Low incidence of severe cGvHD and late NRM in a phase II trial of thymoglobulin, tacrolimus and sirolimus for GvHD prevention.

Chronic GvHD (cGvHD) is the leading cause of late non-relapse mortality (NRM) and morbidity after allogeneic hematopoietic stem cell transplant (AHSCT). We analyzed the late effects of a phase II trial testing the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymoglobulin Thymo) in combination with tacrolimus and sirolimus (TTS) in 47 patients (pts) for the prevention of acute and chronic GvHD after unrelated AHSCT. The median follow-up was 45.2 months. The cumulative incidence of NIH severe cGvHD at 48 months was 6.4% with no new occurrences past 6 months for the entire follow-up period. The overall cumulative incidence of cGvHD was 44.7%. Out of 20 pts who are alive and disease-free at the last follow-up, only 4 pts continue to need systemic immune suppression. We observed low late NRM with only 3 transplant-related deaths after 6 months post transplant. At 4 years of follow-up, the overall cumulative incidence of NRM and disease relapse was 27.7% and 30.0%, respectively. PFS and overall survival (OS) at 4 years were 42 and 47%. At long term follow-up, TTS was associated with low incidence of severe cGvHD and late NRM.

Risk factors and impact of non-Aspergillus mold infections following allogeneic HCT: a CIBMTR infection and immune reconstitution analysis.

Risk factors for non-Aspergillus mold infection (NAMI) and the impact on transplant outcome are poorly assessed in the current era of antifungal agents. Outcomes of 124 patients receiving allogeneic hematopoietic cell transplantation (HCT) diagnosed with either mucormycosis (n=72) or fusariosis (n=52) between days 0 and 365 after HCT are described and compared with a control cohort (n=11 856). Patients with NAMI had more advanced disease (mucormycois: 25%, fusariosis: 23% and controls: 18%; P=0.004) and were more likely to have a Karnofsky performance status (KPS) <90% at HCT (mucormycosis: 42%, fusariosis: 38% and controls: 28%; P=0.048). The 1-year survival after HCT was 22% (15-29%) for cases and was significantly inferior compared with controls (65% (64-65%); P<0.001). Survival from infection was similarly dismal regardless of mucormycosis: 15% (8-25%) and fusariosis: 21% (11-33%). In multivariable analysis, NAMI was associated with a sixfold higher risk of death (P<0.0001) regardless of the site or timing of infection. Risk factors for mucormycosis include preceding acute GvHD, prior Aspergillus infection and older age. For fusariosis, increased risks including receipt of cord blood, prior CMV infection and transplant before May 2002. In conclusion, NAMI occurs infrequently, is associated with high mortality and appears with similar frequency in the current antifungal era.

Favorable impact of pre-transplant ATG on outcomes of reduced-intensity hematopoietic cell transplants from partially mismatched unrelated donors.

Reduced-intensity conditioning (RIC) permits allogeneic hematopoietic progenitor cell transplantation in patients who would not be considered candidates for transplantation using a myeloablative preparative regimen because of age, comorbidities or prior therapy. In the setting of myeloablative transplantation, use of antithymocyte globulin (ATG) can reduce the risk of GVHD without negatively affecting transplant outcomes; however, limited data exist on the impact of ATG in the setting of RIC, particularly when there is HLA-mismatch. We performed a retrospective analysis of 85 patients who received unrelated donor transplants at our institution for hematologic malignancies following conditioning with fludarabine and melphalan (FluMel), with or without rabbit ATG (6 mg/kg). ATG was targeted to patients receiving HLA-mismatched grafts. With a median follow-up of 36 months, those receiving ATG and a mismatched graft had similar rates of acute and chronic GVHD, relapse, and similar OS compared with those receiving HLA-matched grafts without ATG. In a multivariate analysis, HLA-mismatched donor was not associated with a decrement in OS. We conclude that this intermediate dose of ATG is effective in preventing severe GVHD in the setting of HLA-mismatch, without undue compromise of the graft versus tumor effects on which RIC transplants depend.

Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients.

