Pulmonary arterial hypertension in patients treated with interferon.
Eur Respir J. 2014 Dec;44(6):1627-34
Authors: Savale L, Sattler C, Günther S, Montani D, Chaumais MC, Perrin S, Jaïs X, Seferian A, Jovan R, Bulifon S, Parent F, Simonneau G, Humbert M, Sitbon O
Isolated cases of pulmonary arterial hypertension (PAH) in patients treated with interferon (IFN) ? or ? have been reported in the literature. The aim of this study was to describe all consecutive cases of PAH patients with a history of IFN exposure identified in the French reference centre for severe pulmonary hypertension between 1998 and 2012. A total of 53 patients with PAH and a history of IFN therapy were identified. 48 patients had been treated with IFN? for chronic hepatitis C. Most of them had portal hypertension (85%) and 56% had HIV co-infection. Five additional patients had been treated with IFN? for multiple sclerosis. The diagnosis of PAH was made within 3 years after IFN therapy in 66% of patients. Repeated haemodynamic assessment was available in 13 out of 16 patients exposed to IFN after the diagnosis of PAH. Increased pulmonary vascular resistance >20% was observed in 11 out of 13 cases (median 43% increase; IQR 32-67%). In five of these patients, IFN withdrawal resulted in spontaneous haemodynamic improvement. This retrospective analysis suggests that IFN therapy may trigger PAH. However, most of these patients had other risk factors for PAH. A prospective case-control study is necessary to definitively establish a link between IFN exposure and PAH.
PMID: 25323231 [PubMed - indexed for MEDLINE]
ABCB1 regulation through LRPPRC is influenced by the methylation status of the GC -100 box in its promoter.
Epigenetics. 2014 Aug;9(8):1172-83
Authors: Corrêa S, Binato R, Du Rocher B, Ferreira G, Cappelletti P, Soares-Lima S, Pinto LF, Mencalha A, Abdelhay E
One of the potential mechanisms of imatinib mesylate (IM) resistance in chronic myeloid leukemia (CML) is increased level of P-glycoprotein (Pgp). Pgp is an efflux pump capable of activating the multidrug resistance (MDR) phenotype. The gene encoding Pgp (ABCB1) has several binding sites in its promoter region, along with CpG islands and GC boxes, involved in its epigenetic control. In previous work, we performed a proteomic study to identify proteins involved in IM cross-resistance in acute leukemia. Among these proteins, we identified LRPPRC as a potential regulator of ABCB1 transcription via an invMED1 binding site in ABCB1. Interestingly, this invMED1 binding site overlaps with the GC -100 box. In this work, we investigated the potential role of LRPPRC in the regulation of ABCB1 transcriptional activity in CML resistance. In addition, we evaluated the potential connection between this regulation and the methylation status of the ABCB1 promoter in its GC -100 box. Our results show that LRPPRC binds prominently to the ABCB1 promoter in Lucena cells, an IM-resistant cell line. Luciferase assays showed that ABCB1 transcription is positively regulated by LRPPRC upon its knockdown. Pyrosequencing analysis showed that the ABCB1 promoter is differentially methylated at its GC -100 box in K562 cells compared with Lucena cells, and in CML patients with different response to IM. Chromatin immunoprecipitation and Pgp expression after DNA demethylation treatment showed that LRPPRC binding is affected by the methylation status of ABCB1 GC -100 box. Taken together, our findings indicate that LRPPRC is a transcription factor related to ABCB1 expression and highlight the importance of epigenetic regulation in CML resistance.
PMID: 25089713 [PubMed - indexed for MEDLINE]
Polymorphisms in the human organic cation transporter and the multidrug resistance gene: correlation with imatinib levels and clinical course in patients with chronic myeloid leukemia.
