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Cll stem cell transplant

Gera D Te Raa, Arnon P Kater
Despite the availability of novel targeted agents, TP53 defects remain the most important adverse prognostic factor in chronic lymphocytic leukemia (CLL). Detection of deletion of TP53 locus (17p deletion) by fluorescent in situ hybridization (FISH) has become standard and performed prior to every line of treatment as the incidence dramatically increases as relapses occur. As monoallelic mutations of TP53 equally affect outcome, novel methods are being developed to improve detection of TP53 defects and include next-generation sequencing (NGS) and functional assays...
March 2016: Best Practice & Research. Clinical Haematology
Davide Rossi
Richter's syndrome (RS) is the development of an aggressive lymphoma in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL). The incidence rate for RS is ∼0.5% per year of observation. In the presence of clinical suspicious of RS, diagnosis of transformation and choice of the site of biopsy may take advantage of (18)FDG PET/CT. Molecular lesions of tumor suppression regulators (TP53), cell cycle (CDKN2A) and cell proliferation (NOTCH1, MYC) overall account for ∼90% of RS and may be responsible for its aggressive clinical phenotype...
March 2016: Best Practice & Research. Clinical Haematology
I F Khouri, D Sui, E J Jabbour, B I Samuels, F Turturro, G Alatrash, P Anderlini, S Ahmed, B Oran, S O Ciurea, D Marin, A Olson, K K Patel, U R Popat, C Ledesma, T M Kadia, A Ferrajoli, J A Burger, J L Jorgensen, L J Medeiros, R L Bassett, A M Gulbis
Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution...
September 5, 2016: Bone Marrow Transplantation
Emili Montserrat, Peter Dreger
The treatment of patients with chronic lymphocytic leukemia (CLL) whose tumor presents the del(17p)/TP53 mutation is a major challenge. Treatment with chemo(immuno)therapy, immunomodulators, or the anti-CD52 monoclonal antibody alemtuzumab produces transient, unsatisfactory responses. Reduced-intensity-conditioning allotransplantation produces sustained progression-free survival and overall survival (40%-60% at 5 years), equivalent to the cure of the disease, even in cases with adverse biomarkers. Unfortunately, despite improvements in this procedure, the non-relapse mortality continues to be high (15%-30%), and only highly selected patients (young, physically fit, with treatment-sensitive disease, not heavily pretreated, and with a fully matched donor) may benefit from the intervention without incurring unacceptable treatment-related risks...
August 2016: Clinical Lymphoma, Myeloma & Leukemia
Maria-Luisa Schubert, Angela Gabriele Hückelhoven, Jean-Marc Hoffmann, Anita Schmitt, Patrick Wuchter, Leopold Sellner, Susanne Hofmann, Anthony D Ho, Peter Dreger, Michael Schmitt
Novel therapies with chimeric antigen receptor (CAR) transduced T cells (TCs) sparked new hope for patients with relapsed or refractory CD19-positive leukemia or lymphoma even after stem cell therapies. This review focuses on CARs recognizing the B cell antigen CD19. Both retro- and lentiviral vectors are used encoding the different anti-CD19 CAR constructs comprising costimulatory molecules like CD28, CD137/4-1BB and OX40 either alone (2nd generation CARs) or in combination (3rd generation CARs). Current up-to-date published studies on anti-CD19 CAR therapy for acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and Non-Hodgkin lymphoma (NHL) with observed side effects are discussed and an outlook on 59 ongoing trials is given...
August 1, 2016: Human Gene Therapy
Elke Rücker-Braun, Cornelia S Link, Maria Schmiedgen, Antje Tunger, Petra Vizjak, Raphael Teipel, Rebekka Wehner, Denise Kuehn, Yannik F Fuchs, Uta Oelschlaegel, Lothar Germeroth, Marc Schmitz, Martin Bornhäuser, Johannes Schetelig, Falk Heidenreich
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Graft versus leukemia (GvL) effects which are exerted by donor T cells directed against leukemic-associated antigens (LAA) are considered to play a crucial role in disease eradication. While the expansion of cytotoxic T lymphocytes (CTL) specific for cytomegalovirus (CMV) in response to an infection has been shown in multiple studies, data about CTLs mediating GvL effects are limited...
