Identification of Small Molecules that Disrupt Signaling between ABL and Its Positive Regulator RIN1.
PLoS One. 2015;10(3):e0121833
Authors: Ting PY, Damoiseaux R, Titz B, Bradley KA, Graeber TG, Fernández-Vega V, Bannister TD, Chase P, Nair R, Scampavia L, Hodder P, Spicer TP, Colicelli J
Constitutively active BCR-ABL kinase fusions are causative mutations in the pathogenesis of hematopoietic neoplasias including chronic myelogenous leukemia (CML). Although these fusions have been successfully targeted with kinase inhibitors, drug-resistance and relapse continue to limit long-term survival, highlighting the need for continued innovative drug discovery. We developed a time-resolved Förster resonance energy transfer (TR-FRET) -based assay to identify compounds that disrupt stimulation of the ABL kinase by blocking its ability to bind the positive regulator RIN1. This assay was used in a high throughput screen (HTS) of two small molecule libraries totaling 444,743 compounds. 708 confirmed hits were counter-screened to eliminate off-target inhibitors and reanalyzed to prioritize compounds with IC50 values below 10 ?M. The CML cell line K562 was then used to identify five compounds that decrease MAPK1/3 phosphorylation, which we determined to be an indicator of RIN1-dependent ABL signaling. One of these compounds is a thiadiazole, and the other four are structurally related acyl piperidine amides. Notably, these five compounds lower cellular BCR-ABL1 kinase activity by blocking a positive regulatory interaction rather than directly inhibiting ABL catalytic function.
PMID: 25811598 [PubMed - as supplied by publisher]
Our 2015 approach to invasive pulmonary aspergillosis.
Mycoses. 2015 Mar 24;
Authors: Liss B, Vehreschild JJ, Bangard C, Maintz D, Frank K, Grönke S, Michels G, Hamprecht A, Wisplinghoff H, Markiefka B, Hekmat K, Vehreschild MJ, Cornely OA
At the University Hospital of Cologne, in general two patient groups at high risk for invasive aspergillosis receive posaconazole prophylaxis: Acute myelogenous leukaemia patients during remission induction chemotherapy and allogeneic haematopoietic stem cell transplant recipients. Other patients at risk undergo serum galactomannan testing three times weekly. At 72-96 h of persisting fever despite broad-spectrum antibiotics, or at onset of lower respiratory tract symptoms a thoracic computed tomography (CT) scan is performed. Without lung infiltrates on CT, IPA is ruled out. In lung infiltrates not suggestive for IPA mycological confirmation is pursued. In patients without posaconazole prophylaxis empiric caspofungin will be considered. CT findings typical for IPA prompt targeted treatment, and mycological confirmation. Bronchoalveolar lavage (BAL) is most important for cultural identification and susceptibility testing, and facilitates diagnosing other pathogens. BAL performance is virtually independent of platelet counts. If despite suggestive infiltrates BAL does not yield the diagnosis, CT-guided biopsy follows as soon as platelet counts allow. Surgery can also be beneficial in diagnosis and treatment of IPA. If the diagnosis of IPA is not established, mucormycosis is a valid concern. In patients with breakthrough IPA during posaconazole prophylaxis liposomal amphotericin B is the drug of choice. If no posaconazole prophylaxis was given, voriconazole is the treatment of choice for IPA.
PMID: 25808916 [PubMed - as supplied by publisher]
Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation.
Nature. 2015 Mar 5;519(7541):102-5
Authors: Pemovska T, Johnson E, Kontro M, Repasky GA, Chen J, Wells P, Cronin CN, McTigue M, Kallioniemi O, Porkka K, Murray BW, Wennerberg K
The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.
PMID: 25686603 [PubMed - indexed for MEDLINE]
A new rapid and sensitive assay for detecting the T315I BCR-ABL kinase domain mutation in chronic myeloid leukaemia.
