Charalampia Kyriakou

Histologic evolution of angioimmunoblastic T-cell lymphoma in consecutive biopsies: Clinical correlation and insights into natural history and disease progression

Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon, but aggressive nodal peripheral T-cell lymphoma. Little is known of its biology and its natural history has been poorly studied. We report the first comprehensive study on the natural history/histologic progression of AITL by reviewing consecutive biopsies in 31 cases. Immunostaining for CD3, CD20, CD10 and CD21, CD23, CNA-42, CD4, CD8, and Ki 67, in situ hybridization for Epstein-Barr virus (EBV)-encoded RNA and polymerase chain reaction for T-clonality and B-clonality were performed. Histologic progression from AITL with limited nodal involvement and hyperplastic follicles (pattern I) to typical AITL with or without regressed follicles (patterns II and III) was observed in 7 cases, one of which relapsed subsequently as pattern I. Thirteen cases showed typical AITL at presentation and follow-up. Eleven cases where polymerase chain reaction results for T-cell receptor-γ gene rearrangement were directly compared showed an identical band-size in the initial and follow-up biopsies. Seven cases (23%) developed EBV-associated B-cell lymphomas [5 diffuse large B-cell lymphoma (DLBCL) and 2 classic Hodgkin lymphoma]. In 4 cases, a dominant B-cell clone was observed in biopsies lacking evidence of DLBCL. A single case was complicated by EBV-negative DLBCL, whereas another with large cell transformation had a T-cell phenotype. In conclusion, AITL represents a clonal T-cell proliferation with a stable T-cell clone throughout the disease. Partial nodal involvement with hyperplastic follicles is seen in early AITL and at relapse. When “morphologic high-grade transformation” occurs, it is usually due to a secondary (often EBV-associated) B-cell lymphoma, rather than a T-cell neoplasm.

High-dose therapy and autologous stem-cell transplantation in angioimmunoblastic lymphoma: complete remission at transplantation is the major determinant of Outcome-Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.

Purpose Patients with angioimmunoblastic T-cell lymphoma (AITL) have poor prognoses with current conventional chemotherapy. The aim of this study was to evaluate the effect of high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) on patients with AITL. Patients and Methods We report a retrospective, multicenter study of 146 patients with AITL who received ASCT. The source of the stem cells was peripheral blood in 143 patients. The conditioning regimen varied, and 74% of the patients received carmustine and 1,3-bis(2-chloroethyl)-1-nitrosourea; etoposide; ara-C; and melphalan chemotherapy. Results After a median follow-up of 31 months (range, 3 to 174 months), 95 patients (65%) remained alive, and 51 patients (35%) died. Forty-two patients died as a result of disease progression, and nine died as a result of regimen-related toxicity. The cumulative incidence of nonrelapse mortality was 5% and 7% at 12 and 24 months, respectively. The actuarial overall survival (OS) was 67% at 24 m...

Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma

The feasibility and efficacy of a triple regimen of oral weekly cyclophosphamide, monthly pulsed dexamethasone and low‐dose Thalidomide (CDT) was studied in 52 patients with relapsed or refractory multiple myeloma (MM). All 52 patients were evaluable for response with a median follow up of 18 (4–29) months. About 17% achieved complete response (CR), 62% partial response (PR), 11% minimal response (MR), 6% stable disease (SD) and 4% progressive disease (PD), resulting in an objective response rate (≥MR) of 90%. Subsequent to successful response, nine patients received high‐dose therapy (HDT) followed by stem cell transplantation (SCT) and 34 received thalidomide monotherapy as maintenance. Response rate was not influenced by disease status, prior HDT or age. The regimen was successfully delivered to all patients except for one patient who developed abnormal liver function at 7 weeks. Infective complications were minimal and there were no infection‐related deaths. The estimated overall and event‐free survival (EFS) at 2 years was 73% and 34%, respectively, and the median time to progression has not been reached. We conclude that the CDT regimen is safe, well tolerated and effective in patients with relapsed and refractory myeloma.

