adult patients. OBJECTIVES: To characterize the assessment of the blood levels of isavuconazole and their association with efficacy and toxicity. METHODS: From January 2017 to May 2018, blood samples obtained from patients receiving isavuconazole were analysed for therapeutic drug monitoring. Factors influencing the blood concentrations of isavuconazole, such as weight, length of treatment, route of administration and results of selected liver function tests, were analysed in univariate and multivariate models. The receiver operating characteristic (ROC) curve was analysed to detect the best cut-off for isavuconazole toxicity. RESULTS: A total of 264 isavuconazole blood concentrations in 19 patients were analysed. The median value of isavuconazole concentration in all patients during the first 30 days of therapy was 3.69 mg/L (range 0.64-8.13 mg/L). A linear increase of 0.032 mg/L (range 0.023-0.041 mg/L) for each day of treatment (P = 0.002) was observed. In multivariate analysis the association between the length of treatment and higher levels of isavuconazole (P < 0.001) and higher serum GGT and lower isavuconazole levels (P = 0.001) was confirmed. Adverse events, mainly gastrointestinal, were reported in six patients (31.6%). Based on time-dependent and fixed-time ROC curve analysis, 4.87 mg/L and 5.13 mg/L, respectively, were the identified thresholds for toxicity. CONCLUSIONS: Isavuconazole was efficacious and well tolerated. Side effects, mainly gastrointestinal, were associated with prolonged administration and high serum levels.

Visceral leishmaniasis in hematopoietic cell transplantation: Case report and review of the literature.

Visceral leishmaniasis has been recognized as an opportunistic infection affecting people with cellular-immunity impairment, including hematopoietic cell transplantation (HCT) recipients. We describe the case of a young Italian man with Hodgkin lymphoma, who developed visceral leishmaniasis after multiple lines of chemotherapy and allogenic HCT. Literature review of visceral leishmaniasis in HCT recipients was also performed. Eleven patients (median age 50 years, 9 male) developed visceral leishmaniasis after allogenic (n = 9) and autologous (n = 2) HCT. Most of them presented with fever and pancytopenia. Bone marrow examination was the main diagnostic technique; liposomal amphotericin B was the treatment of choice. Four out of eight patients (for whom data are available) experienced visceral leishmaniasis relapse. Visceral leishmaniasis in HCT recipients is a rare event that should be suspected in patients with persistent fever, pancytopenia and possible exposure to Leishmania spp., remembering that - as well as South-East Asia, East Africa and South America - it is endemic in several European regions.

Piperacillin/tazobactam (Tazocin™) seems to be no longer responsible for false-positive results of the galactomannan assay.

OBJECTIVES: Galactomannan (GM) testing is extremely useful for diagnosing invasive aspergillosis in high-risk patients, but false-positive results have been reported in patients treated with piperacillin/tazobactam. The aims of this study are to test if the recent piperacillin/tazobactam (Tazocin™; Pfizer) preparation still contains GM, and if serum GM positivity in haematopoietic stem cell transplant (HSCT) recipients receiving piperacillin/tazobactam can be attributed to this treatment. PATIENTS AND METHODS: Serum samples obtained from 1 October 2009 to 31 October 2010 from HSCT recipients for GM testing were analysed. The difference in the rate of positive results (defined as GM ≥ 0.5) in patients receiving and not receiving piperacillin/tazobactam was evaluated. Piperacillin/tazobactam vials from randomly selected batches were tested. RESULTS: Of 1606 samples drawn in the absence of piperacillin/tazobactam therapy, 25 (1.6%) tested positive for GM versus 10 of 394 samples (2.5%) drawn while on piperacillin/tazobactam (P = 0.18). The median GM result of samples drawn on piperacillin/tazobactam was slightly higher than that of samples drawn in the absence of piperacillin/tazobactam (0.141 versus 0.122; P < 0.001). All 90 piperacillin/tazobactam vials from 30 randomly selected batches tested negative for GM, with a median GM value of 0.057 (range: 0.011-0.320). CONCLUSIONS: Although some residual GM might still be present in piperacillin/tazobactam, currently available brand piperacillin/tazobactam preparations seem no longer responsible for false-positive GM results.

