Michal Sieniawski

Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology

There is no widely accepted standard for antifungal prophylaxis in patients with hematologic malignancies. The Infectious Diseases Working Party of the German Society for Haematology and Oncology assigned a committee of hematologists and infectious disease specialists to develop the recommendations described in this Decision Making and Problem Solving article. There is no widely accepted standard for antifungal prophylaxis in patients with hematologic malignancies. The Infectious Diseases Working Party of the German Society for Haematology and Oncology assigned a committee of hematologists and infectious disease specialists to develop recommendations. Literature data bases were systematically searched for clinical trials on antifungal prophylaxis. The studies identified were shared within the committee. Data were extracted by two of the authors (OAC and MSi). The consensus process was conducted by email communication. Finally, a review committee discussed the proposed recommendations. After consensus was established the recommendations were finalized. A total of 86 trials were identified including 16,922 patients. Only a few trials yielded significant differences in efficacy. Fluconazole 400 mg/d improved the incidence rates of invasive fungal infections and attributable mortality in allogeneic stem cell recipients. Posaconazole 600 mg/d reduced the incidence of IFI and attributable mortality in allogeneic stem cell recipients with severe graft versus host disease, and in patients with acute myelogenous leukemia or myelodysplastic syndrome additionally reduced overall mortality. Aerosolized liposomal amphotericin B reduced the incidence rate of invasive pulmonary aspergillosis. Posaconazole 600 mg/d is recommended in patients with acute myelogenous leukemia/myelodysplastic syndrome or undergoing allogeneic stem cell recipients with graft versus host disease for the prevention of invasive fungal infections and attributable mortality (Level A I). Fluconazole 400 mg/d is recommended in allogeneic stem cell recipients until development of graft versus host disease only (Level A I). Aerosolized liposomal amphotericin B is recommended during prolonged neutropenia (Level B II).

Lymphocyte-Predominant and Classical Hodgkin's Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group

PURPOSE Lymphocyte-predominant Hodgkins lymphoma (LPHL) is rare and differs in histologic and clinical presentation from classical Hodgkins lymphoma (cHL). To shed more light on the prognosis and outcome of LPHL, we reviewed all LPHL patients registered in the German Hodgkin Study Group (GHSG) database, comparing patient characteristics and treatment outcome with cHL patients. PATIENTS AND METHODS We analyzed retrospectively 8,298 HL patients treated within the GHSG trials HD4 to HD12, of whom 394 had LPHL and 7,904 had cHL. RESULTS Complete remission and unconfirmed complete remission after first-line treatment was achieved in 91.6% v 85.9% of patients in early favorable stages, 85.7% v 83.3% of patients in early unfavorable stages, and 76.8% v 77.8% of patients in advanced stages of LPHL compared with cHL, respectively. Tumor control (freedom from treatment failure [FFTF]) for LPHL and cHL patients at a median observation of 50 months was 88% and 82% (P = .0093) and overall survival (OS) was 96% and 92%, respectively (P = .0166). In LPHL patients, negative prognostic factors were advanced stage (P = .0092), Hb less than 10.5 g/dL (P = .0171), and lymphopenia (P = .010) for FFTF. Age >or= 45 years (P = .0125), advanced stage (P = .0153), and Hb less than 10.5 g/dL (P = .0014) were negative prognostic factors for OS. CONCLUSION The better prognosis of LPHL as compared with cHL might allow different treatment strategies, particularly for early-stage LPHL patients.

Outcome of Patients Experiencing Progression or Relapse After Primary Treatment With Two Cycles of Chemotherapy and Radiotherapy for Early-Stage Favorable Hodgkin's Lymphoma

PURPOSE To evaluate treatment outcome of patients with early-stage favorable Hodgkins lymphoma (HL) who experience disease relapse after primary treatment with two cycles of chemotherapy followed by radiotherapy (RT). PATIENTS AND METHODS Of 1,129 patients with early-stage favorable HL enrolled onto the HD7/HD10/HD13 trials of the German Hodgkin Study Group, 42 patients were identified with treatment failure, of whom eight had primary progressive disease, seven had early relapse (< or = 12 months), and 27 had late relapse (> 12 months). We analyzed this group of patients for risk factors, salvage therapy, and treatment outcome. RESULTS The median age was 41 years (range, 19 to 72 years); 24 patients were male, 15 patients had outfield relapse, 13 patients infield relapse, and nine patients outfield and infield relapse. At relapse, 24 patients were treated with conventional salvage chemotherapy, 14 patients were treated with high-dose chemotherapy followed by autologous stem-cell transplantation, and four patients were treated with RT alone. At 36 months median follow-up, freedom from second treatment failure (FF2F) and overall survival (OS) were 52% and 67%, respectively. According to the prognostic score for relapsed HL (duration of first remission, clinical stage, and anemia at relapse), patients with two or three poor prognostic features had a significantly worse outcome compared with patients with none or one of these factors (P < .05 for FF2F and OS). CONCLUSION Relapse after primary treatment with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine followed by RT is rare. In our analysis, results were influenced by a high treatment-related mortality rate. Additional studies are needed to define the optimal salvage therapy.