July 26, 2016: Experimental Hematology
Nadia Mensali, Fan Ying, Vincent Oei Yi Sheng, Weiwen Yang, Even Walseng, Shraddha Kumari, Lars-Egil Fallang, Arne Kolstad, Wolfgang Uckert, Karl Johan Malmberg, Sébastien Wälchli, Johanna Olweus
T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However, CARs recognize all CD19 positive (pos) cells, and durable responses are linked to profound depletion of normal B cells. Here, we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs), in contrast to CARs, are restricted by HLA. Two TCRs recognizing a peptide from CD20 (SLFLGILSV) in the context of foreign HLA-A*02:01 (CD20p/HLA-A2) were expressed as 2A-bicistronic constructs...
May 2016: Oncoimmunology
Jessica Gorgeis, Xu Zhang, Katelin Connor, Stacey Brown, Scott R Solomon, Lawrence E Morris, H Kent Holland, Asad Bashey, Melhem Solh
A second allogeneic hematopoietic stem cell transplantation (HSCT) using the same donor or another fully matched donor is an effective treatment approach for a subset of patients relapsing after a matched related (MRDT) or matched unrelated donor transplant (MUDT). There are limited data on the use of haploidentical transplantation (HIDT) with post-transplant cyclophosphamide in the setting of a second HSCT after an MRDT or MUDT. We analyzed the outcomes of 20 patients who received HIDT with post-transplant cyclophosphamide as a second HSCT after an MRDT (n = 10) or MUDT (n = 10)...
October 2016: Biology of Blood and Marrow Transplantation
Mark-Alexander Schwarzbich, Fabienne McClanahan, John Gribben DSc
Hematopoietic stem cell transplantation (HSCT) is the only established potentially curative treatment option for chronic lymphocytic leukemia (CLL) to date. However, this approach is associated with high toxicity and significant treatment-related morbidity and mortality; thus, it is suitable for only a minority of high-risk patients, given that most persons with CLL have comorbidities and are of advanced age. Until very recently, international guidelines recommended HSCT for physically fit patients who displayed poor-risk features or had only a short response to immunochemotherapy...
June 2016: Oncology (Williston Park, NY)
Lukáš Smolej, Martin Šimkovič
Revolutionary progress has recently changed the landscape of chronic lymphocytic leukemia (CLL). Powerful prognostic factors, especially p53 mutation and/or deletion and IGHV mutation status, have refined individual patient prognosis. Purine analogs and monoclonal antibodies paved the way from palliative treatment to chemoimmunotherapy capable of eradication of minimal residual disease and prolongation of survival. Obinutuzumab (GA-101) and ofatumumab have been recently approved for the treatment of comorbid patients...
April 1, 2016: Archives of Medical Science: AMS
Martin Šimkovič, Monika Motyčková, David Belada, Pavel Vodárek, Rahul Kapoor, Hamna Jaffar, Filip Vrbacký, Pavel Žák, Lukáš Smolej
INTRODUCTION: High-dose methylprednisolone (HDMP) in combination with rituximab is active in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), but serious infections are frequent. Recently published data suggested that high-dose dexamethasone might be equally effective as HDMP despite a lower cumulative dose. MATERIAL AND METHODS: We performed retrospective analysis of 60 patients with relapsed/refractory CLL (median age: 66 years; range: 37-86) treated with rituximab plus dexamethasone (R-dex) at a single tertiary center between September 2008 and October 2012...
April 1, 2016: Archives of Medical Science: AMS
Li Wang, Kourong Miao, Lei Fan, Ji Xu, Hanxin Wu, Jianyong Li, Wei Xu
OBJECTIVE: To investigate the effectiveness and safety of reduced intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT) in ultra high risk chronic lymphocytic leukemia (CLL) patients with the deletion of p53 to deepen the understanding of allo-HSCT in the treatment of CLL. METHODS: In this retrospective study, a total of 4 ultra high risk CLL patients with the deletion of p53 in our center between July 2012 and Jan 2014 were enrolled...
April 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Lukáš Smolej
Despite impressive therapeutic progress represented by the advent of chemoimmunotherapy, chronic lymphocytic leukemia (CLL) remains incurable by conventional modalities. Refractory CLL defined by non-response to treatment or relapse/progression within 6 months is associated with multiple unfavourable prognostic factors such as p53 pathway disruption, deteriorating patient condition, increased risk of severe infections, and poor response to treatment, resulting in a very short overall survival. Therefore, refractory CLL represents a highly challenging situation for the hematologist as well as the patient...
