Chronic Myeloid Leukemia (CML)
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Information for Health Professionals / Researchers (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Chen M, Gallipoli P, DeGeer D, et al.
Targeting primitive chronic myeloid leukemia cells by effective inhibition of a new AHI-1-BCR-ABL-JAK2 complex.
J Natl Cancer Inst. 2013; 105(6):405-23 [PubMed] Free Access to Full Article
BACKGROUND: Imatinib mesylate (IM) induces clinical remission of chronic myeloid leukemia (CML). The Abelson helper integration site 1 (AHI-1) oncoprotein interacts with BCR-ABL and Janus kinase 2 (JAK2) to mediate IM response of primitive CML cells, but the effect of the interaction complex on the response to ABL and JAK2 inhibitors is unknown.
METHODS: The AHI-1-BCR-ABL-JAK2 interaction complex was analyzed by mutational analysis and coimmunoprecipitation. Roles of the complex in regulation of response or resistance to ABL and JAK2 inhibitors were investigated in BCR-ABL (+) cells and primary CML stem/progenitor cells and in immunodeficient NSG mice. All statistical tests were two-sided.
RESULTS: The WD40-repeat domain of AHI-1 interacts with BCR-ABL, whereas the N-terminal region interacts with JAK2; loss of these interactions statistically significantly increased the IM sensitivity of CML cells. Disrupting this complex with a combination of IM and an orally bioavailable selective JAK2 inhibitor (TG101209 [TG]) statistically significantly induced death of AHI-1-overexpressing and IM-resistant cells in vitro and enhanced survival of leukemic mice, compared with single agents (combination vs TG alone: 63 vs 53 days, ratio = 0.84, 95% confidence interval [CI] = 0.6 to 1.1, P = .004; vs IM: 57 days, ratio = 0.9, 95% CI = 0.61 to 1.2, P = .003). Combination treatment also statistically significantly enhanced apoptosis of CD34(+) leukemic stem/progenitor cells and eliminated their long-term leukemia-initiating activity in NSG mice. Importantly, this approach was effective against treatment-naive CML stem cells from patients who subsequently proved to be resistant to IM therapy.
CONCLUSIONS: Simultaneously targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may improve outcomes in patients destined to develop IM resistance.


Sharma N, Dua H, Rosha D
Chronic myeloid leukemia with an unusual paraneoplastic syndrome.
J Assoc Physicians India. 2012; 60:47-8 [PubMed]
We report a 34 year old man who developed bilateral ptosis and predominantly respiratory, truncal and bulbar weakness, and a high titer of anti acetylcholine receptor antibodies along with a diagnosis of Philadelphia chromosome positive Chronic Myeloid Leukemia (CML). The temporal relationship suggests a possible association.


Schürch C, Riether C, Amrein MA, Ochsenbein AF
Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by secreting interferon-γ.
J Exp Med. 2013; 210(3):605-21 [PubMed] Article available free on PMC after 11/09/2013
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia arising from the oncogenic break point cluster region/Abelson murine leukemia viral oncogene homolog 1 translocation in hematopoietic stem cells (HSCs), resulting in a leukemia stem cell (LSC). Curing CML depends on the eradication of LSCs. Unfortunately, LSCs are resistant to current treatment strategies. The host's immune system is thought to contribute to disease control, and several immunotherapy strategies are under investigation. However, the interaction of the immune system with LSCs is poorly defined. In the present study, we use a murine CML model to show that LSCs express major histocompatibility complex (MHC) and co-stimulatory molecules and are recognized and killed by leukemia-specific CD8(+) effector CTLs in vitro. In contrast, therapeutic infusions of effector CTLs into CML mice in vivo failed to eradicate LSCs but, paradoxically, increased LSC numbers. LSC proliferation and differentiation was induced by CTL-secreted IFN-γ. Effector CTLs were only able to eliminate LSCs in a situation with minimal leukemia load where CTL-secreted IFN-γ levels were low. In addition, IFN-γ increased proliferation and colony formation of CD34(+) stem/progenitor cells from CML patients in vitro. Our study reveals a novel mechanism by which the immune system contributes to leukemia progression and may be important to improve T cell-based immunotherapy against leukemia.


Al Salman JM, Husain A
Renal malakolpkia followed by chronic myelogenous leukaemia: treatment challenges case report and literature review.
BMJ Case Rep. 2013; 2013 [PubMed]
Malakoplakia is a rare granulomatous disorder of unknown aetiology and usually affects patients with underlying immunosuppression. This disorder usually involves the genitourinary tract but has been reported in a wide array of anatomical sites. We are presenting, what is to our knowledge, the first case in the literature in which a patient was diagnosed with malakoplakia and after his successful management; he was diagnosed with chronic meylomoncytic leukaemia. All cases of malakoplakia reported in the literature were either preceded or accompanied by an immunosuppressive state.


