Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study.
Cancer. 2010 Jul 29;
Authors: de Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K, Braun TM, Nguyen HQ, Champlin R, Garcia-Manero G
BACKGROUND:: Recurrence is a major cause of treatment failure after allogeneic transplantation for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and treatment options are very limited. Azacitidine is a DNA methyltransferase inhibitor with activity in myeloid disease. The authors hypothesized that low-dose azacitidine administered after transplant would reduce recurrence rates, and conducted a study to determine a safe dose/schedule combination. METHODS:: Forty-five high-risk patients were treated. Median age was 60 years; median number of comorbidities was 3; 67% were not in remission. By using a Bayesian adaptive method to determine the best dose/schedule combination based on time to toxicity, the authors investigated combinations of 5 daily azacitidine doses, 8, 16, 24, 32, and 40 mg/m(2), and 4 schedules: 1, 2, 3, or 4 cycles, each with 5 days of drug and 25 days of rest. Cycle 1 started on Day +40. RESULTS:: Reversible thrombocytopenia was the dose-limiting toxicity. The optimal combination was 32 mg/m(2) given for 4 cycles. Median follow-up was 20.5 months. One-year event-free and overall survival were 58% and 77%, justifying further studies to estimate long-term clinical benefit. No dose significantly affected DNA global methylation. CONCLUSIONS:: Azacitidine at 32 mg/m(2) given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pretreated AML/MDS patients. The trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with greater benefit. Cancer 2010. (c) 2010 American Cancer Society.
PMID: 20672358 [PubMed - as supplied by publisher]
The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients.
Oncotarget. 2010 Jun;1(2):89-103
Authors: Martelli AM, Evangelisti C, Chiarini F, McCubrey JA
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling axis plays a central role in cell proliferation, growth, and survival under physiological conditions. However, aberrant PI3K/Akt/mTOR signaling has been implicated in many human cancers, including acute myelogenous leukemia (AML). Therefore, the PI3K/Akt/mTOR network is considered as a validated target for innovative cancer therapy. The limit of acceptable toxicity for standard polychemotherapy has been reached in AML. Novel therapeutic strategies are therefore needed. This review highlights how the PI3K/Akt/mTOR signaling axis is constitutively active in AML patients, where it affects survival, proliferation, and drug-resistance of leukemic cells including leukemic stem cells. Effective targeting of this pathway with small molecule kinase inhibitors, employed alone or in combination with other drugs, could result in the suppression of leukemic cell growth. Furthermore, targeting the PI3K/Akt/mTOR signaling network with small pharmacological inhibitors, employed either alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit pharmacological inhibitors of the PI3K/Akt/mTOR cascade which show efficacy and safety in the clinical setting are now underway.
PMID: 20671809 [PubMed - as supplied by publisher]
Non random distribution of genomic features in breakpoint regions involved in chronic myeloid leukemia cases with variant t(9;22) or additional chromosomal rearrangements.
Mol Cancer. 2010;9:120
Authors: Albano F, Anelli L, Zagaria A, Coccaro N, Casieri P, Rossi AR, Vicari L, Liso V, Rocchi M, Specchia G
BACKGROUND: The t(9;22)(q34;q11), generating the Philadelphia (Ph) chromosome, is found in more than 90% of patients with chronic myeloid leukemia (CML). As a result of the translocation, the 3′ portion of the ABL1 oncogene is transposed from 9q34 to the 5′ portion of the BCR gene on chromosome 22 to form the BCR/ABL1 fusion gene. At diagnosis, in 5-10% of CML patients the Ph chromosome is derived from variant translocations other than the standard t(9;22). RESULTS: We report a molecular cytogenetic study of 452 consecutive CML patients at diagnosis, that revealed 50 cases identifying three main subgroups: i) cases with variant chromosomal rearrangements other than the classic t(9;22)(q34;q11) (9.5%); ii) cases with cryptic insertions of ABL1 into BCR, or vice versa (1.3%); iii) cases bearing additional chromosomal rearrangements concomitant to the t(9;22) (1.1%). For each cytogenetic group, the mechanism at the basis of the rearrangement is discussed.All breakpoints on other chromosomes involved in variant t(9;22) and in additional rearrangements have been characterized for the first time by Fluorescence In Situ Hybridization (FISH) experiments and bioinformatic analyses. This study revealed a high content of Alu repeats, genes density, GC frequency, and miRNAs in the great majority of the analyzed breakpoints. CONCLUSIONS: Taken together with literature data about CML with variant t(9;22), our findings identified several new cytogenetic breakpoints as hotspots for recombination, demonstrating that the involvement of chromosomes other than 9 and 22 is not a random event but could depend on specific genomic features. The presence of several genes and/or miRNAs at the identified breakpoints suggests their potential involvement in the CML pathogenesis.