Leuk Lymphoma. 2014 Nov;55(11):2525-31
Authors: Vine J, Cohen SB, Ruchlemer R, Goldschmidt N, Levin M, Libster D, Gural A, Gatt ME, Lavie D, Ben-Yehuda D, Rund D
The optimal tyrosine kinase inhibitor for any individual patient with chronic myeloid leukemia (CML) is not predictable. Pharmacogenetic parameters and trough levels of imatinib (IM) have each been independently correlated with response. We therefore studied the human organic cation transporter (hOCT1) and multidrug resistance (MDR1) single nucleotide polymorphisms (SNPs) and correlated these with IM levels and major molecular response (MMR) (3-log reduction) in 84 patients with CML, the first such study performed in Caucasians. We studied MDR1 G2677T and C3435T, and for hOCT1, C480G and A1222G. IM levels varied significantly with dose (< or > 400 mg/day) (p = 0.038) and were significantly lower in 20 patients who lost MMR (p = 0.042). Adjusting for dose, trough IM levels were not significantly correlated with SNPs. Patients with MDR1 3435 TT had significantly longer times to MMR compared to CC/CT genotypes (p = 0.047). Genotypes did not predict treatment failure when controlling for IM levels. We conclude that IM levels, but not the SNPs studied here, determine IM failure.
PMID: 24524306 [PubMed - indexed for MEDLINE]
Correlation of plasma trough levels of imatinib with molecular response in patients with chronic myeloid leukemia.
Leuk Lymphoma. 2014 Nov;55(11):2614-9
Authors: Malhotra H, Sharma P, Bhargava S, Rathore OS, Malhotra B, Kumar M
The present study looked at the correlation between mean trough Imatinib plasma levels and molecular response in 131 CML patients on imatinib. Patients receiving Glivec versus generic Imatinib were also compared. A ROC curve was constructed to estimate a threshold level that correlates with a favourable response. Patients were grouped into Responders (bcr/abl ration by RQ-PCR less than 1) and Non Responders (ration ? 1). The mean trough imatinib plasma level in the responders was significantly higher than in the non responders (p = 0.001). The area under ROC curve was 0.733, with best sensitivity (51.85%) and specificity (89.42%) at a plasma threshold of 0.988 g/ml [1.675 M]. Levels in the patients on Glivec versus generic drug (p > 0.05) were comparable. Trough Imatinib plasma levels may be a marker for suboptimal response and may identify patients in whom increase of drug dose or change in therapy may be indicated.
PMID: 24446903 [PubMed - indexed for MEDLINE]
Unfavorable outcome of chronic myelogenous leukemia in adolescent and young adults treated with tyrosine kinase inhibitors.
Int J Hematol. 2015 Jul 18;
Authors: Sakurai M, Mori T, Karigane D, Tozawa K, Matsuki E, Shimizu T, Yokoyama K, Nakajima H, Kanda Y, Okamoto S
Tyrosine kinase inhibitor (TKI) treatment has dramatically improved the outcome of chronic myelogenous leukemia in the chronic phase (CML-CP). However, one study has reported a less favorable treatment outcome with TKIs in adolescents and young adults (AYA) when compared with older patients. In the present study, we retrospectively reviewed the response to TKIs in a Japanese population of 133 CML-CP patients divided into an AYA group (n = 19) and an older group (n = 114). At diagnosis, AYA patients presented with higher white blood cell counts and lower percentage of basophils, and with lower Hasford scores, but no difference was observed in EUTOS score. Probability of achieving complete cytogenetic response was not statistically different between the groups. However, the probabilities of achieving major and complete molecular responses were significantly lower in the AYA group compared to the older group (61 vs 87 % and 17 vs. 33 % at 24 months, respectively; P < 0.05). In addition, a 7-year event-free survival was significantly lower in the AYA compared to the older adults (58 vs. 80 %, P < 0.05). These results suggest that AYA Japanese patients with CML-CP tend to have an unfavorable outcome on treatment with TKI.
PMID: 26187695 [PubMed - as supplied by publisher]
Acute Myeloid Leukemia and Other Types of Disease Progression in Myeloproliferative Neoplasms.
Am J Clin Pathol. 2015 Aug;144(2):188-206
Authors: Czader M, Orazi A
OBJECTIVES: This session of the Society for Hematopathology/European Association for Haematopathology workshop focused on disease progression in myeloproliferative neoplasms (MPNs).
METHODS: The session included typical and unusual presentations of chronic myelogenous leukemia (CML), BCR-ABL1 positive; Philadelphia chromosome-negative (Ph-neg) MPNs; and mastocytosis.
RESULTS: Cases of CML illustrated various manifestations of progression, with emphasis on criteria defining stages of the disease. Issues were discussed related to the patterns of recurrence in patients receiving tyrosine kinase inhibitor therapy, including leukemic transformation occurring in a Ph-neg clone. Ph-neg MPN cases highlighted diagnostic approaches used to establish accelerated and blast phases, including cases with significant myelofibrosis and when an adequate bone marrow aspirate smear is not available. The session also included rare cases of aggressive mastocytosis.
