Mathieu Kuentz

Randomized Trial of Bone Marrow Versus Lenograstim-Primed Blood Cell Allogeneic Transplantation in Patients With Early-Stage Leukemia: A Report From the Société Française de Greffe de Moelle

PURPOSE To compare hematologic recovery in patients receiving allogeneic blood cell transplantation (BCT) with those receiving allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS One hundred eleven patients with leukemia in the early stages and with HLA-matched sibling donors were randomized in this study. One hundred one underwent transplantation. Standard procedures for collection and transplantation were used. Patients did not receive prophylactic granulocyte colony-stimulating factor after undergoing transplantation. In addition to clinical end points being established, a prospective and comparative economic evaluation of the first 6 months after transplantation was performed. RESULTS Groups were balanced for patient, donor, and transplant characteristics. Blood cell collection led to the collection of a higher number of CD34(+) and CD3(+) cells than did bone marrow collection (P < 10(-6)) without reported side effects for the donor. Patients in the BCT group reached platelet counts of 25 and 50 x 10(9) platelets/L 8 and 11 days earlier than did the BMT group (P < 10(-4) and P < 10(-5)), respectively. This resulted in fewer platelet transfusions during the first 180 days after transplantation (P =.002) for the former group. The time to reach neutrophil counts of 0.5 and 1 x 10(9) neutrophils/L was 6 and 7 days shorter, respectively, in the BCT group than in the BMT group (P < 10(-5)). This quicker hematologic recovery was associated with a shorter length of hospitalization and a decrease in total cost of procedure during the first 6 months. CONCLUSION This study establishes that allogeneic BCT results in quicker hematologic recovery but is associated with a higher occurrence of chronic graft-versus-host disease.

Empirical versus Preemptive Antifungal Therapy for High-Risk, Febrile, Neutropenic Patients: A Randomized, Controlled Trial

BACKGROUND Empirical antifungal therapy is the standard of care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. Recent diagnostic improvements may ensure the early diagnosis of potentially invasive fungal disease. Reserving antifungals for this stage may achieve similar survival rates and reduce treatment toxicity and costs. METHODS In this multicenter, open-label, randomized noninferiority trial, we compared an empirical antifungal strategy with a preemptive one. Empirical treatment was defined as antibacterial treatment of patients who have persistent or recurrent fever. Preemptive treatment was defined as treatment of patients who have clinical, imaging, or galactomannan-antigen-assay evidence suggesting fungal disease. First-line antifungal treatment was amphotericin B deoxycholate (1 mg/kg/day) or liposomal amphotericin (3 mg/kg/day), depending on daily renal function. The primary efficacy outcome was the proportion of patients alive at 14 days after recovery from neutropenia. RESULTS The median duration of neutropenia (neutrophil count, <500 cells/mm3) for the 293 patients enrolled was 18 days (range, 5-69 days). By intention-to-treat analysis, survival was 97.3% with empirical treatment and 95.1% with preemptive treatment. The lower 95% confidence limit for the difference in mortality was -5.9%, which was within the noninferiority margin of -8%. Probable or proven invasive fungal infections were more common among patients who received preemptive treatment than among patients who received empirical treatment (13 of 143 vs. 4 of 150; P < .05), and most infections occurred during induction therapy (12 of 73 patients in the preemptive treatment group vs. 3 of 78 patients in the empirical treatment group were infected during induction therapy; P < .01). Preemptive treatment did not decrease nephrotoxicity but decreased costs of antifungal therapy by 35%. CONCLUSIONS Preemptive treatment increased the incidence of invasive fungal disease, without increasing mortality, and decreased the costs of antifungal drugs. Empirical treatment may provide better survival rates for patients receiving induction chemotherapy.

Allogeneic Marrow Stem-Cell Transplantation From Human Leukocyte Antigen–Identical Siblings Versus Human Leukocyte Antigen–Allelic–Matched Unrelated Donors (10/10) in Patients With Standard-Risk Hematologic Malignancy: A Prospective Study From the French Society of Bone Marrow Transplantation and Cell Therapy

