K. Orlopp

A systematic review of phase‐II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma

The activity of thalidomide in relapsed or refractory multiple myeloma is widely accepted but not yet demonstrated in a randomised‐controlled trial. A systematic review of the published clinical trials of these patients could reduce the possible bias of single phase‐II studies. A systematic search identified 42 communications reporting on 1674 patients. Thirty‐two trials used an escalating dosing regimen and four a fixed dose regimen (one dose with 50 mg/d, three doses with 200 mg/d). The target dose in the dose escalating trials was 800 mg/d in 17 trials, 400–600 mg/d in 10 and 200 mg/d in one trial. The intention‐to‐treat population for efficacy was 1629 patients with a median age of 62 years. The complete and partial (>50% reduction in monoclonal protein) response rate was 29·4% (95%‐confidence interval, 27–32%). The rates for minor responses or stable disease were 13·8% (12–16%) and 11·0% (9–13%). Progressive disease was reported in 9·9% (8–11%). The median overall survival from all trials was reported at 14 months. Severe adverse events (grade III–IV) included somnolence 11%, constipation 16%, neuropathy 6%, rash 3%, thrombo‐embolism 3%, cardiac 2%. In conclusion, thalidomide monotherapy achieved complete and partial responses in 29·4% of patients with relapsed or refractory multiple myeloma.

Utility of a Commercially Available Multiplex Real-Time PCR Assay To Detect Bacterial and Fungal Pathogens in Febrile Neutropenia

ABSTRACT Infection is the main treatment-related cause of mortality in cancer patients. Rapid and accurate diagnosis to facilitate specific therapy of febrile neutropenia is therefore urgently warranted. Here, we evaluated a commercial PCR-based kit to detect the DNA of 20 different pathogens (SeptiFast) in the setting of febrile neutropenia after chemotherapy. Seven hundred eighty-four serum samples of 119 febrile neutropenic episodes (FNEs) in 70 patients with hematological malignancies were analyzed and compared with clinical, microbiological, and biochemical findings. In the antibiotic-naïve setting, bacteremia was diagnosed in 34 FNEs and 11 of them yielded the same result in the PCR. Seventy-three FNEs were negative in both systems, leading to an overall agreement in 84 of 119 FNEs (71%). During antibiotic therapy, positivity in blood culture occurred only in 3% of cases, but the PCR yielded a positive result in 15% of cases. In six cases the PCR during antibiotic treatment detected a new pathogen repetitively; this was accompanied by a significant rise in procalcitonin levels, suggestive of a true detection of infection. All patients with probable invasive fungal infection (IFI; n = 3) according to the standards of the European Organization for Research and Treatment of Cancer had a positive PCR result for Aspergillus fumigatus; in contrast there was only one positive result for Aspergillus fumigatus in an episode without signs and symptoms of IFI. Our results demonstrate that the SeptiFast kit cannot replace blood cultures in the diagnostic workup of FNEs. However, it might be helpful in situations where blood cultures remain negative (e.g., during antimicrobial therapy or in IFI).

Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma.

We designed a multicenter Phase II trial to prospectively evaluate the efficacy and safety of the combination of rituximab with the DHAP regimen (dexamethasone, high-dose cytarabine, cisplatin) in patients who relapsed after or were resistant to a CHOP-like regimen. A total of 53 patients with relapsed or resistant aggressive B-cell NHL were analyzed. The overall response rate was 62.3 percent. With a median follow-up of 24.9 months, median overall and progression-free survivals were 8.5 and 6.7 months, respectively. Immunochemotherapy with rituximab and DHAP proved to be feasible and effective in this patient population.

Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma

Methotrexate (MTX) is an important anticancer drug and the most efficient chemotherapy component in primary CNS lymphoma (PCNSL). A typical side effect of intravenous high-dose MTX is the occurrence of confluent CNS white matter changes (WMC). Because MTX directly interferes with methionine metabolism, we analyzed the impact of genetic variants of methionine metabolism on the occurrence of WMC as a model of MTX toxicity. In a retrospective analysis of 68 PCNSL patients treated with MTX-based polychemotherapy with (n = 42) or without (n = 26) intraventricular treatment, 10 genetic variants influencing methionine metabolism were analyzed. Pearsons chi(2) test and multinominal regression analysis were used to define the relevance of these genetic variants for the occurrence of WMC. In this patient sample, the occurrence of WMC was significantly predicted by the TT genotype of methylenetetrahydrofolate reductase c.677C>T (chi(2) = 8.67; p = 0.013; df = 2), the AA genotype of methylenetetrahydrofolate reductase c.1298A>C (chi(2) = 13.5; p = 0.001; df = 2), and the GG genotype of transcobalamin 2 c.776C>G (chi(2) = 19.73; p < 0.001), in addition to male gender (chi(2) = 11.95; p = 0.001). These data strengthen the hypothesis that MTX effects are influenced by methionine metabolism, which may offer new strategies to improve MTX-based therapies.