Mortality after bloodstream infections in allogeneic haematopoietic stem cell transplant (HSCT) recipients.

PURPOSE: Bloodstream infections (BSIs) are frequent after allogeneic haematopoietic stem cell transplantation (HSCT). The aim of this study was to identify predictors of mortality after BSI in patients who undergo HSCT. METHODS: Patients who underwent HSCT between 1 January 2004 and 31 January 2008 and developed BSI during the first year post-transplantation were included. Variables influencing overall mortality at 7 and 30 days after BSI were analysed. RESULTS: BSIs developed in 149 patients, within a median of 9 days after undergoing HSCT. Early and late mortality were 15 and 27%, respectively. Of the BSI, 54% were due to Gram-positive microorganisms, 33% were due to Gram-negative microogranisms, 10% were polymicrobial and 3% were fungal. The associated 7-and 30-day mortality was respectively 10 and 24% (Gram positive), 22 and 31% (Gram negative; Pseudomonas aeruginosa mortality 67%, all within 7 days), 13 and 27% (polymicrobial) and 40% (fungal, all within 7 days). Early mortality was higher in relapsed disease at HSCT (25.9%, p = 0.01), but lower in early (i.e. within 20 days of HSCT) BSI (11.7%, p = 0.03) and BSI due to Gram-positive infective agents (10%, p = 0.05). Multivariate analysis confirmed a higher mortality in late BSI [odds ratio (OR) 3.29, p = 0.03] and relapsed disease at HSCT (OR 2.2, p = 0.04). Late mortality was associated with the type of underlying disease (OR 0.44 for diseases other than acute leukaemia, p = 0.05) and its status (OR 6.04 for relapse at HSCT, p = 0.001). Appropriate empirical therapy was associated with lower early and late mortality in single Gram-negative BSI (16 vs. 45% for 7-day mortality, p = 0.09; 21 vs. 64% for 30-day mortality, p = 0.02). CONCLUSIONS: BSIs are frequent during the first year after HSCT and are associated with a high mortality rate. The aetiology influenced early mortality, while the type and phase of the underlying disease played a pivotal role in late mortality. Appropriate empirical therapy is crucial in BSI due to Gram-negative infective agents.

Risk factors for enterococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients.

Bacteremia is a well known cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients and enterococci are among the most frequently isolated pathogens. The aim of this study was to identify risk factors for enterococcal bacteremia during the first 30 days after allogeneic HSCT. A retrospective case-control study was performed; for each case, 3 controls were randomly selected among 306 patients transplanted during the study period (January 1, 2004 to December 31, 2007). Odds ratios (OR) with 95% confidence intervals (CI) were calculated for variables influencing the risk for bacteremia. Overall, 33 patients developed enterococcal bacteremia, within a median of 9 days after HSCT (range, 2-24). The cumulative incidence was 10.8%. Multivariate analysis identified the following variables as risk factors for enterococcal bacteremia: donor and transplant type (greater risk for mismatched related or cord blood) (OR=8.98, 95% CI, 1.65-48.99 and OR=7.52, 95% CI, 1.56-36.31, respectively, P=0.047); severe (grades 3-4) mucositis (OR=9.04, 95% CI, 1.97-41.52, P=0.018); pharyngeal enterococcal colonization (OR=4.48, 95% CI, 1.11-18.03, P=0.035); and previous empirical therapy with cephalosporins (OR=4.16, 95% CI, 0.93-18.66 for 1-7 days of therapy, and OR=7.31, 95% CI, 1.78-30.12 for 8-23 days, P=0.018). Higher Karnofsky score (≥50) and previous empirical therapy with glycopeptides were associated with a decreased risk (OR=0.25, 95% CI, 0.06-0.97, P=0.045 and OR=0.11, 95% CI, 0.02-0.59, P=0.010, respectively). The crude mortality at 7 and 30 days was 12% (4/33) and 24% (8/33), respectively. Enterococcal bacteremia is frequent after allogeneic HSCT. The factors associated with this infection are type of transplant, pharyngeal colonization, severe mucositis, and use of cephalosporins. Good general conditions and the use of vancomycin were associated with lower risk of enterococcal bacteremia.

