[Chronic myeloid leukemia: up-to-date management].
Rinsho Ketsueki. 2014 Jan;55(1):42-55
Authors: Nakayama K, Inokuchi K
PMID: 24492036 [PubMed - indexed for MEDLINE]
A Worldwide Support Network For Chronic Myelogenous Leukemia
[Chronic myeloid leukemia: up-to-date management].
Rinsho Ketsueki. 2014 Jan;55(1):42-55
Authors: Nakayama K, Inokuchi K
PMID: 24492036 [PubMed - indexed for MEDLINE]
The methylation status of the DDX43 promoter in Chinese patients with chronic myeloid leukemia.
Genet Test Mol Biomarkers. 2013 Jun;17(6):508-11
Authors: Chen Q, Lin J, Qian J, Deng ZQ, Qian W, Yang J, Li Y, Chen XX, Ma YJ, Ma JC, Liu Q
Aberrant DNA methylation is a common epigenetic alteration and an important feature in human cancers. The DEAD box polypeptide 43 (DDX43) has been found to be overexpressed in various solid tumors and some hematologic malignancies. In the present study, we investigated the methylation status of the DDX43 promoter in 87 Chinese patients with chronic myeloid leukemia (CML) using real-time quantitative methylation-specific polymerase chain reaction and examined the DDX43 transcript in 35 patients using real-time quantitative polymerase chain reaction. DDX43 promoter hypomethylation was observed in 22 (25.3%) CML patients. No significant correlation was found between the hypomethylation of the DDX43 promoter with the age, sex, white blood cell counts, hemoglobin concentration, platelet counts, and chromosomal abnormalities of CML patients (p>0.05). The frequency of DDX43 hypomethylation in patients in the chronic phase, in the accelerated phase, and in blast crisis was 23.4% (15/64), 25.0% (2/8), and 33.3% (5/15), respectively (p>0.05). There was a significant correlation between DDX43 hypomethylation and DDX43 transcript (r=0.469, p=0.004). Our data suggest that hypomethylation of the DDX43 promoter may be an early and frequent molecular event in the development of CML in Chinese patients.
PMID: 23495895 [PubMed - indexed for MEDLINE]
Toxic Tacrolimus Levels After Application of Topical Tacrolimus and Use of Occlusive Dressings in Two Bone Marrow Transplant Recipients with Cutaneous Graft-versus-Host Disease.
Pharmacotherapy. 2014 Apr 3;
Authors: Olson KA, West K, McCarthy PL
Tacrolimus, a macrolide immunosuppressant, is used topically for the treatment of cutaneous manifestations of graft-versus-host disease (GVHD) for rapid, symptomatic relief of pruritus and erythema. Despite the manufacturer’s product information reporting minimal systemic effects of topical tacrolimus, this has not been evaluated in patients with cutaneous GVHD and with occlusive dressings. We describe two patients with cutaneous GVHD who developed toxic tacrolimus levels after receiving several applications of tacrolimus ointment along with occlusive dressings to enhance skin effectiveness. The first patient was a 62-year-old woman with a history of acute myelogenous leukemia (AML) who underwent allogeneic bone marrow transplantation and developed chronic GVHD involving 70% of her body surface area. Her GVHD treatment plan consisted of oral corticosteroids, oral tacrolimus, topical corticosteroids, topical tacrolimus 0.1% ointment twice/day, emollient creams, intravenous rituximab, and photopheresis. The patient’s tacrolimus trough levels rose rapidly over the course of 6 days from less than 2 ng/ml to 23 ng/ml, despite oral tacrolimus dosage adjustments. The second patient was a 25-year-old man who developed severe, chronic skin GVHD after undergoing allogeneic sibling bone marrow transplantation for AML. In addition to intravenous corticosteroids, corticosteroid creams, and oral tacrolimus, the patient also received topical tacrolimus twice/day with occlusive dressings. Over the course of 2 days, his tacrolimus trough levels increased from 7.10 ng/ml to 22.10 ng/ml. Although improvement was noted in both patients’ skin GVHD with application of the occlusive dressings, the practice was discontinued due to increased and erratic systemic tacrolimus absorption. These case reports suggest that substantial use of topical tacrolimus with occlusive dressings in patients with cutaneous GVHD may contribute to increased systemic absorption resulting in toxic tacrolimus levels. Based on the findings from our two patients as well as published case reports, systemic absorption appears to increase with greater skin permeability, skin barrier dysfunction, amount of body surface area applied, and use of occlusive dressings. When one or more of these factors are present, it may be prudent to monitor tacrolimus levels.
