Marc Boogaerts

Efficacy and Safety of Caspofungin for Treatment of Invasive Aspergillosis in Patients Refractory to or Intolerant of Conventional Antifungal Therapy

BACKGROUND Invasive aspergillosis (IA) is an important cause of morbidity and mortality among immunocompromised patients. Echinocandins are novel antifungal molecules with in vitro and in vivo activity against Aspergillus species. METHODS We investigated the efficacy and safety of caspofungin in the treatment of IA. Ninety patients with IA who were refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B, or triazoles were enrolled to receive caspofungin. RESULTS Efficacy was assessed for 83 patients who had infection consistent with definitions of IA and who received >or=1 dose of study drug. Common underlying conditions included hematologic malignancy (48% of patients), allogeneic blood and marrow transplantation (25% of patients), and solid-organ transplantation (11% of patients). Seventy-one patients (86%) were refractory to and 12 patients (14%) were intolerant of previous therapy. A favorable response to caspofungin therapy was observed in 37 (45%) of 83 patients, including 32 (50%) of 64 with pulmonary aspergillosis and 3 (23%) of 13 with disseminated aspergillosis. Two patients discontinued caspofungin therapy because of drug-related adverse events. Drug-related nephrotoxicity and hepatotoxicity occurred infrequently. CONCLUSION Caspofungin demonstrated usefulness in the salvage treatment of IA.

Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients

BACKGROUND A randomised trial comparing filgrastim-mobilised peripheral blood progenitor cell (PBPC) transplants with autologous bone marrow transplantation (ABMT) for haematopoietic stem cell support has not been done. We compared the effects of filgrastim-mobilised PBPC or autologous bone marrow reinfused to lymphoma patients after high-dose chemotherapy in a prospective randomised multicentre trial. METHODS The trial was done at six centres in three European countries. After high-dose chemotherapy (carmustine, etoposide, cytarabine, and melphalan [BEAM protocol]) 58 patients with advanced Hodgkins disease or high-grade non-Hodgkin lymphoma received either filgrastim-mobilised PBPC (n = 27) or bone marrow (n = 31) for haemopoietic reconstitution. FINDINGS The median number of days with platelet transfusions after grafting was 6 in the PBPC transplantation group and 10 in the ABMT group (estimate of treatment difference 5 days, 95% CI 3-7 days). Time to platelet recovery above 20 x 10(9)/L was 16 days in the PBPC transplantation group and 23 days in the ABMT group (p = 0.02). Time to neutrophil recovery above 0.5 x 10(9)/L was also reduced in the PBPC transplantation group (11 vs 14 days, p = 0.005). Patients randomised to PBPC transplantation needed fewer red blood cell transfusions (two vs three, p = 0.002) and spent less time in hospital (17 vs 23 days, p = 0.002). Early post-transplant morbidity and mortality as well as overall survival (median follow-up 311 days) were similar in both groups. There was no notable toxicity ascribed to filgrastim administration or the leucapheresis procedures. INTERPRETATION In patients with lymphoma treated with high-dose chemotherapy, reinfusing filgrastim-mobilised PBPC instead of autologous bone marrow significantly reduced the number of platelet transfusions, the time to platelet and neutrophil recovery, and led to earlier discharge from hospital.

Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia

The Wiskott-Aldrich syndrome protein (WASP; encoded by the gene WAS) and its homologs are important regulators of the actin cytoskeleton, mediating communication between Rho-family GTPases and the actin nucleation/crosslinking factor, the Arp2/3 complex. Many WAS mutations impair cytoskeletal control in hematopoietic tissues, resulting in functional and developmental defects that define the X-linked Wiskott-Aldrich syndrome (WAS) and the related X-linked thrombocytopenia (XLT). These diseases seem to result from reduced WASP signaling, often through decreased transcription or translation of the gene. Here we describe a new disease, X-linked severe congenital neutropenia (XLN), caused by a novel L270P mutation in the region of WAS encoding the conserved GTPase binding domain (GBD). In vitro, the mutant protein is constitutively activated through disruption of an autoinhibitory domain in the wild-type protein, indicating that loss of WASP autoinhibition is a key event in XLN. Our findings highlight the importance of precise regulation of WASP in hematopoietic development and function, as impairment versus enhancement of its activity give rise to distinct spectra of cellular defects and clinical phenotypes.