PURPOSE To investigate the influence of donor type (human leukocyte antigen [HLA] -identical sibling donor versus HLA-A-, HLA-B-, HLA-Cw-, HLA-DRB1-, and HLA-DQB1-identical unrelated donors, or so-called 10/10) on the outcome of patients who underwent allogeneic stem-cell transplantation (alloSCT), adjusting for other prognostic factors, in patients with standard-risk hematologic malignancy. PATIENTS AND METHODS Between March 2000 and January 2003, we prospectively investigated the outcome of 236 consecutive patients with standard-risk malignancy from 12 French centers. Fifty-five patients underwent alloSCT from an unrelated HLA-identical donor at the allelic level, whereas 181 patients received an alloSCT from an HLA-identical sibling. Diagnoses included acute leukemia (n = 175), chronic myeloid leukemia (n = 43), and myelodysplastic syndrome (MDS; n = 18). All patients received unmodified marrow graft following myeloablative conditioning with cyclophosphamide and total-body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and short-course methotrexate in all patients. RESULTS In multivariable analysis, overall survival and transplantation-related mortality were adversely influenced by recipient cytomegalovirus (CMV) -positive serology, age of donor older than 37 years, and the occurrence of acute grade > or = II GVHD. Event-free survival rates were lower for patients with recipient CMV-positive serology. Acute grades II to IV GVHD rates were higher for patients with chronic myeloid leukemia (CML). No factor was found to influence either relapse or acute grades III to IV GVHD. The effect of donor type was nonsignificant for all criteria. CONCLUSION In patients with standard-risk malignancy, transplantation from unrelated HLA-allellically matched donors led to outcomes similar to those from HLA-identical sibling donors.

Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ(0)), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 10(9)/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

Sclerodermatous chronic graft-versus-host disease : analysis of seven cases

BACKGROUND Sclerodermatous chronic graft-versus-host disease is a disabling complication after allogeneic bone marrow transplantation from HLA-identical sibling donors. Only a few series of patients have been reported and the dermatologic features have never been extensively described. OBJECTIVE The purpose of the study was to describe clinical and biologic features of chronic sclerodermatous graft-versus-host disease and to compare them with scleroderma. METHODS We reviewed 196 patients grafted between April 1973 and July 1987 with survival times sufficient to be at risk of chronic graft-versus-host disease. Seven had the sclerodermatous form. RESULTS Most patients had disseminated sclerosis of the trunk and the proximal portions of the limbs. In two cases, atrophy of the skin was predominant, corresponding with a severe clinical evolution. Periorbital pigmentation was observed as an initial manifestation in three cases. Visceral manifestations resembled those observed in scleroderma but histologic and immunologic studies demonstrated clear differences. Response to therapy was variable. CONCLUSION Chronic sclerodermatous graft-versus-host disease may realize two different patterns. Major atrophy is associated with a more severe progression.

Comparison of High-Dose Therapy and Autologous Stem-Cell Transplantation With Conventional Therapy for Hodgkin's Disease Induction Failure: A Case-Control Study

PURPOSE To determine the prognostic factors and outcome of first-line induction failure Hodgkins disease patients who were treated with a salvage regimen of high-dose chemotherapy and autologous stem-cell transplantation, and to compare them with matched, conventionally treated patients. PATIENTS AND METHODS We retrospectively analyzed data relating to 86 Hodgkins disease patients who underwent autologous stem-cell transplantation after failure of the first chemotherapy regimen, either because they did not enter a complete remission and experienced progression of disease less than 3 months after the end of their first-line treatment or because they showed evidence of disease progression during first-line therapy. Graft patients were matched with 258 conventionally treated patients (three controls per case) for age, sex, clinical stage, B symptoms, and time at risk; patient data were obtained from international databases. RESULTS Among the 86 graft patients, the median age at diagnosis was 29 years (range, 14 to 57 years). Thirty-nine percent of patients had stage II disease, 23% had stage III disease, and 38% had stage IV disease. Seventy percent of the patients received chemotherapy and 30% received combined modality therapy; 60% of the patients received a seven- or eight-drug regimen. After this first-line treatment, 91% had disease progression and 9% had a brief partial response. Eighty patients received a second-line treatment; pretransplantation status was as follows: 24% of patients had a complete remission, 38% had a partial remission (PR), 14% had stable disease, and disease progression occurred in 24%. With a median follow-up of 22 months (range, 4 to 105 months) from diagnosis, the 5-year event-free survival and overall survival rates from transplantation were 25% and 35% (95% confidence intervals, 15 to 36 and 23 to 49), respectively. In multivariate analysis, the pretransplantation disease status after salvage therapy was the only significant prognostic factor for survival (PR: relative risk = 2.8, P = .017; progressive disease: relative risk (RR) = 5.26, P < .001). From diagnosis, the 6-year overall survival rates of the graft patients and 258 matched conventionally treated patients were 38% and 29%, respectively (P = .058). CONCLUSION Autologous stem-cell transplantation represents the best therapeutic option currently available for patients with primary induction failure and is associated with acceptable toxicity. Response to second-line treatment before high-dose chemotherapy is the only prognostic factor that can be correlated with survival.

