Posted by rob on July 27, 2010 under Uncategorized | 
Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): A therapeutic advances in childhood leukemia (TACL) consortium study.
Pediatr Blood Cancer. 2010 Sep;55(3):421-9
Authors: Gorman MF, Ji L, Ko RH, Barnette P, Bostrom B, Hutchinson R, Raetz E, Seibel NL, Twist CJ, Eckroth E, Sposto R, Gaynon PS, Loh ML
BACKGROUND: Current event-free survival (EFS) rates for children with newly diagnosed acute myeloid leukemia (AML) approach 50-60%. We hypothesize that further improvements in survival are unlikely to be achieved with traditional approaches such as dose intensive chemotherapy or hematopoietic stem cell transplants, since these therapies have been rigorously explored in clinical trials. This report highlights efforts to assess the response rates and survival outcomes after first or greater relapse in children with AML. PROCEDURE: We performed a retrospective cohort review of pediatric patients with relapsed and refractory AML (rAML) previously treated at TACL institutions between the years of 1995 and 2004. Data regarding disease characteristics at diagnosis and relapse, treatment response, and survival was collected on 99 patients and 164 medullary relapses or treatment failures. RESULTS: The complete response (CR) rate following the second therapeutic attempt was 56 +/- 5%. CR rates following a third treatment attempt was 25 +/- 8% while 17 +/- 7% achieved CR following the fourth through sixth treatments. The 5-year disease-free survival in patients achieving CR following a second therapeutic attempt was 43 +/- 7%. The 5-year EFS and overall survival (OS) rates for all patients receiving a second treatment attempt was 24 +/- 5% and 29 +/- 5%, respectively. CONCLUSIONS: This CR rate following a second therapeutic attempt and OS rate in patients with rAML is consistent with the literature. There are limited published data of CR rates for subsequent relapses. Our data can serve as a historical benchmark to compare outcomes of future therapeutic trials in rAML against traditional chemotherapy regimens. Pediatr Blood Cancer. 2010;55:421-429. (c) 2010 Wiley-Liss, Inc.
PMID: 20658611 [PubMed - in process]
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Hematopoietic stem cell transplantation for T315I-mutated chronic myelogenous leukemia.
Ann Transplant. 2010 Jun 28;15(2):68-70
Authors: Basak GW, Torosian T, Snarski E, Niesiobedzka J, Majewski M, Gronkowska A, Urbanowska E, Jedrzejczak WW
Background: The T315I mutation of BCR/ABL gene is known to produce complete resistance of chronic myelogenous leukemia (CML) to all currently available BCR/ABL inhibitors. The data suggesting poor median survival of these patients may indicate that they should be primary candidates for allogeneic stem cell transplantation (alloSCT). However, evidence on efficiency of this treatment modality in CML with T315I mutation is lacking.<br /> Case Report: A 25-year-old patient was diagnosed with Philadelphia chromosome positive CML in accelerated phase. As he did not have an HLA-identical sibling or fully-matched unrelated bone marrow donor, treatment with low dose tyrosine kinase inhibitor – imatinib was initiated. Despite satisfactory hematological remission, he failed to achieve complete cytogenetic remission within the first year of treatment. Moreover, despite escalation of imatinib dosage, the disease relapsed after further 3 months of treatment. Molecular studies revealed T315I mutation of BCR/ABL gene. He responded poorly to interferon alpha (IFN-alpha) and we decided to perform alloSCT from a partially mismatched (8/10 HLA allele match) unrelated donor. The course of transplantation was complicated by staphylococcal sepsis, grade I skin acute GvHD and limited chronic skin GVHD. However, the goal of alloSCT was achieved and the patient remains in complete molecular remission at week +68 post-transplantation.<br /> Conclusions: The clinical course of this case supports the idea that allogeneic hematopoietic transplantation is a viable treatment option for patients with CML bearing T315I mutation.
PMID: 20657522 [PubMed - in process]
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Posted by rob on under Uncategorized |
Autophagy is a critical mechanism for the induction of the antileukemic effects of arsenic trioxide.
J Biol Chem. 2010 Jul 23;
Authors: Goussetis DJ, Altman JK, Glaser H, McNeer JL, Tallman MS, Platanias LC
Arsenic trioxide (As2O3) exhibits potent antitumor effects in vitro and in vivo, but the precise mechanisms by which it generates such responses are not well understood. We provide evidence that As2O3 is a potent inducer of autophagy in leukemia cells. Such induction of autophagy by As2O3 appears to require activation of the MEK/ERK pathway, but not the AKT/mTOR or JNK pathways. In efforts to understand the functional relevance of arsenic-induced autophagy, we found that pharmacological inhibitors of autophagy or molecular targeting of beclin 1 or Atg7 result in reversal of the suppressive effects of As2O3 on leukemic cell lines and primary leukemic progenitors from acute myelogenous leukemia (AML) patients. Altogether, our data provide direct evidence that autophagic cell death is critical for the generation of the effects of As2O3 on AML cells and raise the potential of modulating of elements of the autophagic machinery as an approach to enhance the antitumor properties of As2O3 and possibly other heavy metal derivatives.
PMID: 20656687 [PubMed - as supplied by publisher]
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