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The current recommendations for active immunization after stem cell transplant (SCT) include 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7) from 3 months after transplant, followed by a 23-valent polysaccharide pneumococcal vaccine (PPV23). However, until now, the immune response to PPV23 after PCV7 has not been assessed after SCT. In the EBMT IDWP01 trial, 101 patients received 1 dose of PPV23 at 12 or 18 months, both after 3 doses of PCV7. The efficacy of PPV23 was assessed 1 month later and at 24 months after transplant by the pneumococcal serotype 1 and 5 antibody levels. Serotype 1 and 5 are not included in PCV7. Although the geometric mean concentrations were significantly higher 1 month after PPV23, for both antigens, the response rates (> or =0.15 microg/mL), in the range of 68-94%, were not different between groups independent of the assessment date. One PPV23 dose after 3 PCV7 doses, already known to increase the response to PCV7, also extends the serotype coverage given 12 or 18 months after transplant., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Invasive pneumococcal disease is a life-threatening complication after allogeneic stem cell transplantation, and at least 20% of cases occur within 1 year after transplantation. The 23-valent pneumococcal polysaccharide vaccine (PPV23) has limited efficacy, especially during the first year after transplantation. The immune response to the conjugated vaccines is expected to be better than that to the polysaccharide vaccine, but the optimal timing of vaccination is not defined. Our objective was to show that a 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) was not inferior when first given 3 months after transplantation, compared with when first given 9 months after transplantation., Methods: We performed a multicenter, randomized, noninferiority study involving 158 patients from 13 European Group for Blood and Marrow Transplantation centers who were randomly allocated at approximately 100 days after myeloablative stem cell transplantation to receive a series of vaccinations (3 doses of PCV7 given 1 month apart) that was started immediately (i.e., 3 months after transplantation) or 6 months later (i.e., 9 months after transplantation). The primary evaluation criterion was the rate of response (antibody level, > or = 0.15 microg/mL for each of the 7 serotypes) at 1 month after the third dose of PCV7. The noninferiority margin was 20%. All patients were followed up for 24 months after transplantation or until death, whichever occurred first., Results: We found that the response rate was not lower after early vaccination (79% [45 of 57 patients]) than after late vaccination (82% [47 of 57 patients]) (difference, -3.5%; 90% confidence interval, -15.6 to 8.6; not significant)., Conclusions: We conclude that PCV7 vaccination at 3 months after stem cell transplantation is not inferior to PCV7 vaccination at 9 months after transplantation. Because invasive pneumococcal disease can occur early, we recommend starting the PCV7 vaccination series at 3 months after transplantation to ensure earlier protection against Streptococcus pneumoniae. However, the early vaccination may result in only short-lasting response and may not prime for a 23-valent pneumococcal polysaccharide vaccine boost as efficiently as the late vaccination.

Purpose: In the era of molecular therapy of chronic myelogenous leukemia (CML) applying BCR-ABL tyrosine kinase inhibitors, the usefulness of molecular end points, in particular, quantitative polymerase chain reaction (PCR) for BCR-ABL in monitoring responses has been broadly accepted. Therefore, we have designed a prospective phase II trial in CML, which, for the first time, evaluated the feasibility and safety of molecular end points as surrogate markers to guide through a stratified treatment algorithm within a multicenter trial., Patients and Methods: As a clinical model, we adopted minimal residual disease (MRD) found in relapse after allogeneic stem cell transplantation (SCT) in CML. Forty-four patients were enrolled and received the BCR-ABL tyrosine kinase inhibitor imatinib (IM) at a starting dose of 400 mg/d. The quality of molecular responses achieved then decided on discontinuation of IM or dose escalation up to 800 mg/d, and finally, on application of donor lymphocyte infusions. Results Seventy percent of patients achieved a complete molecular response (CMR), defined as nested PCR-negativity for BCR-ABL in three consecutive samples. Interestingly, in four out of 10 patients who discontinued IM, CMR was durable even after cessation of IM with a median follow-up of 494 days. This suggests the possibility of long-term tumor control in a subset of patients., Conclusion: The treatment strategy showed that IM treatment was well-tolerated and highly efficacious in MRD after allogeneic SCT. Moreover, this study demonstrated that evaluation of a molecular end point within a multicenter trial can be a safe and effective tool for clinical decision making.

