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Nikolas Herold, Sean G Rudd, Kumar Sanjiv, Juliane Kutzner, Julia Bladh, Cynthia B J Paulin, Thomas Helleday, Jan-Inge Henter, Torsten Schaller
Recently, we demonstrated that sterile α motif and HD domain containing protein 1 (SAMHD1) is a major barrier in acute myelogenous leukemia (AML) cells to the cytotoxicity of cytarabine (ara-C), the most important drug in AML treatment. Ara-C is intracellularly converted by the canonical dNTP synthesis pathway to ara-CTP, which serves as a substrate but not an allosteric activator of SAMHD1. Using an AML mouse model, we show here that wild type but not catalytically inactive SAMHD1 reduces ara-C treatment efficacy in vivo...
June 3, 2017: Cell Cycle
Chrysavgi Lalayanni, Eirini Baldoumi, Sotiris Papayiannopoulos, Konstantia Tziola, Riad Saloum, Achilles Anagnostopoulos
Nelarabine is a purine analogue used for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma mainly as a bridge to stem cell transplantation. The water-soluble prodrug of 9-beta-D-arabinofuranosyl guanine (Ara-G) is phosphorylated within leukemic cells to form ara-G triphosphate (ara-GTP), which terminates DNA chain elongation, resulting in cell death. The drug received accelerated approval by the US Food and Drug Administration (FDA) on October 2005 based on the induction of complete remissions in 2 phase II trials...
November 17, 2016: Current Problems in Cancer
David I Marks, Clare Rowntree
T-cell acute lymphoblastic leukemia (ALL) is a rare disease in adults with inferior survival outcomes compared with those seen in pediatric patients. Although potentially curable with ∼50% survival at 5 years, adult patients with relapsed disease have dismal outcomes with <10% of patients surviving long term. This review will discuss the diagnosis and management of adult patients with newly diagnosed T-cell ALL with an emphasis on the immunophenotypic and genetic analyses required to assign prognosis, risk stratify, and guide post-remission therapy...
March 2, 2017: Blood
Tapan M Kadia, Varsha Gandhi
T-cell acute lymphoblastic leukemia (ALL) and lymphoma (LBL) are aggressive hematologic neoplasms that are treated with combination chemotherapy in the frontline, but have limited options in the relapsed or refractory setting. Based on observations in patients with purine nucleoside phosphorylase (PNP) deficiency, a guanosine nucleoside analogue, arabinosylguanine (ara-G) was developed that provided T-cell specificity. Nelarabine was developed as the water-soluble, clinically useful-prodrug of ara-G and based on its activity was approved for the treatment of relapsed or refractory T-ALL/LBL...
January 2017: Expert Review of Hematology
Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Cecilia Evangelisti, Ester Orsini, Laura Zambonin, Luca Maria Neri, Alberto Maria Martelli, Francesca Chiarini
BACKGROUND: Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, nelarabine could induce a life-threatening, dose-dependent neurotoxicity...
October 24, 2016: Journal of Hematology & Oncology
Pornpun Sripornsawan, Yasuhiro Okamoto, Takuro Nishikawa, Yuichi Kodama, Yuni Yamaki, Koichiro Kurauchi, Takayuki Tanabe, Shunsuke Nakagawa, Yuichi Shinkoda, Naoko Imuta, Yoshifumi Kawano
BACKGROUND: Nelarabine has been used for the treatment of T-cell malignancies including T-acute lymphoblastic leukemia (T-ALL)/T-lymphoblastic lymphoma. However, the mechanisms that underlie the susceptibility or resistance to nelarabine have not been fully elucidated. The aim of this study was to determine the significance of nelarabine transport and metabolism in the context of nelarabine cytotoxicity. PROCEDURE: The expression profiles of six genes in the nelarabine pathway were analyzed in blast cells from six patients with T-ALL as well as in three T-ALL cell lines...