A single amino acid substitution in highly similar endo-PGs from Fusarium verticillioides and related Fusarium species affects PGIP inhibition.

Endo-polygalacturonase (PG) may be a critical virulence factor secreted by several fungi upon plant invasion. The single-copy gene encoding PG in Fusarium verticillioides and in eight other species of the Gibberella fujikuroi complex (F. sacchari, F. fujikuroi, F. proliferatum, F. subglutinans, F. thapsinum, F. nygamai, F. circinatum, and F. anthophilum) was functionally analyzed in this paper. Both the nucleotide and amino acid sequences were highly similar among the 12 strains of F. verticillioides analyzed, as well as among those from the G. fujikuroi complex. The PGs were not inhibited by the polygalacturonase-inhibiting proteins (PGIPs) from the monocot asparagus and leek plants, but were inhibited to variable extents by bean PGIP. PGs from F. verticillioides, F. nygamai and one strain of F. proliferatum were barely inhibited. Residue 97 within PG was demonstrated to contribute to the different levels of inhibition. Together these findings provide new insights into the structural and functional relationships between the PG from the species of the G. fujikuroi complex and the plant PGIP.

Lymphocyte subsets recovery following allogeneic bone marrow transplantation (BMT): CD4+ cell count and transplant-related mortality.

To assess the kinetics of lymphocyte subset recovery, 758 allografted patients were monitored by surface markers (CD3, CD4, CD8, CD56), with a 5-year follow-up. The donor was a matched sibling donor (MSD) (n=502) or an alternative donor (family mismatched or unrelated, AD) (n=256). The stem cell source was bone marrow for all patients. CD4+ cell recovery was influenced -- in univariate analysis -- by three factors: donor type, patient age and GvHD. This was not the case for CD8+ and CD56+ cells. The median CD4+ cell count on day +35 after HSCT was 86/mul. Patients achieving this CD4+ cell count had significantly lower transplant-related mortality (TRM) compared to patients who did not achieve this CD4+ cell count (20 vs 39%, P=0.00001), due to a lower risk of lethal infections (24 vs 47%, P=0.0003). In multivariate analysis MSD (RR 3.45, P=0.0001) and recipient age less than 16 years (RR 3.23, P=0.003) were significantly associated with a better CD4+ cell recovery. CD4+ counts on day +35 was predicted TRM (RR=1.97, P=0.0017) together with acute GvHD grade II-IV (RR 1.59, P=0.0097). No difference of TRM was observed for CD8+ and CD56+ cell counts.

Improved outcome in young adults with de novo acute myeloid leukemia in first remission, undergoing an allogeneic bone marrow transplant.

We assessed the outcome of 170 patients with AML in first complete remission, aged 1-47 years (median 29), who had undergone an allogeneic BMT before or after 1990 (n=80 and n=90, respectively); all patients were prepared with cyclophosphamide and TBI; the median follow-up for surviving patients was 13 years. The donor was an HLA-identical sibling in 164 patients. Transplant-related mortality (TRM) was 30% before and 7% after 1990 (P<0.001); relapse-related death (RRD) was 26 and 11% (P=0.002); and actuarial 10-year survival was 42 and 79% (P<0.00001). Patients transplanted after 1990 were older, had a shorter interval diagnosis-BMT, had less FAB-M3 cases, received a higher dose of TBI, a higher marrow cell dose and combined (cyclosporine+methotrexate) GVHD prophylaxis. Patients relapsing after transplant had an actuarial survival of 0 vs 31% if grafted before or after 1990 (P=0.01), and their median follow-up exceeds 10 years. In conclusion, the overall survival of first remission AML undergoing an allogeneic BMT has almost doubled in the past two decades, despite older age and fewer M3 cases. Improvement has come not only from changes in transplant procedures, but also from effective rescue of patients relapsing after transplant.