PMID: 24700567 [PubMed - as supplied by publisher]
Redox modulation of adjacent thiols in VLA-4 by AS101 converts myeloid leukemia cells from a drug-resistant to drug-sensitive state.
Cancer Res. 2014 Apr 3;
Authors: Layani-Bazar A, Skornik I, Berrebi A, Pauker MH, Noy E, Silberman A, Albeck M, Longo DL, Kalechman Y, Sredni B
Interactions between the integrin VLA-4 on acute myelogenous leukemia (AML) cells with stromal fibronectin is a decisive factor in chemotherapeutic resistance. In this study, we provide a rationale for a drug repositioning strategy to blunt integrin activation in AML cells and restore their sensitivity to chemotherapy. Specifically, we demonstrate that the non-toxic tellurrium compound AS101, currently being evaluated in clinical trials, can abrogate the acquired resistance of AML. Mechanistic investigations revealed that AS101 caused redox inactivation of adjacent thiols in the exofacial domain of VLA-4 after its ligation to stromal fibronectin. This effect triggered cytoskeletal conformational changes that decreased PI3K/Akt/Bcl2 signaling, an obligatory step in chemosensitization by AS101. In a mouse xenograft of AML derived from patient leukemic cells with high VLA-4 expression and activity, we demonstrated that AS101 abrogated drug resistance and prolonged survival in mice receiving chemotherapy. Decreased integrin activity was confirmed on AML cells in vivo. The chemosensitizing activity of AS101 persisted in hosts with defective adaptive and innate immunity, consistent with evidence that integrin deactivation was not mediated by heightening immune attack. Our findings provide a mechanistic rationale to reposition the experimental clinical agent AS101 to degrade VLA-4-mediated chemoresistance and improve clinical responses in AML patients.
PMID: 24699624 [PubMed - as supplied by publisher]
Extramedullary Relapse of the AML Transformed from MDS Following Auto-HSCT: A Case Report.
Cell Biochem Biophys. 2014 Apr 3;
Authors: Wang J, Liu Y, Zhou X, Li Z, Li X, Xiao H
The treatment for AML (Acute myeloid/myelogenous leukemia) transformed from MDS (myelodysplastic syndrome) is difficult and controversial clinically, especially in elder patients. In this case report, we diagnosed a 59-year-old female patient with AML-M2a transformed form MDS which might be caused by her chemotherapy for mastocarcinoma. After achieving complete remission (CR) through combined chemotherapy, autologous peripheral blood stem cell transplantation (auto-PBSCT) was attempted. Following auto-HSCT, marrow showed continuous CR but the patient later developed extramedullary bone-infiltration relapse. Then local radiotherapy has been applied, and the patient now has prolonged survival. This is the first (or a successful) case report of auto-HSCT in an elderly patient with AML transformed from MDS.
PMID: 24696077 [PubMed - as supplied by publisher]
Patient with chronic myeloid leukemia in complete cytogenetic response: what does it mean, and what does one do next?
J Clin Oncol. 2014 Feb 10;32(5):379-84
Authors: Marin D
PMID: 24419129 [PubMed - indexed for MEDLINE]
What does a deep molecular response signify?
J Clin Oncol. 2014 Feb 10;32(5):471-4
Authors: Politi J, Shah NP
PMID: 24297955 [PubMed - indexed for MEDLINE]
Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV.