Prior studies have shown that myeloma patients exhibiting either genetically defined high-risk disease or plasma cell leukemia have a poor outcome with a median overall survival (OS) of ≤3 years. Results of IFM 2005-01 and 02 suggest that relatively limited bortezomib-containing induction regimens did not produce a major survival benefit among these patients. However, results of recent studies suggest that combination therapy may benefit these patients when given early and again later in the treatment. We evaluated a combination maintenance/consolidation regimen (RVD) following autologous stem cell transplant (ASCT) for high-risk patients to evaluate the impact of this approach on outcome. Following initiation of RVD maintenance, 51% of patients achieved stringent complete response (sCR), with 96% achieving at least VGPR as best response. Median progression free survival (PFS) for all patients is 32 months with a 3-year OS of 93%. The regimen was well tolerated with no grade 3/4 neuropathy. Early ASCT followed by RVD maintenance is a promising strategy for high-risk myeloma patients and delivered excellent response rates, and promising PFS and OS.

Advances in antifungal prophylaxis and empiric therapy in patients with hematologic malignancies.

Invasive fungal infection (IFI) is associated with significant morbidity and mortality in patients with hematologic malignancies. There have been significant changes in the epidemiology and outcomes of IFI in this patient population, due in part to advances in transplant procedures, supportive care, and use of newer antifungal agents. A thorough knowledge of risk factors, potential causative organisms, and the safety and efficacy of appropriate antifungal agents is required to optimize treatment. Proper diagnosis of IFI is challenging and the correlation of delays in diagnosis and treatment with poor outcome suggest that earlier intervention may result in more effective management of high-risk patients. Because all risks may not be equal, stratifying high-risk patients may further help target patients most likely to benefit from prophylaxis. This review focuses on various risk factors specific to patients with hematologic malignancies and discusses the use of preemptive, empiric, and prophylactic strategies in the management of IFI in this patient population.

Eosinophilic pulmonary syndrome as a manifestation of GVHD following hematopoietic stem cell transplantation in three patients.

Eosinophilic pulmonary syndrome is an uncommon problem in SCT recipients that can mimic an infectious process. We report the occurrence of eosinophilic pulmonary syndrome in three patients following allogeneic hematopoietic stem cell transplantation (HSCT), and postulate that this entity is part of the clinicopathologic spectrum of pulmonary GVHD. In all three cases, active chronic GVHD of the skin preceded or coincided with the development of pulmonary involvement. Other common features included peripheral blood eosinophilia, diffuse bilateral pulmonary infiltrates and lung biopsies showing pronounced infiltrates of eosinophils involving the small bronchioles. All patients responded promptly to systemic steroid therapy, with improvement of their pulmonary symptoms and the resolution of peripheral blood eosinophilia. Clinicians should be aware that eosinophilic pulmonary syndrome can occur following HSCT, may be associated with other manifestations of chronic GVHD, and generally responds well to corticosteroid therapy.

Posaconazole as salvage treatment of invasive fungal infections in patients with underlying renal impairment.

OBJECTIVES: The aim of this study is to determine the efficacy and safety of posaconazole in patients with underlying renal impairment. Patients and methods We analysed the efficacy and safety of posaconazole in patients with renal impairment in a post hoc subanalysis of a Phase 3, multicentre, open-label trial in patients with invasive fungal infections (IFIs). In the Phase 3 study, 330 patients intolerant of or with IFIs refractory to standard antifungal therapy received posaconazole 800 mg daily in divided doses. In our subanalysis, 238 patients with proven/probable IFIs, including 65 patients with renal impairment (creatinine clearance < 50 mL/min or serum creatinine (sCR) level >2 mg/dL at baseline) and 173 patients with greater renal function [creatinine clearance >/= 50 mL/min (acceptable renal function)], formed the modified intent-to-treat population. Success was defined as complete or partial response, and non-success was defined as stable disease or treatment failure. RESULTS: Overall response rates were similar in the renal impairment group (49%) and in the acceptable renal function (50%) group. Seventeen of the 41 patients with renal impairment and aspergillosis responded. Adverse events occurred in 32/65 (49%) patients with renal impairment and in 72/173 (42%) patients with acceptable renal function. The most common adverse events in both groups were nausea (14% patients with renal impairment versus 8% with acceptable renal function), altered/elevated levels of other medications (8% versus 2%), increased sCR levels (6% versus 0%), vomiting (6% versus 4%), abdominal pain (5% versus 5%) and dizziness (5% versus 1%). CONCLUSIONS: These results suggest that posaconazole is effective and well tolerated in patients with refractory IFIs regardless of renal impairment.

