Lenalidomide induced good clinical response in a patient with multiple relapsed and refractory Hodgkin's lymphoma

<p>Abstract</p> <p>Background</p> <p>A 24-year-old female patient was diagnosed with classic Hodgkin's lymphoma in clinical stage II, and combination chemotherapy followed by radiotherapy was initiated. During the following 5 years, the disease progressed despite several standard therapeutic approaches, including autologous and allogeneic stem cell transplantation.</p> <p>Methods</p> <p>Lenalidomide (25 mg daily) treatment was then initiated in a continuous dosing schedule. Positron emission tomography scans were performed before and during lenalidomide treatment. Hematologic and laboratory values, as well as physical condition were also assessed before and during lenalidomide treatment.</p> <p>Results</p> <p>Four months after continuous lenalidomide treatment, tumor load was significantly reduced, B symptoms had resolved, and the patient's physical condition had improved, allowing her to resume normal daily-living activities. Evaluations after 15 months of lenalidomide treatment indicated limited disease progression. Nevertheless, the patient was feeling well and maintaining a normal active life. Treatment was well tolerated, allowing the patient to remain on continuous dosing, which has now been maintained for 18 months.</p> <p>Conclusion</p> <p>Daily, long-term lenalidomide treatment provided clinical benefit and was well tolerated in a patient with relapsed, advanced classic Hodgkin's lymphoma.</p

Outcomes of allogeneic stem cell transplantation among patients with acute myeloid leukemia presenting active disease: Experience of a single European Comprehensive Cancer Center

Introduction: Allogeneic hematopoietic stem cell transplantation (ASCT) represents a potentially curative approach for patients with relapsed or refractory acute myeloid leukemia (AML). We report the outcome of relapsed/refractory AML patients treated with ASCT.Method: A retrospective cohort from 1994 to 2013 that included 61 patients with diagnosis of relapsed/refractory AML. Outcomes of interest were transplant-related mortality (TRM), incidence of acute and chronic graft-versus-host disease (GVHD), relapse incidence, progression-free survival (PFS) and overall survival (OS). Statistical significance was set at p<0.05.Results: The median age was 61 years (range 1 to 65). The cumulative incidence of 90 days, 1 year, and 3 years TRM were 60%, 26.7%, and 13.3%, respectively (p< 0.001). The incidence of relapse was 21.7% at 1 year, 13% at 3 years, and 8.7% at 5 years. Median OS was estimated to be 8 months (95CI 3.266-12.734) and median PFS, 3 months (95CI 1.835-4.165).Conclusion: In our cohort, TRM in first years after ASCT remains considerable, but ASCT in this setting seems to be a good choice for AML patients with active disease. However, novel approaches are needed to reduce TRM and relapse in this set of patients

Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia

Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial

Molecular classification improves risk assessment in adult BCR-ABL1–negative B-ALL

Genomic classification has improved risk assignment of pediatric but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (NCT00002514) trial accrued 1229 BCR-ABL1-negative adolescent/adult B-ALL patients (aged 14-65 years). While 93% of patients achieved remission, 41% relapsed at a median of 13 months (range 28 days to 12 years). Five-year overall survival (5yr-OS) was 42% (95% CI, 39, 44). Transcriptome sequencing (n=238), gene expression profiling (n=210), cytogenetics (n=197) and fusion PCR (n=274) enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients in the outcome analysis, 29.5% of cases had favorable outcomes with 5yr-OS of 65-80% and were deemed standard-risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5yr-OS of 0-27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); and 20.3% had intermediate-risk genotypes with 5yr-OS of 33-45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like and TP53 mutations occurred in low-hypodiploid (54%) and BCL2/MYC-rearranged patients (33%), but were not independently associated with outcome. Of patients considered high-risk for relapse based on presenting age and WBC count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses which may translate into future therapeutic benefits

A single dose of pegfilgrastim compared with daily filgrastim for supporting neutrophil recovery in patients treated for low-to-intermediate risk acute myeloid leukemia: results from a randomized, double-blind, phase 2 trial