CONCLUSIONS: There was agreement that a definitive diagnosis can be challenging in the absence of documented review of prior diagnostic material and clinical history.
PMID: 26185305 [PubMed - in process]
In Vitro Antileukemic Activity of Xanthosoma sagittifolium (Taioba) Leaf Extract.
Evid Based Complement Alternat Med. 2015;2015:384267
Authors: Caxito ML, Correia RR, Gomes AC, Justo G, Coelho MG, Sakuragui CM, Kuster RM, Sabino KC
Xanthosoma sagittifolium Schott is a herb of the Araceae family, popularly known as taioba, which is consumed as food in some regions of Brazil, Africa, and Asia. This species has already been evaluated for the antifungal activities. However, based on its potential antitumor activity, the present study further aimed to examine the antitumor, as well as chelation, activity of X. sagittifolium leaf extract. Results showed that hydroethanolic extract of X. sagittifolium leaves (HEXs-L) exhibits cytotoxic effects against the immortalized line of human T-lymphocytic (Jurkat) and myelogenous (K562) leukemia cells, but not nontumor RAW 264.7 macrophages or NIH/3T3 fibroblasts. HEXs-L inhibited 50.3% of Jurkat cell proliferation, reducing by 20% cells in G2/M phase, but increasing cells in sub-G1 phase, thereby inducing apoptosis by 54%. In addition, HEXs-L inhibited NO production by 59%, as determined by Griess reaction, and chelated 93.8% of free Fe(II), as demonstrated by ferrozine assay. Phytochemical studies were carried out by ESI-MS, identifying apigenin di-C-glycosides as major compounds. Overall, this work revealed that leaf extract of Xanthosoma sagittifolium presented chelating activity and in vitro antitumor activity, arresting cell cycle and inducing apoptosis of leukemia cells, thus providing evidence that taioba leaves may have practical application in cancer therapy.
PMID: 26180533 [PubMed]
Analyses of genetic and clinical parameters for screening patients with inherited thrombocytopenia with small or normal-sized platelets.
Pediatr Blood Cancer. 2015 Jul 14;
Authors: Ouchi-Uchiyama M, Sasahara Y, Kikuchi A, Goi K, Nakane T, Ikeno M, Noguchi Y, Uike N, Miyajima Y, Matsubara K, Koh K, Sugita K, Imaizumi M, Kure S
BACKGROUND: Childhood thrombocytopenias include immune thrombocytopenic purpura (ITP) and inherited thrombocytopenia; the former is caused by autoantibodies to platelets, whereas the latter can be distinguished by platelet size and underlying genetic mutations. Due to limited methods for the definite diagnosis of ITP, genetic and clinical parameters are required for diagnosing inherited thrombocytopenias with small or normal-sized platelets.
PROCEDURE: In total, 32 Japanese patients with thrombocytopenia with small or normal-sized platelets from 29 families were enrolled. All the patients were under 20 years of age, with family histories of early-onset thrombocytopenia and/or poor response to conventional therapies for ITP. Genotypes and clinical parameters were retrospectively evaluated according to the disease type.
RESULTS: Twelve cases of inherited thrombocytopenia were observed. We identified chromosomal deletions within the WASP gene in two patients with Wiskott-Aldrich syndrome; a missense mutation in a patient with X-linked thrombocytopenia; and mutations in the RUNX1 gene of five patients with familial platelet disorder with propensity to acute myelogenous leukemia, and in the ANKRD26 gene of four patients with autosomal dominant thrombocytopenia-2. All 12 carried germline mutations, three of which were de novo. Furthermore, we observed significantly elevated serum thrombopoietin (TPO) levels and dysplasia of megakaryocytes in patients carrying the RUNX1 and ANKRD26 mutations.
CONCLUSIONS: Genetic analyses and detection of TPO levels and dysmegakaryopoiesis were clinically useful for screening patients with inherited thrombocytopenias, irrespective of the family history. We hypothesize that the WASP, RUNX1, and ANKRD26 genes are important for normal TPO signaling and the network underlying thrombopoiesis. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.
