The Outcome of Allogeneic Hematopoietic Cell Transplantation for Children with FLT3/ITD-Positive Acute Myelogenous Leukemia.
Biol Blood Marrow Transplant. 2014 Aug 16;
Authors: Schechter T, Gassas A, Chen H, Pollard J, Meshinchi S, Zaidman I, Hitzler J, Abdelhaleem M, Ho R, Domm J, Woolfrey A, Frangoul H
FLT3 internal tandem duplication (FLT3/ITD) is a somatic mutation associated with poor outcome when treated with chemotherapy alone. In children, hematopoietic stem cell transplantation (HSCT) is recommended, but very limited data on outcome is reported. We determined the outcome of 29 children with FLT3/ITD positive acute myelogenous leukemia (AML) who underwent allogeneic HSCT in four pediatric centers. Eleven patients (38%) received matched-related donor hematopoietic stem cells and 18 (62%) received alternative donors. Eighteen patients (62%) received total body irradiation (TBI)-based regimens. No patients experienced transplant related mortality (TRM). Eleven patients (38%) experienced relapsed disease. The cumulative incidence of relapse at 2 years was 34.7% (95% CI 20.4-54.9%). 2-years DFS and OS were 65.3% (95% CI 45.1-79.6%) and 82.2% (95% CI 58.5-91.3%), respectively. There was no difference between the DFS of patients who received related donors versus alternative donors, (HR 2.64 (0.79-8.76), p=0.1) using univariate analysis. Patients with higher FLT3/ITD ratio at diagnosis had significantly worse DFS (HR 1.42 (1.04-1.93), p=0.03). The use of TBI in the preparative regimen was associated with superior DFS and OS (HR 0.29 (0.08-0.99), p =0.04) (HR 0.07 (0.01-0.62), p= 0.002), respectively. We conclude that allogeneic HSCT improve DFS and OS in children with FLT3/ITD positive AML compared to what has been reported in those treated with chemotherapy alone.
PMID: 25139215 [PubMed - as supplied by publisher]
Glutathione S-transferase gene polymorphisms and susceptibility to chronic myeloid leukemia.
Tumour Biol. 2014 Jun;35(6):6119-25
Authors: He HR, Zhang XX, Sun JY, Hu SS, Ma Y, Dong YL, Lu J
Glutathione S-transferase (GST), a phase II metabolizing enzyme, plays an important role in the cellar defense system, and its activity may modulate leukemia risk. A large body of evidence has shown the possible relevance of functional polymorphisms of the genes that encode GSTs ?, ?, and ? (GSTM1, GSTP1, and GST1, respectively) to the genetic susceptibility of chronic myeloid leukemia (CML). Because of the lack of available conclusive data, we performed a meta-analysis of all relevant available studies to derive a more precise estimation of the relationship. A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until December 20, 2013, and the extracted data were statistically analyzed using Review Manager version 5.2. Finally, 16 eligible studies were identified in the literature. The GSTT1 null genotype was associated with an increased risk of CML, as were the double null GSTT1 and GSTM1 genotypes. These findings suggest that heritable GST status influences the risk of developing CML and that more attention should be paid to carriers of these susceptibility genes.
PMID: 24659449 [PubMed - indexed for MEDLINE]
Differential expression of BIRC family genes in chronic myeloid leukaemia–BIRC3 and BIRC8 as potential new candidates to identify disease progression.
Br J Haematol. 2014 Mar;164(5):740-2
Authors: Glodkowska-Mrowka E, Solarska I, Mrowka P, Bajorek K, Niesiobedzka-Krezel J, Seferynska I, Borg K, Stoklosa T
PMID: 24266799 [PubMed - indexed for MEDLINE]
The prognostic importance of polypharmacy in older adults treated for acute myelogenous leukemia (AML).
Leuk Res. 2014 Jul 7;
Authors: Elliot K, Tooze JA, Geller R, Powell BL, Pardee TS, Ritchie E, Kennedy L, Callahan KE, Klepin HD
We retrospectively evaluated the prognostic significance of polypharmacy and inappropriate medication use among 150 patients >60 years of age receiving induction chemotherapy for acute myelogenous leukemia (AML). After adjustment for age and comorbidity, increased number of medications at diagnosis (?4 versus ?1) was associated with increased 30-day mortality (OR=9.98, 95% CI=1.18-84.13), lower odds of complete remission status (OR=0.20, 95% CI=0.06-0.65), and higher overall mortality (HR=2.13, 95% CI=1.15-3.92). Inappropriate medication use (classified according to Beers criteria) was not significantly associated with clinical outcomes. Polypharmacy warrants further study as a modifiable marker of vulnerability among older adults with AML.
PMID: 25127690 [PubMed - as supplied by publisher]
A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia.
