T. Gastinne

Features of Epstein-Barr Virus (EBV) reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation

This single centre study assessed the incidence, kinetics and predictive factors of Epstein-Barr Virus (EBV) reactivation and EBV-related lymphoproliferative diseases (LPDs) in 175 consecutive patients who received a reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT). The cumulative incidence of EBV reactivation at 6 months after allo-HSCT defined as an EBV PCR load above 1000 copies of EBV DNA/105 cells was 15%, and none of these patients experienced any sign or symptom of LPD. A total of 17 patients, who had EBV DNA levels exceeding 1000 copies/105 cells on two or more occasions, were pre-emptively treated with rituximab. With a median follow-up of 655 (range, 92–1542) days post allo-HSCT, there was no statistically significant difference in term of outcome between those patients who experienced an EBV reactivation and those who did not. In multivariate analysis, the use of antithymocyte globulin as part of the RIC regimen was the only independent risk factor associated with EBV reactivation (relative risk=4.9; 95% confidence interval, 1.1–21.0; P=0.03). We conclude that patients undergoing RIC allo-HSCT using anti-thymocyte globulin as part of the preparative regimen are at higher risk for EBV reactivation. However, this did not impact on outcome, as quantitative monitoring of EBV viral load by PCR and preemptive rituximab therapy allowed for significantly reducing the risk of EBV-related LPD.

18F-fluorodeoxyglucose–positron emission tomography before, during and after treatment in mature T/NK lymphomas: a study from the GOELAMS group

BACKGROUND In non-cutaneous T-cell/natural killer (T/NK) lymphomas, the prognostic value of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) during or after therapy is unknown. PATIENTS AND METHODS In this retrospective study, 54 T/NK lymphoma patients were assessed using FDG-PET before (n = 40), during (n = 44) and/or after therapy (n = 31). RESULTS FDG-PET showed an abnormal FDG uptake in all cases. Interim FDG-PET was negative in 25 of 44 cases. After completion of therapy, 19 of 31 patients reached complete remission with negative FDG-PET. In ALK+ anaplastic large cell lymphomas, the 4-year progression-free survival (PFS) was 80% and the negative predictive value of post-therapy FDG-PET was 83% (n = 9). In ALK- T/NK lymphomas, the 4-year PFS was 59% for patients with a negative interim FDG-PET versus 46% for patients with a positive interim FDG-PET (P = 0.28, n = 35). Similarly, there was no statistical difference in 4-year PFS between negative and positive post-therapy FDG-PET in these lymphomas (51% and 67%, respectively, P = 0.96). The 4-year cumulative incidence of relapse from a negative post-therapy FDG-PET was 53% in ALK- T/NK lymphomas. CONCLUSIONS Although T/NK lymphomas are FDG-avid at diagnosis, a negative interim or post-therapy FDG-PET does not translate into an improved PFS in ALK- T/NK lymphomas.

Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT.

Patients with hematopoietic malignancies relapsing after allogeneic hematopoietic SCT (allo-HSCT) have a poor prognosis. We retrospectively analyzed the patients who received azacitidine in our center in the course of treatment of their post-transplant relapse. We identified 31 patients. Relapse occurred at a median of 3.7 (1.7–37.6) months following allo-HSCT. Patients received a median number of three cycles (1–12) of azacitidine (7 days, 75 mg/m2 daily). Thirty-nine percent of patients had either a monosomal karyotype or a complex karyotype. Eleven patients (35%) received at least one DLI. Eleven patients responded to azacitidine, with four patients achieving a CR (13%). Median time to best response was 92 (35–247) days, with a median duration of 209 (64–751) days. One-year estimated survival rate was 14%. In conclusion, azacitidine may reinduce durable remissions in very few patients with AML or myelodysplastic syndrome. The toxicity related to azacitidine was high, although it may be difficult to distinguish between treatment-related side effects, namely due to cytopenia and toxicity due to the relapse or disease progression itself. Early administration of azacitidine after transplant followed by DLI should be considered as a pre-emptive therapy for potential relapse in patients with minimal residual disease or high-risk myeloid malignancies.