PMID: 26175287 [PubMed - as supplied by publisher]
Request for the retraction of Cepp review 33: 504-510 (2006).
Clin Exp Pharmacol Physiol. 2013 Apr;40(4):305
Authors: Pushparaj P
PMID: 23551130 [PubMed - indexed for MEDLINE]
Request for retraction: Short interfering RNA (siRNA) as a novel therapeutic.
Clin Exp Pharmacol Physiol. 2013 Apr;40(4):305
Authors: Melendez-Romero A
PMID: 23551129 [PubMed - indexed for MEDLINE]
The importance of Src signaling in sarcoma.
Oncol Lett. 2015 Jul;10(1):17-22
Authors: Chen Q, Zhou Z, Shan L, Zeng H, Hua Y, Cai Z
Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy. Src has been found to enhance proliferation, reduce apoptosis and promote metastasis in certain subtypes of sarcoma, including osteosarcoma, chondrosarcoma and Ewing’s sarcoma. Furthermore, a number of novel effective therapeutic agents, such as SI-83, which target Src have been investigated in vitro and in vivo. Bosutinib and dasatinib, which inhibit Src, have been approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. In addition, vandetanib is approved for the treatment of medullary thyroid cancer. Furthermore, the Src inhibitor, saracatinib, is currently in clinical trials for the treatment of a variety of solid tumors, including breast and lung cancers. Thus, Src is considered to be an important factor in sarcoma progression and may present a novel clinical therapeutic target. This review demonstrates the importance and clinical relevance of Src in sarcoma, and discusses a number of small molecular inhibitors of src kinase, such as dasatinib and sarcatinib, which are currently in clinical trials for the treatment of sarcoma patients.
PMID: 26170970 [PubMed - as supplied by publisher]
Basophilia and megakaryoblastic differentiation in a case of acute myeloid leukemia: An unusual morphological combination.
Hematol Oncol Stem Cell Ther. 2015 Jul 9;
Authors: Sreedharanunni S, Kumar N, Prakash G
Basophilia is commonly associated with chronic myelogenous leukemia, notably in the accelerated phase or during blast crisis. It is also associated with other myeloproliferative neoplasms. However, its association with acute leukemia is very rare and is described in association with acute basophilic leukemia and few acute myeloid leukemias (AMLs) with recurrent genetic abnormalities such as t(6;9)(p23;q34). Herein, we describe the morphological features and discuss the differential diagnosis of a case of AML with the blasts showing previously unreported unusual combination of megakaryoblastic and basophilic differentiation along with peripheral blood and bone marrow basophilia.
PMID: 26169238 [PubMed - as supplied by publisher]
BME, a novel compound of anthraquinone, down regulated P-glycoprotein expression in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells via generation of reactive oxygen species.
Chem Biol Interact. 2015 Jul 10;
Authors: Wang J, Liu L, Cen J, Ji B
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in tumor cells is still a main obstacle for the chemotherapeutic treatment of cancers. Thus, development of effective MDR reversing agents is an important approach in the clinic. The present study revealed that BME, a novel compound of anthraquinone, elevated intracellular accumulation of the P-gp substrates and reduced concentration resulting in 50% inhibition of cell growth (IC50) values for doxorubicin (DOX) in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. Further more, BME was also reported to down regulated P-gp expression accompanying with generation of nontoxic low level of intracellular reactive oxygen species (iROS) and activation of extracellular signal-regulated kinase (ERK)1/2 as well as c-JUN N-terminal kinase (JNK). However, treatment with N-acetyl-cysteine (NAC), U0216 and SP600125 almost abolished actions of the BME mentioned above. These results indicated that the effect of the BME on the P-gp may be involved in generation of nontoxic low level of iROS and activation of ERK1/2 or JNK, which suggested valuable clues to screen and develop P-gp reversing agents.
PMID: 26169035 [PubMed - as supplied by publisher]
A longitudinal evaluation of performance of automated BCR-ABL1 quantitation using cartridge-based detection system.
