Therapy For Chronic Myelogenous Leukemia Research Articles

The Progress of Small Molecule Targeting BCR-ABL in the Treatment of Chronic Myeloid Leukemia.

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease. According to the American Cancer Society's 2021 cancer data report, new cases of CML account for about 15% of all leukemias. CML is generally divided into three stages: chronic phase, accelerated phase, and blast phase. Nearly 90% of patients are diagnosed as a chronic phase. Allogeneic stem cell transplantation and chemotherapeutic drugs, such as interferon IFN-α were used as the earliest treatments for CML. However, they could generate obvious side effects, and scientists had to seek new treatments for CML. A new era of targeted therapy for CML began with the introduction of imatinib, the first-generation BCR-ABL kinase inhibitor. However, the ensuing drug resistance and mutant strains led by T315I limited the further use of imatinib. With the continuous advancement of research, tyrosine kinase inhibitors (TKI) and BCR-ABL protein degraders with novel structures and therapeutic mechanisms have been discovered. From biological macromolecules to classical target protein inhibitors, a growing number of compounds are being developed to treat chronic myelogenous leukemia. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in CML therapy, including TKIs and BCR-ABL protein degrader. The examples provided herein describe the pharmacology activity of small-molecule drugs. These drugs will provide new enlightenment for future treatment directions.

AS1041, a novel derivative of marine natural compound Aspergiolide A, induces senescence of leukemia cells via oxidative stress-induced DNA damage and BCR-ABL degradation

Chronic myelogenous leukemia (CML) is characterized by the constitutive activation of BCR-ABL tyrosine kinase. Imatinib was approved for CML therapy, however, BCR-ABL-dependent drug resistance, especially BCR-ABL-T315I mutation, restricts its clinical application. In this study, we reported anthraquinone lactone AS1041, a synthesized derivative of marine natural compound Aspergiolide A, showed anti-leukemia effect in vitro and in vivo by promoting cell senescence. Mechanistic study revealed the pro-senescence effect of AS1041 was dependent on oxidative stress-induced DNA damage, and the resultant activation of P53/P21 and P16INK4a/Rb. Also, AS1041 promoted ubiquitin proteasome system (UPS)-mediated BCR-ABL degradation, which also contributed to AS1041-induced senescence. In vivo, AS1041-induced senescence promoted tumor growth inhibition. In summary, the in vitro and in vivo antitumor effect of AS1041 suggests it can serve as a pro-senescence agent for alternative antileukemia therapy and imatinib-resistant cancer therapy by enhancing cellular oxidative stress and BCR-ABL degradation.

Herb-drug interaction: Effect of sinapic acid on the pharmacokinetics of dasatinib in rats

Dasatinib (DAS) is a narrow therapeutic index drug and novel oral multitarget inhibitor of tyrosine kinase and approved for the first-line therapy for chronic myelogenous leukemia (CML) and Philadelphia chromosome (Ph + ) acute lymphoblastic leukemia (ALL). DAS, a known potent substrate of cytochrome (CYP) 3A, P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) and is subject to auto-induction. The dietary supplementation of sinapic acid (SA) or concomitant use of SA containing herbs/foods may alter the pharmacokinetics as well as pharmacodynamics of DAS, that may probably lead to potential interactions. Protein expression in rat hepatic and intestinal tissues, as well as the in vivo pharmacokinetics of DAS and the roles of CYP3 A2 and drug transporters Pgp-MDR1 and BCPR/ABCG2, suggested a likely interaction mechanism. The single dose of DAS (25 mg/kg) was given orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The plasma concentration of DAS was estimated by using Ultra-High-Performance Liquid Chromatography Mass spectrometry (UHPLC-MS/MS). The in vivo pharmacokinetics and protein expression study demonstrate that SA pretreatment has potential to alter the DAS pharmacokinetics. The increase in Cmax, AUC and AUMC proposes increase in bioavailability and rate of absorption via modulation of CYP3 A2, PgP-MDR1 and BCPR/ABCG2 protein expression. Thus, the concomitant use of SA alone or with DAS may cause serious life-threatening drug interactions.