Background: Isolated case reports have shown that recipients of allogeneic hematopoietic stem cell transplants (HSCTs) who develop toxoplasmosis may have circulating Toxoplasma gondii DNA in peripheral blood before the onset of clinical symptoms., Methods: We prospectively studied 106 T. gondii-seropositive adult recipients of HSCTs for the incidence of reactivation of toxoplasmosis in the first 6 months after transplantation. Toxoplasmosis infection (TI) was defined by a positive result of polymerase chain reaction (PCR) of peripheral blood specimens, whereas toxoplasmosis disease (TD) was defined as an invasive infection., Results: The incidence of TI was 16% (95% confidence interval [CI], 8%-21%), whereas the incidence of TD was 6% (95% CI, 1%-10%). In the 16 patients with TI, the incidence of disease was 38%, whereas it was 0% in patients without TI (P<.0001). In most patients, the onset of TD or treatment for TI was preceded by an increase in the parasite load in peripheral blood samples, as determined by quantitative PCR., Conclusions: Toxoplasmosis occurs more commonly after HSCT than has previously been suggested, and routine PCR testing of peripheral blood specimens may be an appropriate tool for guiding preemptive therapy in patients at very high risk of developing invasive disease.

Invasive fungal infections are associated with a high morbidity and mortality. They are of growing concern and a severe infectious complication in cancer patients treated with intensive chemotherapy. Within the last five years substantial progress has been demonstrated for non-culture based diagnostics and treatment of invasive fungal infections. Recent developments in the epidemiology, diagnostics and treatment of fungal infections are reviewed and discussed in the context of the current state of art for the management of invasive fungal infections in cancer patients.

Vaccinations are safe and effective in immunocompromised patients. Apparently most vaccines in this patient population are underutilized. General vaccination recommendations are expressed for influenza, diphtheria and tetanus. Pneumococcal, meningococcal und Haemophilus influenzae B immunizations are specially indicated for patients with or developing B-cell-deficiency. Live attenuated vaccines are usually contraindicated. The efficacy of the immunization and its indication can be additionally measured by antibody response, which is usually decreased compared to healthy subjects. Immunocompromised hosts with cancer will benefit from consistent immunization practices. Further clinical trials are urgently warranted.

The risk of infection after allogeneic stem cell transplantation is determined by the underlying disease, the intensity of previous treatments and complications that may have occurred during that time, but above all, the risk of infection is determined by the selected transplantation modality (e.g. HLA-match between the stem cell donor and recipient, T cell depletion of the graft, and others). In comparison with patients treated with high-dose chemotherapy and autologous stem cell transplantation, patients undergoing allogeneic stem cell transplantation are at a much higher risk of infection even after hematopoietic reconstitution, due to the delayed recovery of T and B cell functions. The rate at which immune function recovers after hematopoietic reconstitution greatly influences the incidence and type of post-transplant infectious complications. Infection-associated mortality, for example, is significantly higher following engraftment than during the short neutropenic period that immediately follows transplantation.

Invasive fungal infections cause substantial morbidity and mortality in immunocompromised patients, particularly in those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. Difficulties in diagnosing invasive fungal infections and subsequent delays in treatment initiation lead to unfavourable outcomes and emphasise the importance of prophylaxis. Since the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology in 2009, results of 14 additional clinical studies have been published comprising 2,899 patients and initiating this update. Key recommendations for adult patients are as follows: Posaconazole remains the drug of choice during remission-induction chemotherapy in acute myeloid leukaemia, myelodysplastic syndrome and allogeneic haematopoietic stem cell transplantation with graft versus host disease (AI). In the pre-engraftment period of allogeneic transplantation, several antifungals are appropriate and can be recommended with equal strength: voriconazole (BI), micafungin (BI), fluconazole (BI) and posaconazole (BII). There is poor evidence regarding antifungal prophylaxis in the post-engraftment period of allogeneic haematopoietic stem cell transplantation if no steroids for treatment of graft versus host disease are required. Aerosolised liposomal amphotericin B inhalation in conjunction with fluconazole can be used in patients with prolonged neutropenia (BII). [ABSTRACT FROM AUTHOR]

