Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a Phase I clinical trial.

Thalidomide is an effective agent for advanced refractory or relapsed multiple myeloma (MM), although dose-limiting toxicity (DLT) may limit its use. This Phase I study found that a combination of low-dose thalidomide with bendamustine and prednisolone (BPT) maintained or increased efficacy, whilst avoiding DLT in 28 patients with MM that was refractory or that had relapsed after conventional chemotherapy or high-dose therapy with stem-cell support. BPT comprised fixed doses of bendamustine (60 mg/m(2)) and prednisolone (100 mg), and escalating doses of thalidomide (50, 100, 200 mg). Treatment cycles were repeated every 28 d until the occurrence of maximum response, DLT, or disease progression. Twenty-four patients responded after at least two cycles (four complete remission, six very good partial remission, 14 partial remission). Median progression-free and overall survival for all patients was 11 and 19 months respectively. Only mild/moderate non-haematological side effects were observed and no patient developed dose-limiting haematotoxicity. Transient grade 3-4 neutropenia was reported in 12 patients, and grade 3-4 thrombocytopenia occurred in two patients. We conclude that BPT therapy was well tolerated in patients with relapsed or refractory MM, with a response rate higher than 80%. The maximum tolerated dose of thalidomide was not reached in this study.

Rapid and sustained clearance of circulating lymphoma cells after chemotherapy plus rituximab: clinical significance of quantitative t(14;18) PCR monitoring in advanced stage follicular lymphoma patients.

This study of first-line treatment in advanced-stage follicular lymphoma patients analysed the effects of MCP (mitoxantrone, chlorambucil and prednisolone) chemotherapy alone or in combination with rituximab (R-MCP) on circulating lymphoma cells (CLC) and assessed the prognostic value of a quantitative monitoring of CLC. CLC numbers were determined by quantitative polymerase chain reaction (PCR) for the t(14;18)-translocation or by allele-specific PCR for rearranged immunoglobulin heavy chain genes. We analysed blood samples from 43 patients treated in a randomized trial comparing eight cycles of MCP versus R-MCP. Clearance of CLC at the end of therapy was achieved in 21/25 patients (84%) treated with R-MCP compared with 0/18 after MCP alone (P < 0.0001). A > or = 2 log CLC reduction was associated with a favourable clinical response (P = 0.0004) and prolonged event-free survival (P = 0.02). In R-MCP patients, stable CLC numbers or consistently PCR-negative blood samples were associated with a continuing clinical remission whereas in two patients a relapse was preceded by a > or = 2 log CLC increase. This study demonstrated that R-MCP led to a rapid and sustained eradication of CLC and a > or = 2 log CLC reduction was associated with a superior quality and duration of the clinical response.

Risk factors for breakthrough invasive fungal infection during secondary prophylaxis.

BACKGROUND: Intensive chemotherapy with severe neutropenia is associated with invasive fungal infections (IFIs) leading to high mortality rates. During leukaemia induction chemotherapy, IFI often prohibited further curative treatment, thus predisposing for leukaemia relapse. Continuing myelosuppressive chemotherapy after diagnosis of IFI has become feasible with the now expanding arsenal of safe and effective antifungals. Secondary prophylaxis of IFI is widely administered, but reliable data on outcome and risk factors for recurrent IFI during subsequent chemotherapy are not available. This study determines risk factors for recurrent IFI in leukaemia patients. METHODS: From 25 European cancer centres, 166 consecutive patients with acute myelogenous leukaemia (AML) and a recent history of proven or probable pulmonary IFI were included. Patients were followed for recurrence or breakthrough IFI during the subsequent chemotherapy cycle. RESULTS: Of the 166 patients included, 69 (41.6%) were female, the median age was 53 years (range 2-81) the and 3 (1.8%) were <16 years. Recurrent IFI occurred in 26 patients (15.7%). Multiple logistic regressions yielded predisposing factors: duration of neutropenia [per additional day; odds ratio (OR) 1.043, confidence interval (CI) 1.008-1.078], high-dose cytarabine (OR 3.920, CI 1.120-12.706), number of antibiotics (per antibiotic; OR 1.504, CI 1.089-2.086), partial response as outcome of prior IFI (OR 4.037, CI 1.301-12.524) and newly diagnosed AML (OR 3.823, CI 0.953-15.340). Usage of high efficiency particulate air filter appeared protective (OR 0.198, CI 0.036-1.089). CONCLUSIONS: Duration of neutropenia, high-dose cytarabine, prior antibiotic therapy and a partial response to the first IFI therapy were risk factors for recurrent IFI and should be considered in AML patients with prior pulmonary IFI undergoing further chemotherapy.

The epidemiology and treatment of infections in cancer patients.