J Clin Pathol. 2008 Jul;61(7):863-5
Authors: Khorashad JS, Thelwell N, Milojkovic D, Marin D, Watson JA, Goldman JM, Apperley JF, Foroni L, Reid AG
A significant minority of chronic myeloid leukaemia patients eventually develop resistance to imatinib, often as a result of point mutations within the BCR-ABL kinase domain. Second-line tyrosine kinase inhibitors (TKIs) are effective against mutations that confer imatinib resistance; however, the T315I BCR-ABL mutant has proved resistant to all available TKIs. An assay facilitating early identification of BCR-ABL(T315I) would therefore aid in identifying high-risk patients who may benefit from alternative therapy. This report describes the development of a sensitive T315I mutation detection methodology based on real-time PCR with self-probing fluorescent primers. The technique demonstrated complete concordance with direct sequencing, correctly identifying 34 T315I-positive samples from a total of 61 samples screened. In a limiting dilution assay, the mutated clone was detectable to a level of 1% of total cells. The data show that Scorpions PCR enables rapid screening for BCR-ABL(T315I) in chronic myeloid leukaemia patients and is appropriate for use in a clinical setting.
PMID: 18587017 [PubMed - indexed for MEDLINE]
Patient-Reported Symptoms and Quality of Life ?in Adults With Acute Leukemia: A Systematic Review.
Oncol Nurs Forum. 2015 Mar 1;42(2):E91-E101
Authors: Leak Bryant A, Lee Walton A, Shaw-Kokot J, Mayer DK, Reeve BB
Leukemia has little age predilection; individuals have been diagnosed with the disease at various stages of life. Leukemia is a group of diseases that arise from the abnormal proliferation of mature myeloid and lymphocytic cells (National Cancer Institute [NCI], 2014c). Four types of leukemia exist: acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia, and chronic lymphoblastic leukemia (CLL). The term acute leukemia includes both AML and ALL. Acute leukemia is the most common hematologic cancer in the United States, with 21,800 new diagnoses and 11,900 deaths in 2014 (NCI, 2014a, 2014b). In 2011, an estimated 302,800 people were living with leukemia in the United States (NCI, 2014c). The five-year survival rate of a patient with leukemia is 57% (NCI, 2014c). AML and ALL are both commonly diagnosed in adults (NCI, 2014a, 2014b). ?.
PMID: 25806895 [PubMed - as supplied by publisher]
Narrowband UV-B Phototherapy for Steroid-Refractory Sclerotic Chronic Cutaneous Graft-vs-Host Disease.
JAMA Dermatol. 2015 Mar 25;
Authors: Sorenson E, Holtzman R, Patel V, Logan AC, Koo J, Levin E
Importance: Chronic graft-vs-host disease (GVHD) affects 50% to 70% of patients who receive allogeneic hematopoietic cell transplants (HCTs), and the skin is the most common site of involvement. Chronic cutaneous GVHD can present with sclerotic or nonsclerotic changes of the skin and often requires treatment with systemic immunosuppressants, extracorporeal photopheresis, or phototherapy. We describe the first reported case, to our knowledge, of the effective treatment of sclerotic chronic cutaneous GVHD with narrowband UV-B (NB UV-B) phototherapy.
Observations: A woman in her 40s presented with sclerotic chronic GVHD of the skin 6 years after HCT for treatment of chronic myelogenous leukemia. The patient’s cutaneous disease progressed despite treatment with prednisone and oral tacrolimus. The patient was initiated on NB UV-B phototherapy 3 times per week, resulting in clinically significant improvement of cutaneous lesions over the first 2 months. The NB UV-B regimen allowed for a reduction of prednisone dose and continued control of cutaneous GVHD over 6 months of therapy.
Conclusions and Relevance: Our case report describes the successful use of NB UV-B phototherapy for the treatment of sclerotic chronic cutaneous GVHD. Further study should be performed to evaluate the effectiveness of this therapeutic modality for patients with sclerotic chronic cutaneous GVHD.