Long-term progression-free survival after early autologous transplantation for mantle-cell lymphoma.

Autologous hematopoietic progenitor SCT (HPCT) has been studied both as a consolidative and salvage maneuver in mantle-cell lymphoma (MCL), and may improve failure-free survival rates as well as overall survival. We describe 21 patients with MCL who received autologous HPCT at Emory University Hospital as part of the primary treatment strategy. Sixteen patients were in CR1 and five in PR1 at the time of HPCT. The most commonly used induction chemotherapy was the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) regimen with or without rituximab. At the last follow-up, 17 patients were in continuous CR, and there were four relapses. There were no transplant-related deaths. With a median follow-up of 54 months from HPCT, 5-year progression-free survival and overall survival are 73% and 76%, respectively. Our retrospective analysis provides the longest follow-up to date for patients with MCL who received an autologous HPCT as part of primary treatment. This lengthy follow-up helps define the natural course of MCL after autologous transplantation.

Posaconazole treatment for Apophysomyces elegans rhino-orbital zygomycosis following trauma for a male with well-controlled diabetes.

We report a case of rhino-orbital zygomycosis in a 43-year-old male with well-controlled diabetes mellitus. The patient initially received liposomal amphotericin B, but the infection continued to progress, so posaconazole treatment was begun and eventually led to the cure of his infection. The causative agent was identified as Apophysomyces elegans, an emerging cause of zygomycosis in immunocompetent hosts.

Clinical determinants of quality of life in Paget's disease of bone.

Paget's disease of bone (PDB) can adversely affect quality of life, but relatively little is known about the clinical predictors of reduced quality of life in patients with the disease. Here, we studied quality of life and its determinants in a large cohort of PDB patients who had been enrolled into the PRISM study, a randomized comparative trial of intensive versus symptomatic treatment for PDB. Health-related quality of life was assessed using the Short-Form 36 (SF36) questionnaire and other validated assessment instruments in 1,324 subjects with PDB. Clinical predictors of quality of life were identified by multivariate regression analysis. The physical summary (mean +/- standard deviation) score of the SF36 was substantially reduced in PDB to 36.3 +/- 11.3 compared with the expected population norm of 50 (P < 0.001). The mental summary score was only slightly reduced, to 48.7 +/- 11.8, in PDB; but this was statistically significant (P < 0.001). Bone pain due to PDB, previous bisphosphonate therapy, and increasing age were identified as negative predictors of the SF36 physical summary score (P < 0.001); but serum levels of total alkaline phosphatase (ALP) did not predict physical summary score. We conclude that PDB has a substantial negative impact on health-related quality of life, which mainly affects physical functioning. The lack of correlation between ALP and quality of life observed in this study emphasizes the importance of addressing quality-of-life issues when treating PDB and not just focussing on response of ALP levels.

Posaconazole as salvage therapy for zygomycosis.

Zygomycosis, an infection that is associated with significant morbidity and mortality, is becoming common in immunocompromised patients. Posaconazole is a new extended-spectrum azole antifungal that has demonstrated in vitro and in vivo activity against zygomycetes. This report provides the results from the first 24 patients with active zygomycosis who were enrolled in two open-label, nonrandomized, multicentered compassionate trials that evaluated oral posaconazole as salvage therapy for invasive fungal infections. Posaconazole was usually given as an oral suspension of 200 mg four times a day or 400 mg twice a day. Eleven (46%) of the infections were rhinocerebral. Duration of posaconazole therapy ranged from 8 to 1,004 days (mean, 292 days; median, 182 days). Rates of successful treatment (complete cure and partial response) were 79% in 19 subjects with zygomycosis refractory to standard therapy and 80% in 5 subjects with intolerance to standard therapy. Overall, 19 of 24 subjects (79%) survived infection. Survival was also associated with surgical resection of affected tissue and stabilization or improvement of the subjects' underlying illnesses. Failures either had worsening of underlying illnesses or requested all therapy withdrawn; none of the failures received more than 31 days of posaconazole. Posaconazole oral solution was well tolerated and was discontinued in only one subject due to a drug rash. Posaconazole appears promising as an oral therapy for zygomycosis in patients who receive required surgery and control their underlying illness.