Allogeneic hemopoietic stem cell transplants for patients with relapsed acute leukemia: long-term outcome.

We assessed the long-term outcome of patients with relapsed acute myeloid (n=86) or acute lymphoid leukemia (n=66), undergoing an allogeneic hemopoietic stem cell transplantation in our unit. The median blast count in the marrow was 30%. Conditioning regimen included total body irradiation (TBI) (10-12 Gy) in 115 patients. The donor was a matched donor (n=132) or a family mismatched donor (n=20). Twenty-two patients (15%) survive disease free, with a median follow-up of 14 years: 18 are off medications. The cumulative incidence of transplant related mortality is 40% and the cumulative incidence of relapse related death (RRD) is 45%. In multivariate analysis of survival, favorable predictors were chronic graft-versus-host disease (GvHD) (P=0.0003), donor other than family mismatched (P=0.02), donor age less than 34 years (P=0.02) and blast count less than 30% (P=0.07). Patients with all four favorable predictors had a 54% survival. In multivariate analysis of relapse, protective variables were the use of TBI (P=0.005) and cGvHD (P=0.01). This study confirms that a fraction of relapsed leukemias is cured with an allogeneic transplant: selection of patients with a blast count <30%, identification of young, human leukocyte antigen-matched donors and the use of total body radiation may significantly improve the outcome.

Pectin methylesterase inhibitor.

Pectin methylesterase (PME) is the first enzyme acting on pectin, a major component of plant cell wall. PME action produces pectin with different structural and functional properties, having an important role in plant physiology. Regulation of plant PME activity is obtained by the differential expression of several isoforms in different tissues and developmental stages and by subtle modifications of cell wall local pH. Inhibitory activities from various plant sources have also been reported. A proteinaceous inhibitor of PME (PMEI) has been purified from kiwi fruit. The kiwi PMEI is active against plant PMEs, forming a 1:1 non-covalent complex. The polypeptide chain comprises 152 amino acid residues and contains five Cys residues, four of which are connected by disulfide bridges, first to second and third to fourth. The sequence shows significant similarity with the N-terminal pro-peptides of plant PME, and with plant invertase inhibitors. In particular, the four Cys residues involved in disulfide bridges are conserved. On the basis of amino acid sequence similarity and Cys residues conservation, a large protein family including PMEI, invertase inhibitors and related proteins of unknown function has been identified. The presence of at least two sequences in the Arabidopsis genome having high similarity with kiwi PMEI suggests the ubiquitous presence of this inhibitor. PMEI has an interest in food industry as inhibitor of endogenous PME, responsible for phase separation and cloud loss in fruit juice manufacturing. Affinity chromatography on resin-bound PMEI can also be used to concentrate and detect residual PME activity in fruit and vegetable products.

Expression of the 67-kDa laminin receptor in acute myeloid leukemia cells mediates adhesion to laminin and is frequently associated with monocytic differentiation.