PMID: 25806783 [PubMed - as supplied by publisher]
Induction of heme oxygenase-1 by Na+-H+ exchanger 1 protein plays a crucial role in imatinib-resistant chronic myeloid leukemia cells.
J Biol Chem. 2015 Mar 23;
Authors: Ma D, Fang Q, Wang P, Gao R, Wu W, Lu T, Cao L, Hu X, Wang J
Resistance toward imatinib (IM) and other BCR/ABL tyrosine kinase inhibitors (TKIs) remains troublesome in the treatment of advanced-stage chronic myeloid leukemia (CML). The aim of this study was to estimate the reversal effects of down-regulation of Na+/H+ exchanger 1 (NHE1) on the chemoresistance of BCR-ABL-positive leukemia patients’ cells and cell lines. After treatment with speci?c NHE1 inhibitor cariporide to decrease intracellular pH (pHi), the heme oxygenase-1 (HO-1) levels of K562R cell line and cells from IM-insensitive CML patients decreased. HO-1, as a Bcr/Abl-dependent survival molecule in CML cells, is important to resist TKIs in patients with newly diagnosed CML or IM-resistant CML. Silencing protein kinase C-? (PKC-?) and Nrf-2 or treatment with inhibitors of p38 pathways obviously blocked NHE1-induced HO-1 expression. Furthermore, treatment with HO-1 or p38 inhibitor plus IM increased the apoptosis of K562R cell line and IM-insensitive CML patients’ cells. Inhibiting HO-1 enhanced the activation of caspase-3 and poly(ADP-ribose) polymerase-1. Hence, the results support the anti-apoptotic role of HO-1 induced by NHE1 in K562R cell line and IM-insensitive CML patients, and provide a mechanism by which inducing HO-1 expression via the PKC-?/p38-MAPK (mitogen-activated protein kinase) pathway may promote tumor resistance to oxidative stress.
PMID: 25802333 [PubMed - as supplied by publisher]
The use of medical claims to assess incidence, diagnostic procedures and initial treatment of myelodysplastic syndromes and chronic myelomonocytic leukemia in the Netherlands.
Leuk Res. 2015 Feb;39(2):177-82
Authors: Dinmohamed AG, van Norden Y, Visser O, Posthuma EF, Huijgens PC, Sonneveld P, van de Loosdrecht AA, Jongen-Lavrencic M
Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) may be underreported in cancer registries such as the Netherlands Cancer Registry (NCR). Analysis of Dutch medical claims can complement NCR data on MDS and CMML. We analyzed data on 3681 MDS patients and 235 CMML patients aged ?18 years with initial claims for MDS or CMML from the Dutch nationwide medical claims-based Diagnosis Treatment Combination Information System (DIS) between 2008 and 2010. Clinical information was available in the DIS. MDS and CMML were diagnosed without a bone marrow (BM) examination in almost half of the patients. The age-standardized incidence rate (ASR) per 100,000 in the cohort that underwent BM examinations compared with NCR data was 2.8 vs. 3.3 for MDS and 0.2 vs. 0.4 for CMML in 2008-2010. A conservative treatment approach was associated with increasing age and absence of BM examination in MDS (p<0.001 for both) and CMML patients (p<0.033 for both). In conclusion, the ASR of MDS in the cohort that underwent BM examinations was comparable with the NCR. The majority of elderly patients, either with or without BM examinations, received no therapy. Together, MDS and CMML may be misdiagnosed and inappropriately managed without a BM confirmation.
PMID: 25533930 [PubMed - indexed for MEDLINE]
Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia.