PMID: 20500819 [PubMed - indexed for MEDLINE]
Seven-year response to imatinib as initial treatment versus re-treatment in Chinese patients with chronic myelogenous leukemia in the chronic phase.
Ann Hematol. 2010 Jul 29;
Authors: Jiang H, Chen SS, Jiang B, Jiang Q, Qin YZ, Lai YY, Huang XJ
The purpose of our study is to compare the 7-year response to imatinib monotherapy as an initial treatment and re-treatment in Chinese patients with chronic myelogenous leukemia-chronic phase (CML-CP) patients in a single center in Beijing. A retrospective study of 171 CML-CP patients receiving imatinib monotherapy was done with 73 in the initial treatment group (disease course </=6 months) and 98 in the re-treatment group (disease course >6 months). Cumulative rates of complete cytogenetic response (CCyR) at 6, 12, and 36 months after imatinib treatment in the initial and re-treatment groups were 75%, 89%, and 96%, and 48%, 77% and 84% (p = 0.0002), respectively. The median time to CCyR in the initial and re-treatment groups was 6 months (95% CI, 3.3-8.3) and 9 months (95% CI, 6.4-11.6), respectively (p = 0.0002). Cumulative rates of major molecular responses at 9, 12, and 18 months after imatinib treatment in the initial and re-treatment groups were 31%, 48%, and 60%, and 15%, 25% and 37% (p = 0.017), respectively. The median time to the major molecular response in the initial and re-treatment groups was 15 months (95% CI, 12.3-17.7) and 36 months (95% CI, 25.9-46.0), respectively (p = 0.017). Progression-free survival at 84 months in the initial and re-treatment groups was 97% and 85%, respectively (p = 0.09). Event-free survival at 84 months in the initial and re-treatment groups was 92% and 70%, respectively (p = 0.049). Only two of the 171 patients discontinued imatinib therapy for grade 3/4 adverse events. Our study revealed that CML-CP patients would benefit from early treatment with imatinib.
PMID: 20668855 [PubMed - as supplied by publisher]
Ocular masquerade syndrome as a herald of progression of acute myelogenous leukemia.
Ann Hematol. 2010 Jul 29;
Authors: Gan NY, King LL, Teoh SC
PMID: 20668854 [PubMed - as supplied by publisher]
PR1-Specific T Cells Are Associated with Unmaintained Cytogenetic Remission of Chronic Myelogenous Leukemia After Interferon Withdrawal.