J Clin Oncol. 2014 Feb 10;32(5):415-23
Authors: Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A
PURPOSE: Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival.
PATIENTS AND METHODS: Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ? 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival.
RESULTS: Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression.
CONCLUSION: MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.
PMID: 24297946 [PubMed - indexed for MEDLINE]
Translational Regulation of GPx-1 and GPx-4 by the mTOR Pathway.
PLoS One. 2014;9(4):e93472
Authors: Reinke EN, Ekoue DN, Bera S, Mahmud N, Diamond AM
Glutathione peroxidase activity was previously determined to be elevated in lymphocytes obtained from patients treated with the Bcr-Abl kinase inhibitor imatinib mesylate. In order to expand upon this observation, the established chronic myelogenous leukemia cell lines KU812 and MEG-01 were treated with imatinib and the effect on several anti-oxidant proteins was determined. The levels of GPx-1 were significantly increased following treatment with imatinib. This increase was not due to altered steady-state mRNA levels, and appeared to be dependent on the expression of Bcr-Abl, as no increases were observed following imatinib treatment of cells that did not express the fusion protein. The nutrient-sensing signaling protein, mammalian target of rapamycin (mTOR), can be activated by Bcr-Abl and its activity regulates the translation of many different proteins. Treatment of those same cells used in the imatinib studies with rapamycin, an inhibitor of mTOR, resulted in elevated GPx-1 and GPx-4 protein levels independent of Bcr-Abl expression. These proteins all belong to the selenoprotein family of peptides that contain the UGA-encoded amino acid selenocysteine. Collectively, these data provide evidence of a novel means of regulating anti-oxidants of the selenoprotein family via the mTOR pathway.
PMID: 24691473 [PubMed - in process]
A comparative study of Hasford score and Sokal index in prognostication of the novo chronic myeloid leukemia patients and a search for new prognostic markers.
Indian J Pathol Microbiol. 2013 Jul-Sep;56(3):216-20
Authors: Sinha SK, Sinha S, Mandal PK, Bhattacharyya NK, Pandey A, Gupta P
INTRODUCTION: Chronic myeloid leukemia (CML) is a common myeloproliferative disorder. Based on clinical and hematological parameters, two prognostic scoring systems, i.e., Hasford and Sokal index scoring systems are available to predict survival duration of CML patients on imatinib therapy.
AIMS AND OBJECTIVES: Our study’s objective is to compare Hasford score with Sokal index for the prognostication of de novo CML patients on therapy and find out new prognostic markers.
MATERIALS AND METHODS: This is a retrospective study. The study population comprised 66 patients who were followed up for 60 months. For each patient, at presentation, scoring was performed as per Hasford and Sokal index and Philadelphia chromosome analysis was carried out by conventional cytogenetics. Thereafter, hematological parameters were assessed 3 monthly and conventional cytogenetics was done yearly.
RESULTS: Out of these 66 patients, the number of patients belonging to low, intermediate and high risk categories are 21, 33 and 12 respectively by Hasford score and 12, 32 and 22 respectively by Sokal index. Eight patients, who had been categorized into high risk group by Sokal index but intermediate risk group by Hasford score, have shown better survival possibility as monitored by hematological and cytogenetic parameters. Ten cases, categorized into intermediate risk group by Sokal index but low risk group by Hasford score, is doing well till date.
CONCLUSIONS: This study shows that Hasford score predicts survival of the patients better than Sokal index. However, multicentric study over a large population is needed to give the final verdict.
PMID: 24152497 [PubMed - indexed for MEDLINE]
Phosphorylation of c-Cbl and p85 PI3K Driven by All-trans Retinoic Acid and CD38 Depends on Lyn Kinase Activity.