Lodgement, proliferation, and migration of leukemic cells within bone marrow (BM) microenvironment involves adhesion of these cells to the BM extracellular matrix molecules fibronectin and laminin. The 67-kDa laminin receptor (67LR) is a nonintegrin protein with high affinity for laminin, which plays a critical role in basement membrane invasion and metastasis of cancer cells. By Western blotting, we documented that 67LR was strongly expressed in myelomonocytic THP1 and histiocytic U937 cells and was weakly expressed in promyelocytic HL-60 cells. In HL-60 cells, 67LR expression almost disappeared after retinoic-induced granulocytic differentiation, whereas it strongly increased after phorbol ester-induced monocytic differentiation. We did not detect 67LR expression in normal BM hematopoietic cells, in precursor-B acute lymphoblastic leukemia, in chronic lymphocytic leukemia, or in chronic myeloid leukemia in chronic phase. By contrast, we detected enhanced 67LR expression in 40% of 53 de novo acute myeloid leukemias (AMLs), which frequently exhibited monocytic or myelomonocytic morphology and expressed CD14 and CD11a (P < 0.05). Using a colorimetric assay, we found that the expression pattern of this receptor corresponded to a higher adhesion to laminin; the adhesion was specific because in vitro addition to laminin-coated wells of recombinant 37-kDa laminin receptor precursor (37LRP), which is the cytoplasmic precursor containing both laminin-binding domains of cell surface 67LR, significantly reduced laminin binding of AML cells. The expression of 67LR on AML cell surface did not correlate with other differentiation and integrin antigens such as CD7, CD13, CD33, CD34, CD11b, CD11c, CD49d, CD49e, CD45RA, and CD45RO. In contrast with 67LR behavior in solid tumors, no statistically significant difference was found between 67LR expression and any hematological characteristic of the disease at diagnosis, nor between 67LR expression and outcome of the disease as measured by complete remission rate, disease-free survival, or overall survival. In conclusion, our results indicate that 67LR expression mediates specific adhesion to laminin and that the detection of this molecule may be a valuable addition to other lineage-associated antigens in identifying monocytic-oriented AML.

Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update.

This is a report of 148 patients with hematologic malignancies who received an unmanipulated haploidentical bone marrow transplant (BMT), followed by post-transplant high-dose cyclophosphamide (PT-CY). All patients received a myeloablative conditioning consisting of thiotepa, busulfan, fludarabine (n=92) or TBI, fludarabine (n=56). The median age was 47 years (17-74); 47 patients were in first remission (CR1), 37 in second remission (CR2) and 64 had an active disease; all patients were first grafts. The diagnosis was acute leukemia (n=75), myelodisplastic syndrome (n=24), myelofibrosis (n=16), high-grade lymphoma (n=15) and others (n=18). GVHD prophylaxis consisted in PT-CY on days +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median day for neutrophil engraftment was day +18 (13-32). The cumulative incidence of grades II-IV acute GVHD was 24%, and of grades III-IV GVHD 10%. The incidence of moderate-severe chronic GVHD was 12%. With a median follow-up for the surviving patients of 313 days (100-1162), the cumulative incidence of transplant-related mortality (TRM) is 13%, and the relapse-related death is 23%. The actuarial 22 months overall survival is 77% for CR1 patients, 49% for CR2 patients and 38% for patients grafted in relapse (P<0.001). Major causes of death were relapse (22%), GVHD (2%) and infections (6%). We confirm our initial results, suggesting that a myeloablative conditioning regimen followed by unmanipulated haploidentical BMT with PT-CY, results in a low risk of acute and chronic GVHD and encouraging rates of TRM and overall survival, also for patients with active disease at the time of transplant.

DLI after haploidentical BMT with post-transplant CY.

Forty-two patients relapsing after an unmanipulated haploidentical BM transplant and post-transplant CY (PT-CY), were given 108 DLI, with median interval from transplant of 266 days (range, 67-1372). DLI were given at escalating doses, expressed as CD3+ cells/kg, without GVHD prophylaxis, and ranged from 1 × 10(3) to 1 × 10(7) cells/kg (median 5 × 10(5) cells/kg). The average number of DLI per patient was 2.6 (range, 1-6). The diagnosis was leukemias (n=32) grafted with a myeloablative regimen and Hodgkin's disease (n=10), grafted with a nonmyeloablative regimen. Leukemic patients with molecular relapse (n=20), received DLI alone (n=17) or in association with azacytidine (n=3); leukemic patients with hematologic relapse (n=12) received chemotherapy followed by DLI (n=11) or DLI alone (n=1); Hodgkin patients received DLI following 1-3 courses of chemotherapy. In these three groups the incidence of acute GVHD II-III was 15%, 17% and 10%; response rate was 45%, 33% and 70%; 2-year actuarial survival was 43%, 19% and 80% respectively. This study confirms that escalating doses of DLI can be given in the haploidentical setting with PT-CY, with a relatively low risk of acute GVHD. Response rates and survival are dependent on the underlying disease.