Prognostic index for adult patients with acute myeloid leukemia in first relapse

PURPOSE The treatment of acute myeloid leukemia (AML) in first relapse is associated with unsatisfactory rates of complete responses that usually are short lived. Therefore, a clinically useful prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies at relapse of AML. PATIENTS AND METHODS A prognostic score is presented based on the multivariate analysis of 667 AML patients in first relapse among 1,540 newly diagnosed non-M3 AML patients (age 15 to 60 years) entered onto three successive Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research Collaborative Group trials. RESULTS Four clinically relevant parameters are included in this index (ie, length of relapse-free interval after first complete remission, cytogenetics at diagnosis, age at relapse, and whether previous stem-cell transplantation was performed). Using this stratification system, three risk groups were defined: a favorable prognostic group A (overall survival [OS] of 70% at 1 year and 46% at 5 years), an intermediate-risk group B (OS of 49% at 1 year and 18% at 5 years), and a poor-risk group C (OS of 16% at 1 year and 4% at 5 years). CONCLUSION The prognostic index estimates the outcome of AML patients in first relapse using four commonly applied clinical parameters and might identify patients who are candidates for salvage and investigational therapy.

Use of Circulating Galactomannan Screening for Early Diagnosis of Invasive Aspergillosis in Allogeneic Stem Cell Transplant Recipients

Screening for galactomannan (GM) has been adopted by many European centers as part of the management plan for allogeneic stem cell transplant recipients. However, the temporal onset of GM antigenemia remains unknown. A series of allogeneic stem cell transplant recipients were monitored prospectively, and the relationship between antigenemia and other diagnostic triggers for initiation of antifungal therapy was analyzed. GM detection had a sensitivity of 94.4% and a specificity of 98.8%. Positive and negative predictive values were 94.4% and 98.8%, respectively. This statistical profile was better than that of other triggers, including unexplained fever, new pulmonary infiltrates, isolation of Aspergillus species, and abnormalities seen on computed tomography. Antigenemia preceded diagnosis on the basis of radiologic examination or Aspergillus isolation by 8 and 9 days in 80% and 88.8% of patients, respectively. Antigenemia preceded therapy in 83.3% of patients. Detection of GM was especially useful when patients were receiving steroid treatment or when coexisting conditions masked the diagnosis of invasive aspergillosis. Prospective screening for GM allows earlier diagnosis of aspergillosis than do conventional diagnostic criteria.

Reduced-Intensity Conditioning Compared With Conventional Allogeneic Stem-Cell Transplantation in Relapsed or Refractory Hodgkin's Lymphoma: An Analysis From the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

PURPOSE To compare the clinical outcome in terms of nonrelapse mortality (NRM), relapse rate (RR), overall survival (OS), and progression-free survival (PFS) in patients with relapsed Hodgkins lymphoma (HL) treated with reduced-intensity conditioning (RIC) or myeloablative conditioning followed by allogeneic stem-cell transplantation (alloSCT). PATIENTS AND METHODS A total of 168 patients with HL undergoing a first alloSCT (RIC, n = 89; myeloablative conditioning, n = 79) between January 1997 and December 2001 and registered in the European Group for Blood and Marrow Transplantation database were analyzed. RESULTS NRM was significantly decreased in the RIC group (hazard ratio [HR], 2.85; 95% CI, 1.62 to 5.02; P < .001). OS was better in the RIC group (HR, 2.05; 95% CI, 1.27 to 3.29; P = .04) and there was a trend for better PFS in the RIC group (HR, 1.53; 95% CI, 0.97 to 2.40; P = .07). RR was higher in the RIC group in univariate but not in multivariate analysis. The development of chronic graft-versus-host disease (GVHD) significantly decreased the incidence of relapse, which translated into a trend for a better PFS. CONCLUSION The lower incidence of NRM in the RIC group is encouraging, particularly because these patients experienced adverse pretransplantation characteristics more frequently. This analysis also indicates the existence of a graft-versus-HL effect correlated to the development of GVHD. Additional efforts to reduce the high RR seen in both groups of patients will be necessary to improve the modest PFS (31% v 27%) and OS (59% v 36%) for patients prepared with RIC or myeloablative conditioning.