Background: Patients with acute myeloid leukemia (AML) are often neutropenic as a result of their disease. Furthermore, these patients typically experience profound neutropenia following induction and/or consolidation chemotherapy and this may result in serious, potentially life-threatening, infection. This randomized, double-blind, phase 2 clinical trial compared the efficacy and tolerability of pegfilgrastim with filgrastim for assisting neutrophil recovery following induction and consolidation chemotherapy for de novo AML in patients with low-to-intermediate risk cytogenetics. Methods: Patients (n = 84) received one or two courses of standard induction chemotherapy (idarubicin + cytarabine), followed by one course of consolidation therapy (high-dose cytarabine) if complete remission was achieved. They were randomized to receive either single-dose pegfilgrastim 6 mg or daily filgrastim 5 μg/kg, beginning 24 hours after induction and consolidation chemotherapy. Results: The median time to recovery from severe neutropenia was 22.0 days for both pegfilgrastim (n = 42) and filgrastim (n = 41) groups during Induction 1 (difference 0.0 days; 95% CI: -1.9 to 1.9). During Consolidation, recovery occurred after a median of 17.0 days for pegfilgrastim versus 16.5 days for filgrastim (difference 0.5 days; 95% CI: -1.1 to 2.1). Therapeutic pegfilgrastim serum concentrations were maintained throughout neutropenia. Pegfilgrastim was well tolerated, with an adverse event profile similar to that of filgrastim. Conclusion: These data suggest no clinically meaningful difference between a single dose of pegfilgrastim and multiple daily doses of filgrastim for shortening the duration of severe neutropenia following chemotherapy in de novo AML patients with low-to-intermediate risk cytogenetics

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

Clinical usefulness of doxorubicin (DOX) is limited by the occurrence of multidrug resistance (MDR) associated with the presence of membrane transporters (e.g. P-glycoprotein, MRP1) responsible for the active efflux of drugs out of resistant cells. Doxorubicin is a well-known bioreductive antitumour drug. Its ability to undergo a one-electron reduction by cellular oxidoreductases is related to the formation of an unstable semiquionone radical and followed by the production of reactive oxygen species. There is an increasing body of evidence that the activation of bioreductive drugs could result in the alkylation or crosslinking binding of DNA and lead to the significant increase in the cytotoxic activity against tumour cells. The aim of this study was to examine the role of reductive activation of DOX by the human liver NADPH cytochrome P450 reductase (CPR) in increasing its cytotoxic activity especially in regard to MDR tumour cells. It has been evidenced that, upon CPR catalysis, DOX underwent only the redox cycling (at low NADPH concentration) or a multistage chemical transformation (at high NADPH concentration). It was also found, using superoxide dismutase (SOD), that the first stage undergoing reductive activation according to the mechanism of the redox cycling had the key importance for the metabolic conversion of DOX. In the second part of this work, the ability of DOX to inhibit the growth of human promyelocytic-sensitive leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX) was studied in the presence of exogenously added CPR. Our assays showed that the presence of CPR catalysing only the redox cycling of DOX had no effect in increasing its cytotoxicity against sensitive and MDR tumour cells. In contrast, an important increase in cytotoxic activity of DOX after its reductive conversion by CPR was observed against HL60 as well as HL60/VINC and HL60/DOX cells

IL-4 as a Repurposed Biological Drug for Myocardial Infarction through Augmentation of Reparative Cardiac Macrophages: Proof-of-Concept Data in Mice.

Recent research has shown that reparative (alternatively activated or M2) macrophages play a role in repair of damaged tissues, including the infarcted hearts. Administration of IL-4 is known to augment M2 macrophages. This translational study thus aimed to investigate whether IL-4 administration is useful for the treatment of myocardial infarction. Long-acting IL-4 complex (IL-4c; recombinant IL-4 mixed with anti-IL-4 monoclonal antibody as a stabilizer) was administered after coronary artery ligation in mice. It was observed that IL-4c administration increased accumulation of CD206+F4/80+ M2-like macrophages predominantly in the injured myocardium, compared to the control. Sorted cardiac M2-like macrophages highly expressed wide-ranging tissue repair-related genes. Indeed, IL-4c administration enhanced cardiac function in association with reduced infarct size and enhanced tissue repair (strengthened connective tissue formation, improved microvascular formation and attenuated cardiomyocyte hypertrophy). Experiments using Trib1 -/- mice that had a depleted ability to develop M2 macrophages and other in-vitro studies supported that these IL-4-mediated effects were induced via M2-like macrophages. On the other hand, when administered at Day 28 post-MI, the effects of IL-4c were diminished, suggesting a time-frame for IL-4 treatment to be effective. These data represent proof-of-concept of efficacy of IL-4 treatment for acute myocardial infarction, encouraging its further development.This project was funded by the Heart Research UK Translational Research Grant (RG2653/15/16), British Heart Foundation Programme Grant (RG/15/31236), and Queen Mary Innovation Proof of Concept Grant (2015). The National Institute for Health Researchfunded Barts Cardiovascular Biomedical Research Unit also supported this project.This project was funded by the Heart Research UK Translational Research Grant (RG2653/15/16), British Heart Foundation Programme Grant (RG/15/31236), and Queen Mary Innovation Proof of Concept Grant (2015). The National Institute for Health Research-funded Barts Cardiovascular Biomedical Research Unit also supported this project