Emergence of BCR-ABL kinase domain mutations associated with newly diagnosed chronic myeloid leukemia: a meta-analysis of clinical trials of tyrosine kinase inhibitors.
J Manag Care Spec Pharm. 2015 Feb;21(2):114-22
Authors: Ursan ID, Jiang R, Pickard EM, Lee TA, Ng D, Pickard AS
BACKGROUND: Tyrosine kinase inhibitors (TKIs) are a mainstay of treatment for patients suffering from chronic myeloid leukemia (CML). Testing for various mutations in the BCR-ABL gene may help predict lack of response to specific TKIs where resistance has developed.
OBJECTIVE: To estimate the emergence of BCR-ABL kinase domain mutations associated with newly diagnosed CML patients exposed to first-line TKI treatment.
METHODS: Published studies were identified using a structured search of online databases. Original research studies were included if they reported the incidence of specific BCR-ABL kinase domain point mutations after first-line TKI treatment failure or baseline mutations for second-line TKI treatment following first-line treatment failure. Meta-analysis of mutation rates across studies was based on DerSimonian and Laird’s random-effects model.
RESULTS: Of 1,323 citations, 12 studies met the inclusion criteria, involving a total of 1,698 patients. Overall mutation rates (95% CI) were imatinib 9.7% (6.2%-13.3%); dasatanib 1.7% (0.0%-4.3%); and nilotinib 3.3% (0.0%-7.7%). The most common specific mutations were T315I, E255K, and M351T. T315I mutations constituted 58% (7 of 12) of dasatinib-related mutations and 13% (15 of 117) of imatinib-related mutations.
CONCLUSIONS: Lack of response to TKIs associated with mutation in the BCR-ABL gene was significantly higher in imatinib-treated patients, and all mutations arose after treatment. T315I was a common treatment-emergent mutation. Further research is needed to assess the prognostic value of testing for mutations and the economic implications of treatment-emergent mutations.
PMID: 25615000 [PubMed - indexed for MEDLINE]
Wage-subsidised employment as a result of permanently reduced work capacity in a nationwide cohort of patients diagnosed with haematological malignancies.
Acta Oncol. 2015 May;54(5):743-9
Authors: Horsboel TA, Nielsen CV, Nielsen B, Andersen NT, De Thurah A
BACKGROUND: Patients with haematological malignancies have a poorer labour market prognosis than the general population. We have previously found that they have low rates of return to work, and a higher risk of being granted disability pension, than individuals without a history of these diseases. The aim of this study was to further investigate the labour market prognosis for these patients, by comparing the risk of being granted wage-subsidised (WS) employment as a result of permanently reduced work capacity among patients diagnosed with haematological malignancies to a reference cohort, and to determine if relative risks differ between subtypes of haematological malignancies.
MATERIAL AND METHODS: We combined data from national registers on Danish patients diagnosed with haematological malignancies between 2000 and 2007 and a reference cohort without a history of these diseases. A total of 3194 patients and 28 627 reference individuals were followed until they were granted WS employment, disability pension, anticipatory pension, old age pension, emigration, death or until 26 February 2012, whichever came first.
RESULTS: A total of 310 (10%) patients and 795 (3%) reference individuals had their work capacity permanently reduced to an extent that they were granted WS employment during the follow-up period. Age- and gender-adjusted relative risks differed significantly between the subgroups of haematological malignancies, and four years after diagnosis they ranged from 2.47 (95% CI 1.46-4.16) for patients with Hodgkin lymphoma to 10.83 (95% CI 7.15-16.40) for patients with chronic myeloid leukaemia.
CONCLUSION: All eight subtypes of haematological malignancies were associated with an increased risk of being granted WS employment due to permanently reduced work capacity compared to the reference cohort. The relative risks differed according to haematological malignancy subtype, and the highest was found for patients with chronic myeloid leukaemia.
PMID: 25752974 [PubMed - indexed for MEDLINE]
The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia.