Two Arabidopsis thaliana genes encode functional pectin methylesterase inhibitors.

We have identified, expressed and characterized two genes from Arabidopsis thaliana (AtPMEI-1 and AtPMEI-2) encoding functional inhibitors of pectin methylesterases. AtPMEI-1 and AtPMEI-2 are cell wall proteins sharing many features with the only pectin methylesterase inhibitor (PMEI) characterized so far from kiwi fruit. Both Arabidopsis proteins interact with and inhibit plant-derived pectin methylesterases (PMEs) but not microbial enzymes. The occurrence of functional PMEIs in Arabidopsis indicates that a mechanism of controlling pectin esterification by inhibition of endogenous PMEs is present in different plant species.

Ultrasound-guided fine needle cutting biopsy for the characterization of diffuse liver diseases in bone marrow transplant patients.

Liver disease is a frequent complication in bone marrow transplant recipients and may occur early or late in the post-transplant period. Using ultrasound-guided fine needle (1.2 mm, 18 G) cutting biopsy, we studied six patients with undefined late post-BMT liver disease. No procedure-related complications occurred and all liver biopsies were informative, leading to changes in therapeutic approach. In our small series, the most frequent cause of hepatic damage was drug toxicity. US-guided fine needle cutting biopsy is a useful and easy tool for the work-up of unexplained post-BMT liver disease.

CD34+-enriched donor lymphocyte infusions in a case of pure red cell aplasia and late graft failure after major ABO-incompatible bone marrow transplantation.

A variety of immunohematological complications may occur after ABO-incompatible BMT. We report a CML patient (blood group O) who received a BMT from an HLA-identical sibling (blood group AB). The transplant was followed by normal myeloid and megakaryocytic engraftment, but erythroblastopenia persisted for more than 200 days after BMT. By bone marrow culture studies, a complement-dependent serum inhibitor of hemopoiesis was detected, suggesting immunological inhibition of erythropoiesis. The patient was resistant to a number of treatments such as intravenous gamma-globulins, prednisolone and high-dose erythropoietin. Full engraftment with normal blood counts and marrow cellularity was achieved after two dose-escalating CD34+-enriched donor lymphocyte infusions (DLI). This experience suggests that CD34+-enriched DLI may be an effective treatment for patients with delayed engraftment or late graft failure due to major ABO-incompatibility.

Lamivudine treatment for chronic replicative hepatitis B virus infection after allogeneic bone marrow transplantation.

The risk of severe hepatic damage in patients with chronic hepatitis B virus (HBV) infection is well known; more effective treatments for this infection are needed. Lamivudine is being studied in immunocompetent and immunosuppressed HBV infected patients. We report a patient suffering from chronic replicative HBV infection after allogeneic BMT, who responded to lamivudine therapy. A 24-year-old woman with CML received an allogeneic BMT from her HLA-identical sister in June 1992. Before transplant, her HBV status demonstrated viral contact without active infection (HBsAb+, HBcAb+ IgG, HBeAb+). Four months after BMT mild chronic liver GVHD appeared, requiring immunosuppressive treatment. Antibodies to HBV completely disappeared post-transplant. Acute icteric hepatitis occurred 2 years later, with HBsAg+, high level of HBV-DNA, HBeAg+ and HBcAb IgM+. Lamivudine 100 mg/day rapidly reduced transaminase levels and effected HBV-DNA disappearance within 2 months. The treatment was well tolerated; no hematological side-effects occurred. This preliminary observation warrants further investigation of lamivudine treatment in bone marrow transplanted patients with active HBV infection.

Foscarnet prophylaxis of cytomegalovirus infections in patients undergoing allogeneic bone marrow transplantation (BMT): a dose-finding study.