Jha P, Himanshu D, Jain N, Singh AK
Imatinib-induced Stevens-Johnsons syndrome.
BMJ Case Rep. 2013; 2013 [PubMed]
Imatinib mesylate is a tyrosine kinase inhibitor used widely as the first-line treatment for chronic myeloid leukaemia (CML). The side-effect profile of this drug includes fluid retention, muscle cramps, diarrhoea, myelosuppression and skin rashes. Of these, rashes of the type maculo-papular eruptions and oedema developed most commonly. The cutaneous adverse reactions other than maculo-papular eruptions are rare with imatinib. Severe and life-threatening cutaneous reactions can occur in 5% cases. Here, the author reports a case of newly diagnosed CML that developed Steven-Johnsons syndrome due to imatinib therapy. Patient responded and discharged successfully on withdrawal of the culminating drug.


Kim WS, Lee MJ, Kim DH, et al.
5'-OH-5-nitro-Indirubin oxime (AGM130), an Indirubin derivative, induces apoptosis of Imatinib-resistant chronic myeloid leukemia cells.
Leuk Res. 2013; 37(4):427-33 [PubMed]
Imatinib is a highly effective drug for the treatment of chronic myeloid leukemia (CML) that targets the BCR-ABL kinase. However, a number of patients have CML that is resistant to Imatinib treatment. In this report, we developed AGM130 as a potential therapeutic drug for Imatinib-resistant CML treatment. The AGM130 compound is derived from Indirubin, which is an ingredient of Danggui Longhui Wan and known as a cyclin-dependent kinase (CDK) inhibitor. The water solubility of AGM130 is more enhanced than that of the original form of Indirubin, which has very poor water solubility. Our data showed that the AGM130 compound efficiently decreased the viability of CML-derived K562 cells. Moreover, this compound also efficiently decreased the viability of Imatinib-resistant K562 cells in in vitro and in vivo systems. In addition, like Indirubin, AGM130 also inhibited phosphorylation of retinoblastoma protein (Rb), which is a major substrate of CDK. Conclusively, our data suggest that AGM130 is a strong candidate for treating Imatinib-resistant CML.


Voican I, Vlădăreanu AM, Bumbea H, Begu M
Sudden blast crisis in a chronic myeloid leukemia patient during imatinib therapy.
Rom J Intern Med. 2012 Jul-Sep; 50(3):241-4 [PubMed]
Imatinib mesilate (IM) is the first line therapy for chronic myeloid leukemia (CML) patients in chronic phase. Although it offers a complete cytogenetic response (CCyR) in a majority of patients, there still are some rare cases in which a sudden blast crisis (SBC) evolves. The mechanism of this unexpected event is not yet completely understood. We present the case of a female patient who developed a SBC while being under IM therapy. We do not know for sure which is the role of IM in this event, but current available data suggest that this drug may have a permissive effect on the evolution of some aggressive subclones in the context of restored normal cell population.


Naderi EH, Ugland HK, Diep PP, et al.
Selective inhibition of cell death in malignant vs normal B-cell precursors: implications for cAMP in development and treatment of BCP-ALL.
Blood. 2013; 121(10):1805-13 [PubMed]
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most commonly occurring pediatric cancer. Despite its relatively good prognosis, there is a steady search for strategies to improve treatment effects and prevent the undesired side effects on normal cells. In the present paper, we demonstrate a differential effect of cyclic adenosine monophosphate (cAMP) signaling between normal BCPs and BCP-ALL blasts, pointing to a potential therapeutic window allowing for manipulation of cAMP signaling in the treatment of BCP-ALL. By studying primary cells collected from pediatric BCP-ALL patients and healthy controls, we found that cAMP profoundly decreased basal and DNA damage-induced p53 levels and cell death in malignant cells, whereas normal BCP counterparts displayed slightly augmented cell death when exposed to cAMP-increasing agents. We did not find evidence for a selection process involving generation of increased basal cAMP levels in BCP-ALL cells, but we demonstrate that paracrine signaling involving prostaglandin E2-induced cAMP generation has the potential to suppress p53 activation and cell death induction. The selective inhibitory effect of cAMP signaling on DNA damage-induced cell death in BCP-ALL cells appears to be an acquired trait associated with malignant transformation, potentially allowing the use of inhibitors of this pathway for directed killing of the malignant blasts.