Study Objective. To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infections in recipients of hematopoietic stem cell transplants (HSCTs) who have graft-versus-host disease (GVHD). Design. Pharmacokinetic analysis in a subset of posaconazole-treated patients from a large, multicenter, phase III, randomized, double-blind, double-dummy, parallel-group trial that compared posaconazole with fluconazole. Setting. Ninety international medical centers. Patients. The subset of patients comprised 246 HSCT recipients for whom pharmacokinetic data were available. Intervention. All patients received posaconazole 200 mg oral suspension 3 times/day for a maximum of 16 weeks. Measurements and Main Results. Blood samples were collected after dosing on day 2; at weeks 2, 4, 8, and 12; and on the last day of. oral treatment. After patients had received posaconazole for at least 7 days (i.e., after achieving steady state), both maximum observed posaconazole concentration (Cmax) and average posaconazole concentration (Cav) were determined. Five patients developed invasive fungal infections while receiving treatment. Median Cav and Cmax were 611 and 635 ng/ml, respectively, in these five patients and were 922 and 1360 ng/ml, respectively, in the 241 patients without invasive fungal infection. In patients without invasive fungal infection, posaconazole concentrations were not clinically affected by race, body weight, or age. Median plasma posaconazole concentrations were higher in patients with chronic GVHD than in those with acute GVHD. In 18 patients without invasive fungal infection who experienced diarrhea on the day of sampling, posaconazole concentrations were lower than the concentrations in patients without diarrhea. No relationship was observed between alanine aminotransferase, aspartate aminotransferase, or bilirubin levels and posaconazole concentrations. Conclusion. Posaconazole 200 mg 3 times/day resulted in median plasma drug concentrations sufficiently high to prevent invasive fungal infections in HSCT recipients with GVHD, without compromising patient safety. Plasma posaconazole concentrations are generally unaffected by demographic variables, including race, sex, body weight, and age. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor in response to the article "Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients:A multicenter, randomized trial," by D. J. Winston et al., published in a previous issue.

Background: Invasive fungal infections are an important cause of morbidity and mortality after allogeneic hematopoietic stem-cell transplantation. Methods: In an international, randomized, double-blind trial, we compared oral posaconazole with oral fluconazole for prophylaxis against invasive fungal infections in patients with graft-versus-host disease (GVHD) who were receiving immunosuppressive therapy. The primary end point was the incidence of proven or probable invasive fungal infections from randomization to day 112 of the fixed treatment period of the study. Results: Of a total of 600 patients, 301 were assigned to posaconazole and 299 to fluconazole. At the end of the fixed 112-day treatment period, posaconazole was found to be as effective as fluconazole in preventing all invasive fungal infections (incidence, 5.3% and 9.0%, respectively; odds ratio, 0.56; 95 percent confidence interval [CI], 0.30 to 1.07; P=0.07) and was superior to fluconazole in preventing proven or probable invasive aspergillosis (2.3% vs. 7.0%; odds ratio, 0.31; 95% CI, 0.13 to 0.75; P=0.006). While patients were receiving study medications (exposure period), in the posaconazole group, as compared with the fluconazole group, there were fewer breakthrough invasive fungal infections (2.4% vs. 7.6%, P=0.004), particularly invasive aspergillosis (1.0% vs. 5.9%, P=0.001). Overall mortality was similar in the two groups, but the number of deaths from invasive fungal infections was lower in the posaconazole group (1%, vs. 4% in the fluconazole group; P=0.046). The incidence of treatment-related adverse events was similar in the two groups (36% in the posaconazole group and 38% in the fluconazole group), and the rates of treatment-related serious adverse events were 13% and 10%, respectively. Conclusions: Posaconazole was similar to fluconazole for prophylaxis against fungal infections among patients with GVHD. It was superior in preventing invasive aspergillosis and reducing the rate of deaths related to fungal infections. (ClinicalTrials.gov number, NCT00034645.) N Engl J Med 2007;356:335-47. [ABSTRACT FROM AUTHOR]

Abstract: Patients surviving invasive fungal disease (IFD) and needing further antineoplastic chemotherapy are at high risk of recurrent fungal infection. In the absence of randomised controlled trials in this area, secondary prophylactic regimens are diverse. From 448 patients registered with the Multinational Case Registry of Secondary Antifungal Prophylaxis, we performed an analysis of patients receiving caspofungin (CAS) or itraconazole (ITC). All patients had an underlying haematological malignancy and had been diagnosed with an episode of IFD earlier in their course of treatment. Data collected comprised demographics, underlying disease, first episode of IFD, antifungal prophylaxis, incidence and outcome of breakthrough IFD and survival. A total of 75 patients were evaluated, comprising 28 receiving CAS and 47 receiving ITC. Patients in the CAS group were more likely to have had progression of underlying disease (32.1% vs. 8.5%; P =0.028) as well as incomplete response of initial IFD at baseline (85.7% vs. 57.4%; P =0.005). Allogeneic stem cell transplantation was more prevalent in patients receiving CAS (46.4% vs. 14.9%; P =0.010). There was no difference in the occurrence of breakthrough IFD between both groups (32.1% vs. 31.9%). Treatment outcomes for recurrent IFD and overall mortality did not differ between groups. Both ITC and CAS were equally effective in preventing second episodes of IFD. Patients with uncontrolled first IFD, uncontrolled underlying disease or those receiving stem cell transplantation were more likely to have received CAS prophylaxis. Despite antifungal prophylaxis, risk of breakthrough IFD was high in both groups. [Copyright &y& Elsevier]