Leukemia. 2015 Jan;29(1):76-85
Authors: Schafranek L, Nievergall E, Powell JA, Hiwase DK, Leclercq T, Hughes TP, White DL
Kinase inhibitors block proliferative signals in BCR-ABL1+ leukemic cells, but their capacity to induce apoptosis is poorly understood. Initial studies suggested that very brief exposure to kinase inhibitors was sufficient to induce apoptosis in chronic myeloid leukemia (CML) cells. However, flaws in this experimental model have subsequently been identified, leading to the conclusion that apoptosis only occurs with sustained low-level kinase inhibition. Thus, the minimum duration of complete kinase inhibition required to commit CML cells to death is unknown. Here we confirm that <1?h is insufficient to induce significant commitment to death in BCR-ABL1+ cell lines and in primary CD34+ progenitor cells, and establish that commitment to cell death only occurs if kinase inhibition is maintained for 4?h or more. Remarkably, signal transducer and activator of transcription 5 (STAT5) inhibition in combination with transient (<1?h) tyrosine kinase inhibitor (TKI) exposure proved lethal for CML progenitors, despite the reactivation of Bcr-Abl after 1?h. JAK kinase inhibition did not induce cell death in combination with transient TKI exposure. Thus, STAT5 appears to be a critical determinant of the time-dependent sensitivity of CML progenitor cells to TKI treatment in a Bcr-Abl-dependent, but JAK-independent, manner. We conclude that combining kinase inhibition with STAT5 inhibition represents a promising therapeutic approach in BCR-ABL1+ leukemias.
PMID: 24813920 [PubMed - indexed for MEDLINE]
Biomarkers for personalized oncology: recent advances and future challenges.
Metabolism. 2015 Mar;64(3 Suppl 1):S16-21
Authors: Kalia M
Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells and oncology is a branch of medicine that deals with tumors. The last decade has seen significant advances in the development of biomarkers in oncology that play a critical role in understanding molecular and cellular mechanisms which drive tumor initiation, maintenance and progression. Clinical molecular diagnostics and biomarker discoveries in oncology are advancing rapidly as we begin to understand the complex mechanisms that transform a normal cell into an abnormal one. These discoveries have fueled the development of novel drug targets and new treatment strategies. The standard of care for patients with advanced-stage cancers has shifted away from an empirical treatment strategy based on the clinical-pathological profile to one where a biomarker driven treatment algorithm based on the molecular profile of the tumor is used. Recent advances in multiplex genotyping technologies and high-throughput genomic profiling by next-generation sequencing make possible the rapid and comprehensive analysis of the cancer genome of individual patients even from very little tumor biopsy material. Predictive (diagnostic) biomarkers are helpful in matching targeted therapies with patients and in preventing toxicity of standard (systemic) therapies. Prognostic biomarkers identify somatic germ line mutations, changes in DNA methylation, elevated levels of microRNA (miRNA) and circulating tumor cells (CTC) in blood. Predictive biomarkers using molecular diagnostics are currently in use in clinical practice of personalized oncotherapy for the treatment of five diseases: chronic myeloid leukemia, colon, breast, lung cancer and melanoma and these biomarkers are being used successfully to evaluate benefits that can be achieved through targeted therapy. Examples of these molecularly targeted biomarker therapies are: tyrosine kinase inhibitors in chronic myeloid leukemia and gastrointestinal tumors; anaplastic lymphoma kinase (ALK) inhibitors in lung cancer with EML4-ALk fusion; HER2/neu blockage in HER2/neu-positive breast cancer; and epidermal growth factor receptors (EGFR) inhibition in EGFR-mutated lung cancer. This review presents the current state of our knowledge of biomarkers in five selected cancers: chronic myeloid leukemia, colorectal cancer, breast cancer, non-small cell lung cancer and melanoma.
PMID: 25468140 [PubMed - indexed for MEDLINE]
[Management of advanced stage chronic myeloid leukemia].
Rinsho Ketsueki. 2014 Oct;55(10):1860-9
Authors: Takahashi N
PMID: 25297750 [PubMed - indexed for MEDLINE]
[Treatment of chronic myeloid leukemia in chronic phase].
Rinsho Ketsueki. 2014 Oct;55(10):1853-9
Authors: Matsumura I
PMID: 25297749 [PubMed - indexed for MEDLINE]
Multispectral studies of DNA binding, antioxidant and cytotoxic activities of a new pyranochromene derivative.