PLoS One. 2010;5(7):e11770
Authors: Kanodia S, Wieder E, Lu S, Talpaz M, Alatrash G, Clise-Dwyer K, Molldrem JJ
BACKGROUND: Interferon-alpha (IFN) induces complete cytogenetic remission (CCR) in 20-25% CML patients and in a small minority of patients; CCR persists after IFN is stopped. IFN induces CCR in part by increasing cytotoxic T lymphocytes (CTL) specific for PR1, the HLA-A2-restricted 9-mer peptide from proteinase 3 and neutrophil elastase, but it is unknown how CCR persists after IFN is stopped. PRINCIPAL FINDINGS: We reasoned that PR1-CTL persist and mediate CML-specific immunity in patients that maintain CCR after IFN withdrawal. We found that PR1-CTL were increased in peripheral blood of 7/7 HLA-A2+ patients during unmaintained CCR from 3 to 88 months after IFN withdrawal, as compared to no detectable PR1-CTL in 2/2 IFN-treated CML patients not in CCR. Unprimed PR1-CTL secreted IFNgamma and were predominantly CD45RA+/-CD28+CCR7+CD57-, consistent with functional naÃ¯ve and central memory (CM) T cells. Similarly, following stimulation, proliferation occurred predominantly in CM PR1-CTL, consistent with long-term immunity sustained by self-renewing CM T cells. PR1-CTL were functionally anergic in one patient 6 months prior to cytogenetic relapse at 26 months after IFN withdrawal, and in three relapsed patients PR1-CTL were undetectable but re-emerged 3-6 months after starting imatinib. CONCLUSION: These data support the hypothesis that IFN elicits CML-specific CM CTL that may contribute to continuous CCR after IFN withdrawal and suggest a role for T cell immune therapy with or without tyrosine kinase inhibitors as a strategy to prolong CR in CML.
PMID: 20668669 [PubMed - in process]
Antiproliferative Properties of Type I and Type II Interferon.
Pharmaceuticals (Basel). 2010 Mar 30;3(4):994-1015
Authors: Bekisz J, Baron S, Balinsky C, Morrow A, Zoon KC
The clinical possibilities of interferon (IFN) became apparent with early studies demonstrating that it was capable of inhibiting tumor cells in culture and in vivo using animal models. IFN gained the distinction of being the first recombinant cytokine to be licensed in the USA for the treatment of a malignancy in 1986, with the approval of IFN-alpha2a (Hoffman-La Roche) and IFN-alpha2b (Schering-Plough) for the treatment of Hairy Cell Leukemia. In addition to this application, other approved antitumor applications for IFN-alpha2a are AIDS-related Kaposi’s Sarcoma and Chronic Myelogenous Leukemia (CML) and other approved antitumor applications for IFN-alpha2b are Malignant Melanoma, Follicular Lymphoma, and AIDS-related Kapoisi’s Sarcoma. In the ensuing years, a considerable number of studies have been conducted to establish the mechanisms of the induction and action of IFN’s anti-tumor activity. These include identifying the role of Interferon Regulatory Factor 9 (IRF9) as a key factor in eliciting the antiproliferative effects of IFN-alpha as well as identifying genes induced by IFN that are involved in recognition of tumor cells. Recent studies also show that IFN-activated human monocytes can be used to achieve >95% eradication of select tumor cells. The signaling pathways by which IFN induces apoptosis can vary. IFN treatment induces the tumor suppressor gene p53, which plays a role in apoptosis for some tumors, but it is not essential for the apoptotic response. IFN-alpha also activates phosphatidylinositol 3-kinase (PI3K), which is associated with cell survival. Downstream of PI3K is the mammalian target of rapamycin (mTOR) which, in conjunction with PI3K, may act in signaling induced by growth factors after IFN treatment. This paper will explore the mechanisms by which IFN acts to elicit its antiproliferative effects and more closely examine the clinical applications for the anti-tumor potential of IFN.
PMID: 20664817 [PubMed - as supplied by publisher]
BCR-ABL but not JAK2 V617F inhibits erythropoiesis through the Ras signal by inducing p21CIP1/WAF1.