Pathology. 2015 Jul 10;
Authors: Enjeti A, Granter N, Ashraf A, Fletcher L, Branford S, Rowlings P, Dooley S
An automated cartridge-based detection system (GeneXpert; Cepheid) is being widely adopted in low throughput laboratories for monitoring BCR-ABL1 transcript in chronic myelogenous leukaemia. This Australian study evaluated the longitudinal performance specific characteristics of the automated system.The automated cartridge-based system was compared prospectively with the manual qRT-PCR-based reference method at SA Pathology, Adelaide, over a period of 2.5 years. A conversion factor determination was followed by four re-validations. Peripheral blood samples (n?=?129) with international scale (IS) values within detectable range were selected for assessment. The mean bias, proportion of results within specified fold difference (2-, 3- and 5-fold), the concordance rate of major molecular remission (MMR) and concordance across a range of IS values on paired samples were evaluated.The initial conversion factor for the automated system was determined as 0.43. Except for the second re-validation, where a negative bias of 1.9-fold was detected, all other biases fell within desirable limits. A cartridge-specific conversion factor and efficiency value was introduced and the conversion factor was confirmed to be stable in subsequent re-validation cycles. Concordance with the reference method/laboratory at >0.1-?10 IS was 78.2% and at ?0.001 was 80%, compared to 86.8% in the >0.01-?0.1 IS range. The overall and MMR concordance were 85.7% and 94% respectively, for samples that fell within?±?5-fold of the reference laboratory value over the entire period of study.Conversion factor and performance specific characteristics for the automated system were longitudinally stable in the clinically relevant range, following introduction by the manufacturer of lot specific efficiency values.
PMID: 26166664 [PubMed - as supplied by publisher]
[Imatinib is effective in a 12-month-old boy with chronic myelogenous leukemia: case report and literature review].
Zhonghua Er Ke Za Zhi. 2015 Mar;53(3):194-7
Authors: Pan Y, Wen S, Tian J, Lyu Z, Du Z, Yan L
OBJECTIVE: To summarize the clinical characteristics of an infant with chronic myelogenous leukemia (CML) and the effects of imatinib on the case.
METHOD: The clinical features of an infant with CML, who was treated with imatinib in the Norman Bethune International Peace Hospital at June 2009, were retrospectively analyzed and the reports in literature were reviewed. The 1-year-old boy suffered from recurrent low-degree fever and pallor. He had a moderate anemia, distended abdomen and marked splenomegaly. Bone marrow aspiration revealed CML in chronic phase)CP). The t (9; 22))q34; q11) could be detected and BCR-ABL (p210) was positive. The boy was diagnosed as CML-CP and treated with imatinib 100 mg per day. There were 10 related papers and more than 100 child CML patients were reported as retrieved from CNKI)from its establishment to August 2014) and Wanfang Database)from its establishment to August 2014) when “Child”, ” Chronic” and “Leukemia” were used as keywords. And there were 30 related papers including 400 cases from PubMed Database (from its establishment to August 2014) and one detailed report of an infant with CML was retrieved when “childhood” and “chronic myeloid leukemia” “imatinib” were used as keywords. The clinical effects of imatinib in infant CML cases were analyzed and summarized based on the literature.
RESULT: The boy obtained a complete hematologic response (CHR) at the 6th week of diagnosis, a complete cytogenetic response (CCyR) at the 3rd month and a complete molecular response)CMR) at the 12th month without side effect. This boy grows very well and after a 62-month follow-up, his disease was stable. According to the domestic literature, 5 children CML cases aged 6 -12 years were treated with imatinib without side effects and got complete hematologic response (CHR) after 2-month-therapy. The dose, metabolic characteristics and clinical observation of imatinib can be found in foreign literature and imatinib showed good response with good tolerance in children with CML. Imatinib is regarded as the first line drug for children CML. But it may affect the development of the children.
CONCLUSION: The children with CML-CP had a good response to imatinib, but more experience in the treatment of children with CML with iniatinib is needed.
PMID: 26165016 [PubMed - in process]
Apoptosis Induced by Microbubble-Assisted Acoustic Cavitation in K562 Cells: The Predominant Role of the Cyclosporin A-Dependent Mitochondrial Permeability Transition Pore.