Factors that influence short-term homing of human bone marrow-derived mesenchymal stem cells in a xenogeneic animal model

Human mesenchymal stem cells are potential agents for tissue regeneration, enhancing hematopoietic stem cell transplantation and delivering genes of therapeutic interest. This study shows that tissue homing of systemically administered mesenchymal stem cells can be increased by enforced expression of CXCR4, at least in irradiated hosts. Background Human mesenchymal stem cells are potential agents for tissue regeneration, enhancing hematopoietic stem cell transplantation and delivering genes of therapeutic interest. To implement any of these strategies successfully, we need a better understanding of factors that influence the tissue distribution of systemically administered mesenchymal stem cells. Design and Methods The present study was designed to investigate the short-term tissue homing of mesenchymal stem cells in immunodeficient mouse models, exploring the effects of animal age, duration of ex vivo expansion of mesenchymal stem cells, lentiviral transduction and CXCR4 over-expression. Dye-labeled mesenchymal stem cells (1.5–2.0×106/animal) were injected via the tail vein into unconditioned β2m/NOD/SCID animals. Animals were sacrificed 20–24 hours later and cell suspensions from tissues were examined by flow cytometry for the presence of PKH-positive cells. Results PKH-positive cells were readily detected in the bone marrow, spleen, liver and lungs at 20–24 hours after infusion. The homing of systemically infused mesenchymal stem cells to the bone marrow and spleen of unconditioned β2m/NOD/SCID animals was significantly (>2-fold, p<0.001) higher in younger (<10 weeks) animals, and was reduced with increasing passage number. Despite low surface CXCR4 expression, human mesenchymal stem cells migrated to SDF-1 in vitro, and this was enhanced by over-expression of CXCR4 using lentiviral transduction. Over-expression of CXCR4 by lentiviral transduction (>80%) did not alter the bone marrow homing of mesenchymal stem cells in unconditioned animals, but caused a significant (p<0.05) increase in homing to bone marrow and spleen of animals that had received prior irradiation. Conclusions Tissue homing of systemically administered mesenchymal stem cells is influenced by host factors such as age, is diminished by prolonged in vitro culture, and can be increased by enforced expression of CXCR4, at least in irradiated hosts.

High-Dose Therapy and Autologous Stem-Cell Transplantation in Waldenström Macroglobulinemia: The Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

PURPOSE The role of autologous stem-cell transplantation (ASCT) in Waldenström macroglobulinemia (WM) is not defined. The aim of this study was to analyze the results of ASCT in patients with WM and to determine the prognostic factors that have a significant impact on outcome. PATIENTS AND METHODS We analyzed 158 adult patients with WM reported to the European Group for Blood and Marrow Transplantation (EBMT) between January 1991 and December 2005. Median time from diagnosis to ASCT was 1.7 years (range, 0.3 to 20.3 years), 32% of the patients experienced treatment failure with at least three lines of therapy, and 93% had sensitive disease at the time of ASCT. Conditioning regimen was total-body irradiation-based in 45 patients. Median follow-up for surviving patients was 4.2 years (range, 0.5 to 14.8 years). RESULTS Nonrelapse mortality was 3.8% at 1 year. Ten patients developed a secondary malignancy, with a cumulative incidence of 8.4% at 5 years. Relapse rate was 52.1% at 5 years. Progression-free survival (PFS) and overall survival were 39.7% and 68.5%, respectively, at 5 years and were significantly influenced by number of lines of therapy and chemorefractoriness at ASCT. The achievement of a negative immunofixation after ASCT had a positive impact on PFS after ASCT. When used as consolidation at first response, ASCT provided a PFS of 44% at 5 years. CONCLUSION ASCT is a feasible procedure in young patients with advanced WM. ASCT should not be offered to patients with chemoresistant disease and to those who received more than three lines of therapy.

Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus.

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Brutons tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

Treatment recommendations from the Eighth International Workshop on Waldenström’s Macroglobulinemia

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenströms Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM.

