Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients

We studied telomere length in 32 CML patients who discontinued imatinib after achieving complete molecular remission and 32 age-sex-matched controls. The relative telomere length (RTL) was determined by q-PCR as the telomere to single copy gene (36B4) ratio normalized to a reference sample (K-562 DNA). Age-corrected RTL (acRTL) was also obtained. The 36-month probability of treatment-free remission (TFR) was 59.4 %. TFR patients showed shorter acRTL compared to relapsed (mean ± SD = 0.01 ± 0.14 vs 0.20 ± 0.21; p = 0.01). TFR was significantly higher in CML patients with acRTL ≤0.09 (78.9 vs 30.8 %, p = 0.002). CML stem cells harboring longer telomeres possibly maintain a proliferative potential after treatment discontinuation

Management of imatinib-resistant CML patients

Imatinib has had marked impact on outcomes in chronic myelogenous leukemia (CML) patients for all stages of the disease and is endorsed by international treatment guidelines as the first line option. Although imatinib is highly effective and well tolerated, the development of resistance represents a clinical challenge. Since the most frequently identified mechanism of acquired imatinib resistance is bcr-abl kinase domain point mutations, periodic hematologic, cytogenetic, and molecular monitoring is critical throughout imatinib therapy. Once cytogenetic remission is achieved, residual disease can be monitored by bcr-abl transcript levels as assayed by reverse transcription polymerase chain reaction (RT-PCR). Detection of bcr-abl mutants prior to and during imatinib therapy can aid in risk stratification as well as in determining therapeutic strategies. Thus, mutation screening is indicated in patients lacking or losing hematologic response. Moreover, search for mutations should also be performed when a 3-log reduction of bcr-abl transcripts is not achieved or there is a reproducible increase of transcript levels. In patients harboring mutations which confer imatinib resistance, novel second line tyrosine kinase inhibitors have demonstrated encouraging efficacy with low toxicity. Only the T315I bcr-abl mutant has proved totally resistant to all clinically available bcr-abl inhibitors. Strategies to further increase the rates of complete molecular remissions represent the next frontier in the targeted therapy of CML patients

Gynecomastia during imatinib mesylate treatment for gastrointestinal stromal tumor: a rare adverse event

<p>Abstract</p> <p>Background</p> <p>Imatinib mesylate has been the standard therapeutic treatment for chronic myeloid leukemia, advanced and metastatic gastrointestinal stromal tumor (GIST). It is well tolerated with mild adverse effects. Gynecomastia development during the course of treatment has been rarely reported.</p> <p>Methods</p> <p>Ninety-eight patients with advanced or recurrent GIST were treated with imatinib mesylate. Among the fifty-seven male patients six developed gynecomastia during the treatment. The lesions were confirmed by sonography. Sex hormone levels were determined in six patients with and without the presence of gynecomastia respectively. The patients with gynecomatia were treated with tamoxifene and the sex hormones were assayed before and after tamoxifene treatment.</p> <p>Results</p> <p>In patients with gynecomastia the lump underneath the bilateral nipples was 2.5 to 5 centimeters in diameter. Their serum free testosterone levels ranged between 356.61 and 574.60 ng/dl with a mean ± SD of 408.64 ± 82.06 ng/dl (95% CI 343.03~474.25 ng/dl), which is within the normal range. The level of serum estradiol was 42.89 ± 16.54 pg/ml (95% CI 29.66~56.12 pg/ml). Three patients had higher levels (43.79~71.21 pg/ml) and the others' were within normal range of 27.00~34.91 pg/ml. Six patients without the development of gynecomastia had normal free testosterone. One patient died because of large tumor burden. The sex hormones had no significant changes before and after tamoxifene treatment.(<it>P </it>> 0.05)</p> <p>Conclusions</p> <p>Testosterone levels were not decreased in the six GIST patients with gynecomastia. Three patients had increased serum estradiol level which suggests that imbalance of sex hormones may be the cause of gynecomastia during treatment with imatinib mesylate.</p