Supremacy of nanoparticles in the therapy of chronic myelogenous leukemia.

The reciprocal translocation of the ABL gene from chromosome 9 to chromosome 22 near the BCR gene gives rise to chronic myelogenous leukemia (CML). The translocation results in forming the Philadelphia chromosome (BCR-ABL) tyrosine kinase. CML results in an increase in the number of white blood cells and alteration in tyrosine kinase expression. CML prognosis includes three stages, namely chronic, accelerated, and blast. The diagnosis method involves a CT scan, biopsy, and complete blood count. However, due to certain disadvantages, early diagnosis of CML is not possible by traditional methods. Nanotechnology offers many advantages in diagnosing and treating cancer. We searched PubMed, Scopus and Google Scholar using the keywords Philadelphia chromosome, bionanotechnology, tyrosine kinase pathway, half-life, passive targeting, and organic and inorganic nanoparticles. The relevant papers and the classical papers in this field were selected to write about in this review. The sensitivity and specificity of an assay can be improved by nanoparticles. Utilizing this property, peptides, antibodies, aptamers, etc., in the form of nanoparticles, can be used to detect cancer at a much earlier stage. The half-life of the drug is also increased by nanoformulation. The nanoparticle-coated drugs can easily escape from the immune system. Depending on their type, nanoparticles can be categorized into organic, inorganic and hybrid. Each type has its advantages. Organic nanoparticles have good biocompatibility, inorganic nanoparticles increase the half-life of the drugs. In this review, we highlight the nanoparticles involved in treating CML.

DNA self-assembly nanoflower reverse P-glycoprotein mediated drug resistance in chronic myelogenous leukemia therapy.

Introduction: Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder caused by the BCR-ABL chimeric tyrosine kinase. Vincristine (VCR) is widely used in leukemia therapy but is hindered by multidrug resistance (MDR). Methods: We prepared DNA nanoflower via self-assembly for the delivery of VCR and P-glycoprotein small interfering RNA (P-gp siRNA). Results and Discussion: The as-prepared nanoflower had a floriform shape with high loading efficiency of VCR (80%). Furthermore, the nanoflower could deliver VCR and P-gp siRNA into MDR CML cells and induce potent cytotoxicity both in vitro and in vivo, thus overcoming MDR of CML. Overall, this nanoflower is a promising tool for resistant CML therapy.

Targeting Poly(ADP)ribose polymerase in BCR/ABL1-positive cells

BCR/ABL1 causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL). In addition to the deregulatory effects of its kinase activity on cell proliferation, BCR/ABL1 induces genomic instability by downregulating BRCA1. PARP inhibitors (PARPi) effectively induce cell death in BRCA-defective cells. Therefore, PARPi are expected to inhibit growth of CML and Ph1-ALL cells showing downregulated expression of BRCA1. Here, we show that PARPi effectively induced cell death in BCR/ABL1 positive cells and suppressed colony forming activity. Prevention of BCR/ABL1-mediated leukemogenesis by PARP inhibition was tested in two in vivo models: wild-type mice that had undergone hematopoietic cell transplantation with BCR/ABL1-transduced cells, and a genetic model constructed by crossing Parp1 knockout mice with BCR/ABL1 transgenic mice. The results showed that a PARPi, olaparib, attenuates BCR/ABL1-mediated leukemogenesis. One possible mechanism underlying PARPi-dependent inhibition of leukemogenesis is increased interferon signaling via activation of the cGAS/STING pathway. This is compatible with the use of interferon as a first-line therapy for CML. Because tyrosine kinase inhibitor (TKI) monotherapy does not completely eradicate leukemic cells in all patients, combined use of PARPi and a TKI is an attractive option that may eradicate CML stem cells.

