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The present study aimed at describing the outcome of patients with HIV-associated lymphomas following autologous hematopoietic stem cell transplantation (autoHCT) in the rituximab and combined antiretroviral therapy (cART) era. Eligible for this retrospective study were HIV-positive patients with lymphoma who received autoHCT between 2007 and 2013. A total of 118 patients were included with a median age of 45 years (range 24-66). Underlying diagnoses were diffuse large B cell lymphoma in 47%, Hodgkin lymphoma in 24%, Burkitt lymphoma in 18%, and plasmablastic lymphoma in 7% of patients. Disease status at autoHCT was complete remission in 44%, partial remission (PR) in 38%, and less than PR in 18% of the patients. With a median follow-up of 4 years, 3-year non-relapse mortality, incidence of relapse, progression-free survival (PFS) and overall survival (OS) were 10%, 27%, 63% and 66%, respectively. By multivariate analysis, disease status less than PR but not CD4+ cell count at the time of autoHCT was a significant predictor of unfavorable PFS and OS. In conclusion, in the era of cART and chemoimmunotherapy, the outcome of autoHCT for HIV-related lymphoma is driven by lymphoma-dependent risk factors rather than by characteristics of the HIV infection.

Introduction : The addition of neurokinin-1 receptor antagonists (NK 1 RAs) to standard prophylaxis of 5-hydroxytryptamine-3 RA (5-HT 3 RA) plus dexamethasone more effectively prevents chemotherapy-induced nausea and vomiting (CINV) associated with highly and moderately emetogenic chemotherapy. Areas covered : This review presents the evidence base for the use of oral and intravenous (IV) NK 1 RAs, focusing on the pharmacologic and clinical properties as a class, and highlighting differences between agents. A PubMed literature search was conducted from 2000 to 2018. Expert opinion : Adherence to international antiemetic guidelines remains a clinical challenge. Strategies to simplify antiemetic regimens and facilitate their administration may improve compliance and treatment outcomes. The use of fixed-combination antiemetics offers clinical utility, in combining an NK 1 RA with a 5-HT 3 RA in a single oral dose. The use of long-lasting NK 1 RAs and administering CINV prophylaxis closer to the time of chemotherapy may also assist with guideline and treatment compliance, diminishing the need for home-based administration, and potentially reducing resource utilization. The availability of IV and oral formulations of NK 1 RAs and NK 1 RA-5-HT 3 RA fixed combinations offers further utility, particularly for those patients unsuited for oral administration. However, safety considerations with respect to injection site toxicity and hypersensitivity reactions of the new NK 1 RA IV formulations deserve close attention.

Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 = "dose-dense") and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 = "standard"). 387 evaluable patients were randomly assigned to S-HAM (N = 203) and to standard double induction (N = 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CR i ) was not significantly different (P = 0.202) between S-HAM (77%) and double induction (72%). The median overall survival was 35 months after S-HAM and 25 months after double induction (P = 0.323). Duration of critical leukopenia was significantly reduced after S-HAM (median 29 days) versus double induction (median 44 days)-P < 0.001. This translated into a significantly shortened duration of hospitalization after S-HAM (median 37 days) as compared to standard induction (median 49 days)-P < 0.001. In conclusion, dose-dense induction therapy with the S-HAM regimen shows favorable trends but no significant differences in ORR and OS compared to standard double induction. S-HAM significantly shortens critical leukopenia and the duration of hospitalization by 2 weeks.

Objectives: Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99)., Patients and Results: Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections., Conclusions: The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C-containing regimen was associated with a lower relapse rate in high-risk APL., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Dose density during early induction has been demonstrated to be one of the prime determinants for treatment efficacy in acute myeloid leukemia (AML). The German AML Cooperative Group has therefore piloted a dose-dense induction regimen sequential high-dose AraC and mitoxantrone followed by pegfilgrastim (S-HAM) in which 2 induction cycles are applied over 11 to 12 days instead of 25 to 29 days as used in conventional double induction, thereby increasing dose density 2-fold. Of 172 de novo AML patients (excluding acute promyelocytic leukemia), 61% reached a complete remission, 22% a complete remission with incomplete peripheral recovery, 7% had persistent leukemia, 10% died (early death) resulting in an overall response rate of 83%. Kaplan-Meier estimated survival at 2 years was 61% for the whole group (patients with unfavorable karyotypes, 38%; patients with favorable karyotypes, 69%; patients with intermediate karyotypes, 75%) after S-HAM treatment. Importantly, the compression of the 2 induction cycles into the first 11 to 12 days of treatment was beneficial for normal hematopoiesis as demonstrated by a significantly shortened duration of critical neutropenia of 31 days compared with 46 days after conventionally timed double induction.