Zhang B, Li M, McDonald T, et al.
Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-β-catenin signaling.
Blood. 2013; 121(10):1824-38 [PubMed] Article available free on PMC after 07/03/2014
Tyrosine kinase inhibitors (TKIs) are highly effective in treatment of chronic myeloid leukemia (CML) but do not eliminate leukemia stem cells (LSCs), which remain a potential source of relapse. TKI treatment effectively inhibits BCR-ABL kinase activity in CML LSCs, suggesting that additional kinase-independent mechanisms contribute to LSC preservation. We investigated whether signals from the bone marrow (BM) microenvironment protect CML LSCs from TKI treatment. Coculture with human BM mesenchymal stromal cells (MSCs) significantly inhibited apoptosis and preserved CML stem/progenitor cells following TKI exposure, maintaining colony-forming ability and engraftment potential in immunodeficient mice. We found that the N-cadherin receptor plays an important role in MSC-mediated protection of CML progenitors from TKI. N-cadherin-mediated adhesion to MSCs was associated with increased cytoplasmic N-cadherin-β-catenin complex formation as well as enhanced β-catenin nuclear translocation and transcriptional activity. Increased exogenous Wnt-mediated β-catenin signaling played an important role in MSC-mediated protection of CML progenitors from TKI treatment. Our results reveal a close interplay between N-cadherin and the Wnt-β-catenin pathway in protecting CML LSCs during TKI treatment. Importantly, these results reveal novel mechanisms of resistance of CML LSCs to TKI treatment and suggest new targets for treatment designed to eradicate residual LSCs in CML patients.


Bisen A, Claxton DF
Tyrosine kinase targeted treatment of chronic myelogenous leukemia and other myeloproliferative neoplasms.
Adv Exp Med Biol. 2013; 779:179-96 [PubMed]
Myeloproliferative neoplasms (MPNs) include Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) and the Ph- diseases primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). Since FDA approval of imatinib in 2001, CML treatment has been focused on tyrosine kinase inhibitors. With these targeted therapies, imatinib-resistant CML has emerged as a major problem. Second generation tyrosine kinase inhibitors (TKIs) have allowed for effective treatment of some patients with imatinib resistance, but bcr-abl mutants such as T315I remain problematic. Additional agents are in development and are discussed here. New clinical issues with TKI treatment include premature termination of therapy due to adverse-effects, the cost of therapy, and the apparently indefinite duration of treatment in patients who have achieved complete molecular response (CMR). In contrast to Ph+ CML, targeted therapy for Ph- MPNs is novel and of less clear therapeutic potential. New insights into Ph- MPNs include alterations in the JAK-STAT signaling pathway, particularly as mediated by the JAK2 V617F mutation. The recent development of multiple JAK2 inhibitors has provided hope for the rational and effective management of these disorders. Recently, ruxolitinib was approved as therapy for PMF. Current data suggests, however, that given its vital cell signaling function, the therapeutic benefit of targeting Jak kinases in general, or JAK2 specifically may be less than that derived from ABL-directed TKI treatment of CML. This review focuses on the current treatment options for CML and Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) and limitations faced in current clinical practice.


Liu Y, Song Y, Ma W, et al.
Decreased microRNA-30a levels are associated with enhanced ABL1 and BCR-ABL1 expression in chronic myeloid leukemia.
Leuk Res. 2013; 37(3):349-56 [PubMed]
Chronic myeloid leukemia (CML) is associated with overexpression of BCR-ABL1, a nonreceptor tyrosine kinase critical for malignant transformation. We investigated whether non-coding microRNAs (miRNAs) targeting BCR-ABL1 mRNA contribute to the pathogenesis of CML. Indeed, miR-30a targeted BCR-ABL1 and was underexpressed in bone marrow from CML patients. In K562 leukemia cells, overexpression of miR-30a reduced ABL1 and BCR-ABL1 protein expression, decreased proliferation, and arrested cell cycle progression between G1 and S. These findings strongly suggest that miR-30a acts as a tumor suppressor by downregulating ABL1 and BCR-ABL1 expression. Upregulation of miR-30a in hematopoietic cells may have therapeutic efficacy against CML.


