Ulrich Mey

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.

Neutropenic enterocolitis in adults: systematic analysis of evidence quality.

Abstract:  Objective: Neutropenic enterocolitis is a life‐threatening complication occurring most frequently after intensive chemotherapy in acute leukaemias. The literature is heterogenous and a systematic review is lacking. Methods: Following a systematic search we categorised all relevant reports according to their quality and extracted evidence to answer the questions: Which diagnostic criteria are appropriate? What is the incidence of neutropenic enterocolitis? Are there good quality studies supporting specific interventions: Which empiric antimicrobial therapy is recommendable? Is neutropenic enterocolitis without surgical emergency complications an indication for bowel resection? Results: We found and analysed 145 articles of these reports: 64 were reports of single cases, 30 papers reported of two or three cases, 13 were narrative reviews, 34 were retrospective case series of more than three cases and four were prospective diagnostic studies. There were no prospective trials or case control studies on the therapy of neutropenic enterocolitis. There was no consensus on diagnostic criteria. We discuss the difficulty to define diagnostic criteria without having a disease definition. Histology is mostly not available in the living patients. We suggest applying a combination of clinical and radiological criteria: fever, abdominal pain and any bowel wall thickening >4 mm detected by ultrasonography (US) or computed tomography. We calculated a pooled incidence rate from 21 studies of 5.3% (266/5058; 95% CI: 4.7%–5.9%) in patients hospitalised for haematological malignancies, for high‐dose chemotherapy in solid tumours or for aplastic anaemia. Conclusions: This systematic review provides diagnostic criteria for neutropenic enterocolitis, presents a quantitative synthesis on its incidence and discusses its treatment recommendations. Prospective studies are clearly warranted.

Allogeneic dendritic cells fused with tumor cells: preclinical results and outcome of a clinical phase I/II trial in patients with metastatic renal cell carcinoma.

Therapeutic vaccination with dendritic cells (DC) can lead to tumor regression in animal models and has shown promising results in the first clinical trials of metastatic renal cell carcinoma and malignant melanoma. In vitro data and results of a clinical phase I/II trial using DC tumor fusions in patients with progressive metastatic renal cell carcinoma are presented here. In addition to toxicity and feasibility, complex immune monitoring was a point of interest. DC precursor cells were obtained from the peripheral blood mononuclear cells (PBMCs) of healthy donors and were fused with either allogeneic (8 patients) or autologous (4 patients) renal tumor cells. In total, 12 patients with progressive metastatic renal cell carcinoma were treated with an average of 2.8 x 10(7) tumor cells fused with 1.8 x 10(7) DC each administered on days 0, 28, and 56 intradermally. Fusion efficacy for the tumor cells used was 14.3% +/- 7.8%. Cell viability was 59.8% +/- 6.8% after fusion and irradiation. We observed no adverse effects and no difference in clinical outcome between the allogeneic and the autologous treatment. Eight patients remained in a progressive disease state and four patients in a stable disease state. T-cell immunity was carefully monitored before, during, and after treatment. Delayed-type hypersensitivity (DTH) reaction using tumor cells was positive after treatment in 7 of 12 patients, 2 of whom were found to have stable disease. An increase in the reactivity against recall antigens was seen in most patients. Interestingly, cytotoxicity of peripheral blood lymphocytes (PBLs) against renal cell carcinoma cells increased during treatment as well as the percentage of interferon-gamma-secreting cells. This effect was significantly enhanced within the group that had stable disease. The lack of adverse effects together with positive immunologic signs justifies further investigation of this novel therapeutic approach. Further studies are necessary to test for clinical effectiveness in patients with tumors, especially those with less advanced disease.

Abdominal infections in patients with acute leukaemia: a prospective study applying ultrasonography and microbiology

Summary.  A prospective study of 62 chemotherapy‐ induced neutropenic episodes in patients with acute leukaemia was conducted to determine the incidence and causes of abdominal infections, and to assess the diagnostic value of the combined use of ultrasonography (US) and microbiology. Each patient underwent US of liver, gallbladder and complete bowel before chemotherapy, on days 2–4 after the end of chemotherapy and in cases of fever, diarrhoea or abdominal pain. US was combined with a standardized clinical examination and a broad spectrum of microbiological investigations. From January to August 2001, 243 US examinations were performed. The overall incidence of abdominal infectious diseases was 17·7% (11 out of 62, 95% confidence interval (CI): 9–29%). Four patients (6·5%) developed neutropenic enterocolitis; two of them died, two survived. Bowel wall thickening (BWT) > 4 mm in these four patients ranged from 5·8 to 23·6 mm and was detected only in one patient with mucositis. In three other patients (4·8%) Clostridium difficile, and in one patient (1·6%) Campylobacter jejuni, caused enterocolitis without BWT. Cholecystitis was diagnosed in three patients (4·8%) and hepatic candidiasis was strongly suspected in one patient. Abdominal infections caused by gastroenteritis viruses, cytomegalovirus (CMV) or Cryptosporidium were not observed. We conclude that in neutropenic patients with acute leukaemia receiving chemotherapy: (i) BWT is not a feature of chemotherapy‐induced mucositis and should therefore be considered as sign of infectious enterocolitis; (ii) viruses, classic bacterial enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Aeromonas, Vibrio subsp., enterohaemorrhagic Escherichia coli) and Cryptosporidium have a very low incidence; and (iii) abdominal infections may be underestimated when US is not used in every patient with abdominal pain.