Upfront allogeneic stem-cell transplantation for patients with nonlocalized untreated peripheral T-cell lymphoma: an intention-to-treat analysis from a single center

BACKGROUND Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous diseases with dismal outcome when treated with chemotherapy alone. Because allogeneic stem-cell transplantation (allo-SCT) can cure relapse/refractory patients, we hypothesized that upfront allo-SCT may provide a better outcome. Therefore, all patients that presented with advanced PTCL in our institution at diagnosis were scheduled to undergo upfront allo-SCT after induction chemotherapy. PATIENTS AND METHODS The aim of the present work was to assess the feasibility and toxicity of upfront allo-SCT. From 2004 to 2012, 49 newly diagnosed PTCL patients were scheduled to receive upfront allo-SCT. A human leukocyte antigen-matched donor was found for 42 patients: related to the patient in 15 cases, unrelated in 20 cases, and suitable cord blood units were used in 7 cases. RESULTS After induction chemotherapy, 17 patients reached complete remission and 29 (60%) proceeded to upfront allo-SCT. For all patients, the 1 and 2-year overall survival (OS) rates were 59% [95% confidence interval (CI) 47-75] and 55% (95% CI 43-71), respectively. The most frequent reason we did not proceed to allo-SCT was disease progression or insufficient response after induction. For transplanted patients, the 1- and 2-year OS were 76% (95% CI 62-93) and 72.5% (95% CI 58-91), respectively. Toxicity-related mortality (TRM) 1 year after allo-SCT was only 8.2% (95% CI 0-18.5). The 2-year progression-free survival (PFS) rate of patients who did not proceed to allo-SCT (n = 20) was below 30%. The disease status at the time of transplantation was a strong predictive marker for both PFS and OS in transplant patients. CONCLUSIONS Upfront allo-SCT in PTCLs is feasible with low TRM, and it provides long-term disease control. However, one-third of patients remain chemo-refractory and, thus, new therapeutic approaches are warranted. The role of upfront allo-SCT compared with other therapeutic approaches in PTCLs requires investigation in randomized studies.

Escalated lymphodepletion followed by donor lymphocyte infusion can induce a graft-versus-host response without overwhelming toxicity

Treatment of relapse of hematological malignancies following allogeneic hematopoietic SCT (allo-HSCT) remains very challenging and relies usually on the readministration of chemotherapy combined with donor lymphocyte infusion (DLI). To enhance DLI effectiveness, lymphodepletion (LD) with fludarabine (Flu) and/or CY before the injection of lymphocytes is an attractive modality to modify the immune environment, leading possibly to suppression of regulatory T cells (Treg) and exposing the patient to cytokine activation. However, LD before DLI may lead to induction of deleterious GVHD. To avoid inducing overwhelming toxicity, we proceeded by escalating doses of both LD and DLI. Eighteen patients with various non-CML hematological malignancies who relapsed following allo-HSCT were treated with chemotherapy and LD-DLI or LD-DLI upfront. T-cell subpopulation and DC levels as well as cytokine plasma levels (IL-7, IL-15) were measured before and following LD-DLI. Cumulative incidence of acute grade II–IV GVHD was 29.4% similar to that reported in patients receiving DLI without LD. In addition, Flu alone with low dose of DLI was not associated with severe GHVD. CY/Flu at the respective doses of 600 mg/m2 on day 1 and Flu 25 mg/m2/day on days 1–3 did not result in a marked decrease of Treg cells, nor in endogenous IL-7 and IL-15 production. However, a peripheral expansion of DCs was observed. These findings suggest that the escalated dose procedure appears safe and prevent overwhelming toxicity. A dose-limiting toxicity has not yet been reached.