February 2017: Pediatric Blood & Cancer
Yusuke Higuchi, Kenji Tokunaga, Yuko Watanabe, Toshiro Kawakita, Naoko Harada, Shunichiro Yamaguchi, Kisato Nosaka, Hiroaki Mitsuya, Norio Asou
We present a patient with T-cell lymphoblastic lymphoma (T-LBL) harboring t(6;11)(q27;q23) that converted to acute monoblastic leukemia at relapse. A 27-year-old man developed T-LBL with a mediastinal mass. He exhibited several recurrences in the central nervous system and marrow. A fifth relapse occurred in the marrow, with 42.8% blasts with CD4, CD5, CD7, CD10, CD33, CD34, HLA-DR and cytoplasmic (cy) CD3. While achieving complete remission with nelarabine, sixth relapse occurred in the marrow with 6.8% blasts, which had characteristics of monoblastic features, 2 months later...
2016: Cancer Genetics
Sumeet G Dua, Miral D Jhaveri
Nelarabine is one of the newer and novel drugs approved by the USA Food and Drug Administration for treatment of relapsed and resistant acute lymphoblastic leukemia. Although there are a few accounts of the neurologic toxicity of nelarabine in the oncological literature, it has never been discussed from a radiologic stand point to our knowledge. We describe a case of nelarabine-induced myelopathy and review the existing literature in an attempt to characterize the MRI features helpful in making an early diagnosis of this elusive entity...
July 2016: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Matthew P Burke, Kayla M Borland, Vladislav A Litosh
Nucleoside and nucleobase antimetabolites have substantially impacted treatment of cancer and infections. Their close resemblance to natural analogs gives them the power to interfere with a variety of intracellular targets, which on one hand gives them high potency, but on the other hand incurs severe side effects, especially of the chemotherapeutics used against malignancies. Therefore, the development of novel nucleoside analogs with widened therapeutic windows represents an attractive target to synthetic organic and medicinal chemists...
2016: Current Topics in Medicinal Chemistry
Tomohiro F Nishijima, Thomas C Shea, William A Wood, Peter M Voorhees, Katarzyna Jamieson
No abstract text is available yet for this article.
2016: Leukemia & Lymphoma
Noelle V Frey, Selina M Luger
The long-term prognosis of adult patients with relapsed Philadelphia chromosome-negative acute lymphoblastic lymphoma (ALL) is poor. Allogeneic stem cell transplant in second remission is the only curative approach and is the goal when feasible. There is no standard chemotherapy regimen for relapsed disease, although a few agents are approved for use in this setting. The bispecific CD19-directed CD3 T-cell engager, blinatumomab, has recently been granted accelerated approval by the US Food and Drug Administration for relapsed or refractory disease of B-cell lineage...
July 30, 2015: Blood
Mark R Litzow, Adolfo A Ferrando
T-cell immunophenotype of acute lymphoblastic leukemia (T-ALL) is an uncommon aggressive leukemia that can present with leukemic and/or lymphomatous manifestations. Molecular studies are enhancing our understanding of the pathogenesis of T-ALL, and the discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation. The use of pediatric intensive combination chemotherapy regimens in adolescents and young adults has significantly improved the outcome of patients with T-ALL...
August 13, 2015: Blood
Mahnur Haider, Syed Ahsan Rizvi, Pashtoon Murtaza Kasi
Nelarabine (ara-G; Arranon; compound 506U78) is an antineoplastic purine analog used for the treatment of refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). The drug was granted accelerated approval in October 2005 by the US Food and Drug Administration (FDA) given the efficacy (induction of complete responses) noted in 2 single-arm trials (one in pediatric setting and one in adult patient population). The main spectra of toxicities that have been reported in these clinical trials and subsequent studies are hematological and neurological...
2015: Case Reports in Hematology
Dan Douer, Deborah A Thomas
Acute lymphoblastic leukemia (ALL) occurs in both children and adults. Significant improvements in survival outcomes have been realized over the last decade for all age groups with de novo ALL. Frontline treatment incorporates a tailored approach, based on factors such as the patient’s age and the disease subtype. Children, adolescents, and young adults are likely to receive intensifying or deintensifying chemotherapy regimens using standard chemotherapeutics (eg, anthracyclines, vincristine, asparaginase) based on risk stratification...