Blood Cancer J. 2014;4:e238
Authors: Seymour JF, Kim DW, Rubin E, Haregewoin A, Clark J, Watson P, Hughes T, Dufva I, Jimenez JL, Mahon FX, Rousselot P, Cortes J, Martinelli G, Papayannidis C, Nagler A, Giles FJ
Aurora kinase overexpression has been observed in patients with hematologic malignancies. MK-0457, a pan-aurora kinase inhibitor that also inhibits the ABL T315I mutant, was evaluated to treat patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) with the T315I mutation. Adults with Ph+ chronic phase (CP)-, accelerated phase (AP)- or blast phase (BP)-CML, or ALL and documented BCR-ABL T315I mutation were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40?mg/m(2)/h, 32?mg/m(2)/h or 24?mg/m(2)/h. Fifty-two patients (CP, n=15; AP, n=14; BP, n=11; Ph+ ALL, n=12) were treated. Overall, 8% of patients achieved major cytogenetic response; 6% achieved unconfirmed complete or partial response; 39% had no response. Two patients (CP CML) achieved complete hematologic response. No patients with advanced CML or Ph+ ALL achieved major hematologic response. The most common adverse event (AE) was neutropenia (50%). The most common grade 3/4 AEs were neutropenia (46%) and febrile neutropenia (35%). MK-0457 demonstrated minimal efficacy and only at higher, intolerable doses; lower doses were tolerated and no unexpected toxicities were observed. These data will assist in the development of future aurora kinase inhibitors and in the selection of appropriate target patient populations.Blood Cancer Journal (2014) 4, e238; doi:10.1038/bcj.2014.60; published online 15 August 2014.
PMID: 25127392 [PubMed - as supplied by publisher]
Treatment of FANCA Cells with Resveratrol and N-Acetylcysteine: A Comparative Study.
PLoS One. 2014;9(8):e104857
Authors: Columbaro M, Ravera S, Capanni C, Panfoli I, Cuccarolo P, Stroppiana G, Degan P, Cappelli E
Fanconi anemia (FA) is a genetic disorder characterised by chromosome instability, cytokine ipersensibility, bone marrow failure and abnormal haematopoiesis associated with acute myelogenous leukemia. Recent reports are contributing to characterize the peculiar FA metabolism. Central to these considerations appears that cells from complementation group A (FANCA) display an altered red-ox metabolism. Consequently the possibility to improve FA phenotypical conditions with antioxidants is considered. We have characterized from the structural and biochemical point of view the response of FANCA lymphocytes to N-acetyl-cysteine (NAC) and resveratrol (RV). Surprisingly both NAC and RV failed to revert all the characteristic of FA phenotype and moreover their effects are not super imposable. Our data suggest that we must be aware of the biological effects coming from antioxidant treatment.
PMID: 25126945 [PubMed - as supplied by publisher]
AEG-1 Regulates Retinoid X Receptor and Inhibits Retinoid Signaling.
Cancer Res. 2014 Aug 15;74(16):4364-77
Authors: Srivastava J, Robertson CL, Rajasekaran D, Gredler R, Siddiq A, Emdad L, Mukhopadhyay ND, Ghosh S, Hylemon PB, Gil G, Shah K, Bhere D, Subler MA, Windle JJ, Fisher PB, Sarkar D
Retinoid X receptor (RXR) regulates key cellular responses such as cell growth and development, and this regulation is frequently perturbed in various malignancies, including hepatocellular carcinoma (HCC). However, the molecule(s) that physically govern this deregulation are mostly unknown. Here, we identified RXR as an interacting partner of astrocyte-elevated gene-1 (AEG-1)/metadherin (MTDH), an oncogene upregulated in all cancers. Upon interaction, AEG-1 profoundly inhibited RXR/retinoic acid receptor (RAR)-mediated transcriptional activation. Consequently, AEG-1 markedly protected HCC and acute myelogenous leukemia (AML) cells from retinoid- and rexinoid-induced cell death. In nontumorigenic cells and primary hepatocytes, AEG-1/RXR colocalizes in the nucleus in which AEG-1 interferes with recruitment of transcriptional coactivators to RXR, preventing transcription of target genes. In tumor cells and AEG-1 transgenic hepatocytes, overexpressed AEG-1 entraps RXR in cytoplasm, precluding its nuclear translocation. In addition, ERK, activated by AEG-1, phosphorylates RXR that leads to its functional inactivation and attenuation of ligand-dependent transactivation. In nude mice models, combination of all-trans retinoic acid (ATRA) and AEG-1 knockdown synergistically inhibited growth of human HCC xenografts. The present study establishes AEG-1 as a novel homeostatic regulator of RXR and RXR/RAR that might contribute to hepatocarcinogenesis. Targeting AEG-1 could sensitize patients with HCC and AML to retinoid- and rexinoid-based therapeutics. Cancer Res; 74(16); 4364-77. ©2014 AACR.