Cell Signal. 2014 Mar 28;
Authors: Congleton J, Shen M, Macdonald R, Malavasi F, Yen A
The leukocyte antigen CD38 is expressed after all-trans retinoic acid (ATRA) treatment in HL-60 myelogenous leukemia cells and promotes induced myeloid differentiation when overexpressed. We found that Vav1 and SLP-76 associate with CD38 in two cell lines, and that these proteins complex with Lyn, a Src family kinase (SFK) upregulated by ATRA. SFK inhibitors PP2 and dasatinib, which enhance ATRA-induced differentiation, were used to evaluate the involvement of Lyn kinase activity in CD38-driven signaling. Cells treated with ATRA for 48hours followed by one hour of PP2 incubation show SFK/Lyn kinase inhibition. We observed that Lyn inhibition blocked c-Cbl and p85/p55 PI3K phosphorylation driven by the anti-CD38 agonistic mAb IB4 in ATRA-treated HL-60 cells and untreated CD38+ transfectants. In contrast, cells cultured for 48hours following concurrent ATRA and PP2 treatment did not show Lyn inhibition, suggesting ATRA regulates the effects on Lyn. 48hours of co-treatment preserved CD38-stimulated c-Cbl and p85/p55 PI3K phosphorylation indicating Lyn kinase activity is necessary for these events. In contrast another SFK inhibitor (dasatinib) which blocks Lyn activity with ATRA co-treatment prevented ATRA-induced c-Cbl phosphorylation and crippled p85 PI3K phosphorylation, indicating Lyn kinase activity is important for ATRA-propelled events potentially regulated by CD38. We found that loss of Lyn activity coincided with a decrease in Vav1/Lyn/CD38 and SLP-76/Lyn/CD38 interaction, suggesting these molecules form a complex that regulates CD38 signaling. Lyn inhibition also reduced Lyn and CD38 binding to p85 PI3K, indicating CD38 facilitates a complex responsible for PI3K phosphorylation. Therefore, Lyn kinase activity is important for CD38-associated signaling that may drive ATRA-induced differentiation.
PMID: 24686085 [PubMed - as supplied by publisher]
Rapamycin combined with celecoxib enhanced antitumor effects of mono treatment on chronic myelogenous leukemia cells through downregulating mTOR pathway.
Tumour Biol. 2014 Mar 30;
Authors: Li J, Xue L, Hao H, Li R, Luo J
Chronic myelogenous leukemia is a neoplasm of myeloid progenitor cells. We recently found that rapamycin could induce G0/G1 phase arrest and apoptosis and inhibit proliferation of K562 cells through inhibiting mammalian target of rapamycin (mTOR) pathway. However, whether rapamycin has synergistic effects with other drugs in chronic myelogenous leukemia (CML) therapies remain unclear. Therefore, we examined the effect of rapamycin combined with celecoxib on K562 cells in vitro. The survival rates showed a significant decrease in rapamycin + celecoxib treatment group. The combination treatment also increased the G0/G1 phase cells as compared to rapamycin or celecoxib treatment alone (P?<?0.05), accompanied with the decreased population of S phase cells. Meanwhile, the rate of apoptosis was 15.87?±?2.21 % in rapamycin + celecoxib treatment group, significantly higher than that in mono treatment group (P?<?0.05). Western blot and reverse transcription PCR (RT-PCR) analysis showed that the expressions of mTOR, 4E-BP1, and p70S6K were all significantly decreased in K562 cells after rapamycin + celecoxib treatment (P?<?0.05). In conclusion, rapamycin combined with celecoxib could induce cell cycle arrest and apoptosis and decrease the expressions of mTOR, 4E-BP1, and p70S6K. It suggested that the combination could enhance the antitumor effects of mono treatment on CML cells through downregulating mTOR pathway.
PMID: 24682932 [PubMed - as supplied by publisher]
Clofarabine in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin) in patients with previously untreated intermediate and bad-risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): phase I results of an ongoing phase I/II study of the leukemia groups of EORTC and GIMEMA (EORTC GIMEMA 06061/AML-14A trial).