Inhibition of casein kinase 2 induces cell death in tyrosine kinase inhibitor resistant chronic myelogenous leukemia cells.

Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by the BCR-ABL oncogene. Despite the high performance of treatment with tyrosine kinase inhibitors (TKI), about 30% of patients develop resistance to the therapy. To improve the outcomes, identification of new targets of treatment is needed. Here, we explored the Casein Kinase 2 (CK2) as a potential target for CML therapy. Previously, we detected increased phosphorylation of HSP90β Serine 226 in patients non-responding to TKIs imatinib and dasatinib. This site is known to be phosphorylated by CK2, which was also linked to CML resistance to imatinib. In the present work, we established six novel imatinib- and dasatinib-resistant CML cell lines, all of which had increased CK2 activation. A CK2 inhibitor, CX-4945, induced cell death of CML cells in both parental and resistant cell lines. In some cases, CK2 inhibition also potentiated the effects of TKI on the cell metabolic activity. No effects of CK2 inhibition were observed in normal mononuclear blood cells from healthy donors and BCR-ABL negative HL60 cell line. Our data indicate that CK2 kinase supports CML cell viability even in cells with different mechanisms of resistance to TKI, and thus represents a potential target for treatment.

Prostate cancer, chronic myelogenous leukemia and multiple myeloma in a single patient: a case report and review of the literature

BackgroundSynchronous or metachronous multiple primary malignancies (MPMs) are a known phenomenon. These occurrences may be spontaneous or related to environmental risk factors or genetic predisposition. Chronic myelogenous leukemia (CML) and Multiple myeloma (MM) are two uncommon hematologic malignancies, arises from two different cell lineage. The coexistence of CML and MM that is a rare phenomenon, with only 29 cases reported in the literature. To the best of our, this combination of triple primary cancers has not been reported in a single patient.Case presentationHerein, we reported a case of an 85-year-old Iranian male with three confirmed primary malignant neoplasms. The patient presented with synchronous prostate cancer and CML, in august 2016. He received imatinib and nilotinib for CML and hormonal therapy for prostate cancer. He remained in good control at further follow-ups for about 5 years. In the follow-up period and after 61 months treatment with tyrosine kinase inhibitors (TKIs), CML was undetectable in molecular tests, but the presence of serum M-protein, abnormal plasma cells in the bone marrow, and CRAB criteria was compatible with MM.ConclusionWe must evaluate the possibility of multiple primary cancers during cancer treatment and follow-up and it may be worthwhile to monitor serum electrophoresis and protein levels in TKIs-treated patients.

MODELING THE DYNAMICS OF CHRONIC MYELOGENOUS LEUKEMIA THROUGH FRACTIONAL-CALCULUS

Although the therapy of chronic myelogenous leukemia (CML) has progressed because of imatinib (IM) and other tyrosine kinase inhibitors (TKIs), the majority of patients still do not recover. To better regulate the remaining leukemic cell population, TKI combo therapy may be improved with a deeper understanding of the underlying mechanisms. We employed a mathematical system which incorporated the intricate phenomena of immune system to CML. We use a fractional derivative framework in this work to understand the dynamics of CML. Additionally, in our work, we concentrate on the qualitative characterization and dynamical behavior of CML interactions. For the proposed model, we examine the singularity and existence using fixed point theorems by Banach and Schaefer. We provide the necessary criteria for our suggested fractional model’s Ulam–Hyers stability. The influence of the factors on the dynamics of CML is highlighted by closely examining the solution paths by using a numerical scheme. To be more precise, we emphasized how the suggested system’s dynamic and chaotic behavior varied depending on the fractional order and other system factors. Policymakers are advised to consider the most crucial elements of CML dynamics. In order to inform policymakers and health authorities about the systems essential for control and treatment, it is crucial to investigate the dynamic characteristics of CML disease.