Being Grateful for My Stupid Little Life : Why We Need Movies

More and more I’m convinced the current cultural paradigm leaves us too thin. The practical and objective approach to reality doesn’t attend to the complexity and mystery of the created world; it doesn’t attend to the complexity and mystery of our humanity. Posting about how movies help make sense of our experiences from In All Things - an online hub committed to the claim that the life, death, and resurrection of Jesus Christ has implications for the entire world. http://inallthings.org/being-grateful-for-my-stupid-little-life-why-we-need-movies

MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia

Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR's tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance. Coherently, pharmacological blockade of MEK1/2 induces dissociation of the pentameric MEK1/2/BCR::ABL1/BCR/ABL1 complex and causes a concurrent BCRY360/Y177, BCR::ABL1(Y360/Y177) and cytoplasmic ABL1(Y412/T735) dephosphorylation thereby provoking the rescue of the BCR's anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia

Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability

Imatinib has revolutionised the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST). Using a nonlinear mixed effects population model, individual estimates of pharmacokinetic parameters were derived and used to estimate imatinib exposure (area under the curve, AUC) in 58 patients. Plasma-free concentration was deduced from a model incorporating plasma levels of alpha1-acid glycoprotein. Associations between AUC (or clearance) and response or incidence of side effects were explored by logistic regression analysis. Influence of KIT genotype was also assessed in GIST patients. Both total (in GIST) and free drug exposure (in CML and GIST) correlated with the occurrence and number of side effects (e.g. odds ratio 2.7±0.6 for a two-fold free AUC increase in GIST; P<0.001). Higher free AUC also predicted a higher probability of therapeutic response in GIST (odds ratio 2.6±1.1; P=0.026) when taking into account tumour KIT genotype (strongest association in patients harbouring exon 9 mutation or wild-type KIT, known to decrease tumour sensitivity towards imatinib). In CML, no straightforward concentration–response relationships were obtained. Our findings represent additional arguments to further evaluate the usefulness of individualising imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients

Advances in the treatment of chronic myeloid leukemia

Although imatinib is firmly established as an effective therapy for newly diagnosed patients with chronic myeloid leukemia (CML), the field continues to advance on several fronts. In this minireview we cover recent results of second generation tyrosine kinase inhibitors in newly diagnosed patients, investigate the state of strategies to discontinue therapy and report on new small molecule inhibitors to tackle resistant disease, focusing on agents that target the T315I mutant of BCR-ABL. As a result of these advances, standard of care in frontline therapy has started to gravitate toward dasatinib and nilotinib, although more observation is needed to fully support this. Stopping therapy altogether remains a matter of clinical trials, and more must be learned about the mechanisms underlying the persistence of leukemic cells with treatment. However, there is good news for patients with the T315I mutation, as effective drugs such as ponatinib are on their way to regulatory approval. Despite these promising data, accelerated or blastic phase disease remains a challenge, possibly due to BCR-ABL-independent resistance

Two different point mutations in ABL gene ATP-binding domain conferring Primary Imatinib resistance in a Chronic Myeloid Leukemia (CML) patient: A case report

Imatinib (Gleevec) is the effective therapy for BCR-ABL positive CML patients. Point mutations have been detected in ATP-binding domain of ABL gene which disturbs the binding of Gleevec to this target leading to resistance. Detection of mutations is helpful in clinical management of imatinib resistance. We established a very sensitive (ASO) PCR to detect mutations in an imatinib-resistant CML patient. Mutations C944T and T1052C were detected which cause complete partial imatinib resistance, respectively. This is the first report of multiple point mutations conferring primary imatinib resistance in same patient at the same time. Understanding the biological reasons of primary imatinib resistance is one of the emerging issues of pharmacogenomics and will be helpful in understanding primary resistance of molecularly-targeted cancer therapies. It will also be of great utilization in clinical management of imatinib resistance. Moreover, this ASO-PCR assay is very effective in detecting mutations related to imatinib resistance