DHAP in combination with rituximab vs DHAP alone as salvage treatment for patients with relapsed or refractory diffuse large B-cell lymphoma: a matched-pair analysis

The addition of rituximab to chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) has been shown to improve outcome in first-line therapy. However, in patients with relapsed or refractory disease, the value of adding rituximab to salvage chemotherapy is less clearly defined. This study performed a matched-pair analysis of patients with relapsed or refractory DLBCL by comparing the combination of dexamethasone, high-dose cytarabine and cisplatin (DHAP) with rituximab to DHAP alone. Sixty-seven patients with relapsed or refractory DLBCL were collected from two prospective phase II trials from Germany and Italy. Twenty-three patient pairs treated with either DHAP in combination with rituximab or DHAP alone could be analysed after matching for important prognostic factors. The addition of rituximab to the DHAP regimen led to higher complete and similar overall remission rates. However, differences with regard to complete remission rates failed to reach statistical significance, thereby necessitating further evaluation of the role of combined immunochemotherapy in this patient population.

False positivity of the Aspergillus galactomannan Platelia ELISA because of piperacillin/tazobactam treatment: does it represent a clinical problem?

OBJECTIVES False-positive results of the galactomannan (GM) ELISA caused by concurrent administration of piperacillin/tazobactam have been reported in patients with febrile neutropenia. PATIENTS AND METHODS This prospective study investigated different sampling times in 30 patients receiving piperacillin/tazobactam for febrile neutropenia. RESULTS Prior to the first piperacillin/tazobactam infusion, a median GM index of 0.2 [interquartile range (IQR) 0.1-0.3] was noted; in two patients (7%) the index was 0.5. Immediately after piperacillin/tazobactam infusion, the median index increased to 0.3 (IQR 0.2-0.4, P = 0.002) leading to 21% (7/30) false-positive results, if > or = 0.5 is assumed as the cut-off level. GM indices before the next piperacillin/tazobactam infusion were not increased (median 0.2, IQR 0.2-0.35, P > 0.05), but 10% (3/30) were still > or = 0.5. With a cut-off level of > 0.7, no false-positive results were noted at any sampling time point. CONCLUSIONS We conclude that the clinical relevance of false-positive GM results during piperacillin/tazobactam treatment is small if samples are collected prior to infusion and if a cut-off level of > 0.7 is used.

An Audit of Efficacy and Toxicity of Teicoplanin Versus Vancomycin in Febrile Neutropenia: Is the Different Toxicity Profile Clinically Relevant?

Background:Glycopeptides are often used for persistent fever in neutropenic patients. This study compares efficacy and toxicity of teicoplanin and vancomycin.Patients and Methods:Hundred consecutive neutropenic patients with hematological malignancies and persistent fever after 72 h of first-line antibiotic therapy (91% piperacillin/tazobactam) were treated with teicoplanin (800 mg on day 1, then 400 mg/day) + piperacillin/tazobactam + gentamicin from 08/96 to 09/00 (group T) or with vancomycin (2 g/day) + meropenem + levofloxacin from 10/00 to 04/02 (group V). Success was defervescence (≥ 7 days) in absence of any sign of continuing infection. Nephrotoxicity was monitored daily as increase in serum creatinine.Results:Fifty patients were analyzed in each group. Efficacy was evaluated in patients with piperacillin/tazobactam as first-line therapy only. Treatment was successful in 76% in group T (n = 42) and 59% in group V (n = 49), p = 0.118. Toxicity was evaluated in all patients. The median increase of creatinine was 11% (interquartile range 0%–30%) in group T and 17% (0%–74%) in group V, p = 0.062. In patients who received concomitant amphotericin B (given for 7 days and 6 days, respectively, p = 0.525), median creatinine increased from 0.9 mg/dl (0.8–1.1) to 1.2 mg/dl (0.9–1.5) in group T and from 0.9 mg/dl (0.8–1.08) to 1.55 mg/dl (1.33–2.23) in group V (p < 0.001). This led to a doubling of creatinine in 2/23 (9%) patients of group T and in 9/16 (56%) patients of group V (p = 0.003). A multivariate analysis revealed that concomitant use of amphotericin B (p < 0.001) and treatment with vancomycin (p = 0.002) were independently associated with nephrotoxicity.Conclusion:Teicoplanin and vancomycin were comparably effective in patients with neutropenia and persistent fever, but – if combined with amphotericin B – vancomycin was significantly more nephrotoxic than teicoplanin.