April 8, 2016: Current Cancer Drug Targets
Davide Rossi, Gianluca Gaidano
Richter syndrome (RS) is the development of an aggressive lymphoma in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL). The incidence rate RS is ~0.5% per year of observation. Two biomarkers (NOTCH1 mutations and subset 8 configuration of the B-cell receptor) may help identifying CLL patients at risk of RS to be considered for close monitoring and a careful biopsy policy. In the presence of clinical features suspicious of RS, diagnosis of transformation and choice of the site of biopsy may take advantage of fluorine 18 fluorodeoxyglucose ((18)FDG) positron emission tomography (PET)/computed tomography (CT)...
April 2016: Seminars in Oncology
Kami Maddocks, Jeffrey A Jones
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and remains incurable outside of the setting of allogeneic stem cell transplant. While the standard therapy for both initial and relapsed CLL has traditionally included monoclonal antibody therapy in combination with chemotherapy, there are patients with high-risk disease features including unmutated IgVH, del(11q22) and del(17p13) that are associated with poor overall responses to these therapies with short time to relapse and shortened overall survival...
April 2016: Seminars in Oncology
J R Passweg, H Baldomero, P Bader, C Bonini, S Cesaro, P Dreger, R F Duarte, C Dufour, J Kuball, D Farge-Bancel, A Gennery, N Kröger, F Lanza, A Nagler, A Sureda, M Mohty
A record number of 40 829 hematopoietic stem cell transplantation (HSCT) in 36 469 patients (15 765 allogeneic (43%), 20 704 autologous (57%)) were reported by 656 centers in 47 countries to the 2014 survey. Trends include: continued growth in transplant activity, more so in Eastern European countries than in the west; a continued increase in the use of haploidentical family donors (by 25%) and slower growth for unrelated donor HSCT. The use of cord blood as a stem cell source has decreased again in 2014...
June 2016: Bone Marrow Transplantation
M van Gelder, M H van Oers, W G Alemayehu, M C J Abrahamse-Testroote, J J Cornelissen, M E Chamuleau, P Zachée, M Hoogendoorn, M Nijland, E J Petersen, A Beeker, G-J Timmers, L Verdonck, M Westerman, O de Weerdt, A P Kater
Allogeneic stem cell transplantation (alloSCT) remains the only curative option for CLL patients. Whereas active disease at the time of alloSCT predicts poor outcome, no standard remission-induction regimen exists. We prospectively assessed outcome after cisplatin-containing immune-chemotherapy (R-DHAP) followed by alloSCT in 46 patients (median age 58 years) fulfilling modified European Society for Blood and Marrow Transplantation (EBMT) CLL Transplant Consensus criteria being refractory to or relapsed (R/R) <1 year after fludarabine or <2 years after fludarabine-based immunochemotherapy or R/R with del(17p)...
June 2016: Bone Marrow Transplantation
Candida Vitale, Alessandra Ferrajoli
The term Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma. RS is a rare complication with an aggressive clinical course, bearing an unfavorable prognosis. In the majority of cases, CLL transforms into RS as diffuse large B cell lymphoma (DLBCL), and a clonal relation between the two processes can be found. However, clonally unrelated RS can occur and transformations to other histologies beside DLBCL have been described. Recent data have shed some light on genetic characteristics that can influence and drive the transformation from CLL to RS...
February 2016: Current Hematologic Malignancy Reports
Silvia Montoto
Histologic transformation (HT) is a frequent event in the clinical course of patients with indolent lymphoma. Most of the available data in the literature comes from studies on transformation of follicular lymphoma (FL), as this is the most common indolent lymphoma; however, HT is also well documented following small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL), lymphoplasmacytic lymphoma (LPL), or marginal zone lymphoma (MZL), amongst other types of lymphoma, albeit most of the studies on transformation in these subtypes are case reports or short series...
2015: Hematology—the Education Program of the American Society of Hematology
Monica Else, Rachel Wade, David Oscier, Daniel Catovsky
With 10+ years follow-up in the Leukaemia Research Fund (LRF) CLL4 trial, we report the effect of salvage therapy, and the clinical/biological features of the 10-year survivors treated for chronic lymphocytic leukaemia (CLL). Overall survival (OS) was similar in the three randomized arms. With fludarabine-plus-cyclophosphamide (FC), progression-free survival (PFS) was significantly longer (P < 0.0001), but OS after progression significantly shorter, than in the chlorambucil or fludarabine arms (P < 0...
January 2016: British Journal of Haematology
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