Kim DD, Lee H, Kamel-Reid S, Lipton JH
BCR-ABL1 transcript at 3 months predicts long-term outcomes following second generation tyrosine kinase inhibitor therapy in the patients with chronic myeloid leukaemia in chronic phase who failed Imatinib.
Br J Haematol. 2013; 160(5):630-9 [PubMed]
The BCR-ABL1 transcript level at 3 months can predict long-term outcomes following frontline therapy with Imatinib or Dasatinib in chronic myeloid leukaemia (CML) patients. However, data is lacking for second-generation tyrosine kinase inhibitor (2GTKI) therapy after Imatinib failure. A total of 112 patients with CML in chronic phase receiving 2GTKI after Imatinib failure were reviewed. Treatment outcomes including complete cytogenetic (CCyR), major molecular (MMR) and molecular response 4.5 (4.5 log reduction of BCR-ABL1 transcript level, MR(4.5) ), treatment failure, progression-free and overall survival (OS) were compared according to BCR-ABL1 transcript levels at 3 or 6 months, divided into <1%(IS) , 1-10%(IS) and ≥ 10%(IS) . BCR-ABL1 transcript level at 3 months showed better correlation with OS (P < 0.001) than that at 6 months (P = 0.147). Better OS was also observed in the patients achieving <1%(IS) (100%) and 1-10%(IS) (100%) than those with ≥ 10%(IS) at 3 months (70.6%, P < 0.001). Those with <1%(IS) showed the best CCyR, MMR and MR(4.5) rates; 1-10%(IS) , intermediate; and ≥ 10%(IS) , the lowest CCyR, MMR and MR(4.5) rates. The group with <1%(IS) at 3 months maintained significantly lower BCR-ABL1 transcript level compared to other two groups. In conclusion, the BCR-ABL1 transcript level at 3 months is the most relevant surrogate for outcomes following 2GTKI therapy after Imatinib failure.


Jiang Q, Crews LA, Barrett CL, et al.
ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.
Proc Natl Acad Sci U S A. 2013; 110(3):1041-6 [PubMed] Article available free on PMC after 07/03/2014
The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, whole-transcriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU.1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.


Oyekunle A, Zander AR, Binder M, et al.
Outcome of allogeneic SCT in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy.
Ann Hematol. 2013; 92(4):487-96 [PubMed]
The introduction of tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) led to a dramatic change in the role of allogeneic stem cell transplantation (SCT) with a rapid decline in the number of patients receiving SCT in first chronic phase (CP1). We evaluated 68 consecutive patients in all phases of CML (male/female = 39:29, 27 in CP1), who received SCT from related/unrelated donors (related/unrelated = 23:45) under myeloablative or reduced intensity conditioning (MAC/RIC = 45:23). Forty-eight patients (71 %) received TKIs pre-SCT, 20 patients post-SCT (29 %). Overall survival (OS) of CP1 patients achieved a plateau of 85 % at 10 months. Relapse-free survival (RFS) of CP1 patients was 85 % at 1 and 2 years, and 81 % at 5 years. Multivariate analysis showed adverse OS and RFS for patients transplanted >CP1 (hazard ratio (HR) = 6.61 and 4.62) and those who had grade III-IV aGvHD (HR = 2.45 and 1.82). Patients with advanced CML had estimated OS of 65 and 47 %; and RFS of 41 and 32 % at 1 and 2 years respectively. Therefore, for patients with advanced CML phases, allogeneic SCT provides an acceptable chance of cure. Transplant research should focus on improving conditioning regimens and post-SCT management for this subgroup of CML patients.


Khorashad JS, Kelley TW, Szankasi P, et al.
BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships.
Blood. 2013; 121(3):489-98 [PubMed] Article available free on PMC after 17/01/2014
BCR-ABL1 compound mutations can confer high-level resistance to imatinib and other ABL1 tyrosine kinase inhibitors (TKIs). The third-generation ABL1 TKI ponatinib is effective against BCR-ABL1 point mutants individually, but remains vulnerable to certain BCR-ABL1 compound mutants. To determine the frequency of compound mutations among chronic myeloid leukemia patients on ABL1 TKI therapy, in the present study, we examined a collection of patient samples (N = 47) with clear evidence of 2 BCR-ABL1 kinase domain mutations by direct sequencing. Using a cloning and sequencing method, we found that 70% (33/47) of double mutations detected by direct sequencing were compound mutations. Sequential, branching, and parallel routes to compound mutations were common. In addition, our approach revealed individual and compound mutations not detectable by direct sequencing. The frequency of clones harboring compound mutations with more than 2 missense mutations was low (10%), whereas the likelihood of silent mutations increased disproportionately with the total number of mutations per clone, suggesting a limited tolerance for BCR-ABL1 kinase domain missense mutations. We conclude that compound mutations are common in patients with sequencing evidence for 2 BCR-ABL1 mutations and frequently reflect a highly complex clonal network, the evolution of which may be limited by the negative impact of missense mutations on kinase function.