June 2014: Clinical Advances in Hematology & Oncology: H&O
Gail J Roboz, Elias J Jabbour, Stefan Faderl, Dan Douer
Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy characterized by proliferation of immature lymphoid cells throughout the bone marrow and peripheral blood. Most cases are diagnosed before the age of 20 years. Adults have a worse prognosis than children. Approximately half of adult ALL patients relapse after their initial treatment. There is no standard treatment for ALL; strategies vary according to the patient’s age, comorbidities, and Philadelphia chromosome status. Regimens used in pediatric patients are being adapted for use in adults...
December 2014: Clinical Advances in Hematology & Oncology: H&O
Stuart S Winter, Kimberly P Dunsmore, Meenakshi Devidas, Nancy Eisenberg, Barbara L Asselin, Brent L Wood, Marcia S Leonard Rn, John Murphy, Julie M Gastier-Foster, Andrew J Carroll, Nyla A Heerema, Mignon L Loh, Elizabeth A Raetz, Naomi J Winick, William L Carroll, Stephen P Hunger
BACKGROUND: Nelarabine has shown impressive single agent clinical activity in T-cell acute lymphoblastic leukemia (T-ALL), but has been associated with significant neurotoxicities in heavily pre-treated patients. We showed previously that it was safe to add nelarabine to a BFM-86 chemotherapy backbone (AALL00P2). Children's Oncology Group (COG) AALL0434 is a Phase III study designed to test the safety and efficacy of nelarabine when incorporated into a COG augmented BFM-based regimen, which increases exposure to agents with potential neurotoxicity compared to the historical AALL00P2 regimen...
July 2015: Pediatric Blood & Cancer
Maria Chiara Tisi, Giuseppe Ausoni, Maria Gabriella Vita, Tommaso Tartaglione, Mario Balducci, Luca Laurenti, Patrizia Chiusolo, Stefan Hohaus, Simona Sica
Eleven cases of neurological defects in T-ALL patients treated with nelarabine have been described in the last 4 years, seven of these after stem cell transplantation (SCT) for T Lymphoblastic Lymphoma (T-LBL). Most of these patients had an unfavorable outcome or irreversible neurological damage. We now report the case of a 41-year-old woman suffering from T-LBL who presented with severe, but reversible myelopathy after receiving nelarabine-based treatment and mediastinal radiotherapy, and we provide a review of the literature on the topic...
2015: Mediterranean Journal of Hematology and Infectious Diseases
Katharine Patrick, Ajay Vora
PURPOSE OF REVIEW: In this article, new insights into the clinical and biological features of paediatric T-lineage acute lymphoblastic leukaemia (ALL) and their impact on treatment outcome have been described. RECENT FINDINGS: T-lineage ALL has considerable phenotypic and biological heterogeneity. Compared with B-lineage ALL, the prognostic significance of the presenting white cell count is weaker and the rate of decline in minimal residual disease is slower in patients with T-lineage ALL...
February 2015: Current Opinion in Pediatrics
Sameer A Parikh, Mark R Litzow
Although the prognosis of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) has steadily improved over the past decade, less than 50% of patients maintain their remission at 5 years. Several approaches have been explored in the past few years including: monoclonal antibodies - either 'naked' (rituximab) or in combination with an immunotoxin (calicheamicin or maytansin), plant toxin (ricin), or bacterial toxin (Pseudomonas or diphtheria), and a novel bispecific T-cell-engaging antibody (blinatumomab); chimeric antigen therapy using autologous T cells that target CD19-expressing ALL; and novel agents such as proteasome inhibitors, liposomal vincristine, hypomethylating agents, nelarabine and NOTCH1 inhibitors...
November 2014: Future Oncology
Hee Young Ju, Che Ry Hong, Hee Young Shin
Treatment outcomes of pediatric cancers have improved greatly with the development of improved treatment protocols, new drugs, and better supportive measures, resulting in overall survival rates greater than 70%. Survival rates are highest in acute lymphoblastic leukemia, reaching more than 90%, owing to risk-based treatment through multicenter clinical trials and protocols developed to prevent central nervous system relapse and testicular relapse in boys. New drugs including clofarabine and nelarabine are currently being evaluated in clinical trials, and other targeted agents are continuously being developed...
October 2014: Korean Journal of Pediatrics
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