Ann Hematol. 2014 Mar 29;
Authors: Willemze R, Suciu S, Muus P, Halkes CJ, Meloni G, Meert L, Karrasch M, Rapion J, Vignetti M, Amadori S, de Witte T, Marie JP
This study aims to determine the maximum tolerated dose (MTD) of clofarabine combined with the EORTC-GIMEMA 3?+?10 induction regimen (idarubicin?+?cytosine arabinoside) in adults with untreated acute myelogenous leukemia or high-risk myelodysplastic syndrome. In this phase I trial, 25 patients (median age 56 years) received 5 days of clofarabine as 1-h infusion (arm A) or push injection (arm B) at the dose level of 5?×?10 or 5?×?15 mg/m(2)/day in an algorithmic dose escalation 3?+?3 design. A consolidation course (intermediate dose cytosine arabinoside, idarubicin) was planned for patients in complete remission (CR). Primary endpoint was safety and tolerance as measured by dose limiting toxicity (DLT); secondary endpoints were response rate, other grade III/IV toxicities, and hematological recovery after induction and consolidation. Five DLTs were observed (in arm A: one DLT at 10 mg/m(2)/day, three at 15 mg/m(2)/day; in arm B: one DLT at 15 mg/m(2)/day). Three patients receiving 15 mg/m(2)/day were withdrawn due to adverse events not classified as DLT. Prolonged hypoplasia was observed in five patients. CR?+?complete remission with incomplete recovery were achieved in 21 patients (11/12 (92 %) receiving clofarabine 10 mg/m(2)/day; 10/13 (77 %) receiving clofarabine 15 mg/m(2)/day). Clofarabine, 5?×?10 mg/m(2)/day, resulted in one DLT and no early treatment withdrawals. MTD of clofarabine combined with cytosine arabinoside and idarubicin is 5?×?10 mg/m(2)/day.
PMID: 24682421 [PubMed - as supplied by publisher]
Polycythemia vera developed after a major molecular response to imatinib mesylate treatment in a patient with chronic myelogenous leukemia.
Rinsho Ketsueki. 2014;55(3):360-365
Authors: Jomen W, Kuroda H, Matsuno T, Sato M, Yamada M, Abe T, Sakurai T, Fujii S, Maeda M, Fujita M, Kato J, Nojiri S
A 68-year-old man complained of dizziness and was referred to our hospital by his primary physician for evaluation of an elevated leukocyte count. In April 2002, soon after the chronic phase of chronic myeloid leukemia had been diagnosed, he was treated with imatinib. In March 2010, imatinib treatment was completed and the BCR/ABL fusion gene had become undetectable by real time quantitative PCR. Subsequently, leukocyte counts and the hematocrit gradually rose. In August 2012, a bone marrow aspirate showed hypercellular marrow with marked erythroid hyperplasia and the presence of the JAK2 gene V617F mutation. He was diagnosed with polycythemia vera. Phlebotomy and chemotherapy were started in addition to imatinib administration. Shortly thereafter complete blood counts returned to normal levels.
PMID: 24681942 [PubMed - as supplied by publisher]
Immune reconstitution after allogeneic hematopoietic stem cell transplantation is associated with selective control of JC virus reactivation.
Biol Blood Marrow Transplant. 2014 Mar 27;
Authors: Tan CS, Broge TA, Ngo L, Gheuens S, Viscidi R, Bord E, Rosenblatt J, Wong M, Avigan D, Koralnik IJ
JCV causes progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. The mechanism of JCV reactivation and immunity in a transplanted immune system remains unclear. We prospectively studied 30 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT), and collected blood and urine samples pre-HSCT, 3, 6, and 12-18 months after HSCT. Pre-HSCT, JCV DNA was detected in 7/30 urine, 5/30 PBMC and 6/30 plasma samples. While JC viruria remained stable after HSCT with detection in 5/21 samples, viremia was detected in only 1/22 plasma and none of 22 PBMC samples 12-18 months after HSCT. Prevalence of anti-JCV IgG was 83% pre-HSCT and decreased to 72% at 12-18 months. Anti-JCV IgM was rarely detected. JCV-specific CD4(+) and CD8(+) T cell responses increased 12-18 months after HSCT. While JC viruria correlated directly with detection of anti-JCV IgG, the cellular immune response to JCV measured by ELISpot was inversely correlated with anti-JCV IgG response. The diagnosis of acute myelogenous leukemia and age groups were two independent patient factors associated with significantly reduced cellular immune responses to JCV. This prospective study in HSCT patients provides a model of interactions between the host immune response and viral activation in multiple compartments during the recovery of the immune system.