Ultrasound Med Biol. 2015 Jul 8;
Authors: Zhao L, Feng Y, Shi A, Zong Y, Wan M
Acoustic cavitation of microbubbles has been described as inducing tumor cell apoptosis that is partly associated with mitochondrial dysfunction; however, the exact mechanisms have not been fully characterized. Here, low-intensity pulsed ultrasound (1 MHz, 0.3-MPa peak negative pressure, 10% duty cycle and 1-kHz pulse repetition frequency) was applied to K562 chronic myelogenous leukemia cells for 1 min with 10% (v/v) SonoVue microbubbles. After ultrasound exposure, the apoptotic index was determined by flow cytometry with annexin V-fluorescein isothiocyanate/propidium iodide. In addition, mitochondrial membrane potential (??m) was determined with the JC-1 assay. Translocation of apoptosis-associated protein cytochrome c was evaluated by Western blotting. We found that microbubble-assisted acoustic cavitation can increase the cellular apoptotic index, mitochondrial depolarization and cytochrome c release in K562 cells, compared with ultrasound treatment alone. Furthermore, mitochondrial dysfunction and apoptosis were significantly inhibited by cyclosporin A, a classic inhibitor of the mitochondrial permeability transition pore; however, the inhibitor of Bax protein, Bax-inhibiting peptide, could not suppress these effects. Our results suggest that mitochondrial permeability transition pore opening is involved in mitochondrial dysfunction after exposure to microbubble-assisted acoustic cavitation. Moreover, the release of cytochrome c from the mitochondria is dependent on cyclosporin A-sensitive mitochondrial permeability transition pore opening, but not formation of the Bax-voltage dependent anion channel complex or Bax oligomeric pores. These data provide more insight into the mechanisms underlying mitochondrial dysfunction induced by acoustic cavitation and can be used as a basis for therapy.
PMID: 26164288 [PubMed - as supplied by publisher]
The incidence, risk factors, and outcomes of primary poor graft function after unmanipulated haploidentical stem cell transplantation.
Ann Hematol. 2015 Jul 9;
Authors: Sun YQ, He GL, Chang YJ, Xu LP, Zhang XH, Han W, Chen H, Chen YH, Wang Y, Wang FR, Wang JZ, Liu KY, Huang XJ
Primary poor graft function (PGF) is a severe complication after allogeneic stem cell transplantation (SCT). The incidence, risk factors, and outcomes of PGF have not been well described, especially in the haploidentical SCT setting. We retrospectively reviewed patients who received haploidentical SCT at Peking University Institute of Hematology between January 1, 2011, and December 31, 2012. PGF was defined as persistent neutropenia (?0.5?×?10(9) L(-1)), thrombocytopenia (platelets ?20?×?10(9) L(-1)), and/or hemoglobin ?70 g L(-1) after engraftment with hypocellular bone marrow and full donor chimerism, without concurrent graft-versus-host disease or disease relapse. Incidence was calculated from all patients. Of the 464 total patients, 26 (5.6 %) developed primary PGF. The risk factors were analyzed and compared with control patients with good graft function who were selected using the case-pair method. Finally, 104 patients were selected as a control group according to the matching conditions: (1) the type (acute leukemia, myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML)) and status (standard risk, high risk) of underlying disease, (2) sex, (3) year in which the transplantation was received, and (4) a 1:4 ratio of case-control. No factors were found to be associated with primary PGF. Compared to cases with good graft function, patients with primary PGF experienced poor overall survival (34.6 vs. 82.7 %, p?<?0.001). Of the 26 primary PGF patients, only nine achieved hematopoietic recovery and survived. In conclusion, primary PGF is a rare but life-threatening complication after haploidentical SCT, and effective therapies need to be explored.
PMID: 26152553 [PubMed - as supplied by publisher]
An update on allogeneic hematopoietic progenitor cell transplantation for myeloproliferative neoplasms in the era of tyrosine kinase inhibitors.
Bone Marrow Transplant. 2014 Nov;49(11):1352-9
Authors: Adekola K, Popat U, Ciurea SO
Myeloproliferative neoplasms are a category of diseases that have been traditionally amenable to allogeneic hematopoietic progenitor cell transplantation. Current developments in drug therapy have delayed transplantation for more advanced phases of the disease, especially for patients with CML, whereas transplantation remains a mainstream treatment modality for patients with advanced myelofibrosis and chronic myelomonocytic leukemia. Reduced-intensity conditioning has decreased the treatment-related mortality, and advances in the use of alternative donors for transplantation could extend the use of this procedure to an increasing number of patients with improved safety and efficacy. Here we review the current knowledge about allogeneic transplantation for myeloproliferative neoplasms and discuss the most important aspects to be considered when contemplating transplantation for patients with these diseases. Janus kinase 2 inhibitors offer the promise to improve spleen size and performance of patients with myelofibrosis and extend transplantation for patients with more advanced disease.