These guidelines from the infectious diseases working party (AGIHO) of the German Society of Hematology and Oncology (DGHO) give recommendations for the management of adults with neutropenia and the diagnosis of sepsis. The guidelines are written for clinicians and focus on pathophysiology, diagnosis, and treatment of sepsis. The manuscript contains evidence-based recommendations for the assessment of the quality and strength of the data.

A convenient liquid chromatography-tandem mass spectrometry method for the quantification of the triazole antifungal agent voriconazole in plasma samples is described. Fenbuconazole is used as an internal standard. After protein precipitation, automated solid-phase extraction is applied. Electrospray ionization in the positive mode is used and the following mass transitions are recorded: voriconazole, 350-->127; and fenbuconazol, 337-->125. The analytical run time is 4 min. The response was linear from 78 to 5000 microg/L. The total coefficient of variation (n=16) was 12.6% for a low-concentration pool (143 microg/L), 4.7% for a medium-concentration pool (419 microg/L), and 5.0% for a high-concentration pool (4304 microg/L). The method is proposed for future investigations that should be performed to test the hypothesis that therapeutic drug monitoring of voriconazole is clinically useful.

We studied 228 consecutive stem cell transplant recipients, screened for reactivation of human herpesvirus-6 (HHV-6) in peripheral blood and other specimens as clinically indicated by means of qualitative polymerase chain reaction. Among them, 197 received an allograft and 31 autograft. Ninety-six of 228 patients (42.1%) showed HHV-6 reactivation in peripheral blood and 129 of 228 (56.6%) demonstrated HHV-6 in at least one of the specimens tested. 41.9% of patients were asymptomatic when HHV-6 was identified. Clinical features, noted when HHV-6 was detected, included interstitial or alveolar pneumonia, gastroduodenal and colorectal disease, bone marrow suppression and liver disease. However, based on clinical and histopathological criteria, HHV-6 was considered a causal agent in only a minority of patients, in particular, those suffering from bone marrow suppression (n = 11), gastroduodenitis (five), colitis (three), interstitial/alveolar pneumonia (five), skin rash (one), pericarditis (two) and encephalitis (one). HHV-6 reactivation was significantly associated with the occurrence of graft-versus-host disease [odds ratio (OR) 5.31], Epstein-Barr virus coinfection (OR 8.89) and unrelated donor transplantation (OR 5.67) indicating an increased stage of immunosuppression.

This retrospective trial was performed to determine risk factors, incidence and severity of ifosfamide-induced encephalopathy in correlation with patient and treatment characteristics. Patients receiving ifosfamide were included consecutively with no restrictions concerning disease, prior chemotherapy or disease stage. Incidence and severity of encephalopathy were graduated according to common toxicity criteria. Between July 2001 and July 2002, 60 patients (32 male, 28 female, median age 47.5 years) were included; 26.6% of the patients (n = 16) developed neurological symptoms [grade 1: 6.7% (n = 4); grade 2: 3.3% (n = 2); grade 3: 11.7% (n = 7); grade 4: 5% (n = 3)]. Encephalopathy occurred for the first time in 87.5% (n = 14) in chemotherapy courses 1 and 2. In 56.25% (n = 9) of these 16 patients only one episode was observed. There was no significant difference concerning age (38 versus 50 years, p = 0.08) and dosage (median 2.9 versus 2.8 g, p = 0.74) between patients with and without encephalopathy. No risk factors could be identified by this study, suggesting an individual predisposition in each patient. On the other hand, ifosfamide can be administered in older patients without increased risk of neurotoxicity.

Patients developing fever in neutropenia are at high risk of infection-related complications. Their outcome is influenced by the degree of severity (sepsis, severe sepsis and septic shock). Sepsis describes clinical syndromes resulting from systemic inflammatory response. Diagnosis of sepsis is based on simple clinical criteria. Treatment of neutropenic patients with sepsis does not differ from sepsis treatment in non-neutropenic patients. A variety of treatment options have failed (e.g. anti-cytokine strategies, anti-endotoxin antibodies), however, in recent years successful targeted treatment, the use of activated protein C or the substitution of hydrocortisol has been shown to reduce mortality rates. The outcome of neutropenic sepsis is influenced by the underlying disease as well, however survival rates of neutropenic patients treated on the intensive care unit have improved during the past decade. This paper focuses on pathophysiology, diagnosis and treatment of sepsis. Evidence based medicine (EBM) criteria are used to grade treatment recommendations [50].

