Amsterdam, Netherlands
Amsterdam, Netherlands

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Van Gelder M.,Maastricht University | Van Oers M.H.,Lymphoma and Myeloma Center | Alemayehu W.G.,Erasmus Medical Center | Abrahamse-Testroote M.C.J.,Erasmus Medical Center | And 11 more authors.
Bone Marrow Transplantation | Year: 2016

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). Twenty-nine patients received ≥3 cycles of R-DHAP and sixteen <3 cycles (4 because of disease progression, 8 for toxicity and 4 toxic deaths). Overall rate of response to R-DHAP was 58%, 31 (67%) proceeded to alloSCT after conditioning with fludarabine and 2 Gy TBI. Twenty (65%) remained free from progression at 2 years after alloSCT, including 17 without minimal residual disease. Intention-to-treat 2-year PFS and overall survival of the 46 patients were 42 and 51% (35.5 months median follow-up); del(17p) or fludarabine refractoriness had no impact. R-DHAP followed by alloSCT is a reasonable treatment to be considered for high-risk CLL patients without access or resistance to targeted therapies. © 2016 Macmillan Publishers Limited.

Te Raa G.D.,University of Amsterdam | Leeksma A.C.,University of Amsterdam | Yigittop H.,MRC Holland | Laddach N.,MRC Holland | And 13 more authors.
Cell Death and Disease | Year: 2015

The ATM-p53 DNA-damage response (DDR) pathway has a crucial role in chemoresistance in CLL, as indicated by the adverse prognostic impact of genetic aberrations of TP53 and ATM. Identifying and distinguishing TP53 and ATM functional defects has become relevant as epigenetic and posttranscriptional dysregulation of the ATM/p53 axis is increasingly being recognized as the underlying cause of chemoresistance. Also, specific treatments sensitizing TP53- or ATM-deficient CLL cells are emerging. We therefore developed a new ATM-p53 functional assay with the aim to (i) identify and (ii) distinguish abnormalities of TP53 versus ATM and (iii) enable the identification of additional defects in the ATM-p53 pathway. Reversed transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) was used to measure ATM and/or p53-dependent genes at the RNA level following DNA damage using irradiation. Here, we showed that this assay is able to identify and distinguish three subgroups of CLL tumors (i.e., TP53-defective, ATM-defective and WT) and is also able to detect additional samples with a defective DDR, without molecular aberrations in TP53 and/or ATM. These findings make the ATM-p53 RT-MLPA functional assay a promising prognostic tool for predicting treatment responses in CLL. © 2015 Macmillan Publishers Limited All rights reserved.

te Raa G.D.,University of Amsterdam | Kater A.P.,University of Amsterdam | Kater A.P.,Lymphoma and Myeloma Center
Best Practice and Research: Clinical Haematology | Year: 2016

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. TP53 defects highly affect outcome of immunochemotherapy but also alter response durations of tyrosine kinase inhibitors. Although BCR-targeting agents and Bcl-2-inhibitos have achieved durable responses in some patients with TP53 defects, long-term follow-up is currently lacking. In this review biological and clinical consequences of TP53 dysfunction as well as applicability of currently available methods to detect TP53 defects are described. In addition, proposed novel therapeutic strategies specifically for patients with TP53 dysfunction are discussed. In summary, the only curative treatment option for TP53-defective CLL is still allogeneic hematopoietic stem cell transplantation. Other treatment strategies such as rationale combinations of agents with different (TP53 independent) targets, including kinase inhibitors and inhibitors of anti-apoptotic molecules but also immunomodulatory agents need to be further explored. © 2016 Elsevier Ltd

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