Impact of Initiating Oral Anticancer Agent Therapy for Chronic Myelogenous Leukemia Among Adults with Multiple Chronic Conditions

Background: The availability of oral anticancer agents (OAA) has facilitated adults’ ability to manage independently their treatment for chronic myelogenous leukemia (CML). However, pre-existing chronic disease is common among patients with cancer and initiating OAA therapy increases treatment burden on adults with both CML and multiple chronic conditions (MCC). The objective of this research was to examine adherence to OAAs in adult patients with CML who were treatment naïve and initiating an OAA and to assess whether such initiation affected adherence to medications for existing chronic conditions. Methods: This was a retrospective cohort study that used MarketScan commercial claims and a 20% sample of Medicare claims for 2013-2018 to assess medication use in adults with CML. To be included in the analysis, patients must have met the following criteria: 1) at least 18 years old; 2) diagnosed with and had 2+ claims for an OAA indicated for CML; 3) continuously enrolled 12 months before and after OAA initiation; and 4) treated for (2+ fills before and after OAA initiation) at least 2 select chronic conditions (diabetes, hypertension, or hyperlipidemia plus at least 1 other chronic condition). The proportion of days covered (PDC) metric determined medication adherence for all included medication classes and was compared for the 12 months before and after OAA initiation by Wilcoxon signed-rank tests and McNemar's tests. Multivariable logistic regression identified predictors of OAA adherence in the first year following initiation while controlling for available demographic and clinical characteristics. Difference-in-differences models assessed changes in adherence to select comorbid chronic disease medications prior to and following OAA initiation. Results: The final analysis included 256 and 658 adults with CML and MCC with commercial or Medicare coverage, respectively. Mean first-year OAA adherence was 84.5% (SD: 15.8) and 80.1% (SD: 20.1) for commercial and Medicare patients, respectively, and these corresponded to 78.1% and 67.1% of commercially insured adults and Medicare members being deemed adherent to their OAA (PDC > 80%). An increase in comorbidity burden was associated with a lower odds of OAA adherence and was the sole significant predictor in the Medicare models: OR=0.92 (95% CI: 0.87-0.97) in Medicare; OR=0.78 (95% CI: 0.67-0.90) in commercial. Among those with commercial insurance, the odds of initial OAA adherence were higher among those with any ED visit (OR=2.49; 95% CI: 1.07-5.84), but lower among those with an inpatient admission (OR=0.46; 95% CI: 0.22-0.94). Compared to the year before OAA initiation, average adherence to statins declined in the subsequent year among Medicare members on statins, but significant improvements were observed among those commercially insured on antihypertensives or antidiabetics (Figure Panel A). However, compared to the first 6 months post-OAA initiation, mean PDCs in the second half of the year post-OAA initiation were noticeably lower, irrespective of comorbidity or payer cohort, with PDC declines ranging from 4.2 (antihypertensives, Medicare) to 10.1 (antidiabetics, commercial) percentage points (Figure Panel B). Conclusion: Using nationally representative claims data, this study found that initial OAA adherence was generally good among adults with CML, and a majority of patients reached accepted thresholds of adequate OAA use. Using a range of patients’ characteristics, few differences in OAA adherence were observed in multivariable analyses, but consistent evidence pointed to poorer adherence as comorbidity burden increased. Additionally, limited changes in adherence to oral antidiabetic, antihypertensive, or lipid-lowering agents were observed over the first year following OAA initiation, but results suggest this pattern may not be maintained over the entire year post-OAA initiation. Consequently, these findings imply a need for careful monitoring of medication use in patients with CML and MCC over the course of time given the risk for eventual declines in comorbid chronic disease medication adherence. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anti-tumor efficacy of Habb-e-Asgandh as an adjuvant therapy in chronic myelogenous leukemia in vitro