Serum Aspergillus Galactomannan Antigen Testing by Sandwich ELISA: Practical Use in Neutropenic Patients

The double sandwich ELISA detecting Aspergillus galactomannan (GM) was prospectively evaluated for the diagnosis of invasive aspergillosis (IA) in 50 haematological patients at risk for IA. Serum samples were collected once weekly as long as the risk factors persisted. Six patients had proven or probable IA (3 A. fumigatus, 1 A. flavus, 1 A. niger, 1 A. ustus) and the GM titres were parallel to the clinical evolution of IA. Six of nine patients with suspected IA had at least two consecutive serum GM titres above 1 ng/ml and died with increasing titres, whereas the GM-negative patients survived. Positive GM titres did not anticipate the isolation of fungi. Unfortunately, positive GM titres did not anticipate the initiation of antifungal therapy, based on clinical suspicion. Moreover, if a true-positive result was defined as two consecutive positive serum samples, four patients out of 35 without proven, probable or suspected IA were positive. Then, the rate of false-positive results was high (12%) in the range previously reported. Nevertheless, the GM ELISA appears useful to assess IA and to follow the efficacy of antifungal treatment.

Acute promyelocytic leukemia in 57 previously untreated patients

Fifty‐seven patients in initial phase of acute promyelocytic leukemia (APL) were treated in the same department with heparin infusion, platelet transfusions, and two related induction regimens both including cytosine arabinoside and daunorubicin. Clinical and biological findings at presentation were studied. The complete remission (CR) rate was 53%. Twenty‐seven patients (47%) died during the initial course of the disease, either before day 5 (early death [ED], n = 7) or after day 5 (death in aplasia [DA], n = 20). Most ED was due to intracerebral hemorrhage (6/7), especially when large hemorrhages had been seen on fundus oculi examination. Most DA was due to multivisceral failure (9/20). No correlation was found between initial disseminated intravascular coagulation (DIC) and death. However, the worsening of coagulation parameters during induction therapy, with or without initial DIC, significantly increased the occurrence of renal and respiratory failure which were particularly frequent during the first month. The median duration of survival was short (3.5 months) and the median duration of CR (11 months) was similar to that of other acute myeloid leukemias treated with the same regimens. The possible causes of the high mortality observed during the initial courses of APL and the possible benefit of a more graduate induction chemotherapy are discussed.

Allogeneic Hematopoietic Stem-Cell Transplantation After Nonmyeloablative Preparative Regimens: Impact of Pretransplantation and Posttransplantation Factors on Outcome

PURPOSE To analyze the impact of pre- and posttransplantation factors on the outcome of allogeneic transplantation after nonmyeloablative conditioning regimens. PATIENTS AND METHODS Ninety-two allogeneic transplantations after nonmyeloablative preparative regimens were reported to the Société Française de Greffe de Moelle Registry registry. Initial diagnoses were lymphoid diseases (n = 22), myeloma (n = 14), acute leukemia and myelodysplasia (n = 41), chronic myelogenous leukemia (n = 12), and solid tumors (n = 3). Forty-six patients had previously received a transplant, and 49 had progressive disease before transplantation. Three types of conditioning regimens were used with fludarabine or antithymocyte globulins. Eighty-nine patients underwent transplantation, 60 from peripheral-blood progenitor cells. Eighty-six patients received graft-versus-host disease (GHVD) prophylaxis for a median duration of 53 days. RESULTS Seventy-nine patients engrafted, with 40 complete and 21 mixed chimerisms. The acute GHVD rate at 3 months was 50% +/- 11%. Fifty-two patients achieved complete remission and 12, partial remission. At 18 months after transplantation, the overall survival (OS) and the transplant-related mortality (TRM) were 32% +/- 12% and 38% +/- 14%, respectively. Initial diagnosis and disease status before transplantation significantly influenced survival. Age and GHVD prophylaxis type significantly influenced TRM. We also showed an impact of GHVD prophylaxis duration on OS and TRM. In multivariate analysis, three factors remained of prognostic value on OS: initial diagnosis, disease status at transplantation, and GHVD prophylaxis duration. CONCLUSION This series shows encouraging results from nonmyeloablative conditioning regimens before allotransplantation and demonstrates the impact of some pre- and posttransplantation factors on outcome after transplantation.

Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients

Summary:Although the efficacy and safety of voriconazole to treat invasive fungal infections have been demonstrated in prospective trials, its use for secondary prophylaxis to prevent reactivation of these infections remains unknown. Delaying the scheduled treatment of leukemia until complete resolution of fungal infection may have major implications for prognosis. We report 11 leukemic patients with previous aspergillus (n=10) and candida (n=1) infection who received voriconazole 400 mg/day intravenously or orally for between 44 and 245 days. Nine patients were scheduled for allogeneic stem cell transplant, and two for consolidation therapy for acute leukemia. None of the patients had a relapse of fungal infection, and scheduled treatment was delayed only once. Voriconazole was well tolerated, except in one patient who had abnormal liver tests secondary to hepatic graft-versus-host disease, and one who had visual disturbances. This small but homogeneous series indicates that voriconazole may be useful to prevent fungal relapse during at-risk periods in leukemic patients. Prospective trials are warranted to confirm these encouraging results.