Giannoudis A, Wang L, Jorgensen AL, et al.
The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia.
Blood. 2013; 121(4):628-37 [PubMed]
Although the prognosis of chronic myeloid leukemia (CML) patients treated with imatinib is good, many fail to develop an optimal response or lose one. This heterogeneity could be attributed to the presence of human organic cation transporter-1 (hOCT1) single nucleotide polymorphisms (SNPs). In the present study, we analyzed the effect of 23 hOCT1 SNPs on imatinib treatment outcome in newly diagnosed CML patients using MassARRAY sequencing and pyrosequencing. The only SNP associated with outcome was M420del (rs35191146), with patients with the M420del demonstrating an increased probability of imatinib treatment failure. In CML cell lines transfected with M420del and/or M408V, M420del significantly decreased imatinib uptake, but this effect was countered if the M408V (rs628031) SNP was also present. A similar effect was seen for the uptake of the hOCT1 substrates TEA(+) and ASP(+). Finally, apparent hOCT1 mRNA levels were studied using both our earlier primers covering the M420del and another set that did not. Different mRNA expression was observed, explaining the disparity in published data on the prognostic importance of hOCT1 mRNA and highlighting the importance of avoiding common SNP sites in primer design. These data demonstrate that the common M420del SNP can modulate the outcome of imatinib treatment.


Traulsen A, Lenaerts T, Pacheco JM, Dingli D
On the dynamics of neutral mutations in a mathematical model for a homogeneous stem cell population.
J R Soc Interface. 2013; 10(79):20120810 [PubMed] Article available free on PMC after 06/02/2014
The theory of the clonal origin of cancer states that a tumour arises from one cell that acquires mutation(s) leading to the malignant phenotype. It is the current belief that many of these mutations give a fitness advantage to the mutant population allowing it to expand, eventually leading to disease. However, mutations that lead to such a clonal expansion need not give a fitness advantage and may in fact be neutral--or almost neutral--with respect to fitness. Such mutant clones can be eliminated or expand stochastically, leading to a malignant phenotype (disease). Mutations in haematopoietic stem cells give rise to diseases such as chronic myeloid leukaemia (CML) and paroxysmal nocturnal haemoglobinuria (PNH). Although neutral drift often leads to clonal extinction, disease is still possible, and in this case, it has important implications both for the incidence of disease and for therapy, as it may be more difficult to eliminate neutral mutations with therapy. We illustrate the consequences of such dynamics, using CML and PNH as examples. These considerations have implications for many other tumours as well.


Chang T, Krisman K, Theobald EH, et al.
Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice.
J Clin Invest. 2013; 123(1):335-9 [PubMed] Article available free on PMC after 06/02/2014
Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm (MPN) that is refractory to conventional chemotherapy. Conditional inactivation of the Nf1 tumor suppressor in hematopoietic cells of mice causes a progressive MPN that accurately models JMML and chronic myelomonocytic leukemia (CMML). We characterized the effects of Nf1 loss on immature hematopoietic populations and investigated treatment with the MEK inhibitor PD0325901 (hereafter called 901). Somatic Nf1 inactivation resulted in a marked expansion of immature and lineage-committed myelo-erythroid progenitors and ineffective erythropoiesis. Treatment with 901 induced a durable drop in leukocyte counts, enhanced erythropoietic function, and markedly reduced spleen sizes in mice with MPN. MEK inhibition also restored a normal pattern of erythroid differentiation and greatly reduced extramedullary hematopoiesis. Remarkably, genetic analysis revealed the persistence of Nf1-deficient hematopoietic cells, indicating that MEK inhibition modulates the proliferation and differentiation of Nf1 mutant cells in vivo rather than eliminating them. These data provide a rationale for performing clinical trials of MEK inhibitors in patients with JMML and CMML.