Significant changes in the epidemiology of infectious complications in cancer patients have emerged during the past decade. Among blood culture isolates from febrile neutropenic patients, Gram-positive pathogens have become predominant, and an increasing spread of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci must be taken into consideration. Risk factors such as indwelling venous catheters or chemotherapy-induced mucosal damage are associated with an increased incidence of Gram-positive infections. Invasive fungal infections, particularly invasive aspergillosis, have become most important in severely neutropenic patients and are associated with fatality rates of 40-60%. The use of nucleoside analogues and the CD52-antibody alemtuzumab induce a long-lasting lymphopenia facilitating the occurrence of opportunistic infections specifically caused by viruses and fungi. In elderly patients undergoing intensive myelosuppressive chemotherapy, infectious complications may be managed as successfully as in younger patients by appropriate antimicrobial therapy. The broad use of fluoroquinolones for antibacterial prophylaxis in neutropenic patients may lead to very high resistance rates among Gram-negative bacilli such as E. coli. In patients given moxifloxacin for infection prevention, unacceptably large numbers of Clostridium difficile-associated enterocolitis have been reported.

Single versus sequential high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: a prospective randomized multicenter trial of the German Testicular Cancer Study Group.

PURPOSE: To compare single versus sequential high-dose chemotherapy (HDCT) as first or subsequent salvage treatment in patients with relapsed or refractory germ cell tumors (GCTs). PATIENTS AND METHODS: Between November 1999 and November 2004, 230 patients were planned to be recruited in a prospective, randomized, multicenter trial comparing one cycle of cisplatin 100 mg/m2, etoposide 375 mg/m2, and ifosfamide 6 g/m2 (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m2 and etoposide 1,500 mg/m2 (CE; arm A) versus three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m2, etoposide 1,800 mg/m2, and cyclophosphamide 6,400 mg/m2 (CEC; arm B). RESULTS: The study was stopped prematurely after recruitment of 216 patients as a result of excess treatment-related mortality in arm B. One hundred eleven (51%) of 216 patients were randomly assigned to sequential HDCT, and 105 (47%) of 216 patients were randomly assigned to single HDCT. Five (2%) of 216 patients had to be excluded because of non-GCT histologies at review. With a median follow-up time of 36 months, 109 (52%) of 211 patients were alive, and 91 (43%) of 211 patients were progression free. At 1 year, event-free, progression-free, and overall survival rates were 40%, 53%, and 80%, respectively, in arm A compared with 37%, 49%, and 61%, respectively, in arm B (P > .05 for all comparisons). Treatment-related deaths, mainly as a result of sepsis and cardiac toxicity, were less frequent in arm A (four of 108 patients, 4%) compared with arm B (16 of 103 patients, 16%; P < .01). CONCLUSION: We found no difference in survival probabilities between single HDCT using CE and sequential HDCT using CEC. Sequential HDCT was better tolerated and resulted in fewer treatment-related deaths.

Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients.

Morbidity and mortality caused by invasive Aspergillus infections are increasing. This is because of the higher number of patients with malignancies treated with intensive immunosuppressive therapy regimens as well as their improved survival from formerly fatal bacterial infections, and the rising number of patients undergoing allogeneic haematopoietic stem cell or organ transplantation. Early initiation of effective systemic antifungal treatment is essential for a successful clinical outcome in these patients; however, clinical clues for diagnosis are sparse and early microbiological proof of invasive aspergillosis (IA) is rare. Clinical diagnosis is based on pulmonary CT scan findings and non-culture based diagnostic techniques such as galactomannan or DNA detection in blood or bronchoalveolar lavage samples. Most promising outcomes can be expected in patients at high risk for aspergillosis in whom antifungal treatment has been started pre-emptively, backed up by laboratory and imaging findings. The gold standard of systemic antifungal treatment is voriconazole, which has been proven to be significantly superior to conventional amphotericin B and has led to a profound improvement of survival rates in patients with cerebral aspergillosis. Liposomal amphotericin B at standard dosages appears to be a suitable alternative for primary treatment, while caspofungin, amphotericin B lipid complex or posaconazole have shown partial or complete response in patients who had been refractory to or intolerant of primary antifungal therapy. Combination therapy with two antifungal compounds may be a promising future strategy for first-line treatment. Lung resection helps to prevent fatal haemorrhage in single patients with pulmonary lesions located in close proximity to larger blood vessels, but is primarily considered for reducing the risk of relapse during subsequent periods of severe immunosuppression. Strict reverse isolation appears to reduce the incidence of aspergillosis in allogeneic stem cell transplant recipients and patients with acute myeloid leukaemia undergoing aggressive anticancer therapy. Well designed, prospective randomised studies on infection control measures effective to prevent aspergillosis are lacking. Prophylactic systemic antifungal treatment with posaconazole significantly improves survival and reduces IA in acute myeloid leukaemia patients and reduces aspergillosis incidence rates in patients with intermediate-to-severe graft-versus-host reaction emerging after allogeneic haematopoietic stem cell transplantation. Voriconazole prophylaxis may be suitable for prevention of IA as well; however, the results of large clinical trials are still awaited.

Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study.

PURPOSE: Rituximab has been shown to be active in follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. We conducted a randomized trial comparing mitoxantrone, chlorambucil, and prednisolone (MCP) chemotherapy plus rituximab with MCP alone. PATIENTS AND METHODS: Previously untreated patients with stage III or IV CD20+ indolent or mantle cell lymphoma were randomly assigned to either eight 28-day cycles of MCP plus rituximab (R-MCP; n = 181) or eight cycles of MCP alone (n = 177). All patients who achieved a complete or partial remission were treated with interferon maintenance until relapse. Herein, we report the results from the primary analysis population of patients with FL, who constituted the majority of patients (56%) recruited to the trial (n = 201; R-MCP, n = 105; MCP, n = 96). RESULTS: Rates of overall and complete response were significantly higher in the R-MCP arm than the MCP arm (overall response, 92% v 75%, respectively; P = .0009; complete response, 50% v 25%, respectively; P = .004). With a median follow-up time of 47 months, median event-free survival (EFS) and progression-free survival (PFS) times were significantly prolonged with R-MCP compared with MCP (EFS, not reached v 26 months, respectively; P < .0001; PFS, not reached v 28.8 months, respectively; P < .0001), and overall survival (OS) was significantly improved with R-MCP compared with MCP (4-year OS rate, 87% v 74%, respectively; P = .0096). CONCLUSION: The R-MCP regimen significantly improves complete and overall response rates, EFS, PFS, and OS in patients with previously untreated advanced FL, without a clinically significant increase in toxicity.

Voriconazole: a broad spectrum triazole for the treatment of serious and invasive fungal infections.

For many years, serious systemic fungal infections have been treated with amphotericin B or narrow-spectrum azole antifungals. These treatments have been effective in many patients, but are associated with tolerability or pharmacokinetic concerns, or suboptimal antifungal activity in some patient groups. Voriconazole is a second-generation triazole with an extended spectrum of activity offering the potential to treat life-threatening fungal infections. The drug is available for intravenous or oral administration and has been shown to be effective in invasive aspergillosis, fluconazole-susceptible and -resistant candidiasis, and infections caused by various other fungal pathogens, including some formerly refractory organisms. Voriconazole is generally well tolerated with transient visual disturbances, liver enzyme abnormalities and skin rashes being the most common adverse events reported, but these rarely lead to treatment discontinuation.

Defining clinical failure for salvage studies.

In patients with invasive aspergillosis (IA), there are numerous clinical settings where stable disease or progression of findings or deterioration of the patient's condition does not indicate failure, and subsequent response to a 'salvage' antifungal is not necessarily attributable to this drug. Many patients, in whom pulmonary aspergillosis emerges during profound neutropenia, show enlargement of their lesions on computer tomography (CT) scans, eventually accompanied by clinical deterioration, during hematopoietic recovery. This may in fact represent the recruitment of neutrophils and monocytes to the pulmonary 'battlefield', resulting in a favorable clinical outcome also without changing antifungal treatment. Infarcted tissue may contain vital filamentous fungi, because it is poorly penetrated by the antifungal, not indicating a lack of efficacy of this drug against the respective fungal pathogen. In patients treated with an echinocandin, serum galactomannan levels may increase despite successful treatment. Piperacillin-tazobactam or other semi-synthetic beta-lactam antibiotics may cause false positive serum Aspergillus galactomannan levels. Patients primarily treated with a lipid formulation of AmB (LF-AmB), who are switched to a 'salvage' antifungal, will unequivocally receive a combination therapy due to the persistence of high LF-AmB concentrations in tissue. Criteria to define 'clinical refractoriness', 'resistance', 'non-response' or 'failure' respectively should be re-defined. One option to establish a more valid definition would be to use a composite score including clinical as well as radiological and microbiological or mycological criteria. The latter may include non-culture based methods such as serum galactomannan. Assessment should not be made earlier than after seven days of full-dose systemic antifungal treatment. However, in individual cases, e.g. a patient with hematopoietic recovery, who shows an increasing volume of pulmonary aspergillosis and clinical deterioration, it may be recommended to refrain from switching the patient to another regimen and continue the current antifungal treatment for another seven days before failure is stated. Clinical studies on second-line antifungal treatment for IA should be randomized and blinded, patients should be evaluated separately with respect to their reason for 'failure' of primary antifungal treatment, and stratified according to their previous antifungal treatment. Ideally, the first-line regimen would be standardized. Host criteria such as neutropenia or graft-versus-host disease (GVHD) should be clearly defined and documented with respect to their course over time, and patients should be stratified according to these criteria. A three-arm study (continuation of primary antifungal vs. combination of primary antifungal with a 'salvage' drug vs. the 'salvage' drug alone) would be ideal.