This is a dose-finding study using foscarnet for CMV prophylaxis after allogeneic bone marrow transplantation (BMT) in 20 high risk patients (unrelated donors, or T cell depleted, and/or advanced disease). Foscarnet was started on day +1 after BMT and continued until day +100. We explored four different dose levels, patients being entered at the lowest dose level until one patient experiences CMV-reactivation, identified as two consecutive positive CMV antigenemias (CMVAg-emia). The four dose levels expressed as mg/kg/day between days 1 and 30 (induction) and between days 31 and 100 (maintenance) were respectively: dose level I = 60/30 (n = 5); dose level II = 120/60 (n = 4); dose level III = 120/90 (n = 5) and dose level IV = 120/120 (n = 6). All patients showed engraftment: PMN > or =0.5 x 109/l at a median interval of 16, 21, 17, 15 days after BMT, and Plt > or =30x10(9)/l on days 19, 16, 17, 17 respectively. CMVAg-emia was seen in 10 patients at a median interval of 53 days post-BMT (range 33-89) with a median of 10 CMV antigen+ cells (range 1-16). There was a dose effect of foscarnet on CMVAg-emia: respectively 4/5 patients (80%), 2/4 (50%), 3/5 (60%) and 1/6 (18%) at dose levels I, II, III, IV (P = 0.1). CMV disease was seen in 3/9 (33%) at dose levels I, II and 0/11 at dose levels III, IV (P = 0. 07). The median number of CMV antigen-positive cells at diagnosis of CMV infection was different: 13 in dose levels I-II and two in dose levels III-IV (P = 0.01). Increased creatininine was seen in 15 patients with a mean of 1.8 mg% (range 1.5-5.7) and was the cause of discontinuation in nine patients (45%). Renal toxicity was reversible in all nine patients. Overall actuarial TRM at 2 years was 31%: 47% for patients at dose levels I-II and 19% for patients at dose levels III-IV. In conclusion, foscarnet exhibits a dose-dependent prophylactic effect on CMVAg-emia, CMV disease and transplant-related mortality with acceptable and reversible renal toxicity.

Early predictors of transplant-related mortality (TRM) after allogeneic bone marrow transplants (BMT): blood urea nitrogen (BUN) and bilirubin.

Transplant-related mortality (TRM) following allo- geneic bone marrow transplantation (BMT) remains a major concern and early identification of patients at risk may be clinically relevant. In this study we describe a predictive score based on bilirubin and blood urea nitrogen (BUN) levels on day +7 after BMT. The patient population consisted of 309 consecutive patients who underwent BMT from sibling (n = 263) or unrelated donors (n = 46) for hematologic disorders between December 1990 and December 1996. Of 27 laboratory tests taken on day +7 after BMT, serum bilirubin (P = 0.02) and BUN (P = 0.007) were found to be independent predictors of TRM in multivariate analysis. The median levels of bilirubin (0.9 mg/dl) and of BUN (21 mg/dl) were then used as a cut-off and a score of 1 was given for values equal/greater than the median. There were 216 patients with scores 0-1 (low risk) on day +7 (bilirubin <0.9 and/or BUN <21) and 93 patients with score 2 (high risk) (bilirubin >/=0.9 and BUN >/=21): the latter had more grade III-IV acute graft-versus-host disease (P = 0.03), slower neutrophil (P = 0.02) and slower platelet engraftment (P = 0.002). The actuarial 5 year TRM is 22% for low risk vs44% for high risk patients (P = 0.0003). For HLA-identical siblings TRM is 20% vs35% (P = 0.01), for unrelated donors it is 20% vs 65% (P = 0.01). Day +7 score was highly predictive of TRM on multivariate analysis (hazard ratio 1.9, P < 0.01), after adjustment for year of transplant (P < 0.00001), unrelated vs sibling donors (P = 0.001), patient age (P = 0.01) and diagnosis (P = 0.01). These results were validated on an independent group of 82 allogeneic BMT recipients in a pediatric Unit who showed an actuarial TRM of 16% for low risk vs 46% for high risk patients (P = 0.002). This study suggests that it may be possible to identify patients with different risks of TRM on day +7 after BMT: high risk patients could be eligible for programs designed to intensify prophylaxis of post-transplant complications.