Latagliata R, Isidori A, Breccia M, et al.
Complete clearance of Ph+ metaphases after 3 months is a very early indicator of good response to imatinib as front-line treatment in chronic myelogenous leukemia.
Acta Haematol. 2013; 129(2):126-34 [PubMed]
AIM: To address the incidence and the prognostic role of a very early standard complete cytogenetic response (CCyR) or all Ph- metaphases (MET-, when <20 cells were evaluable).
METHODS: We revised 182 chronic phase chronic myelogenous leukemia patients treated with frontline imatinib (IM) at two institutions from June 2002 to June 2011.
RESULTS: After 3 months of treatment, 138 patients (75.8%) achieved CCyR/MET- while 44 patients (24.2%) still presented Ph+ metaphases (MET+) (<33%, 24 patients; ≥33%, 20 patients). On univariate analysis, palpable spleen enlargement (p < 0.001), WBC count >100.0 × 10(9)/l at onset (p < 0.001), and male gender (p = 0.019) had a negative impact on achievement of CCyR/MET- at 3 months. Among patients with CCyR/MET- after 3 months, there were 15 failures (10.8%) compared to 21 (47.7%) among patients with MET+ (p < 0.001). The 5-year overall survival was 97.0% in patients CCyR/MET- at 3 months and 91.8% in patients MET+ at 3 months (p = 0.277); the 5-year progression-free survival was 88.2% in patients CCyR/MET- at 3 months and 48.4% in patients MET+ at 3 months (p < 0.001).
CONCLUSIONS: The achievement of CCyR/MET- at 3 months seems to have prognostic relevance and could be a very early and useful indicator of an excellent response to IM beyond European LeukemiaNet guidelines.


Liu M, Zhao X, Zhao J, et al.
Induction of apoptosis, G₀/G₁ phase arrest and microtubule disassembly in K562 leukemia cells by Mere15, a novel polypeptide from Meretrix meretrix Linnaeus.
Mar Drugs. 2012; 10(11):2596-607 [PubMed] Article available free on PMC after 06/02/2014
Mere15 is a novel polypeptide from Meretrix meretrix Linnaeus with cytotoxicity in solid cancer cells. In this study, we investigated its activity on human K562 chronic myelogenous leukemia cells. Mere15 inhibited the growth of K562 cells with IC₅₀ values of 38.2 μg/mL. Mere15 also caused concentration dependent induction of apoptosis, with overproduction of reactive oxygen species and loss of mitochondrial membrane potential. Moreover, Mere15 arrested cell cycle progression at G₀/G₁ phase of K562 cells in a concentration dependent manner. In addition, Mere15 caused the disassembly of the microtubule cytoskeleton in K562 cells and inhibited the polymerization of tubulin in a cell free system via interaction with tubulin. We concluded that Mere15 was cytotoxic to K562 leukemia cells and the cytotoxicity was related to the apoptosis induction, cell cycle arrest and microtubule disassembly. These results implied that Merer15 was a broad spectrum anticancer polypeptide, not only cytotoxic to various solid cancer cells but also to the chronic myelogenous leukemia cells. Mere15 may have therapeutic potential for the treatment of leukemia.


Cortes JE, Kantarjian H, Shah NP, et al.
Ponatinib in refractory Philadelphia chromosome-positive leukemias.
N Engl J Med. 2012; 367(22):2075-88 [PubMed]
BACKGROUND: Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.
METHODS: In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).
RESULTS: Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.
CONCLUSIONS: Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).


Gandia P, Arellano C, Lafont T, et al.
Should therapeutic drug monitoring of the unbound fraction of imatinib and its main active metabolite N-desmethyl-imatinib be developed?
Cancer Chemother Pharmacol. 2013; 71(2):531-6 [PubMed]
PURPOSE: The European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both imatinib and its main active metabolite (N-desmethyl-imatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations.
PATIENTS AND METHODS: The quantification of unbound fraction of imatinib and N-desmethyl-imatinib was performed using plasma ultrafiltration coupled with LC-MS/MS measurement. 60 pre-dose plasma samples were obtained at steady state within TDM in 44 chronic myeloid leukemia patients.
RESULTS: The mean unbound fractions of imatinib and N-desmethyl-imatinib were 2.94 and 5.10 %, respectively, with inter-individual variability (CV in %) of 57 % for imatinib and 71 % for the metabolite. For 11 patients, repeated blood sampling gave a mean intra-individual variability of 28 % for imatinib and 34 % for N-desmethyl-imatinib. No correlation was observed between these measured individual imatinib unbound fraction values and those obtained using an equation based on AGP levels previously proposed by Widmer et al. The mean N-desmethyl-imatinib/imatinib ratio was determined for both total (0.69) and unbound (1.10) concentrations, with inter-individual variabilities of 71 and 86 %, respectively.
CONCLUSION: The large inter-individual variability for the unbound fraction of both imatinib and N-desmethyl-imatinib warrants further evaluation of the pharmacokinetic-pharmacodynamic relationship as a potential relevant marker of imatinib therapeutic outcomes.