Pharmacogenomics J. 2014 Aug;14(4):328-35
Authors: Di Paolo A, Polillo M, Capecchi M, Cervetti G, Baratè C, Angelini S, Guerrini F, Fontanelli G, Arici R, Ciabatti E, Grassi S, Bocci G, Hrelia P, Danesi R, Petrini M, Galimberti S
The aim of the study was to investigate any possible influence of polymorphisms of transmembrane transporters human organic cation transporter 1 (hOCT1), ABCB1, ABCG2 on imatinib pharmacokinetics in 33 men and 27 women (median age and range, 56 and 27-79 years, respectively) affected by chronic myeloid leukemia. A population pharmacokinetic analysis was performed to investigate imatinib disposition in every patient and the role of transporter polymorphisms. Results showed that the ?1-acid glycoprotein and the c.480C>G genotype of hOCT1 had a significant effect on apparent drug clearance (CL/F) being responsible, respectively, for a 20% and 10% decrease in interindividual variability (IIV) of CL/F (from 50.1 up to 19.6%). Interestingly, 25 patients carrying at least one polymorphic c.480?G allele had a significant lower CL/F value with respect to the 35 c.480CC individuals (mean±s.d., 9.6±1.6 vs 12.1±2.3?l?h(-1), respectively; P<0.001). In conclusion, the hOCT1 c.480C>G SNP may significantly influence imatinib pharmacokinetics, supporting further analyses in larger groups of patients.
PMID: 24589908 [PubMed - indexed for MEDLINE]
PDQ Cancer Information Summaries
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute myeloid leukemia and other myeloid malignancies. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Evolution of BCR/ABL gene mutation in CML is time dependent and dependent on the pressure exerted by tyrosine kinase inhibitor.
PLoS One. 2015;10(1):e0114828
Authors: Vaidya S, Vundinti BR, Shanmukhaiah C, Chakrabarti P, Ghosh K
BACKGROUND: Mutations in the ABL kinase domain and SH3-SH2 domain of the BCR/ABL gene and amplification of the Philadelphia chromosome are the two important BCR/ABL dependent mechanisms of imatinib resistance. Here, we intended to study the role played by TKI, imatinib, in selection of gene mutations and development of chromosomal abnormalities in Indian CML patients.
METHODS: Direct sequencing methodology was employed to detect mutations and conventional cytogenetics was done to identify Philadelphia duplication.
RESULTS: Among the different mechanisms of imatinib resistance, kinase domain mutations (39%) of the BCR/ABL gene were seen to be more prevalent, followed by mutations in the SH3-SH2 domain (4%) and then BCR/ABL amplification with the least frequency (1%). The median duration of occurrence of mutation was significantly shorter for patients with front line imatinib than those pre-treated with hydroxyurea. Patients with high Sokal score (p = 0.003) showed significantly higher incidence of mutations, as compared to patients with low/intermediate score. Impact of mutations on the clinical outcome in AP and BC was observed to be insignificant. Of the 94 imatinib resistant patients, only 1 patient exhibited duplication of Philadelphia chromosome, suggesting a less frequent occurrence of this abnormality in Indian CML patients.
CONCLUSION: Close monitoring at regular intervals and proper analysis of the disease resistance would facilitate early detection of resistance and thus aid in the selection of the most appropriate therapy.
PMID: 25629972 [PubMed - indexed for MEDLINE]
[Chronic lymphocytic leukemia with concomitant chronic myeloid leukemia: a case report].
Zhonghua Xue Ye Xue Za Zhi. 2014 Dec;35(12):1099
Authors: Cui L, Quan B, Liu X, Zhang Z, Zhang J
PMID: 25543705 [PubMed - indexed for MEDLINE]
[SHP-1 gene in the disease progression of chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2014 Dec;35(12):1074-8
Authors: Li Y, Wang X, Yang L, Pan Y, Shang Y, Luo J
OBJECTIVE: To investigate the profile of promoter methylation and expression of SHP-1 gene in the progression of chronic myeloid leukemia (CML).