PMID: 25089599 [PubMed - indexed for MEDLINE]
Resistance to daunorubicin, imatinib, or nilotinib depends on expression levels of ABCB1 and ABCG2 in human leukemia cells.
Chem Biol Interact. 2014 Aug 5;219:203-10
Authors: Kosztyu P, Bukvova R, Dolezel P, Mlejnek P
The effect of ABCB1 (P-gp, (P-glycoprotein), MDR1) and ABCG2 (BCRP1, (breast cancer resistance protein 1)) expressions on cell resistance to daunorubicin (DRN), imatinib, and nilotinib was studied in human leukemia cells. We used a set of cells derived from a parental K562 cell line, expressing various levels of ABCB1 and ABCG2, respectively. The function of ABCB1 and ABCG2 was confirmed using calcein AM and pheophorbide A accumulation assays, respectively. These assays indicated distinct differences in activities of ABCB1 and ABCG2 which corresponded to their expression levels. We observed that the resistance to DRN and imatinib was proportional to the expression level of ABCB1. Similarly, the resistance to nilotinib and imatinib was proportional to the expression level of ABCG2. Importantly, K562/DoxDR05 and K562/ABCG2-Z cells with the lowest expressions of ABCB1 and ABCG2, respectively, failed to reduce the intracellular levels of imatinib to provide a significant resistance to this drug. However, the K562/DoxDR05 and K562/ABCG2-Z cells significantly decreased the intracellular levels of DRN and nilotinib, respectively, thereby mediating significant resistances to these drugs. Only cells which expression of ABCB1 or ABCG2 exceeded a certain level exhibited a significantly decreased intracellular level of imatinib, and this effect was accompanied by a significantly increased resistance to this drug. Our results clearly indicated that resistance to anticancer drugs mediated by main ABC transporters, ABCB1 and ABCG2, strongly depends on their expressions at protein levels. Importantly, resistance for one drug might be maintained while resistance for other ones might become undetectable at low transporter expression levels.
PMID: 24954033 [PubMed - indexed for MEDLINE]
[Relationship between cytopenia and cytogenetic response in imatinib mesylate treated Ph-positive chronic myeloid leukemia in chronic phase patients].
Beijing Da Xue Xue Bao. 2003 Apr 18;35(2):136-40
Authors: Jiang Q, Chen S, Jiang B, Jiang H, Lu Y, Huang X, Lu D
OBJECTIVES: To evaluate the relationship between cytopenia and cytogenetic response in Imatinib mesylate treated Ph-positive chronic myeloid leukemia (CML) in chronic phase patients.
METHODS: Fifty-four patients with Ph + CML in chronic phase received oral administration of Imatinib 400 or 600 mg once a day for 18 months.
RESULTS: In the early phase of Imatinib treatment, rates of severe leukopenia (leukocyte < 2.0 x 10(9) L-1), anemia (hemoglobin < 100 g.L-1) and severe thrombocytopenia (platelet < 50 x 10(9) L-1) were 14.8%, 37.0% and 27.8%, respectively. Hemocytes recovered in most patients with continued therapy. Treatment was interrupted or dosage reduced in a few patients. The lower the hemoglobin and higher the platelet before the regime, the lower the nadir of leukocytes and hemoglobin counts during the treatment. The lower the platelet count before the regime, the lower the nadir of platelets during the treatment. Risk factors for severe leukopenia were thrombocytosis (> or = 500 x 10(9) L-1) and basophilia > or = 5% before the treatment. Risk factors for severe thrombocytopenia were thrombocytopenia (< 100 x 10(9) L-1) and basophilia > or = 5% before the treatment. During the 12-month treatment with Imatinib, the statistically significant lower probabilities of cytogenetic response were observed at all checked points in patients with severe leukopenia, at the end of 3 and 6 months in patients with anemia, at the end of 3 months in patients with severe thrombocytopenia.
CONCLUSION: Cytopenia is a common side effect in patients with CML in chronic phase treated with Imatinib mesylate. Severe leukopenia is associated with a sustained lower major cytogenetic response, whereas anemia and severe thrombocytopenia influence more for the first 6 months.
PMID: 12920827 [PubMed - indexed for MEDLINE]