Management of Paget's disease of bone.

Paget's disease of bone is a common condition with a strong genetic component, characterized by focal increases in bone turnover, affecting one or more bones throughout the skeleton. Paget's disease can be asymptomatic but is frequently associated with bone pain, bone deformity, pathological fracture, secondary osteoarthritis and deafness. Inhibitors of osteoclastic bone resorption, such as bisphosphonates and calcitonin, suppress bone turnover and improve bone pain in Paget's disease. Many patients also require therapy with analgesics and anti-inflammatory agents, since pain in Paget's disease can arise not only from increased bone turnover but also from complications such as osteoarthritis and nerve compression syndromes, which do not respond well to antiresorptive therapy. Comparative studies have shown that second- and third-generation bisphosphonates, such as tiludronate, alendronate and risedronate, are more effective than etidronate at inhibiting bone turnover in Paget's disease but they have not been found to be significantly more effective in controlling bone pain. Importantly, none of the treatments that are currently available for Paget's disease have been shown to prevent complications such as deafness, fracture or bone deformity, or to alter the natural history of the disease. More research is required to define the long-term effects of antiresorptive treatment on clinical outcomes in Paget's disease, so that clinicians and their patients can make better-informed choices about the risks and benefits of treatment.

Does patient controlled analgesia delay the diagnosis of compartment syndrome following intramedullary nailing of the tibia?

We report on four cases in which the diagnosis of compartment syndrome was delayed by the administration of patient controlled analgesia (PCA) following intramedullary nailing of tibial shaft fractures. We believe that this poses a diagnostic problem and can lead to lasting sequelae as decompression is delayed. We recommend extra vigilance with the use of PCA in patients with intramedullary nailing following tibial shaft fractures.

Susceptibility of three different strains of juvenile Atlantic halibut (Hippoglossus hippoglossus L.) cultured at two different temperatures to Vibrio anguillarum and temperature effect on antibody response.

Three geographically distinct-reared strains (Canadian, Icelandic, Norwegian) of juvenile Atlantic halibut (Hippoglossus hippoglossus L.) cultured at optimal and super-optimal growth temperatures (12 and 18 degrees C respectively), were challenged with a virulent isolate of Vibrio anguillarum by injection. The halibut were injected intraperitoneally with 100 microl of the bacterial suspension (1 x 10(6) cells per fish). After challenge, temperature and strain-related differences in survival were observed. Canadian and Icelandic halibut cultured at the super-optimal temperature of 18 degrees C were significantly more susceptible to infection than those strains cultured at 12 degrees C. Total mortality at 18 degrees C for the Canadian and Icelandic strains was 56.4 and 61.85% respectively, compared to 32 and 26.6% respectively at 12 degrees C. Norwegian halibut were significantly more resistant to infection with V. anguillarum at 18 degrees C compared to the other strains, with total mortality of 13.3%. There was no significant difference in total mortality of Norwegian halibut at 18 or 12 degrees C (13.3, 25% respectively). The specificity of the antibodies in sera from challenged halibut cultured at 18 degrees C was primarily to LPS. Immunoblots showed the presence of antibodies against O-side chain antigens. This reaction was strongest in sera from the Norwegian halibut strain compared with the Canadian and Icelandic halibut, which suggests that the difference in resistance to challenge may be ascribable to the presence of antibodies to LPS. Specific antibody levels, as measured by ELISA, increased with increasing temperature and strain differences were apparent, however these did not relate to disease resistance.