Mucormycosis treated with posaconazole: review of 96 case reports.

Mucormycosis is an emerging invasive fungal infection, primarily affecting immunocompromised patients. The disease is difficult to diagnose and mortality reaches 40% even if treated adequately. Depending on site of infection and risk factors, surgical debridement in combination with systemically active antifungal drugs are the mainstay treatment strategies. Lipid-based amphotericin B is the treatment of choice for first-line therapy while posaconazole may be a promising alternative. We performed a PubMed search on reports of patients with mucormycosis treated with posaconazole. From 2003 to 2011, 96 cases have been published. Diagnosis was based on histology alone in 2 (2.1%) and microbiological evidence in 67 (69.8%), while no data on the diagnostic approach was reported in 27 (28.1%) patients. The most frequent pathogens were Rhizopus spp. (31.2%), followed by Mucor spp. (14.6%). The site of infection was predominantly rhino-orbital (38.5%, of which 43% also had central nervous system [CNS] involvement), followed by disseminated disease (22.1%). A complete response was achieved in 62 (64.6%), partial response in 7 (7.3%) patients, and stable disease in 1 (1%). Overall mortality was 24% (lacking data for three patients). In published case reports on posaconazole treatment for mucormycosis, the drug was frequently and successfully used in combination or as second line therapy.

Prophylaxis of invasive fungal infections in patients with hematological malignancies and solid tumors Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

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.

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.

Efficacy of caspofungin and itraconazole as secondary antifungal prophylaxis: analysis of data from a multinational case registry.

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.

Successful carboxypeptidase G2 rescue of a high-risk elderly Hodgkin lymphoma patient with methotrexate intoxication and renal failure.

High-dose methotrexate (MTX) is often used in the treatment of malignant diseases. Despite careful management, acute MTX-associated toxicity due to renal failure can occur. Treatment of these side effects is often difficult with high mortality rates and, in particular, the elderly patients are at high-risk [1]. Carboxypeptidase G2 (CPDG2), an enzyme capable of breaking down MTX, is a new agent available for the treatment of acute methotrexate intoxication. There are numerous publications documenting successful CPDG2 rescue in MTX-induced renal dysfunction, but there is still little known about the usage of CPDG2 in elderly patients. We report an elderly man who was successfully treated with CPDG2 after developing renal failure and MTX-associated toxicity refractory to leucovorin rescue. A 61-year-old man was treated with the German Hodgkin Study Group salvage protocol for relapsed and refractory Hodgkin lymphoma. This treatment consisted of two cycles of conventional salvage chemotherapy (DHAP: dexamethasone, cisplatin and cytarabine) followed by high-dose sequential chemotherapy (cyclophosphamide, methotrexate with vincristine, as well as etoposide) and a final myeloablative course (BEAM: carmustine, melphalan, etoposide and cytarabine) with autologous stem cell transplantation. Before the administration of MTX, the required diagnostic procedures including liver, kidney and cardiac function tests were performed. Regarding kidney function, the serum creatinine level was 93 mmol/l (reference values 60 – 117 mmol/l), the urea serum level was 5.3 mmol/l (reference values 3.4 – 8.7 mmol/l) and potassium serum level was 3.8 mmol/l (reference values 3.7 – 4.7 mmol/l). There was no evidence of ascites or pericardial fluid as assessed using ultrasonography. MTX (8000 mg/m) was intravenously administered over 8 h. Adequate hydration with 3000 ml of 0.9% NaCl was maintained throughout the treatment. Urine alkalinization (pH 47.5) was achieved with 8.4% sodium bicarbonate and all other drugs were stopped. The next day, a rapid increase of serum creatinine level from 90 to 200 mmol/l was observed and MTX-level measured 24 h after the end of the infusion was elevated: 286 mmol/l (normal value from study protocol: 510 mmol/l). The patient was diagnosed with acute renal failure caused by MTX intoxication. On admission to intensive care unit, he was somnolent, disoriented with tenderness over the liver and urine bladder. He was also pyrexial with a temperature of 408C. Full blood count revealed a white cell count of 7.2610/l, platelets of 28610/l, and Hb of 7.4 g/dl. Serum creatinine level was 265 mmol/l, liver transaminases were elevated (ALAT, 392 U/l and ASPAT, 395 U/l), C-reactive protein was 119 mg/l. Adequate hydration in accordance to the fluid balance measurements and the alkalinization with 8.4% solution of sodium bicarbonate (urine pH was 8.0) were continued. The daily dosage of leukovorine was increased from 240 to 2200 mg and a single dose of vancomycin was