Nadezda Basara

Reduced Intensity Conditioning Compared With Myeloablative Conditioning Using Unrelated Donor Transplants in Patients With Acute Myeloid Leukemia

PURPOSE Reduced intensity conditioning regimen (RIC) is increasingly used in hematopoietic stem cell transplantation (HSCT). Unrelated donor (UD) transplants have more complications. We wanted to examine if RIC is a valid treatment option using UD in acute myeloblastic leukemia (AML). PATIENTS AND METHODS Between 1999 and 2005, 401 patients with AML were treated with RIC and 1,154 received myeloablative conditioning (MAC), using UD and reported to the European Group for Blood and Marrow Transplantation Registry. Patients < and > or = 50 years of age were analyzed separately. RESULTS Patients receiving RIC were older, received transplants more recently, received peripheral blood stem cells more frequently, and were treated with total-body irradiation less often. In multivariable analysis, in patients younger than 50 years of age, nonrelapse mortality (NRM) was similar using RIC (hazard ratio [HR], 0.85; P = .41), relapse was increased (HR, 1.46; P = .02) and leukemia-free survival (LFS) was the same (HR, 0.88; P = .28), as compared with MAC. In patients > or = 50 years of age, NRM was decreased in the RIC group (HR, 0.64; P = .04), relapse probability was not significantly different (HR, 1.34; P = .16) and LFS was similar (HR, 1.04; P = .79) compared with MAC. CONCLUSION RIC-UD transplants are associated with higher relapse in AML patients younger than 50 years of age and decreased NRM in those > or = 50 years compared with MAC-UD. LFS was similar after both conditioning regimens, regardless of age. Therefore, RIC-UD extend the use of allotransplants for elderly patients and strategies that decrease relapse should be considered mainly in younger patients with AML.

High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation

Nelarabine, a purine analog with T-cell specific action, has been approved for relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL). This is a report of a single-arm phase 2 study conducted in adults (18-81 years of age) with relapsed/refractory T-ALL/LBL. After 1 or 2 cycles, 45 of 126 evaluable patients (36%) achieved complete remission (CR), 12 partial remission (10%), and 66 (52%) were refractory. One treatment-related death was observed, and 2 patients were withdrawn before evaluation. A total of 80% of the CR patients were transferred to stem cell transplantation (SCT). Overall survival was 24% at 1 year (11% at 6 years). After subsequent SCT in CR, survival was 31% and relapse-free survival 37% at 3 years. Transplantation-related mortality was 11%. Neurologic toxicities of grade I-IV/grade III-IV were observed in 13%/4% of the cycles and 16%/7% of the patients. This largest study so far with nelarabine in adults showed impressive single-drug activity in relapsed T-ALL/T-LBL. The drug was well tolerated, even in heavily pretreated patients. A high proportion of CR patients were transferred to SCT with low mortality but a high relapse rate. Exploration of nelarabine in earlier stages of relapse (eg, increasing minimal residual disease), in front-line therapy, and in combination is warranted.

Second Allograft for Hematologic Relapse of Acute Leukemia After First Allogeneic Stem-Cell Transplantation From Related and Unrelated Donors: The Role of Donor Change

PURPOSE To evaluate the role of a second allogeneic hematopoietic stem-cell transplantation (HSCT2) given for relapsed acute leukemia (AL) after related or unrelated first hematopoietic stem-cell transplantation (HSCT1) and to analyze the role of donor change for HSCT2 in both settings. PATIENTS AND METHODS We performed a retrospective registry study on 179 HSCT2s given for relapse after HSCT1 from matched related donors (n = 75) or unrelated donors (n = 104), using identical or alternative donors for HSCT2. Separate analyses were performed according to donor at HSCT1. RESULTS Independent of donor, 74% of patients achieved complete remission after HSCT2, and half of these patients experienced relapse again. Overall survival (OS) at 2 years was 25% ± 4% (39% ± 7% after related HSCT2; 19% ± 4% after unrelated HSCT2). Long-term survivors were observed even after two unrelated HSCT2s. Multivariate analysis for OS from HSCT2 confirmed established risk factors (remission duration after HSCT1: hazard ratio [HR], 2.37; 95% CI, 1.61 to 3.46; P < .001; stage at HSCT2: HR, 0.53; 95% CI, 0.34 to 0.83; P = .006). Outcome of HSCT2 was better after related HSCT1 than after unrelated HSCT1 (2-year OS: 37% ± 6% v 16% ± 4%, respectively; HR, 0.68; 95% CI, 0.47 to 0.98; P = .042, multivariate Cox regression). After both related and unrelated HSCT1, selecting a new donor for HSCT2 did not result in a relevant improvement in OS compared with HSCT2 from the original donor; however, donor change was not detrimental either. CONCLUSION After relapse from allogeneic HSCT1, HSCT2 can induce 2-year OS in approximately 25% of patients. Unrelated HSCT2 is feasible after related and unrelated HSCT1. Donor change for HSCT2 is a valid option. However, a clear advantage in terms of OS could not be demonstrated.