Rapid hematopoietic engraftment following fractionated TBI conditioning and transplantation with CD34(+) enriched hematopoietic progenitor cells from partially mismatched related donors.

Nineteen adult patients with poor-risk hematologic malignancy received T cell-depleted (TCD) hematopoietic progenitor cell (HPC) transplant from partially mismatched related donors (PMRD). The preparative regimen (FITFA) included fractionated TBI, thiotepa, fludarabine, and horse (n = 3) or rabbit (n = 16) anti-thymocyte anti-sera (ATG). GVHD prophylaxis consisted of TCD by positive/negative selection using the Isolex 300i system and pre-transplant ATG with no post-transplant immunosuppression. The mean number (+/-s.d.) of transplanted CD34(+) and CD3(+) cells were 8.9 x 10(6)/kg +/-4.3 (range 2.6-19.3) and 1.4 x 10(4)/kg +/-1.2 (range 0.3-4.6) respectively. Seventeen patients evaluable for neutrophil engraftment achieved an ANC >0.5 x 10(9)/l at a median of 12 days (range 9-27), with evidence of full donor chimerism. Thirteen patients died of the following causes: relapse (n = 6), infections (n = 5), interstitial pneumonia (n = 1), and unknown causes (n = 1) None of the recipients of rabbit ATG required therapy for acute or chronic GVHD. Five patients are alive and disease-free at a median time of 303 days post transplant (range 100-660). The FITFA preparative regimen using fractionated TBI is well tolerated and is sufficiently immunosuppressive to allow rapid and stable donor origin hematopoietic engraftment without 'mega' doses of CD34(+) cells. Combination of stringent ex vivo TCD and pre-transplant ATG is effective GVHD prophylaxis.

The effect of temperature on non-specific defence parameters of three strains of juvenile Atlantic halibut (Hippoglossus hippoglossus L.).

The effect of temperature (8, 12, 15 and 18 degrees C) on a variety of non-specific defence and haematological parameters was examined in three geographically distinct reared strains (Canadian, Icelandic, Norwegian) of Atlantic halibut. The results indicate that temperature exerts a considerable influence on some blood parameters (packed cell volume and the percentage population of leucocytes in peripheral blood) and on some humoral parameters (serum lysozyme activity and serum protein levels) of halibut. A high temperature of 18 degrees C caused a decrease in the number of circulating blood cells and an increase in serum lysozyme levels; effects consistent with those reported within the literature for stress. The different strains of halibut exhibited differing responses with respect to differential counts of peripheral blood lymphocytes and thrombocytes, and to serum protein concentrations, serum lysozyme activity, serum iron content, unsaturated iron binding capacity of serum and O2- production by kidney macrophages.

The kinetics of the hypoferraemic response and changes in levels of alternative complement activity in diploid and triploid Atlantic salmon, following injection of lipopolysaccharide.

To study any possible effects of triploidy on the kinetics of the response of two non-specific disease factors, full sibling diploid and triploid Atlantic salmon were injected intraperitoneally with either lipopolysaccharide (1 mg kg(-1) body weight) or saline. Individually marked fish were repetitively blood sampled for up to 19 days. Total serum protein concentrations remained constant throughout the experiment indicating that the sampling regime did not cause haemodilution. The alternative complement pathway activity (measured by the titre of haemolytic activity against rabbit erythrocytes) in the serum of saline injected fish remained constant but in LPS-injected fish it fell to barely detectable levels 2 days after injection, but recovered to pre-treatment levels by about day 5. Triploid fish took slightly longer to reach full recovery levels than diploids. All groups of fish showed a hypoferraemic response, suggesting that the sampling regime was at least partially responsible. However, the response was more rapid and pronounced in the LPS-injected fish. In the latter, serum iron concentrations decreased to very low levels by day 2 post-injection in the diploid fish and by day 3 in the triploid fish. Pre-treatment iron levels were re-established by about 15 days post-injection in all groups. The data show only slight differences between the diploid and triploid fish, but the longer time taken for the triploids to recover complement activity and the slower onset of the hypoferraemic response following injection of LPS, suggest that they may be at a disadvantage compared with their diploid siblings in their defence against bacterial infections.