J Biol Chem. 2010 Jul 27;
Authors: Tokunaga M, Ezoe S, Tanaka H, Satoh Y, Fukushima K, Matsui K, Shibata M, Tanimura A, Oritani K, Matsumura I, Kanakura Y
BCR-ABL is a causative tyrosine kinase (TK) of chronic myelogenous leukemia (CML). In CML patients, although myeloid cells are remarkably proliferating, erythroid cells are rather decreased and anemia is commonly observed. This phenotype is quite different from that observed in polycythemia vera (PV) caused by JAK2 V617F, whereas both oncogenic TKs activate common downstream molecules at the level of hematopoietic stem cells (HSCs). To clarify this mechanism, we investigated the effects of BCR-ABL and JAK2 V617F on erythropoiesis. Enforced expression of BCR-ABL but not of JAK2 V617F in murine LSK (Lineage(-)Sca-1(hi)CD117(hi)) cells inhibited the development of erythroid cells. Among several signaling molecules downstream of BCR-ABL, an active mutant of N-Ras (N-RasE12) but not of STAT5 or phosphatidylinositol 3-kinase (PI3-K) inhibited erythropoiesis, while N-RasE12 enhanced the development of myeloid cells. BCR-ABL activated Ras signal more intensely than JAK2 V617F, and inhibition of Ras by manumycin A, a farnesyltransferase inhibitor, ameliorated erythroid colony formation of CML cells. As for the mechanisms of Ras-induced suppression of erythropoiesis, we found that GATA-1, an erythroid-specific transcription factor, blocked Ras-mediated mitogenic signaling at the level of MEK through the direct interaction. Furthermore, enforced expression of N-RasE12 in LSK cells derived from p53-, p16(INK4a)/p19(ARF)-, and p21(CIP1/WAF1)-null/wild-type mice revealed that suppressed erythroid cell growth by N-RasE12 was restored only by p21(CIP1/WAF1) deficiency, indicating that a cyclin-dependent kinase (CDK) inhibitor, p21(CIP1/WAF1), plays crucial roles in Ras-induced suppression of erythropoiesis. These data would, at least partly, explain why respective oncogenic TKs cause different disease phenotypes.
PMID: 20663870 [PubMed - as supplied by publisher]
Interaction of CJZ3, a lomerizine derivative, with ATPase activity of human P-glycoprotein in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells.
Pharmazie. 2010 Jul;65(7):515-9
Authors: Ji BS, Li M, He L
P-Glycoprotein, a 170-180 kDa membrane glycoprotein that mediates multidrug resistance, hydrolyses ATP to efflux a broad spectrum of hydrophobic agents. To observe the interaction of a P-gp reversal agent with P-gp ATPase activity should provide further insights into the mechanisms of P-gp modulator. In this study, we analysed the effect of CJZ3, a lomerizine derivative, on the adenosine triphosphatase (ATPase) activity of human P-glycoprotein. The results showed that the basal P-gp ATPase activity was increased by CJZ3 with half-maximal activity concentration (Km) of 6.8 +/- 1.5 microM, CJZ3 may interact with P-gp with a higher affinity and exhibit a more potent effect than verapamil (Ver). Kinetic analysis indicated a noncompetitive inhibition of Ver-stimulated P-gp ATPase activity and a competitive inhibition of CJX2-stimulated P-gp ATPase activity by CJZ3, moreover, the effect of CsA on CJZ3-stimulated and Ver-stimulated P-gp ATPase activity showed a non-competitive and a competitive inhibition respectively. CJZ3 and CJX2 can bind P-gp either on overlapping sites or distinct but interacting sites, while CJZ3 and Ver as well as CsA can bind P-gp on separated sites in K562/DOX cells.
PMID: 20662321 [PubMed - in process]
A unique BCR-ABL1 transcript with the insertion of intronic sequence from BCR and ABL1 genes in a patient with Philadelphia-positive chronic myeloid leukemia: a case study.
Cancer Genet Cytogenet. 2010 Aug;201(1):57-61
Authors: Sadia H, Siddiqui RT, Nasim A
The BCR-ABL1 fusion gene results from a reciprocal translocation rearrangement, t(9;22)(q34;q11.2), and is a hallmark of chronic myeloid leukemia (CML). The breakpoint on chromosome 9 is mostly 5′ to ABL1 exon 2, whereas on chromosome 22, the breakpoint can occur in various regions involving the major breakpoint cluster region (M-bcr) in CML and the minor breakpoint cluster region (m-bcr) in acute lymphoblastic leukemia. Described here is a rare case of Philadelphia-positive CML with intronic splice sites. This atypical BCR-ABL1 transcript was detected along with a classic e13a2 transcript, using reverse transcription polymerase chain reaction (RT-PCR). Nucleotide sequence analysis revealed a joining of BCR intron 13 with ABL1 intron 1a. Both transcripts were detected when the patient was on hydroxyurea treatment; with imatinib mesylate therapy, the atypical transcript disappeared. To our knowledge, this is the first report of BCR-ABL1 transcript with breakpoint occurring within both BCR and ABL1 introns and fusion of intronic sequences from both BCR and ABL1 genes.