CD4+ T lymphocyte counts after autologous transplantation in multiple myeloma: A retrospective study

The risk for opportunistic infections is correlated with low CD4+ T lymphocyte counts in patients with HIV. We performed a retrospective analysis in 54 patients with multiple myeloma undergoing high-dose melphalan chemotherapy + autologous peripheral blood stem cell transplantation to better define the value of routine control of CD4+ T lymphocyte counts in this important patient group. In 61% of our patients, CD4+ T lymphocyte counts after recovery from neutropenia were <200/µl and <100/µl in 24% (median = 181/µl). Overall survival, progression-free survival, response to antineoplastic therapy and frequency of post-transplant infections were not significantly different when patients with CD4+ T lymphocyte counts <200/µl and >200/µl were compared. However, overall survival was significantly shorter in the subgroup of 13 patients with very low CD4+ T lymphocyte counts (<100/µl) (P = 0.036). In 79.6% of all patients, at least one infection NCI-CTC grade II – IV developed within 100 days post-transplant. Opportunistic infections were rare. This analysis suggests that patients with CD4+ T lymphocyte counts < 100/µl may have a poorer prognosis.

Acute central nervous symptoms in oncologic patients

ZusammenfassungBei onkologischen Patienten können tumorbedingt oder therapieassoziiert akute zentral nervöse Symptome auftreten. Diese können sich in Bewusstseinsstörungen, in einem akuten hirnorganischen Psychosyndrom, in fokalen neurologischen Symptomen, in epileptischen Anfällen oder in einer Kombinationen dieser Symptome äußern. Sie können durch zerebrale Metastasen, Blutungen, Ischämien oder Infektionen, durch metabolische Störungen oder durch therapiebedingte Neurotoxizität verursacht sein. Klinisches Bild, diagnostisches Vorgehen und Behandlungsmöglichkeiten bzw. Prophylaxe solcher akuter zentralnervöser Komplikationen werden in dieser Übersicht dargestellt.AbstractOncologic patients may suffer from acute central nervous system disorders either related to the disease itself or to its therapy. These disorders may present as a disturbance of consciousness, as mental changes, as focal neurological signs, as epileptic seizures or as a combination of these. Symptoms may be caused by cerebral metastases, hemorrhage, ischemia or infectious complication, by metabolic changes or by treatment sequealae. This article will focus on clinical presentation, diagnostic workup and possible therapy or prophylaxis of these complications.

Akute zentralnervse Symptome@@@Acute central nervous symptoms in oncologic patients

ZusammenfassungBei onkologischen Patienten können tumorbedingt oder therapieassoziiert akute zentral nervöse Symptome auftreten. Diese können sich in Bewusstseinsstörungen, in einem akuten hirnorganischen Psychosyndrom, in fokalen neurologischen Symptomen, in epileptischen Anfällen oder in einer Kombinationen dieser Symptome äußern. Sie können durch zerebrale Metastasen, Blutungen, Ischämien oder Infektionen, durch metabolische Störungen oder durch therapiebedingte Neurotoxizität verursacht sein. Klinisches Bild, diagnostisches Vorgehen und Behandlungsmöglichkeiten bzw. Prophylaxe solcher akuter zentralnervöser Komplikationen werden in dieser Übersicht dargestellt.AbstractOncologic patients may suffer from acute central nervous system disorders either related to the disease itself or to its therapy. These disorders may present as a disturbance of consciousness, as mental changes, as focal neurological signs, as epileptic seizures or as a combination of these. Symptoms may be caused by cerebral metastases, hemorrhage, ischemia or infectious complication, by metabolic changes or by treatment sequealae. This article will focus on clinical presentation, diagnostic workup and possible therapy or prophylaxis of these complications.