Spectrochim Acta A Mol Biomol Spectrosc. 2015 Mar 9;145:353-359
Authors: Dehkordi MF, Dehghan G, Mahdavi M, Hosseinpour Feizi MA
The binding properties of a new pyranochromene derivative, 2-amino-4-(3-hydroxyphenyl)-5-oxo-4H, 5H-pyrano-[3, 2-c] chromene-3-carbonitrile (3-HC) with calf thymus DNA (ctDNA) have been investigated by UV-vis absorption, circular dichroism, fluorescence spectroscopy and viscosity measurement. These results indicated that 3-HC can interact with DNA through non-intercalative mode and the intrinsic binding constant (Kb) for 3-HC with DNA was estimated to be 3.6×10(3)M(-1). The antioxidant activity experiments show that 3-HC also exhibit good antioxidant activity in DPPH free radical scavenging and ferric reducing ability methods. Moreover, 3-HC exhibited cytotoxic activity against K562, human chronic myelogenous leukemia cells, with IC50 value of 146?M and the cells responded to the treatment with mostly through apoptosis.
PMID: 25795609 [PubMed - as supplied by publisher]
Dasatinib as the salvage therapy for chronic myeloid leukemia with blast crisis and central nervous system involvement: A case report.
Oncol Lett. 2015 Apr;9(4):1957-1961
Authors: Lai SW, Huang TC, Chen JH, Wu YY, Chang PY
BCR-ABL tyrosine-kinase inhibitors are the first-line therapy for the majority of patients with chronic myelogenous leukemia (CML). Up to 20% of patients who have imatinib-treated CML in blast crisis (BC) experience a relapse in the central nervous system (CNS) due to the poor penetration of the drug by the blood-brain barrier. The present case reports a successful experience of using dasatinib-based combination therapy to treat a 22-year-old female who presented with initial symptoms of intermittent fever and easy bruising under the diagnosis of CML in BC. Although the patient eventually succumbed to profound sepsis, the CNS involvement was treated successfully using dasatinib-based combination therapy (cranial radiation and de-escalated intrathecal chemotherapy). This case demonstrates that dasatinib may be a viable option for those who are not medically fit for or are otherwise unwilling to receive high-dose chemotherapy. It appears that dose intensity is essential for optimal efficacy and should be maintained at 150 mg daily as far as possible.
PMID: 25789076 [PubMed - as supplied by publisher]
Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management.
Am J Hematol. 2015 Feb;90(2):162-73
Authors: Tefferi A, Barbui T
DISEASE OVERVIEW: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms, respectively characterized by erythrocytosis and thrombocytosis. Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation.
DIAGNOSIS: PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. Differential diagnosis in ET includes reactive thrombocytosis, chronic myeloid leukemia, and prefibrotic myelofibrosis. Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations occur in approximately 55%, 25%, and 3% of ET patients, respectively. The same molecular markers are also present in prefibrotic myelofibrosis, which needs to be morphologically distinguished from ET. Survival and leukemic/fibrotic transformation: Median survivals are ?14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Life-expectancy in ET is inferior to the control population. JAK2/CALR mutational status does not affect survival in ET. Risk factors for survival in ET and PV include advanced age, leukocytosis, and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Thrombosis risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis: high-risk is defined by the presence of age >60 years or presence of thrombosis history; low-risk is defined by the absence of both of these two risk factors. Recent data consider JAK2V617F and cardiovascular risk factors as additional risk factors. Presence of extreme thrombocytosis might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding.
RISK-ADAPTED THERAPY: The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. In low risk patients, this is accomplished by the use of low-dose aspirin and phlebotomy (hematocrit target <45%) in PV. In high risk (for thrombosis) patients, treatment with hydroxyurea is additionally recommended. Treatment with busulfan or interferon-? is usually effective in hydroxyurea failures and the additional value of JAK inhibitor therapy in such cases is limited. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis.
PMID: 25611051 [PubMed - indexed for MEDLINE]
How I treat newly diagnosed chronic myeloid leukemia in 2015.