Prophylaxis with mycophenolate mofetil and CsA can decrease the incidence of severe acute GVHD after antithymocyte globulin-based reduced-intensity preparative regimen and allo-SCT from HLA-matched unrelated donors

Prophylaxis with mycophenolate mofetil and CsA can decrease the incidence of severe acute GVHD after antithymocyte globulin-based reduced-intensity preparative regimen and allo-SCT from HLA-matched unrelated donors

The role of FDG-PET scanning in assessing lymphoma in 2012

Positron emission tomography (PET) has a proven role in the assessment diffuse large B-cell lymphoma (DLBCL) and Hodgkins lymphoma (HL). The clinical impact of PET carried out at the end of the patients course of treatment is undeniable and recommendations must be followed in the interpretation of these examinations. PET is highly recommended as part of the initial investigations of these diseases because it can be used as a reference for the interpretation at treatment completion and allows disease spread to be assessed with greater sensitivity and specificity than when computed tomography (CT) is used. It seems to be certain that PET is useful for interim examinations too, in terms of assessing prognosis in DLBCL and HL, although its impact in terms of early changes to treatment is still to be determined. The criteria for interpreting the results of these early assessments are still evolving and the annual meetings in Menton, France, of groups of experts are leading towards a uniform interpretation method. In other types of lymphoma, PET can be useful for confirming local disease staging, especially in follicular lymphoma, and for guiding biopsy in patients with low-grade lymphoma that is suspicious for transformation into more aggressive disease. Several studies are in agreement that PET is valuable for assessing prognosis at treatment completion in FL and mantle cell lymphoma, but prospective studies are needed for this new indication to be validated.

FDG-PET in Follicular Lymphoma Management.

18-Fluoro-deoxyglucose positron emission tomography/computerised tomography (FDG PET/CT) is commonly used in the management of patients with lymphomas and is recommended for both initial staging and response assessment after treatment in patients with diffuse large B-cell lymphoma and Hodgkin lymphoma. Despite the FDG avidity of follicular lymphoma (FL), FDG PET/CT is not yet applied in standard clinical practice for patients with FL. However, FDG PET/CT is more accurate than conventional imaging for initial staging, often prompting significant management change, and allows noninvasive characterization to guide assessment of high-grade transformation. For restaging, FDG PET/CT assists in distinguishing between scar tissue and viable tumors in residual masses and a positive PET after induction treatment would seem to predict a shorter progression-free survival.

Factors predicting allogeneic PBSCs yield after G-CSF treatment in healthy donors