Efficace F, Cardoni A, Cottone F, et al.
Tyrosine-kinase inhibitors and patient-reported outcomes in chronic myeloid leukemia: a systematic review.
Leuk Res. 2013; 37(2):206-13 [PubMed]
The main objective of this systematic review is to quantify and to summarize all studies that have included health-related quality of life (HRQOL) or, any other type of patient-reported outcomes (PROs), in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Nine papers were found and none of these were published before 2003. Overall, 3290 CML patients were enrolled in the studies reviewed. Four studies reported HRQOL data on patients treated with imatinib only. The most solid data in this area indicate that CML patients receiving TKIs have a worse HRQOL profile when compared to their peers, without cancer, in the general population and interventions to improve HRQOL outcomes are thus needed. Our review revealed the paucity of evidence-based data in this area. However, HRQOL assessment in these studies emphasize the unique information provided by the patient's perspective. Urgent efforts are needed to provide solid PROs data to complement current knowledge on clinical efficacy of TKIs.


Goldman JM, Marin D
Is imatinib still an acceptable first-line treatment for CML in chronic phase?
Oncology (Williston Park). 2012; 26(10):901-7 [PubMed]
The introduction of the tyrosine kinase inhibitor (TKI) imatinib (Gleevec) into clinical practice resulted in a very dramatic prolongation of survival for most, but not all, patients with chronic myeloid leukemia in chronic phase (CML-CP). A leukemia with a median survival of about 5 years was transformed into one for which the survival in many cases promises to be comparable to that of normal persons of similar age. The more recently available TKIs, namely nilotinib (Tasigna) and dasatinib (Sprycel), produce more rapid responses but have not yet shown any overall survival advantage compared with long-term administration of imatinib. They are, however, useful in treating imatinib intolerance or resistance. There are currently two choices for initial treatment of CML-CP: (1) starting all new patients on imatinib and changing to a second-generation TKI in those who fail or who are predicted to fare badly, or (2) starting all new patients on a second-generation TKI. This choice may be based primarily on considerations of cost or possible side effects.


Horn M, Glauche I, Müller MC, et al.
Model-based decision rules reduce the risk of molecular relapse after cessation of tyrosine kinase inhibitor therapy in chronic myeloid leukemia.
Blood. 2013; 121(2):378-84 [PubMed]
Molecular response to imatinib (IM) in chronic myeloid leukemia (CML) is associated with a biphasic but heterogeneous decline of BCR-ABL transcript levels. We analyzed this interindividual heterogeneity and provide a predictive mathematical model to prognosticate the long-term response and the individual risk of molecular relapse on treatment cessation. The parameters of the model were determined using 7-year follow-up data from a randomized clinical trial and validated by an independent dataset. Our model predicts that a subset of patients (14%) achieve complete leukemia eradication within less than 15 years and could therefore benefit from discontinuation of treatment. Furthermore, the model prognosticates that 31% of the patients will remain in deep molecular remission (MR(5.0)) after treatment cessation after a fixed period of 2 years in MR(5.0), whereas 69% are expected to relapse. As a major result, we propose a predictor that allows to assess the patient-specific risk of molecular relapse on treatment discontinuation and to identify patients for whom cessation of therapy would be an appropriate option. Application of the suggested rule for deciding about the time point of treatment cessation is predicted to result in a significant reduction in rate of molecular relapse.


Vandyke K, Fitter S, Drew J, et al.
Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: evidence for site-specific skeletal effects.
J Clin Endocrinol Metab. 2013; 98(1):67-76 [PubMed]
CONTEXT: Imatinib is a tyrosine kinase inhibitor that has been successfully used to treat Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Kit(+) gastrointestinal stromal tumors. We have previously shown that imatinib therapy is associated with an increase in trabecular bone volume.
OBJECTIVE: In the present study, we performed a prospective analysis of bone indices in imatinib-treated CML patients to determine the mechanism responsible for this altered bone remodeling. DESIGN, PATIENTS, AND INTERVENTION: This study assessed the effects of high-dose (600 mg/d) imatinib on bone parameters in newly diagnosed chronic-phase Philadelphia chromosome-positive CML patients (n = 11) enrolled in the TIDEL II study. At baseline and after 6, 12, and 24 months of treatment, serum markers of bone remodeling were quantitated, dual-energy x-ray absorptiometry analysis of bone mineral density (BMD) was carried out, and a bone biopsy was collected for histological and micro-computed tomography analysis.
RESULTS: Our studies show that the increase in trabecular bone volume and trabecular thickness after imatinib treatment was associated with a significant decrease in osteoclast numbers, accompanied by a significant decrease in serum levels of a marker of osteoclast activity. In contrast, osteoblast numbers were not altered by up to 24 months of imatinib treatment. Notably, we also found that imatinib caused a site-specific decrease in BMD at the femoral neck.
CONCLUSIONS: These data suggest that imatinib therapy dysregulates bone remodeling, causing a generalized decrease in osteoclast number and activity that is not counterbalanced by a decrease in osteoblast activity, leading to increased trabecular bone volume. Further long-term investigations are required to determine the causes and consequences of the site-specific decrease in BMD at the femoral neck.