METHODS: The expression level of SHP-1 mRNA and protein in bone marrow or peripheral blood mononuclear cells from CML patients were detected by Western blot and SYBR Green-based qRT-PCR. The methylation status of SHP-1 were assessed by methylation-specific polymerase chain reaction (MSP) assay. K562 cells were infected with the lentiviral plasmids pEX-SHP-1-puro-Lv105 (K562-SHP-1) or pEX-EGFP-puro-Lv105 (K562-EGFP). The levels of proteins and phosphorylated proteins were detected by Western blot. qRT-PCR assay was used to test the level of BCR-ABL mRNA.
RESULTS: The relative levels of SHP-1 mRNA were sharply decreased in advanced stages CML compared to chronic phase (CP)-CML (0.79±0.37 vs 1.18±0.64, P= 0.009). The level of SHP-1 protein was lower in advanced stages CML compared to CP-CML (0.57±0.02 vs 1.02±0.04, P=0.039). The frequency of SHP-1 gene promoter methylation at selected loci in CP-CML was 23.8% (10/42), and the methylated regions were detected in all advanced CML samples (P<0.01). SHP-1 was stably transfected into K562 cells and selected with puromycin. Overexpression of SHP-1 inhibited the proliferation and induced the apoptosis of K562 cells, meanwhile leaded to G0/G1 phase arrest. After transfection, the level of BCR-ABL mRNA was not affected in K562-SHP-1 cells (1.32±0.34) compared to K562-EGFP cells (1.18±0.20, P=0.644), but overexpression of SHP-1 caused a slight decrease in BCR-ABL protein in K562-SHP-1 cells compared to K562 -EGFP cells (0.78±0.15 vs 1.27±0.24, P=0.040). Overexpression of SHP-1 resulted in a remarkable decrease in MYC protein, phosphorylated forms of JAK2, STAT5, Akt and MAPK. However, the un-phosphorylated forms of these molecules were not significantly affected.
CONCLUSION: Decreased expression of SHP-1 caused by aberrant promoter hypermethylation may play a key role in the progression of CML by dysregulation of BCR-ABL, Akt, MAPK, MYC, JAK2 and STAT5 signaling.
PMID: 25543700 [PubMed - indexed for MEDLINE]
[Second-generation tyrosine kinase inhibitors: the first-line treatment strategy of chronic myeloid leukemia patients?].
Zhonghua Xue Ye Xue Za Zhi. 2014 Dec;35(12):1049-52
Authors: Jiang Q
PMID: 25543695 [PubMed - indexed for MEDLINE]
Acute pediatric leg compartment syndrome in chronic myeloid leukemia.
Orthopedics. 2014 Nov;37(11):e1036-9
Authors: Cohen E, Truntzer J, Trunzter J, Klinge S, Schwartz K, Schiller J
Acute compartment syndrome is an orthopedic surgical emergency and may result in devastating complications in the setting of delayed or missed diagnosis. Compartment syndrome has a variety of causes, including posttraumatic or postoperative swelling, external compression, burns, bleeding disorders, and ischemia-reperfusion injury. Rare cases of pediatric acute compartment syndrome in the setting of acute myeloid leukemia and, even less commonly, chronic myeloid leukemia have been reported. The authors report the first known case of pediatric acute compartment syndrome in a patient without a previously known diagnosis of chronic myeloid leukemia. On initial examination, an 11-year-old boy presented with a 2-week history of progressive left calf pain and swelling after playing soccer. Magnetic resonance imaging scan showed a hematoma in the left superficial posterior compartment. The patient had unrelenting pain, intermittent lateral foot parethesias, and inability to bear weight. Subsequently, he was diagnosed with acute compartment syndrome and underwent fasciotomy and evacuation of a hematoma. Laboratory results showed an abnormal white blood cell count of 440×10(9)/L (normal, 4.4-11×10(9)) and international normalized ratio of 1.3 (normal, 0.8-1.2). Further testing included the BCR-ABL1 fusion gene located on the Philadelphia chromosome, leading to a diagnosis of chronic myeloid leukemia. Monotherapy with imatinib mesylate (Gleevec) was initiated. This report adds another unique case to the growing literature on compartment syndrome in the pediatric population and reinforces the need to consider compartment syndrome, even in unlikely clinical scenarios.