Final Results of a Prospective Evaluation of the Predictive Value of Interim Positron Emission Tomography in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP-14 (SAKK 38/07)

PURPOSE Our main objective was to prospectively determine the prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) after two cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone given every 14 days (R-CHOP-14) under standardized treatment and PET evaluation criteria. PATIENTS AND METHODS Patients with any stage of diffuse large B-cell lymphoma were treated with six cycles of R-CHOP-14 followed by two cycles of rituximab. PET/CT examinations were performed at baseline, after two cycles (and after four cycles if the patient was PET-positive after two cycles), and at the end of treatment. PET/CT examinations were evaluated locally and by central review. The primary end point was event-free survival at 2 years (2-year EFS). RESULTS Median age of the 138 evaluable patients was 58.5 years with a WHO performance status of 0, 1, or 2 in 56%, 36%, or 8% of the patients, respectively. By local assessment, 83 PET/CT scans (60%) were reported as positive and 55 (40%) as negative after two cycles of R-CHOP-14. Two-year EFS was significantly shorter for PET-positive compared with PET-negative patients (48% v 74%; P = .004). Overall survival at 2 years was not significantly different, with 88% for PET-positive versus 91% for PET-negative patients (P = .46). By using central review and the Deauville criteria, 2-year EFS was 41% versus 76% (P < .001) for patients who had interim PET/CT scans after two cycles of R-CHOP-14 and 24% versus 72% (P < .001) for patients who had PET/CT scans at the end of treatment. CONCLUSION Our results confirmed that an interim PET/CT scan has limited prognostic value in patients with diffuse large B-cell lymphoma homogeneously treated with six cycles of R-CHOP-14 in a large prospective trial. At this point, interim PET/CT scanning is not ready for clinical use to guide treatment decisions in individual patients.

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.

Invasive fungal infections in neutropenic enterocolitis: A systematic analysis of pathogens, incidence, treatment and mortality in adult patients

BackgroundNeutropenic enterocolitis is a life-threatening complication most frequently occurring after intensive chemotherapy in acute leukaemias. Gramnegative bacteria constitute the most important group of causative pathogens. Fungi have also been reported, but their practical relevance remains unclear. The guidelines do not address concrete treatment recommendations for fungal neutropenic enterocolitis.MethodsHere, we conducted a metaanalysis to answer the questions: What are frequency and mortality of fungal neutropenic enterocolitis? Do frequencies and microbiological distribution of causative fungi support empirical antimycotic therapy? Do reported results of antimycotic therapy in documented fungal neutropenic enterocolitis help with the selection of appropriate drugs? Following a systematic search, we extracted and summarised all detail data from the complete literature.ResultsAmong 186 articles describing patients with neutropenic enterocolitis, we found 29 reports describing 53 patients with causative fungal pathogens. We found no randomised controlled trial, no good quality cohort study and no good quality case control study on the role of antifungal treatment. The pooled frequency of fungal neutropenic enterocolitis was 6.2% calculated from all 860 reported patients and 3.4% calculated from selected representative studies only. In 94% of the patients, Candida spp. were involved. The pooled mortality rate was 81.8%. Most authors did not report or perform antifungal therapy.ConclusionIn patients with neutropenic enterocolitis, fungal pathogens play a relevant, but secondary role compared to bacteria. Evidence concerning therapy is very poor, but epidemiological data from this study may provide helpful clues to select empiric antifungal therapy in neutropenic enterocolitis.

Advances in the treatment of hairy-cell leukaemia.

Hairy-cell leukaemia (HCL) is an uncommon B-cell chronic lymphoproliferative disorder that accounts for about 2% of all leukaemias. Although the disease is generally indolent in its natural course, the majority of patients require treatment for life-threatening infections due to pancytopenia or symptomatic splenomegaly. During the past 20 years, remarkable progress has been made in the treatment of HCL. Since the introduction of interferon-alpha, splenectomy, which was formerly the standard therapy, has been rarely used. With the purine analogues cladribine and pentostatin, response rates are even better than with interferon-alpha and long-lasting remissions can be achieved in most patients. Therefore, these agents are now considered the treatment of choice. Recently, immunotherapeutic approaches which use monoclonal antibodies have increased the number of therapeutic options for HCL and offer promising salvage strategies for patients who relapse or who are refractory to treatment with purine analogues. In this review the different treatment options available are discussed and recommendations for the clinical management of the HCL are summarised.

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.

Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group

BACKGROUND Advanced stage Hodgkins lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkins lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkins lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPPescalated) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. METHODS In this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkins lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPPescalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPPescalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPPescalated (BEACOPPescalated group) or BEACOPPescalated plus rituximab (R-BEACOPPescalated group). PET-2 was assessed using a 5-point scale with 18FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPPescalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPPescalated (day 0 and day 3 in cycle 4, day 1 in cycles 5-8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. FINDINGS Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPPescalated group (n=220) or the R-BEACOPPescalated group (n=220). With a median follow-up of 33 months (IQR 25-42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0-95·7) for patients in the BEACOPPescalated group and 93·0% (89·4-96·6) for those in the R-BEACOPPescalated group (difference 1·6%, 95% CI -4·0 to 7·3; log rank p=0·99). Common grade 3-4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPPescalated group vs 211 [96%] of 220 patients in the R-BEACOPPescalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPPescalated group and ten (5%) of 220 in the R-BEACOPPescalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPPescalated group and three (1%) in the R-BEACOPPescalated group, all of them due to infection. INTERPRETATION The addition of rituximab to BEACOPPescalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkins lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkins lymphoma. FUNDING Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.