PMID: 20633771 [PubMed - indexed for MEDLINE]
Imatinib (Gleevec) as a paradigm of targeted cancer therapies.
Keio J Med. 2010 Mar;59(1):1-3
Authors: Druker B
PMID: 20375651 [PubMed - indexed for MEDLINE]
New opportunities to treat the T315I-Bcr-Abl mutant in chronic myeloid leukaemia: tyrosine kinase inhibitors and molecules that act by alternative mechanisms.
Curr Med Chem. 2010;17(13):1220-45
Authors: Schenone S, Brullo C, Botta M
Resistance to the Bcr-Abl inhibitors approved for the treatment of chronic myeloid leukaemia (CML) may arise from different mechanisms, including Bcr-Abl amino acid mutations, gene amplification and mechanisms independent of Bcr-Abl. The T315I mutation at the gatekeeper residue is very frequent in advanced phases of the disease and is one of the main causes of resistance, disrupting important contact points between the inhibitors and the enzyme. Different strategies have been implemented to overcome this resistance, including the synthesis of new Bcr-Abl ATPcompetitive or non-ATP-competitive inhibitors, dual Aurora/Bcr-Abl inhibitors and multi-targeted kinase inhibitors. An alternative approach is the use of other compounds that do not bind directly to the Bcr-Abl protein; instead, these molecules act on several downstream pathways, regulated by or linked in different ways to Bcr-Abl, that lead to the malignant transformation of the cells. For this reason, farnesyl transferase inhibitors, MAPK inhibitors, Rac guanosine triphosphatase inhibitors, PI3K inhibitors, JAK inhibitors, Hsp90 inhibitors, mTOR inhibitors, PP2A activators and apoptosis inducers have been tested, alone or in combination with ATP-competitive inhibitors, against CML cell lines. This review discusses compounds that act on Bcr-Abl or different cell pathways and reports on the molecules active against the T315I mutation, particularly the most recent findings in this field. New molecules that are claimed by recent patents to be active on this mutation are also reported. When possible, the review will focus on medicinal chemistry in terms of chemical structure, mechanism of action and structure-activity relationships.
PMID: 20166937 [PubMed - indexed for MEDLINE]
Abstract The purpose of our study is to compare the 7-year response to imatinib monotherapy as an initial treatment and re-treatment
in Chinese patients with chronic myelogenous leukemia-chronic phase (CML-CP) patients in a single center in Beijing. A retrospective
study of 171 CML-CP patients receiving imatinib monotherapy was done with 73 in the initial treatment group (disease course
?6 months) and 98 in the re-treatment group (disease course >6 months). Cumulative rates of complete cytogenetic response
(CCyR) at 6, 12, and 36 months after imatinib treatment in the initial and re-treatment groups were 75%, 89%, and 96%, and
48%, 77% and 84% (p?=?0.0002), respectively. The median time to CCyR in the initial and re-treatment groups was 6 months…
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]
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]
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]
We report here a patient first diagnosed with Fanconi anemia at age 10. Bone marrow transplantation was performed at age 23 and repeated after an episode of rejection at age 25. Hematologic findings returned to normal, but chronic graft-versus-host disease persisted. Esophageal cancer developed at age 35. Invasion of the bronchus and aorta by the tumor was suspected on computed tomography. Chemoradiotherapy was administered to down-stage the tumor, using low-dose cisplatin and 5-fluorouracil. After two courses of chemotherapy with cisplatin (total dose, 100 mg) and 5-fluorouracil (5000 mg) plus radiotherapy (30 Gy), Grade 3 diarrhea and bone marrow suppression developed, and treatment was discontinued. After resolution of toxicity, a good response to the neoadjuvant therapy was seen on com…
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]
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]
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]