Am J Hematol. 2015 Feb;90(2):156-61
Authors: Gambacorti-Passerini C, Piazza R
The initial treatment for chronic myeloid leukemia in chronic phase (CP-CML) represents a complex process, which includes a prompt and precise diagnosis, the choice among three available tyrosine kinase inhibitors (TKIs), and the initial management of care for these patients, which will protract over a very long period of time. This manuscript summarizes different data on activity, side effects, and supportive measures available for each TKI, the need for particular care in the logistical organization of CML management, the scenario which will be opened by the future availability of generic imatinib. The opinion of the authors is that imatinib remains the first-line treatment for CP-CML; this strategy, accompanied by intensive monitoring and possible dose modification/drug switch after the initial 3-12 months of treatment presently assures a normal life expectancy to the population of newly diagnosed patients with CP-CML.
PMID: 25370814 [PubMed - indexed for MEDLINE]
Incidence of persistent/late chronic anemia in newly diagnosed patients with chronic myeloid leukemia responsive to imatinib.
Am J Hematol. 2015 Feb;90(2):105-8
Authors: Latagliata R, Volpicelli P, Breccia M, Vozella F, Romano A, Montagna C, Molica M, Finsinger P, Carmosino I, Serrao A, Zacheo I, Santopietro M, Salaroli A, Alimena G
In patients with chronic myeloid leukemia (CML) responsive to imatinib, it is still unknown whether the long-lasting treatment could induce the appearance of a persistent/late chronic anemia. To highlight this issue, we revised 128 patients with CML (M/F 64/64, median age at diagnosis 56.9 years, interquartile range 43.0-69.3) treated at our Institution with 1st line imatinib for at least 36 months and in stable complete cytogenetic response. At the 36th month of imatinib, a chronic anemia (Hb?<?12 g/dl for?>?6 months) was present in 38/128 patients (29.6%): the anemia was moderate (Hb?>?8???10 g/dl) in 12 patients (9.3%) and mild (Hb?>?10?<?12 g/dl) in 26 patients (20.3%). All patients with persistent/late chronic anemia had a low reticulocyte count and 8/38 a condition of iron deficiency without clinical and instrumental signs of chronic blood loss. Four out of 38 patients (10.5%) needed red cell transfusions during the follow-up. At a landmark analysis from the 36th month of imatinib treatment, cumulative 4-year overall survival (OS) for patients with chronic anemia was 94.4% (CI 95% 83.8-100) compared to 93.5% (CI 95% 87.2-99.8) for patients without chronic anemia (P?=?0.617). In conclusion, the occurrence of a late chronic anemia during long-lasting treatment with imatinib has been observed in about 30% of our responsive patients: its occurrence does not seem to affect OS, but its real impact should be evaluated on a larger cohort of patients.
PMID: 25349084 [PubMed - indexed for MEDLINE]
Anti-CD20 antibody induces the improvement of cytokine-induced killer cell activity via the STAT and MAPK/ERK signaling pathways.
Exp Ther Med. 2015 Apr;9(4):1215-1222
Authors: Deng QI, Bai X, Lv HR, Xiao X, Zhao MF, Li YM
There is a current requirement for novel therapeutic strategies for the treatment of hematopoietic tumors. Residual tumor cells are the main origin of tumor relapse. The aim of this study was to eliminate the residual tumor cells of hematopoietic tumors. Cytokine-induced killer (CIK) cells are used in immunotherapy to deplete the residual cells. However, it is necessary to increase the antitumor activity and clinical applicability of CIK cells. The present study investigated the antitumor activity of CIK cells to the SU-DHL2 human B-cell lymphoma and K562 human chronic myelogenous leukemia cell lines. CD3(+)CD56(+) cells from healthy donors were expanded in culture with cytokines and anti-CD20 monoclonal antibody (mAb; rituximab) to generate CIK cells. A preliminary investigation of their mechanism was then performed. The increase in the cytotoxicity of the CIK cells induced by the anti-CD20 mAb was associated with an increase in the expression of cytotoxic factors. The expression of components of the signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways was found to increase. Upregulation of the expression of STAT1, STAT3 and STAT5 is important as these co-stimulatory molecules enhance T-cell proliferation. Activation of the MAPK signaling pathway is a possible mechanism for the anti-apoptosis effect on the proliferation of CIK cells. In conclusion, anti-CD20 mAb may play an important role in the improvement of CIK-mediated cytotoxicity to tumor cells. These observations may aid in the improvement of the effects of immunotherapy in depleting the residual cells of hematopoietic tumors. Thus, the use of CIK cells cultured with anti-CD20 mAb could be a novel therapeutic strategy for the depletion of chemotherapy-resistant or residual cells in anaplastic large and B-cell lymphoma.