Morbidity and mortality in patients with malignancies, especially leukemia and lymphoma, are increased by invasive fungal infections. Since diagnosis of invasive fungal infection is often delayed, antifungal prophylaxis is an attractive approach for patients expecting prolonged neutropenia. Antifungal prophylaxis has obviously attracted much interest resulting in dozens of clinical trials since the late 1970s. The non-absorbable polyenes are probably ineffective in preventing invasive fungal infections, but may reduce superficial mycoses. Intravenous amphotericin B and the newer azoles were used in clinical trials, but their role in antifungal prophylaxis is still not well defined. Allogeneic stem cell transplant recipients are at particularly high risk for invasive fungal infections. Other well described risk factors are neutropenia >10 days, corticosteroid therapy, sustained immunosuppression, graft versus host disease, and concomitant viral infections. The enormous study efforts are contrasted by a scarcity of risk stratified evidence based recommendations for clinical decision making. The objective of this review accumulating information on about 10.000 patients is to assess evidence based criteria primarily regarding the efficacy of antifungal prophylaxis in neutropenic cancer patients.

Approximately 85% of patients with acute leukemia undergoing intensive antileukemic treatment develop infections and/or fever during neutropenic phases; in about 50% of these patients clinical, microbiological or clinical and microbiological evidence of infections can be obtained. The response rate is significantly lower in documented infections than in fever of unknown origin (FUO). Evidence-based recommendations for diagnosis and treatment procedures are presented, reflecting study results and expert opinions.

In this paper a method for the simultaneous quantification of the anti-fungal drug itraconazole and its co-active metabolite hydroxyitraconazole in plasma employing liquid chromatography tandem-mass spectrometry and automated solid-phase extraction is described. The method proved rugged, enables short turn-around times and is highly specific. Since there is growing evidence for the importance of therapeutic drug monitoring of itraconazole in the prophylaxis and treatment of invasive fungal infections, the method described here is of interest for a large number of tertiary care hospital laboratories.

Background: Tumor necrosis factor alpha (TNF) and its cellular and soluble (s) receptors (TNF-R) are important mediators in acute myeloid leukemia (AML) and infectious complications during cytoreductive therapy. We investigated the serum concentrations of sTNF-RII in previously untreated patients with AML at the onset of cytoreductive therapy and in non-febrile chemotherapy-associated neutropenia., Patients and Methods: Of 54 eligible patients with AML, serum concentrations of sTNF-RII could be evaluated in 25 non-neutropenic, non-febrile and in 11 neutropenic, non-febrile patients., Results: At baseline, non-neutropenic, non-febrile AML patients showed high median serum sTNF-RII concentrations of 3,804 pg/mL. In neutropenia, there was a non-significant trend (p = 0.18) to lower median sTNF-RII levels of 3,246 pg/mL., Conclusions: Serum sTNF-RII concentrations in non-febrile AML patients before chemotherapy are in the range of levels reached in uncomplicated febrile episodes in otherwise healthy individuals. This must be taken into account when evaluating the cytokine profile for sepsis in patients with therapy-associated neutropenia. Concentrations are still elevated in neutropenia, suggesting that a normal number of leukocytes is not necessarily required for the activation of the TNF ligand/TNF receptor system in AML.

Serum erythropoietin (EPO) determination is useful in the diagnosis of renal anemia. In anemic patients with normal renal function increased EPO concentrations are typically found, however, so far hemoglobin-related reference ranges for serum EPO had not been established. In a cross-sectional manner we determined serum EPO in 280 patients with anemia and normal serum concentrations of creatinine and urea. Each 70 consecutive anemic patients with hemoglobin concentrations within four intervals were included (<8 g/dL; 8.1-9.0 g/dL; 9.1-10.0 g/dL; 10.1-11.0 g/dL). 97 patients were from surgical disciplines, 183 were from internal disciplines. Serum EPO was determined by use of an automated sandwich immunoassay that is standardized according to the WHO 2nd IRP 67/343. The ranges between the 20th and 80th percentile of EPO concentrations for the four specified hemoglobin intervals were as follows: Hb <8 g/dL, EPO 61.8-366 IU/L; Hb 8.1-9.0 g/dL, EPO 43.3-242 IU/L; Hb 9.1-10.0 g/dL, EPO 31.8-113 IU/L; Hb 10.1-11.0 g/dL, EPO 22.3-71.2 IU/L. Since no complete diagnostic evaluation of the patients' renal and respiratory functions was performed in this cross-sectional study we propose the 20th percentile of EPO concentrations as a preliminary hemoglobin-related reference range; serum EPO concentrations below this percentile speak for a contribution of EPO deficiency in the individual etiology of anemia.