PMID: 25125681 [PubMed - in process]
Triple opportunistic pulmonary cavitary disease after cord blood transplantation.
Transpl Infect Dis. 2014 Aug 14;
Authors: Kaneko T, Milner DA, Marty FM, Colson YL
Opportunistic infectious diseases in patients are variable and depend on the host as well as the type of immunosuppression. Cord blood transplant recipients appear to be particularly vulnerable to infectious complications. Sequential or concurrent opportunistic infectious diseases can be particularly difficult to manage and have increased mortality. We present a young patient, status post cord blood transplantation for acute myelogenous leukemia, who developed a large pulmonary mass-like infection with Aspergillus, cytomegalovirus, and Mycobacterium avium complex. Radiological, surgical, and pathological features are described.
PMID: 25124296 [PubMed - as supplied by publisher]
Vanishing bile duct syndrome after allogeneic bone marrow transplantation: is it the end of the road?
Turk J Gastroenterol. 2013;24(4):359-62
Authors: Bakanay ?M, Bilgin AU, Bekta? M, Idilman R, Erden E, Arat M, Arslan Ö
In this paper, we report the case of a 19-year-old male patient who presented with lymphoblastic phase of chronic myeloid leukemia and received an allogeneic bone marrow transplant from his cousin. The patient experienced severe, steroid-refractory acute graft versus-host disease of skin, gastrointestinal tract and liver that required further immunosuppression. However, hepatic graft-versus-host disease was complicated with vanishing bile duct syndrome, characterized by progressive destruction of small intrahepatic bile ducts, which was refractory to all available therapies and eventually led to end-stage liver disease. The pathogenesis and treatment of graft-versus-host disease after allogeneic hematopoietic cell transplantation is discussed with an emphasis on liver transplantation for intractable hepatic graft-versus-host disease.
PMID: 24254270 [PubMed - indexed for MEDLINE]
Evaluation of clinical performance of the major BCR-ABL mRNA detection kit which enables conversion to international standard scale using the reference material calibrator.
Rinsho Ketsueki. 2014 May;55(5):534-40
Authors: Miyamura K, Okamoto S, Usui N, Hino M, Akashi K, Nakaseko T, Takahashi N, Nakatani K, Takahashi K, Nobori T, Naoe T
In a multicenter study, we evaluated the Major BCR-ABL mRNA/ABL mRNA quantification kit (M135R), which uses reference material included in the kit designed to report results using the international scale (IS). In total, 127 samples were studied. A good correlation was observed between M135R results and home-brew RT-qPCR results, which are reported on the IS using a conversion factor (r=0.90; n=115). However, the correlation coefficient between M135R results and Amp-CML results was relatively low (r=0.56; n=108). A good correlation was observed between M135R results from the two assay sites (r=0.94; n=115). The subset analysis of samples from the two assay sites showed M135R to have a good correlation even in the low IS range (r=0.98; IS?1%). M135R showed high sensitivity and accuracy for detecting minimal residual disease and is considered to be a useful tool for treatment response assessment and for early detection of recurrence in CML patients.
PMID: 24881918 [PubMed - indexed for MEDLINE]
Management of chronic myeloid leukemia for Japanese patients in the era of TKIs.
Rinsho Ketsueki. 2014 May;55(5):497-507
Authors: Usui N
PMID: 24881914 [PubMed - indexed for MEDLINE]
Predictive factors of successful treatment-free remission for patients with chronic myeloid leukemia.
Rinsho Ketsueki. 2014 May;55(5):489-96
Authors: Takahashi N
PMID: 24881913 [PubMed - indexed for MEDLINE]
Monocytic crisis of chronic myeloid leukemia in the era of tyrosine kinase inhibitor.
J Clin Exp Hematop. 2013;53(3):227-33
Authors: Tsunemine H, Arima H, Itoh K, Sakane-Ishikawa E, Akasaka H, Kodaka T, Takahashi T
A 47-year-old man was diagnosed with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in October 2005. He could not receive treatment with imatinib mesylate due to his economic circumstances. He was consequently treated with hydroxyurea with partial hematological remission until June 2008. Although imatinib mesylate was started thereafter, the adherence to this treatment was poor because of his occupational circumstances. In September 2009, imatinib mesylate was switched to nilotinib, with a subsequent phase of acceleration of the disease, presumably due to his poor adherence to the treatment. Dasatinib was started in September 2010, with transient hematological response and final blastic crisis of the disease in January 2011, regardless of improved adherence. Blast cells showed immature monocytic morphology and were positive for ?-naphtylbutyrate esterase staining. They also expressed surface CD14 and CD64 antigens. A diagnosis of rare monocytic crisis of CML was made. He was treated with low-dose nilotinib following cytoreduction with MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy. Severe leucopenia without circulating leukemic cells continued for about 2 months with sustained hepatosplenomegaly, and he died of pneumonia in March 2012. Necropsy showed severe bone marrow hypoplasia with focal infiltration of mature leukemic cells and similar infiltration in the liver.