Voriconazole Pharmacokinetics and Safety in Immunocompromised Children Compared to Adult Patients

ABSTRACT The aim of this study was to investigate the pharmacokinetics and safety of voriconazole after intravenous (i.v.) administration in immunocompromised children (2 to 11 years old) and adults (20 to 60 years old) who required treatment for the prevention or therapy of systemic fungal infections. Nine pediatric patients were treated with a dose of 7 mg/kg i.v. every 12 h for a period of 10 days. Three children and 12 adults received two loading doses of 6 mg/kg i.v. every 12 h, followed by a maintenance dose of 5 mg/kg (children) or 4 mg/kg (adults) twice a day during the entire study period. Trough voriconazole levels in blood over 10 days of therapy and regular voriconazole levels in blood for up to 12 h postdose on day 3 were examined. Wide intra- and interindividual variations in plasma voriconazole levels were noted in each dose group and were most pronounced in the children receiving the 7-mg/kg dose. Five (56%) of them frequently had trough voriconazole levels in plasma below 1 μg/ml or above 6 μg/ml. The recommended dose of 7 mg/kg i.v. in children provides exposure (area under the concentration-time curve) comparable to that observed in adults receiving 4 mg/kg i.v. The children had significantly higher Cmax values; other pharmacokinetic parameters were not significantly different from those of adults. Voriconazole exhibits nonlinear pharmacokinetics in the majority of children. Voriconazole therapy was safe and well tolerated in pediatric and adult patients. The European Medicines Agency-approved i.v. dose of 7 mg/kg can be recommended for children aged 2 to <12 years.

Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents

Background Limited data are available on characteristics of viral encephalitis in patients after allogeneic stem cell transplantation. Design and Methods We analyzed 2,628 patients after allogeneic stem cell transplantation to identify risk factors and characteristics of viral encephalitis. Results Viral encephalitis occurred in 32 patients (1.2%, 95% confidence interval 0.8%–1.6%) and was associated with the use of OKT-3 or alemtuzumab for T-cell depletion (P<0.001) and an increased mortality (P=0.011) in comparison to patients without viral encephalitis. Detected viruses included human herpesvirus-6 (28%), Epstein-Barr virus (19%), herpes simplex virus (13%), JC virus (9%), varicella zoster virus (6%), cytomegalovirus (6%) and adenovirus (3%). More than one virus was identified in 16% of the patients. The median onset time was 106 days after allogeneic stem cell transplantation for the total group of 32 patients, but onset times were shortest in those with human herpesvirus-6 encephalitis and longest in those with JC virus-associated progressive multifocal leukoencephalopathy. The probability of a sustained response to treatment was 63% (95% confidence interval 44%–82%) with a median survival of 94 (95% confidence interval 36–152) days after onset, but significant variation was found when considering different causative viruses. Patients with herpes simplex virus encephalitis had the most favorable outcome with no encephalitis-related deaths. Conclusions The use of OKT-3 or alemtuzumab for in vivo T-cell depletion is associated with an increased risk of viral encephalitis after allogeneic stem cell transplantation. Different viruses are frequently associated with distinct characteristics such as onset time, response to treatment and outcome.

