Hematopoietic progenitor cell collection in patients with chronic myelogenous leukemia in complete cytogenetic remission after imatinib mesylate therapy.

Leuk Lymphoma. 2010 Jul 27;

Authors: Bashir Q, De Lima MJ, McMannis JD, Garcia-Manero G, Shpall E, Kantarjian H, Cortes JE, O’Brien SM, Jones D, Qazilbash M, Wei W, Giralt SA, Champlin RE, Hosing C

The introduction of BCR-ABL tyrosine kinase inhibitors such as imatinib has changed the treatment of chronic myelogenous leukemia (CML). More than 75% of patients achieve complete cytogenetic remission (CCR) after treatment with imatinib, which provides an opportunity to collect minimally involved hematopoietic progenitor stem cell (HPC) products. In order to assess the feasibility of HPC collection in patients with CML, we prospectively enrolled 24 patients who achieved CCR on therapy with imatinib. Two patients could not undergo HPC collection because of coagulopathy. A CD34+ cell yield of >/=2.0 x 10(6)/kg body weight was obtained in 16/22 (73%) patients. Patients who stopped imatinib for at least 3 weeks prior to HPC collection had significantly higher CD34+ cell yields (median: 6.52 x 10(6)/kg body weight) when compared with patients who continued imatinib through the collection (median: 3.74 x 10(6)/kg body weight). Mobilization with granulocyte colony-stimulating factor (G-CSF) did not increase the levels of BCR-ABL transcript. With a mean follow-up of 46 months, all patients but one were in CCR. In conclusion, a significant number of CD34+ cells can be safely collected in patients with CML who are on imatinib therapy, but CD34+ cell yields improve when imatinib is temporarily withheld.

PMID: 20658954 [PubMed - as supplied by publisher]

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Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl.

Cancer Cell. 2010 Jul 13;18(1):74-87

Authors: Gregory MA, Phang TL, Neviani P, Alvarez-Calderon F, Eide CA, O’Hare T, Zaberezhnyy V, Williams RT, Druker BJ, Perrotti D, Degregori J

Although Bcr-Abl kinase inhibitors have proven effective in the treatment of chronic myeloid leukemia (CML), they generally fail to eradicate Bcr-Abl(+) leukemia cells. To identify genes whose inhibition sensitizes Bcr-Abl(+) leukemias to killing by Bcr-Abl inhibitors, we performed an RNAi-based synthetic lethal screen with imatinib mesylate in CML cells. This screen identified numerous components of a Wnt/Ca(2+)/NFAT signaling pathway. Antagonism of this pathway led to impaired NFAT activity, decreased cytokine production, and enhanced sensitivity to Bcr-Abl inhibition. Furthermore, NFAT inhibition with cyclosporin A facilitated leukemia cell elimination by the Bcr-Abl inhibitor dasatinib and markedly improved survival in a mouse model of Bcr-Abl(+) acute lymphoblastic leukemia (ALL). Targeting this pathway in combination with Bcr-Abl inhibition could improve treatment of Bcr-Abl(+) leukemias.

PMID: 20609354 [PubMed - indexed for MEDLINE]

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Chronic myeloid leukemia: mechanisms of blastic transformation.

J Clin Invest. 2010 Jul 1;120(7):2254-64

Authors: Perrotti D, Jamieson C, Goldman J, Skorski T

The BCR-ABL1 oncoprotein transforms pluripotent HSCs and initiates chronic myeloid leukemia (CML). Patients with early phase (also known as chronic phase [CP]) disease usually respond to treatment with ABL tyrosine kinase inhibitors (TKIs), although some patients who respond initially later become resistant. In most patients, TKIs reduce the leukemia cell load substantially, but the cells from which the leukemia cells are derived during CP (so-called leukemia stem cells [LSCs]) are intrinsically insensitive to TKIs and survive long term. LSCs or their progeny can acquire additional genetic and/or epigenetic changes that cause the leukemia to transform from CP to a more advanced phase, which has been subclassified as either accelerated phase or blastic phase disease. The latter responds poorly to treatment and is usually fatal. Here, we discuss what is known about the molecular mechanisms leading to blastic transformation of CML and propose some novel therapeutic approaches.

PMID: 20592475 [PubMed - indexed for MEDLINE]

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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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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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Ring chromosome 18 abnormality in acute myelogenous leukemia: the clinical dilemma.

J Hematol Oncol. 2010 Jul 22;3(1):25

Authors: Sivendran S, Gruenstein S, Malone AK, Najfeld V

ABSTRACT: The ring chromosome is a circular, structural abnormality composed of either multiple chromosomes or a single chromosome with loss of genetic material at one or both ends. This chromosomal rearrangement is often unstable with frequent recombinations and may be accompanied by either loss or amplification of genetic material.1 Considering that ring chromosomes are rare in acute myelogenous leukemia (AML), it is difficult to risk stratify patient prognosis, particularly when the ring chromosome occurs as the sole abnormality. Here we report a case of a ring chromosome 18 abnormality in a patient with newly diagnosed AML with monocytic differentiation. Cytogenetic analysis demonstrated 46,XY,r(18)(p11q21) karyotype in 19 of 34 evaluated metaphase cells. The patient received induction chemotherapy and subsequent allogeneic cord blood transplant from a sex-matched donor, and remained in hematologic and cytogenetic remission for 120 days post transplant. Soon after, he developed post transplant lymphoproliferative disorder and died of multi-organ failure. Although r(18) chromosomal abnormalities were not classified in the recent updated evidence-and expert opinion-based recommendations for the diagnosis and management of AML (likely due to the small number of reported cases), the patient was treated as high risk with stem cell transplantation. This was based on the unstable nature of the ring chromosome and the poor outcomes described in the literature of patients with sole ring 18 abnormalities.

PMID: 20649984 [PubMed - as supplied by publisher]

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A non-coding cationic lipid DNA complex produces lasting anti-leukemic effects.

Cancer Biol Ther. 2010 Sep 13;10(6)

Authors: Keasey N, Herse Z, Chang S, Liggitt DH, Lay M, Fairman J, Claxton DF

Cationic lipid DNA complex (CLDC) is an immunostimulatory preparation that has significant anti-leukemic effects in multiple murine models of leukemia: BCR-ABL(+) myelogenous leukemia in C3H/HeJ animals and myelomonocytic leukemia in BALB/c mice. Following leukemic challenge, CLDC treatment inhibits tumor cell growth in vivo and extends survival, sometimes resulting in apparent eradication of tumor cells. CLDC induces multiple cytokines including interferon-gamma (IFNgamma), and intravenous treatment results in a more rapid and robust response than subcutaneous treatment. IFNgamma is induced in a dose-dependent manner, and tachyphylaxis results from repeated doses of CLDC. Tachyphylaxis of therapeutic effects is exacerbated at higher doses, thus the optimal survival benefits are seen at intermediate doses. Animals whose leukemia has been successfully treated with CLDC exhibit a survival advantage when faced with a secondary leukemic challenge, suggesting the existence of an adaptive anti-leukemic response. This work demonstrates the effectiveness of CLDC in multiple experimental leukemias and is consistent with a stimulation of a lasting TH(1) anti-leukemic immune response.

PMID: 20647744 [PubMed - as supplied by publisher]

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Occurrences of opportunistic infections in chronic myelogenous leukemia patients treated with imatinib mesylate.

Leuk Res. 2010 Jun 18;

Authors: Anthony N, Shanks J, Terebelo H

PMID: 20646761 [PubMed - as supplied by publisher]

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