PMID: 24680976 [PubMed - as supplied by publisher]
[Tyrosine kinase inhibitors (TKI): a new revolution in the treatment of chronic myeloid leukemia (CML)].
Gac Med Mex. 2013 Nov-Dec;149(6):646-54
Authors: Avilés-Vázquez S, Chávez-González A, Mayani H
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia associated with the t(9,22)(q34:q11) reciprocal translocation, also known as Philadelphia chromosome (Ph). As a result of such abnormality, a chimeric gene (bcr-abl) is produced that is translated into a chimeric protein (BCR-ABL), a constitutively activated tyrosine kinase. Major cell dysfunctions result from this abnormal kinase activity, including increased proliferation and reduced apoptosis. Based on the structure of BCR-ABL, several molecules have been designed that inhibit its kinase activity. Five such molecules have already been brought into the clinic for the treatment of Ph+ CML patients. Good results have been obtained in terms of patients’ remission rates and quality of life. Some major problems, however, have been observed. Firstly, a significant proportion of patients develop resistance to the drugs; secondly, it is clear that such drugs affect most of the leukemic cells, but do not eliminate leukemia stem cells. Thus, important CML-related challenges remain to be solved in the near future.
PMID: 24276188 [PubMed - indexed for MEDLINE]
STAT pathway in the regulation of zoledronic acid-induced apoptosis in chronic myeloid leukemia cells.
Biomed Pharmacother. 2013 Jul;67(6):527-32
Authors: Kiper HD, Tezcanli Kaymaz B, Gokbulut AA, Selvi N, Avci CB, Kosova B, Iskender G, Yandim MK, Gunduz C, Sahin F, Baran Y, Saydam G
In this study, we aimed to evaluate the cytotoxic and apoptotic effects of zoledronic acid on K562 chronic myeloid leukemia (CML) cells and to examine the roles of STAT genes on zoledronic acid-induced apoptosis. The results showed that zoledronic acid decreased proliferation, and induced apoptosis in K562 cells in a dose- and time-dependent manner. mRNA and protein levels of STAT3, -5A and -5B genes were significantly reduced in zoledronic acid-treated K562 cells. These data indicated that STAT inhibition by zoledronic acid may be therapeutic in CML patients following the confirmation with clinical studies.
PMID: 23725755 [PubMed - indexed for MEDLINE]
A significant proportion of patients with chronic myeloid leukemia and suboptimal response according to European Leukemia Net criteria have excellent prognosis without treatment change.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2013 Jun;157(2):181-8
Authors: Rohon P, Faber E, Divoka M, Rozmanova S, Friedecky D, Jarosova M, Indrak K
BACKGROUND: The Recommendations of the European Leukemia Net (ELN) have become an essential tool in the management and prognosis of patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). However, the definition of suboptimal response remains under discussion.
METHODS: We used conventional cytogenetics for the detection of clonal changes in Ph-positive and negative clones. RT-PCR and sequencing were carried out on peripheral blood leukocytes to detect the type of BCR-ABL1 transcript. The BCR-ABL1 mutational status was assessed using sequencing of RT-PCR products. High performance capillary electrophoresis for determination of imatinib (IMA) plasma concentration was used.