Pavey T, Hoyle M, Ciani O, et al.
Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia: systematic reviews and economic analyses.
Health Technol Assess. 2012; 16(42):iii-iv, 1-277 [PubMed]
BACKGROUND: Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML).
OBJECTIVE: This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML.
DATA SOURCES: Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011.
REVIEW METHODS: A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis.
RESULTS: Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY.
LIMITATIONS: Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions.
CONCLUSIONS: From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML.
FUNDING: The Health Technology Assessment Programme of the National Institute for Health Research.


Karl M, Krumbholz M, Tauer JT, et al.
Identification of the genomic BCR-ABL1 fusion sequence from blood specimen stored on filter paper.
Leuk Res. 2013; 37(1):117-9 [PubMed]
Chronic myeloid leukaemia (CML) is characterized by the Philadelphia chromosome resulting in the BCR-ABL1 gene whose mRNA transcript detection is commonly used for diagnosis and monitoring of therapeutic response. However, in collected blood specimen degradation of mRNA has to be considered during storage and transport thus jeopardizing the analysis. We here describe an alternative DNA-based technique applied after long-term blood storage. DNA was isolated from dried blood stains from CML patients stored on filter paper (Guthrie cards) after a median period from diagnosis of 11 years (range: 5-12 years) and analyzed with a two round long-range multiplex PCR (MLR-PCR) to identify the genomic BCR-ABL1 breakpoint. Patient-specific individual BCR-ABL1 fusion sites were successfully detected in 10 out of 13 patients. Dried blood stains represent a valuable resource for genomic DNA analyses. Long term preservation is easily manageable in paper envelopes with the patient's medical files with a minimum of financial costs and efforts. Such the cooperation between laboratories and hospitals separated by long distances is facilitated rendering possible offering specialized genomic analyses to patients with CML virtually everywhere around the world. This technique may also be a valuable approach for diagnostic procedures on a high molecular level in related haematological malignancies.


Chen L, Guérin A, Xie J, et al.
Monitoring and switching patterns of patients with chronic myeloid leukemia treated with imatinib in community settings: a chart review analysis.
Curr Med Res Opin. 2012; 28(11):1831-9 [PubMed]
OBJECTIVES: Monitoring treatment response is an integral part of chronic myeloid leukemia (CML) treatment. The guidelines recommend regular monitoring using standard methods (e.g., real-time quantitative polymerase chain reaction based on the international scale for molecular response) and treatment adjustment when failure is detected among patients treated with imatinib. The objective of this study was to assess the real-world monitoring and therapy adjustment in this patient population in the US.
METHODS: Twenty-nine physicians from community practices across the US participated in an online chart review. Adult patients with chronic phase CML who initiated imatinib as first-line therapy during 2006-2010 were selected. Information was collected up to 36 months after imatinib initiation, including response monitoring, response status, and therapy adjustment upon treatment failure.
RESULTS: The study included 297 eligible patients. By 18 months, 47% of patients had received cytogenetic response assessment continuously as recommended by the guidelines. The corresponding proportion was 39% for continuous molecular response assessment. Among patients who experienced treatment failure by 18 months, only 14%-38% of patients switched to a second-generation tyrosine kinase inhibitor as recommended by the National Comprehensive Cancer Network and the European Leukemia Net guidelines.
LIMITATIONS: Major limitations included limited generalizability and the inability to accurately assess molecular response due to the variations in testing methods during the study period.
CONCLUSIONS: Based on the guidelines, the rates of treatment monitoring and switching upon failure were low, demonstrating the need for improvement in CML care in community settings in the US.


Trask PC, Cella D, Powell C, et al.
Health-related quality of life in chronic myeloid leukemia.
Leuk Res. 2013; 37(1):9-13 [PubMed]
The increased survival associated with treatments for CML emphasize the importance of understanding the HRQOL of newly diagnosed and previously treated CML patients with all phases of disease. Functional Assessment of Cancer Therapy-Leukemia results from a phase 3 and a phase 2 trial are reported for over 900 1st, 2nd, 3rd line CP, AP, and BP patients. Physical Well-being and Leukemia symptoms were worse for patients in later lines of therapy. Individuals with AP and BP CML had poorer HRQOL than individuals with CP CML. HRQOL of CML patients was predominantly consistent with the longitudinal clinical trajectory of the disease.


This page last updated: 22nd May 2013
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