IntroductionChronic myeloid leukemia (CML) is a myeloproliferative hematological malignancy wherein the increased relapsed cases and lack of drug effectiveness generates a need to identify an effective treatment regimen. A unani formulation, Habb-e-Asgandh (HEA) is being used for treatment of ailments such as arthritis, however, its role in CML therapeutics has not been reported yet. Hence, anti-leukemic efficacy of HEA was assessed alone or in combination with standard chemotherapeutic, imatinib in CML cell line K562. MethodsThe anti-leukemic effect of HEA was evaluated on cell cytotoxicity by MTT assay, cell cycle analysis by propidium iodide staining, apoptotic assay by Annexin-V assay, mitochondrial membrane potential (MMP) by JC1 staining. Further, effect of drug treatment on oxidative stress and cell migration was determined by ORAC assay and transwell migration assay respectively. Lastly, changes in angiogenic marker (VEGF) and inflammatory marker (IL-6) were examined by ELISA. ResultsHEA induced cytotoxicity of leukemic cells which increased further when co-treated with imatinib. The combinatorial treatment of HEA with imatinib potentiates anti-tumor effect by inducing cell apoptosis with disruption of MMP even at low concentrations. Subsequent studies revealed that tumor killing property of HEA increased the ROS generation. Furthermore, HEA in combination with imatinib dramatically reduced cell migration along with expression of VEGF and IL-6. ConclusionThis maiden study demonstrated that HEA possesses anti-leukemic potential in vitro. This formulation potentiates the effect of imatinib even at low concentrations suggesting the utilization of HEA as a novel adjuvant therapy for the better management of CML in future.

An Unexpected Finding on Screening Colonoscopy in a Patient With Chronic Myelogenous Leukemia

Question: A 64-year-old woman presented for screening colonoscopy. Her only medical history included chronic myelogenous leukemia (CML) diagnosed 1 year prior that was improving and in the chronic phase with dasatinib 50 mg/d. She denied taking any other medications. The patient denied having any prior colonoscopies or any family history of colorectal cancer. She also denied any melena or hematochezia. She did report weight loss, which she attributed to her CML. On colonoscopy, multiple small polyps were seen throughout the colon ranging from 3 to 6 mm that were too numerous to count (Figure A). The polyps were friable and seemed to have mucous caps. A few of these polyps were removed from the transverse and sigmoid colon for pathological analysis (Figure B and C). What is the diagnosis? Look on page 58 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Inflammatory reactive polyposis caused by dasatinib is a rare phenomenon and has only been described once in the Japanese literature.1Kobayashi M. Ikezawa K. Yamaura M. et al.[Inflammatory reactive polyposis caused by dasatinib: a case report].Nihon Shokakibyo Gakkai Zasshi. 2018; 115 ([In Japanese]): 977-984PubMed Google Scholar Our patient had polyps with mucoid discharge similar in appearance to those described in the Japanese paper. It was determined that the patient’s polyposis was caused by inflammation that was triggered by dasatinib. Four months after discontinuing dasatinib in the Japanese patient, a repeat colonoscopy revealed significant improvement in the polypoid lesions. In the case of our patient, we did not advise discontinuing dasatinib because she was on a low dose and did not tolerate other therapies for CML. The patient remained asymptomatic on follow-up. To our knowledge, this is the first case of dasatinib-induced inflammatory polyposis described in the English literature. Cases of hemorrhagic colitis secondary to dasatinib already exist. With dasatinib becoming a widely used therapy for Imatinib resistant CML, it is prudent to monitor for complications. Dasatinib is taken orally, making the gastrointestinal tract particularly vulnerable to complications. It is important to be aware of the inflammatory effects of dasatinib and this warrants further laboratory and clinical studies.2Nakamura S. Kino I. Akagi T. Inflammatory myoglandular polyps of the colon and rectum. A clinicopathological study of 32 pedunculated polyps, distinct from other types of polyps.Am J Surg Pathol. 1992; 16: 772-779Crossref PubMed Scopus (63) Google Scholar It is unknown if prolonged polyposis owing to dasatinib is a benign process or may eventually result in malignancy3Fei F. Yu Y. Schmitt A. et al.Dasatinib inhibits the proliferation and function of CD4+CD25+ regulatory T cells.Br J Haematol. 2009; 144: 195-205Crossref PubMed Scopus (60) Google Scholar The mechanism of polyposis has also not yet been elucidated and it is necessary to accumulate more cases to further our understanding. Therefore, it is important to offer screening colonoscopies to these patients at regular intervals.