PMID: 24369225 [PubMed - indexed for MEDLINE]
A single nucleotide polymorphism in cBIM is associated with a slower achievement of major molecular response in chronic myeloid leukaemia treated with imatinib.
PLoS One. 2013;8(11):e78582
Authors: Augis V, Airiau K, Josselin M, Turcq B, Mahon FX, Belloc F
PURPOSE: BIM is essential for the response to tyrosine-kinase inhibitors (TKI) in chronic myeloid leukaemia (CML) patients. Recently, a deletion polymorphism in intron 2 of the BIM gene was demonstrated to confer an intrinsic TKI resistance in Asian patients. The present study aimed at identifying mutations in the BIM sequence that could lead to imatinib resistance independently of BCR-ABL mutations.
EXPERIMENTAL DESIGN: BIM coding sequence analysis was performed in 72 imatinib-treated CML patients from a French population of our centre and in 29 healthy controls (reference population) as a case-control study. Real-time quantitative PCR (RT qPCR) was performed to assess Bim expression in our reference population.
RESULTS: No mutation with amino-acid change was found in the BIM coding sequence. However, we observed a silent single nucleotide polymorphism (SNP) c465C>T (rs724710). A strong statistical link was found between the presence of the T allele and the high Sokal risk group (p?=?0.0065). T allele frequency was higher in non responsive patients than in the reference population (p?=?0.0049). Similarly, this T allele was associated with the mutation frequency on the tyrosine kinase domain of BCR-ABL (p<0.001) and the presence of the T allele significantly lengthened the time to achieve a major molecular response (MMR). Finally, the presence of the T allele was related to a decreased basal expression of the Bim mRNA in the circulating mononuclear cells of healthy controls.
CONCLUSION: These results suggest that the analysis of the c465C>T SNP of BIM could be useful for predicting the outcome of imatinib-treated CML patients.
PMID: 24223824 [PubMed - indexed for MEDLINE]
Germination of spores of certain Clostridium species in the presence of penicillin.
Antibiot Chemother (Northfield Ill). 1951 Jun;1(3):198-202
Authors: WYNNE ES, HARRELL K
PMID: 24541114 [PubMed - indexed for MEDLINE]
[Prolonged urethane therapy of chronic myeloid leukemia].
Arch Inn Med. 1951 Mar;1(6):692-8
Authors: BAUR E
PMID: 24540628 [PubMed - indexed for MEDLINE]
Rev Esp Pediatr. 1948 Mar-Apr;4(2):172-83
Authors: AVIGNON M
PMID: 18876587 [PubMed - indexed for MEDLINE]
Authors: BERNARD J, MASSE NP
PMID: 20257367 [PubMed - indexed for MEDLINE]
Authors: RAYNARD R, IMBERT C, D’ESHOUGUES JR
PMID: 18919857 [PubMed - indexed for MEDLINE]
Nonmyeloablative Allogeneic Hematopoietic Stem-Cell Transplantation for GATA2 Deficiency.
Biol Blood Marrow Transplant. 2014 Aug 8;
Authors: Grossman J, Cuellar-Rodriguez J, Gea-Banacloche J, Zerbe C, Calvo K, Hughes T, Hakim F, Cole K, Parta M, Freeman A, Holland SM, Hickstein DD
We treated 14 patients with GATA2 deficiency using a nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) regimen. Four patients received peripheral blood stem cells (PBSC) from matched-related donors (MRD), four patients received PBSC from matched-unrelated donors (URD), four patients received HSC from umbilical cord blood donors (UCB), and two patients received bone marrow cells from haploidentical related donors. MRD and URD recipients received conditioning with three days of fludarabine and 200cGy total body irradiation (TBI). Haploidentical related donor recipients and UCB recipients received cyclophosphamide and two additional days of fludarabine along with the 200 cGY TBI. MRD, URD, and UCB recipients received tacrolimus and sirolimus for post-transplant immunosuppression, whereas haploidentical recipients received high-dose cyclophosphamide followed by tacrolimus and mycophenolate mofetil. Eight patients are alive with reconstitution of the severely deficient monocyte, B-cell, and Natural Killer (NK) cell populations and reversal of the clinical phenotype at a median follow-up of 3.5 years. Two patients rejected the donor graft (one URD and one UCB), and one MRD recipient relapsed with myelodysplastic syndrome (MDS) post-transplant. We are currently using a high-dose conditioning regimen with busulfan and fludarabine in patients with GATA2 deficiency to achieve more consistent engraftment and eradication of the malignant myeloid clones.
PMID: 25111582 [PubMed - as supplied by publisher]