RESULTS: A retrospective study of 110 patients diagnosed with chronic-phase (CP) CML treated with IMA or 2(nd) generation TKIs in the years 2000-2009 focused on analysis of patients with suboptimal response according to ELN criteria. 40 patients were administered IMA as first-line therapy and 70 had been pretreated with interferon-alpha (IFN-?) with or without Ara-C and/or hydroxyurea (HU) for a median 12 months (range, 1-92 months). After adjusting for the ELN criteria, major molecular response (MMR) was achieved after median 34 and 39 months in 66.7% and 41.7% of patients after the first and second-line IMA therapy with suboptimal response defined as lack of achievement of MMR at the 18(th) month of treatment, respectively. In comparison to patients with optimal response, patients with suboptimal response did not show significant differences in overall survival (OS) or progression-free survival (PFS). Cytogenetic assays demonstrated additional chromosome abnormalities (ACAs): chromosome 8 trisomy in a Ph-negative clone during the IMA treatment (in 1 case) and der(9q) in Ph-positive clone (in 2 cases); in patients receiving first-line IMA only chromosome 8 trisomy was observed which was associated with myelodysplastic syndrome – this was the only case where hematopoietic stem cell transplantation (HSCT) was performed. During the treatment with IMA in both subgroups no regulatory mutations in the ABL kinase domain were confirmed.
CONCLUSION: We believe that the category of suboptimal response should be redefined or withdrawn from the ELN 2009 recommendations for management of CML patients treated with TKIs. Patients with suboptimal response who have no additional risks (additional cytogenetic abnormalities or BCR-ABL1 regulatory mutations) may remain on IMA treatment while patients with these risks should be switched to the 2(nd) generation TKIs.
PMID: 22660209 [PubMed - indexed for MEDLINE]
Isolation of Mycobacterium branderi, an unusual species from an acute myelogenous leukemia patient.
Avicenna J Med. 2014 Jan;4(1):17-9
Authors: Marjani M, Farshidpour M, Tabarsi P, Sheikholslami FM, Farnia P
We report a case of pulmonary infection caused by Mycobacterium branderi, a slow growing non-tuberculosis mycobacteria, in a patient with acute myelogenous leukemia. The pulmonary disease was treated successfully with the combination of Ciprofloxacin, Doxycycline and Clarithromycin. M. branderi may be considered as an opportunistic pathogen, especially among immunologically compromised patients.
PMID: 24678467 [PubMed]
Lineage-specific function of Engrailed-2 in the progression of chronic myelogenous leukemia to T-cell blast crisis.
Cell Cycle. 2014 Mar 25;13(11)
Authors: Abollo-Jiménez F, Campos-Sánchez E, Toboso-Navasa A, Vicente-Dueñas C, González-Herrero I, Alonso-Escudero E, González M, Segura V, Blanco O, Martínez-Climent JA, Sánchez-García I, Cobaleda C
In hematopoietic malignancies, oncogenic alterations interfere with cellular differentiation and lead to tumoral development. Identification of the proteins regulating differentiation is essential to understand how they are altered in malignancies. Chronic myelogenous leukemia (CML) is a biphasic disease initiated by an alteration taking place in hematopoietic stem cells. CML progresses to a blast crisis (BC) due to a secondary differentiation block in any of the hematopoietic lineages. However, the molecular mechanisms of CML evolution to T-cell BC remain unclear. Here, we have profiled the changes in DNA methylation patterns in human samples from BC-CML, in order to identify genes whose expression is epigenetically silenced during progression to T-cell lineage-specific BC. We have found that the CpG-island of the ENGRAILED-2 (EN2) gene becomes methylated in this progression. Afterwards, we demonstrate that En2 is expressed during T-cell development in mice and humans. Finally, we further show that genetic deletion of En2 in a CML transgenic mouse model induces a T-cell lineage BC that recapitulates human disease. These results identify En2 as a new regulator of T-cell differentiation whose disruption induces a malignant T-cell fate in CML progression, and validate the strategy used to identify new developmental regulators of hematopoiesis.
PMID: 24675889 [PubMed - as supplied by publisher]