G-CSF mobilized PBSCs are increasingly used in allo-SCT due to their relative ease of collection and because higher CD34þ cell doses may be associated with improved transplant outcomes in some settings. However, some healthy donors may show poor mobilization response to G-CSF and poor subsequent CD34þ apheresis yields. Therefore, identifying donors at risk for poor mobilization and a reliable estimate of a healthy donor’s CD34þ cell mobilization response to G-CSF and subsequent CD34þ cells yield could be of value in optimizing transplantation approaches. The aim of this single center report was to analyze factors associated with the total CD34þ PBSC yield in an ethnically homogeneous Caucasian population of 95 healthy allogeneic adult donors. All donors received G-CSF dosed at 10mg/kg/day (Filgrastim, Amgen, France) for 5 days followed by leukapheresis. Complete blood counts (total WBC, Hb, Plts) were measured for all donors at baseline before G-CSF administration, before and after PBSC collection. Peripheral blood CD34þ cell counts were also measured before apheresis. Sixty-nine donors (73%) were healthy sibling donors, whereas 26 (27%) were healthy volunteer donors for HLA-identical unrelated transplants. All donors were undergoing their first PBSC mobilization (study period 2004–2008). Donors’ demographic characteristics are summarized in Table 1. Briefly, the median (range) age, weight and height were 47 (18–81) years, 69 (43–106) kg and 170 (150–187) cm, respectively. The median body mass index (BMI) was 23.9 (15.2–35.7) kg/m. As per the institutional policy, the targeted total number of CD34þ stem cells was between 4 and 8 10/kg recipient body weight to be collected in a maximum of three consecutive aphaeresis sessions while continuing G-CSF administration. Assessments were based on recipient body weight. Overall, the median number of the total collected CD34þ cells was 6.25 10/kg (range, 1.7–16.6), with 16 donors (17%) yielding less than 4 10/kg CD34þ stem cells. After the first apheresis, the median number of collected CD34þ cells was 4.9 10/kg (range, 1.0–16.6). Thirty-two donors (34%) underwent more than one apheresis session. No life-threatening adverse events were encountered during the mobilization and collection process. However, 11 donors (12%) experienced some adverse events during the collection process (bone pain, headache, hypotension, arrhythmia and general discomfort). Of note, no dose reduction was performed because of side effects, and none of these side effects resulted in severe morbidity or any mortality. In univariate analysis, female gender, lower weight and height, pre-G-CSF and post G-CSF Hb levels, and low CD34þ cell counts before first apheresis, were associated with significantly lower total CD34þ stem cells yields (o6.25 10/kg). In multivariate analysis, male donor gender and higher post-G-CSF CD34þ cell counts before the first apheresis were most strongly associated with a higher (46.25 10/kg) total number of collected CD34þ stem cells (OR1⁄4 6.17, 95% CI (2.39–15.93), P1⁄4 0.0001; and OR1⁄4 3.95, 95% CI (1.53–10.19), P1⁄4 0.004, respectively). A CD34þ cell yield o2 10/kg of recipient weight is usually the accepted definition of a ‘poor mobilization’. However, for the purpose of this analysis and from a practical standpoint, we chose to focus on those donors with a CD34þ stem cell yield o4 10/kg, which can be considered as a ‘non-optimal’ yield. Thus, when considering the group of 16 donors with a ‘non-optimal’ CD34þ stem cells yield (o4 10/kg), in multivariate analysis, we found that a higher post-G-CSF CD34þ cell count before the first apheresis was the strongest parameter significantly associated with a higher total number of collected CD34þ PBSCs (OR1⁄4 6.36, 95% CI (1.68–24.15), P1⁄4 0.006; Table 2). Earlier studies have yielded conflicting data regarding the effect of various donor demographic, laboratory and other factors on peak donor CD34þ mobilization responses and apheresis cell yields. Recently, Vasu et al. identified age,

Features of EBV reactivation after reduced intensity conditioning unrelated umbilical cord blood transplantation

This single centre study assessed the incidence, kinetics and predictive factors of EBV reactivation and EBV-related lymphoproliferative diseases (LPD) in 33 consecutive patients who received a reduced intensity conditioning (RIC) before umbilical cord blood transplantation (UCBT). During the first 6 months after UCBT, weekly all patients were DNA-PCR screened in the peripheral blood for EBV reactivation and were clinically monitored for clinical features attributable to EBV. The cumulative incidences of EBV reactivation (defined as an EBV load >1000 EBV copies per 105 cells measured at least once during follow-up) at 6 months and 2 years after UCBT were 9 (95% confidence interval (CI), 2–22%) and 17% (95% CI, 6–33%), respectively. In 28 patients (85%), the EBV load remained negative at all times, and none of these patients experienced any sign of LPD. Five patients (15%) experienced at least one EBV reactivation episode. EBV reactivation was observed at a median of 132 days (range, 85–438) after UCBT. Two patients developed EBV-related LPD (cumulative incidence, 6% at 3 years). With a median follow-up of 468 days (range, 92–1277) post UCBT, the OS was 62% at 3 years. Five patients died of disease progression and seven patients died of transplant-related complications, including one case of EBV-related LPD. Univariate analysis did not identify any significant risk factor associated with EBV reactivation. We conclude that patients undergoing RIC UCBT are at risk for EBV reactivation, with the need for close EBV monitoring and the use of preemptive rituximab treatment as some cases may progress to life-threatening LPD.