The Oncology Care Model and Adherence to Oral Cancer Drugs: A Difference-in-Differences Analysis.

Adherence to oral cancer drugs is suboptimal. The Oncology Care Model (OCM) offers oncology practices financial incentives to improve the value of cancer care. We assessed the impact of OCM on adherence to oral cancer therapy for chronic myelogenous leukemia (CML), prostate cancer, and breast cancer. Using 2014-2019 Medicare data, we studied chemotherapy episodes for Medicare fee-for-service beneficiaries prescribed tyrosine kinase inhibitors (TKIs) for CML, antiandrogens (ie, enzalutamide, abiraterone) for prostate cancer, or hormonal therapies for breast cancer in OCM-participating and propensity-matched comparison practices. We measured adherence as the proportion of days covered and used difference-in-difference (DID) models to detect changes in adherence over time, adjusting for patient, practice, and market-level characteristics. There was no overall impact of OCM on improved adherence to TKIs for CML (DID = -0.3%, 90% confidence interval [CI] = -1.2% to 0.6%), antiandrogens for prostate cancer (DID = 0.4%, 90% CI = -0.3% to 1.2%), or hormonal therapy for breast cancer (DID = 0.0%, 90% CI = -0.2% to 0.2%). Among episodes for Black beneficiaries in OCM practices, for whom adherence was lower than for White beneficiaries at baseline, we observed small improvements in adherence to high cost TKIs (DID = 3.0%, 90% CI = 0.2% to 5.8%) and antiandrogens (DID = 2.2%, 90% CI = 0.2% to 4.3%). OCM did not impact adherence to oral cancer therapies for Medicare beneficiaries with CML, prostate cancer, or breast cancer overall but modestly improved adherence to high-cost TKIs and antiandrogens for Black beneficiaries, who had somewhat lower adherence than White beneficiaries at baseline. Patient navigation and financial counseling are potential mechanisms for improvement among Black beneficiaries.

Protective effect of Bosutinib with caspase inhibitors on human K562 cells

IntroductionCancer therapy has become increasingly focused on molecularly targeted medications. Despite the fact that multi-cytotoxic medication regimens have proven to be highly effective, many investigations in targeted treatments have focused on a single agent. The precise molecular mechanism of action of second-generation BCR–ABL tyrosine kinase inhibitors, which includes different targets and pathways, can help rationalize therapy in chronic myelogenous leukemia (CML) and other diseases affected by BCR–ABL tyrosine kinase inhibitors (TKIs). AimThe purpose of this study was to analyze if bosutinib (BOS) combined with Boc-D-FMK effectively suppressed proliferation and induced apoptosis in K562 cells to a lesser extent, implying that bosutinib is an effective leukemia treatment and that its combination with Boc-D-FMK is a mild chemotherapeutic agent against leukemia. MethodsIn this study, bosutinib was obtained together with other materials to perform a cell culture experiment with human cell lines, as well as additional drug treatment. Furthermore, cell viability (MTT assay) and flow cryometry such as viability and cell cycle assays are performed. The target profile of the dual SRC/ABL inhibitor bosutinib was studied in this study as a first kinase inhibitor to target K562 cells, which has recently been linked to the proliferation of myelogenous leukaemia cells, these results suggest the effectiveness of inhibitory activity on cell viability/proliferation, alone generated a potent value of 250 nM (39.27 ± 1.17) for 48 h as optimal dose. ResultsThe cytotoxic effect of bosutinib on the K562 cell line was assessed in vitro using the MTT assay, and the cytotoxicity was further clarified using cell viability and cell cycle assays. Guava Cell Assay software validated the activation of apoptosis. Sub-G1, G0/G1, S, and G2/M phases are depicted. Cell cycle research revealed that K562 cells treated with bosutinib accumulated much more in the sub-G1 phase, which was later validated by a drop peak at the G2/M phase. ConclusionIn conclusion, the nature of bosutinib's reduction of cancer cell growth may open the door to future research into the development of green synthesis medicines, particularly for cancer treatment.

JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) is a hematological malignancy that highly depends on the BCR-ABL1/STAT5 signaling pathway for cell survival. First-line treatments for CML consist of tyrosine kinase inhibitors that efficiently target BCR-ABL1 activity. However, drug resistance and intolerance are still therapeutic limitations in Ph+ cells. Therefore, the development of new anti-CML drugs that exhibit alternative mechanisms to overcome these limitations is a desirable goal. In this work, the antitumoral activity of JKST6, a naphthoquinone-pyrone hybrid, was assessed in imatinib-sensitive and imatinib-resistant human CML cells. Live-cell imaging analysis revealed JKST6 potent antiproliferative activity in 2D and 3D CML cultures. JKST6 provoked cell increase in the subG1 phase along with a reduction in the G0/G1 phase and altered the expression of key proteins involved in the control of mitosis and DNA damage. Rapid increases in Annexin V staining and activation/cleavage of caspases 8, 9 and 3 were observed after JKST6 treatment in CML cells. Of interest, JKST6 inhibited BCR-ABL1/STAT5 signaling through oncokinase downregulation that was preceded by rapid polyubiquitination. In addition, JKST6 caused a transient increase in JNK and AKT phosphorylation, whereas the phosphorylation of P38-MAPK and Src was reduced. Combinatory treatment unveiled synergistic effects between imatinib and JKST6. Notably, JKST6 maintained its antitumor efficacy in BCR-ABL1-T315I-positive cells and CML cells that overexpress BCR-ABL and even restored imatinib efficacy after a short exposure time. These findings, together with the observed low toxicity of JKST6, reveal a novel multikinase modulator that might overcome the limitations of BCR-ABL1 inhibitors in CML therapy.

How I treat chronic-phase chronic myelogenous leukemia

AbstractWhen imatinib, the first tyrosine kinase inhibitor (TKI) developed for use in chronic myelogenous leukemia (CML), was approved in 2001, the treatment of this disease was forever changed. Significant reductions in the molecular burden of disease were seen with the first-generation TKI imatinib and, with the addition of dasatinib (2006), nilotinib (2007), bosutinib (2012), and ponatinib (2013), deeper and more rapid reductions were noted. Physicians could begin to tailor TKI therapy to individual patients, and patients who did not respond to or could not tolerate first-line therapy now had options. Importantly, the number of patients who developed accelerated or blast phase disease decreased dramatically. Research in CML continues to evolve; by presenting illustrative cases, this article reviews some of the newer aspects of clinical care in this disease. Updated information regarding bosutinib and asciminib, the latter currently in clinical trials, will be presented; bosutinib is of particular interest as the drug's transit through the United States Food and Drug Administration highlights the question of what is considered optimal response to TKI therapy. The challenge of understanding the cardiac safety data of ponatinib and the unique dosing schedule based on individual response will be discussed. Lastly, two cases will focus on features of TKI treatment that, remarkably, have become part of the treatment algorithm: family planning for women with CML and stopping therapy after meeting a specific treatment milestone.