An EORTC International Multicenter Randomized Trial (EORTC Number 19923) Comparing Two Dosages of Liposomal Amphotericin B for Treatment of Invasive Aspergillosis

This is the first completed prospective randomized clinical efficacy trial of antifungals in the treatment of invasive aspergillosis (IA) and the first to compare the clinical efficacy of two dosages of liposomal amphotericin B (L-AmB) for IA in neutropenic patients with cancer or those undergoing bone marrow transplantation. Eighty-seven of 120 patients were eligible and evaluable. Clinical responses were documented for 26 (64%) of 41 patients receiving 1 mg/(kg.d) (L-AmB-1) and 22 (48%) of 46 receiving 4 mg/(kg.d) (L-AmB-4). Radiologic response rates were similar: 24 (58%) of the L-AmB-1 recipients and 24(52%) of the L-AmB-4 recipients. The six-month survival rates were 43% (L-AmB-1) and 37% (L-AmB-4). These differences were not significant. The numbers of deaths directly due to IA at 6 months were similar: 9 (22%) of 41 L-AmB-1 recipients and 9 (20%) of 46 L-AmB-4 recipients. No other variable independently influenced survival, apart from central nervous system IA. L-AmB is effective in treating approximately 50%-60% of patients who have IA. A 1-mg/(kg.d) dosage is as effective as a 4-mg/(kg.d) dosage, and no advantages to use of the higher, more expensive, dosage has been observed.

Prognostic factors in the myelodysplastic syndromes: importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosomal analysis

An analysis of clinical, haematological, histological and cytogenetic data was performed in 85 consecutive patients with myelodysplastic syndromes (MDS). The criteria for diagnosis of refractory anaemia (RA), acquired idiopathic sideroblas‐tic anaemia (AISA) and chronic myelomonocytic leukaemia (CMML) were clearly defined, since the inclusion criteria provided by the FAB co‐operative group are imprecise. None of these patients has received chemotherapy during the follow‐up period. The median survival of the whole group was only 15 months, with less than 10% of the patients surviving after 5 years. Fifteen patients (17.6%) were still alive at time of analysis, 31 (36.5%) have developed acute myeloid leukaemia (AML) and only one of them is still alive; 30 (35.3%) died of infectious and/or haemorrhagic complications. Patients who developed AML had a shorter survival (median survival time 9.5 versus 15 months) but this difference was not significant (P = 0.10). Factors with prognostic value are in order of significance: abnormal localized immature myeloid precursors (= ALIP) in the trephine biopsy. circulating myeloblasts, excess of blasts in the bone marrow smears, age, FAB classification and granulocyte count. In comparison to refractory anaemia with excess of blasts (RAEB), CMML and RAEB in transformation (RAEBt), patients with RA and AISA had a lower incidence of evolution to AML (11% versus 56%), but a higher mortality rate from infections and/or bleeding (59.2% versus 29%). ALIP negative cases were only found among patients with RA and AISA, whereas ALIP positivity was observed in all cases of RAEB and RAEBt. in 10/11 patients with CMML and in almost half the cases of RA and AISA. In RA and AISA patients survival was significantly different between

Allogeneic Hematopoietic Stem-Cell Transplantation for Patients 50 Years or Older With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia

PURPOSE This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients. PATIENTS AND METHODS We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC). RESULTS The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P < .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P < .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = .01), use of an unrelated donor (P = .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P = .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P < .01) was the major independent variable associated with an inferior 4-year overall survival. CONCLUSION Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes.

Prevalence and Causes of Anaemia in a Geriatric Hospitalized Population

Of 732 consecutive patients admitted to an acute geriatric ward, 178 (24%) were found to be anaemic (haemoglobin of 115 g/l or below). An appropriate cause responsible for anaemia was identified in 83%. The anaemia of chronic disorders (ACD) (35%) and iron deficiency anaemia (15%) were the commonest causes. The spectrum of disorders associated with ACD is much broader than the classical category of infectious, inflammatory and malignant disorders. The relatively high prevalence of the myelodysplastic syndrome (5%) is striking and this syndrome as a cause of anaemia in geriatric patients deserves more attention than it has so far received. No obvious cause was found in 17%. The clinical significance of this finding remains unclear.