PMID: 25780412 [PubMed - as supplied by publisher]
A Phase I Study of Targeted, Dose-Escalated Intravenous Busulfan in Combination With Etoposide as Myeloablative Therapy for Autologous Stem Cell Transplantation in Acute Myeloid Leukemia.
Clin Lymphoma Myeloma Leuk. 2015 Feb 14;
Authors: Mannis GN, Andreadis C, Logan AC, Damon LE, Benet LZ, Ai WZ, Gaensler KM, Kaplan LD, Koplowicz YB, Linker CA, Olin RL, Sayre PH, Smith CC, Sudhindra A, Venstrom JM, Wolf JL, Martin TG
BACKGROUND: Busulfan and etoposide have been used as myeloablative therapy for autologous hematopoietic stem cell transplantation (HSCT) in adults with acute myeloid leukemia (AML) for > 20 years. The use of targeted intravenous (I.V.) busulfan has significantly improved the tolerability and efficacy of this regimen. We designed a dose-escalation study to examine the maximum tolerated dose (MTD) of targeted I.V. busulfan with bolus etoposide as preparative therapy for autologous HSCT in AML.
PATIENTS AND METHODS: In this single-center, phase I study, adult AML patients received I.V. busulfan targeted to either an area under the curve (AUC) of 1250 (cohort 1) or 1400 (cohort 2) ?mol/min over 16 doses. Dose adjustments based on plasma pharmacokinetics occurred before doses 2 and 11. Etoposide 60 mg/kg I.V. was administered 24 hours after the last busulfan dose and 3 days before stem cell infusion.
RESULTS: Twelve patients with intermediate-risk AML in first complete remission were treated. All patients in cohort 1 and 5 patients (83%) in cohort 2 were within 10% of the target AUC. The MTD was not reached, although Grade ? 3 mucositis occurred in 3 patients (50%) in cohort 1 and in 4 patients (66%) in cohort 2, limiting further dose escalation. Two-year relapse-free survival was 33% in cohort 1 versus 67% in cohort 2 (P = .08).
CONCLUSION: Etoposide and targeted, dose-escalated I.V. busulfan as myeloablative therapy for autologous HSCT in AML is safe, with mucositis being the most significant toxicity. A phase II study is warranted to further evaluate the activity and safety of busulfan targeted to AUC 1400 ?mol/min.
PMID: 25776193 [PubMed - as supplied by publisher]
Characteristics of Bacteremia in Pediatric Oncology Patients Based on Pathogen Classification as Associated with the Gastrointestinal Mucosa or Skin.
Infect Control Hosp Epidemiol. 2015 Mar 16;:1-4
Authors: Flagg A, Worley S, Foster CB
Factors favoring blood stream infections associated with gastrointestinal mucosa versus skin organisms were explored. An observed difference was attributable to bacteremia from oral flora in patients with acute myelogenous leukemia or mucositis. Our data do not support the conclusion that isolation of enteric Gram-negatives is unrelated to the central catheter. Infect Control Hosp Epidemiol 2015;00(0): 1-4.
PMID: 25773335 [PubMed - as supplied by publisher]