Tracking in vivo dynamics of NK cells transferred in patients undergoing stem cell transplantation

Haploidentical stem cell transplantation (haploSCT) offers an alternative treatment option for advanced leukemia patients lacking a HLA‐compatible donor. Transfer of NK cells represents a promising therapeutic option in combination with SCT, as NK cells can promote graft versus leukemia with low risk of GVH disease. In this study, we show results from a phase I/II trial in which 24 acute myeloid leukemia patients underwent haploSCT in combination with early transfer of unmodified NK cells and observed a promising 2‐year overall survival rate of 37%. By performing immunomonitoring and subsequent principal component analysis, we tracked donor NK‐cell dynamics in the patients and distinguished between NK cells reconstituting from CD34+ precursors, giving rise over time to a continuum of multiple differentiation stages, and adoptively transferred NK cells. Transferred NK cells displayed a mature phenotype and proliferated in vivo during the early days after haploSCT even in the absence of exogenous IL‐2 administration. Moreover, we identified the NK‐cell phenotype associated with in vivo expansion. Thus, our study indicates a promising path for adoptive transfer of unmodified NK cells in the treatment of high‐risk acute myeloid leukemia.

Long-term survival of sorafenib-treated FLT3-ITD–positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation

BACKGROUND Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. METHODS We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD-positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. FINDINGS With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. INTERPRETATION Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD-positive AML relapsing after allo-SCT.

Determination of Saliva Trough Levels for Monitoring Voriconazole Therapy in Immunocompromised Children and Adults

To evaluate the reliability and practical use of saliva for therapeutic drug monitoring of the antifungal agent voriconazole in immunocompromised patients, a paired-sample study was conducted. Plasma and saliva trough levels were measured in seven children and nine adults who required treatment for the prevention or therapy of systemic fungal infections. The pediatric patients received a voriconazole dosage of 7 mg/kg intravenously twice a day. Adults were treated with two loading doses of 6 mg/kg intravenously followed by a maintenance dose of 4 mg/kg intravenously twice a day. Based on 104 paired plasma/saliva specimens, we found a significant correlation between the voriconazole concentrations in blood and saliva (r > 0.95). The median saliva/plasma voriconazole concentration ratio was 0.34 in children and 0.40 in adults. Intra- and interpatient variability in the saliva/plasma ratios were 22% and 23% in children and 16% and 24% in adults, respectively. Thirty-three percent of plasma trough levels were below 1.0 μg/mL or above 6.0 μg/mL and occurred in six pediatric and four adult patients. Monitoring of salivary concentrations proved to be a realistic alternative in patients when blood drawing is difficult. Especially in therapeutic drug monitoring, an easier sample collection being noninvasive and painless is more acceptable to patients, particularly children.

Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study

Salvage therapy followed by high‐dose therapy (HDT) remains a mainstay for patients with relapsed lymphoma, however no optimal regimen has been defined. Here we report on the results of R‐DexaBEAM (rituximab, dexamethasone, carmustine, etoposide, cytarabine, melphalan) followed by HDT. Patients aged 18–65 years, Eastern Cooperative Oncology Group performance score 0–2, with relapsed/refractory B‐cell non‐Hodgkin lymphoma (NHL) were eligible. R‐Dexa‐BEAM was given for two cycles followed by stem cell mobilization and HDT. Primary endpoint of the trial was progression‐free‐survival (PFS). One hundred and three patients were included: aggressive NHL (aNHL): diffuse large B‐cell lymphoma 55, mantle cell lymphoma 7, follicular lymphoma (FL) grade 3: 5, indolent Lymphoma (iNHL): FL grade 1–2: 29, marginal zone lymphoma 6, Immunocytoma 1. The overall response rate after salvage therapy was 62% for aNHL and 78% for iNHL patients. 66% of patients with aNHL and 86% with iNHL underwent HDT. Treatment‐related mortality for HDT was 1·3%. For aNHL patients, the median PFS was 0·83 years with 44% alive at the median follow‐up of 7·3 years. Corresponding figures for iNHL were: median PFS 3·7 years and 72% alive after 8 years. The combination of rituximab with DexaBEAM followed by HDT resulted in high response rates and sustained remissions in responders. R‐DexaBEAM followed by HDT can be considered a valid salvage option for NHL.