PMID: 25361367 [PubMed - indexed for MEDLINE]
Clonal dominance and clonal evolution in a patient with a “chronic myeloid neoplasm”: a challenge in management.
Leuk Lymphoma. 2015 Jan;56(1):239-41
Authors: Burgstaller S, Webersinke G, Thaler J
PMID: 24766465 [PubMed - indexed for MEDLINE]
The evolution of treatment strategies for patients with chronic myeloid leukemia relapsing after allogeneic bone marrow transplant: can tyrosine kinase inhibitors replace donor lymphocyte infusions?
Leuk Lymphoma. 2015 Jan;56(1):128-34
Authors: Zeidner JF, Zahurak M, Rosner GL, Gocke CD, Jones RJ, Smith BD
The optimal treatment for chronic myeloid leukemia (CML) relapsing following allogeneic bone marrow transplant (alloBMT) is unknown. We performed a single-center retrospective analysis of 71 consecutive patients undergoing alloBMT for CML from 1995 to 2008. A multi-state model was used to quantify cumulative incidences of complete molecular response (CMR) and death following alloBMT. The primary analysis was comparison of three treatment interventions (tyrosine kinase inhibitor: TKI, donor lymphocyte infusion: DLI, and TKI + DLI) for relapsed disease post-alloBMT. Forty-five (63%) patients relapsed post-alloBMT (molecular relapse: n = 16, cytogenetic relapse: n = 20, hematologic relapse: n = 2, advanced phase relapse: n = 7) and 40 patients underwent one of three treatments: TKI-only (n = 13), DLI-only (n = 11) or TKI + DLI (n = 16). Although not statistically significant, the TKI-only group had the highest cumulative incidence of CMR and lowest cumulative incidence of death compared to DLI and TKI + DLI. These data support the finding that TKI therapy is active in the post-alloBMT setting.
PMID: 24712979 [PubMed - indexed for MEDLINE]
Omacetaxine mepesuccinate in patients with advanced chronic myeloid leukemia with resistance or intolerance to tyrosine kinase inhibitors.
Leuk Lymphoma. 2015 Jan;56(1):120-7
Authors: Khoury HJ, Cortes J, Baccarani M, Wetzler M, Masszi T, Digumarti R, Craig A, Benichou AC, Akard L
Omacetaxine mepesuccinate promotes apoptosis by inhibiting the production of short-lived oncoproteins. The efficacy and safety of omacetaxine in patients with advanced chronic myeloid leukemia (CML) previously treated with tyrosine kinase inhibitors were assessed in two phase II trials (CML-202 and CML-203). Fifty-one patients in accelerated phase (AP-CML) and 44 in myeloid blast phase (BP-CML) received subcutaneous omacetaxine 1.25 mg/m(2) twice daily days 1-14 every 28 days until hematologic response/improvement or any cytogenetic response, then days 1-7 every 28 days until disease progression. The primary endpoint was maintenance or attainment of a major hematologic response (MHR). Cytogenetic responses were also evaluated. MHR was 37% in patients with AP-CML and 9% with BP-CML (22% and 5% in those with a history of T315I). Most grade 3/4 adverse events were related to myelosuppression, and were generally manageable. Omacetaxine demonstrates activity and an acceptable safety profile in pretreated patients with advanced CML, irrespective of mutational status.
PMID: 24650054 [PubMed - indexed for MEDLINE]
Non-steady-state hematopoiesis regulated by the C/EBP? transcription factor.