Allogeneic Stem-Cell Transplantation in Patients With Waldenström Macroglobulinemia: Report From the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

PURPOSE Allogeneic stem-cell transplantation (alloSCT) is a curative therapeutic option for patients with low-grade lymphoid malignancies. Information regarding alloSCT in Waldenström macroglobulinemia (WM) is limited. This study presents the long-term outcome of a large series of patients with WM treated with alloSCT. PATIENTS AND METHODS A total of 86 patients received allograft by using either myeloablative (MAC; n = 37) or reduced-intensity conditioning (RIC; n = 49) regimens and were retrospectively studied. The median age was 49 years (range, 23 to 64 years); 47 patients had received three or more previous lines of therapy, and eight patients had experienced failure on a prior autologous stem-cell transplantation. A total of 59 patients (68.6%) had chemotherapy-sensitive disease at the time of alloSCT. Median follow-up of the surviving patients was 50 months (7 to 142 months). RESULTS Nonrelapse mortality (NRM) at 3 years was 33% for MAC and 23% for RIC. The overall response rate was 75.6%. The relapse rates (RRs) at 3 years were 11% for MAC and 25% for RIC. Fourteen patients received donor lymphocyte infusions (DLIs) for disease relapse. PFS and OS at 5 years were 56% and 62% for MAC and 49% and 64% for RIC, respectively. The occurrence of chronic graft-versus-host disease (cGVHD) was associated with a higher NRM and a lower RR, leading to an improvement in PFS. CONCLUSION alloSCT can induce durable remissions in a selected population of young and heavily pretreated patients with WM. The low RR, the achievement of additional disease responses after DLIs, and the lower RR in patients developing cGVHD suggest the existence of a clinically relevant graft-versus-WM effect.

A new xenograft model of myeloma bone disease demonstrating the efficacy of human mesenchymal stem cells expressing osteoprotegerin by lentiviral gene transfer

We describe a new model of myeloma bone disease in which β2m NOD/SCID mice injected with KMS-12-BM cells develop medullary disease after tail vein administration. Micro-computed tomography analysis demonstrated significant bone loss in the tibiae and vertebrae of diseased animals compared to controls, with loss of cortical bone (P<0.01), as well as trabecular bone volume, thickness and number (P<0.05 for all). Bone marrow of diseased animals demonstrated an increase in osteoclasts (P<0.01) and reduction in osteoblasts (P<0.01) compared to control animals. Both bone loss and osteoclast increase correlated with the degree of disease involvement. Mesenchymal stem cells (MSCs) were lentivirally transduced to express human osteoprotegerin (hOPG). Systemic administration of OPG expressing MSC reduced osteoclast activation (P<0.01) and trabecular bone loss in the vertebrae (P<0.05) and tibiae of diseased animals, to levels comparable to non-diseased controls. Because of its predominantly medullary involvement and quantifiable parameters of bone disease, the KMS-12-BM xenogeneic model provides unique opportunities to test therapies targeted at the bone marrow microenvironment.

Mapping EORTC QLQ-C30 and QLQ-MY20 to EQ-5D in patients with multiple myeloma.

BackgroundIn oncology, health-related quality of life (HRQoL) data are often collected using disease-specific patient questionnaires while generic, patient-level utility data required for health economic modeling are often not collected.MethodsWe developed a mapping algorithm for multiple myeloma that relates HRQoL scores from the European Organization for Research and Treatment of Cancer (EORTC) questionnaires QLQ-C30 and QLQ-MY20 to a utility value from the European QoL-5 Dimensions (EQ-5D) questionnaire. Data were obtained from 154 multiple myeloma patients who had participated in a multicenter cohort study in the UK or Germany. All three questionnaires were administered at a single time point. Scores from all 19 domains of the QLQ-C30 and QLQ-MY20 instruments were univariately tested against EQ-5D values and retained in a multivariate regression model if statistically significant. A 10-fold cross-validation model selection method was also used as an alternative testing means. Two models were developed: one based on QLQ-C30 plus QLQ-MY20 scores and one based on QLQ-C30 scores alone. Adjusted R-squared, correlation coefficients, and plots of observed versus predicted EQ-5D values were presented for both models.ResultsMapping revealed that Global Health Status/QoL, Physical Functioning, Pain, and Insomnia were significant predictors of EQ-5D utility values. Similar results were observed when QLQ-MY20 scores were excluded from the model, except that Emotional Functioning and became a significant predictor and Insomnia was no longer a significant predictor. Adjusted R-squared values were of similar magnitude with or without inclusion of QLQ-MY20 scores (0.70 and 0.69, respectively), suggesting that the EORTC QLQ-MY20 adds little in terms of predicting utility values in multiple myeloma.ConclusionsThis algorithm successfully mapped EORTC HRQoL data onto EQ-5D utility in patients with multiple myeloma. Current mapping will aid in the analysis of cost-effectiveness of novel therapies for this indication.