Cancer Sci. 2015 Jul;106(7):797-802
Authors: Hirai H, Yokota A, Tamura A, Sato A, Maekawa T
Steady-state hematopoiesis responds to extracellular stimuli to meet changing demands and also to pathologically altered intracellular signaling. Granulocyte production increases following infection or in response to cytokine stimulation, and activation of the CCAAT/enhancer-binding protein ? (C/EBP?) transcription factor is required for such stress-induced granulopoiesis, whereas C/EBP? plays a critical role in maintaining steady-state granulopoiesis. Different roles of these C/EBP transcription factors in different modes of hematopoiesis are evolutionally conserved from zebrafish to humans. In addition to reactions against infections, C/EBP? is responsible for cancer-driven myelopoiesis, which promotes cancer progression, at least in part, by abrogating the immune response in the cancer microenvironment. The BCR-ABL fusion protein activates emergency-specific pathway of granulopoiesis by upregulating C/EBP?. This in turn causes chronic phase chronic myeloid leukemia, which is characterized by myeloid expansion. The C/EBP? transcription factor also plays a role in other hematological malignancies of both myeloid and lymphoid lineage origin. Thus, elucidation of the upstream and downstream networks surrounding C/EBP? will lead to the development of novel therapeutic strategies for diseases mediated by non-steady-state hematopoiesis.
PMID: 25940801 [PubMed - indexed for MEDLINE]
Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies.
Cancer Sci. 2015 Jul;106(7):896-901
Authors: Ogura M, Uchida T, Terui Y, Hayakawa F, Kobayashi Y, Taniwaki M, Takamatsu Y, Naoe T, Tobinai K, Munakata W, Yamauchi T, Kageyama A, Yuasa M, Motoyama M, Tsunoda T, Hatake K
We carried out a multicenter dose-escalation phase I study of oral OPB-51602, a signal transducer and activator of transcription 3 phosphorylation inhibitor, in patients with relapsed or refractory hematological malignancies to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity. Twenty patients were treated with OPB-51602 at doses of 1, 2, 3, 4, and 6 mg in the “3 + 3″ dose escalation design. The most common treatment-related adverse events included nausea (55%), peripheral sensory neuropathy (45%), and diarrhea (40%). The most frequently observed grade 3 or 4 drug-related adverse events were neutropenia (20%), leukopenia (15%), lymphopenia (10%), and thrombocytopenia (10%). The MTD was 6 mg, with dose-limiting toxicities of grade 3 lactic acidosis and increased blood lactic acid levels observed in one of three patients and grade 1-2 peripheral neuropathy in three of three patients. The recommended dose was determined to be 4 mg. OPB-51602 was rapidly absorbed, and exposure tended to increase in a dose-dependent manner. Accumulation of OPB-51602 was seen with 4 weeks of multiple treatments. No clear therapeutic response was observed. Durable stable disease was observed in two patients with acute myeloid leukemia and one with myeloma. In conclusion, the MTD of OPB-51602 was 6 mg. OPB-51602 was safe and well tolerated in a dose range of 1-4 mg. However, long-term administration at higher doses was difficult with the daily dosing schedule, and no response was seen. Therefore, further clinical development of OPB-51602 for hematological malignancies with a daily dosing schedule was terminated.
PMID: 25912076 [PubMed - indexed for MEDLINE]
Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes.
Bone Marrow Transplant. 2015 Oct 5;
Authors: Vrhovac R, Labopin M, Ciceri F, Finke J, Holler E, Tischer J, Lioure B, Gribben J, Kanz L, Blaise D, Dreger P, Held G, Arnold R, Nagler A, Mohty M
Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5-79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 >225 days, presence of CR at RIC2, patient’s Karnofsky performance status >80 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients’ favourable outcome.Bone Marrow Transplantation advance online publication, 5 October 2015; doi:10.1038/bmt.2015.221.
PMID: 26437057 [PubMed - as supplied by publisher]
An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians.
Korean J Fam Med. 2015 Sep;36(5):197-202
Authors: Granatowicz A, Piatek CI, Moschiano E, El-Hemaidi I, Armitage JD, Akhtari M
Chronic myeloid leukemia (CML) accounts for approximately 15% of adult leukemias. Forty percent of patients with CML are asymptomatic, in whom the disease is detected solely based on laboratory abnormalities. Since the introduction of tyrosine kinase inhibitor therapy in 2001, CML has become a chronic disease for the majority of patients. Primary care physicians may be the first to recognize a new diagnosis of CML. In patients with known CML, the primary care physician may be the first to detect disease progression or adverse effects to therapy. This article provides an overview of the clinical presentation, diagnostic approach, and treatment considerations of CML.
PMID: 26435808 [PubMed]
A thirty-five nucleotides BCR-ABL1 insertion mutation of controversial significance confers resistance to imatinib in a patient with chronic myeloid leukemia (CML).
Exp Mol Pathol. 2015 Aug;99(1):16-8
Authors: Marcé S, Cortés M, Zamora L, Cabezón M, Grau J, Millá F, Feliu E
Tyrosine kinase inhibitors (TKI) have improved the management of patients with chronic myeloid leukemia (CML). However, a significant proportion of patients does not achieve the optimal response or are resistant to TKI. ABL1 kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Although deletion or insertion of nucleotides in BCR-ABL1 has rarely been described, we identified a CML patient with an already described 35 nucleotides insertion (BCR-ABL1(35INS)) of controversial significance, that confers resistance to imatinib but sensitivity to dasatinib.
PMID: 25913326 [PubMed - indexed for MEDLINE]
A study on stability and medical implications for a complex delay model for CML with cell competition and treatment.
J Theor Biol. 2014 Dec 21;363:30-40
Authors: R?dulescu IR, Cândea D, Halanay A
We study a mathematical model describing the dynamics of leukemic and normal cell populations (stem-like and differentiated) in chronic myeloid leukemia (CML). This model is a system of four delay differential equations incorporating three types of cell division. The competition between normal and leukemic stem cell populations for the common microenvironment is taken into consideration. The stability of one steady state is investigated. The results are discussed via their medical interpretation.
PMID: 25128235 [PubMed - indexed for MEDLINE]
Increased p53 protein expression as a potential predictor of early relapse after hematopoietic stem cell transplantation in children with acute myelogenous leukemia.
Pediatr Transplant. 2015 Oct 3;
Authors: Mattsson K, Honkaniemi E, Barbany G, Gustafsson B
Dysregulation of genes involved in the cell cycle such as TP53, P21, P16, and PTEN plays a key role in oncogenesis. We have earlier reported increased expression of the TP53 encoded protein p53, in bone marrow samples from pediatric patients with more aggressive, rare chronic myeloid malignancies. The aim of this study was to investigate protein expression of p53, p21, p16, and PTEN before and after HSCT in pediatric patients with AML and evaluate whether any potential alterations could predict relapse after HSCT. Paraffin-embedded bone marrow samples from 34 pediatric patients with AML were collected retrospectively from time of diagnosis as well as pre- and post-HSCT. IHC was performed on tissue microarrays with antibodies against p53, p21, p16, and PTEN. Study material was analyzed by independent t-tests and nonlinear regression. t-Tests showed a statistical significant difference in p53 (p = 0.010) with overexpression in the group of patients who relapsed compared to the relapse-free patients at >3-6 months post-HSCT. Analysis of p53 protein expression by IHC may be a potential predictor for relapse after HSCT in children with AML.
PMID: 26432780 [PubMed - as supplied by publisher]
Concomitant JAK2 V617F-positive polycythemia vera and BCR-ABL-positive chronic myelogenous leukemia treated with ruxolitinib and dasatinib.
Blood Cancer J. 2015;5:e351
Authors: Zhou A, Knoche EM, Engle EK, Fisher DA, Oh ST
PMID: 26430722 [PubMed - as supplied by publisher]