Remisja wolna od leczenia w praktyce klinicznej: opis grupy 6 chorych na przewlekłą białaczkę szpikową, po zaprzestaniu leczenia nilotynibem — doświadczenie jednego ośrodka

In the last 20 years major goals of therapy of chronic myelogenous leukemia (CML) have changed. This leukemia, which was previously a fatal disease, has indeed become a chronic disease thanks to the use of tyrosine kinase inhibitors (TKIs), with life expectancy close to that in the general population. Excellent treatment effectiveness with the achievement of long-term, stable, deep molecular response was the motivation for attempts to stop the therapy with the intention of maintaining remission (TFR, treatment-free remission). Based on many clinical trials with over 3,000 patients and several years of follow-up, it is known that 40–60% of patients will maintain molecular remission and remain untreated, while the rest of them will require TKI to be restarted. Information on the procedure to be followed appeared in scientific societies’ recommendations and some centers treating CML patients have made attempts to stop the therapy. This work describes a group of six patients in the TFR phase after discontinuation of nilotinib used in the first-line treatment.

Skuteczne odstawienie nilotynibu po nietolerancji terapii imatynibem

Wobec wysokiej skuteczności terapii przewlekłej białaczki szpikowej (CML) w fazie przewlekłej inhibitorami kinaz tyrozynowych (TKI) w ostatnich latach coraz istotniejszym celem terapeutycznym staje się zapewnienie pacjentom wysokiej jakości życia, dzięki ograniczaniu toksyczności leczenia, a optymalnie — uzyskaniu remisji wolnej od leczenia (TFR). Można go osiągnąć poprzez efektywne zarządzanie działaniami niepożądanymi TKI oraz próbę zaprzestania leczenia u chorych, którzy osiągnęli stabilną DMR. Poniżej przedstawiono opis przypadku pacjentki z CML, u której z powodu licznych działań niepożądanych terapii imatynibem wdrożono nilotynib. Mimo bardzo dobrej subiektywnej tolerancji w przebiegu leczenia obserwowano hiperlipidemię i hiperglikemię. Ze względu na utrzymującą się stabilną DMR po kilku latach nilotynib odstawiono. Blisko rok od tego momentu pacjentka pozostaje w TFR.

KDM6A promotes imatinib resistance through YY1-mediated transcriptional upregulation of TRKA independently of its demethylase activity in chronic myelogenous leukemia

Rationale: Despite landmark therapy of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs), drug resistance remains problematic. Cancer pathogenesis involves epigenetic dysregulation and in particular, histone lysine demethylases (KDMs) have been implicated in TKI resistance. We sought to identify KDMs with altered expression in CML and define their contribution to imatinib resistance.Methods: Bioinformatics screening compared KDM expression in CML versus normal bone marrow with shRNA knockdown and flow cytometry used to measure effects on imatinib-induced apoptosis in K562 cells. Transcriptomic analyses were performed against KDM6A CRISPR knockout/shRNA knockdown K562 cells along with gene rescue experiments using wildtype and mutant demethylase-dead KDM6A constructs. Co-immunoprecipitation, luciferase reporter and ChIP were employed to elucidate mechanisms of KDM6A-dependent resistance.Results: Amongst five KDMs upregulated in CML, only KDM6A depletion sensitized CML cells to imatinib-induced apoptosis. Re-introduction of demethylase-dead KDM6A as well as wild-type KDM6A restored imatinib resistance. RNA-seq identified NTRK1 gene downregulation after depletion of KDM6A. Moreover, NTRK1 expression positively correlated with KDM6A in a subset of clinical CML samples and KDM6A knockdown in fresh CML isolates decreased NTRK1 encoded protein (TRKA) expression. Mechanistically, KDM6A was recruited to the NTRK1 promoter by the transcription factor YY1 with subsequent TRKA upregulation activating down-stream survival pathways to invoke imatinib resistance.Conclusion: Contrary to its reported role as a tumor suppressor and independent of its demethylase function, KDM6A promotes imatinib-resistance in CML cells. The identification of the KDM6A/YY1/TRKA axis as a novel imatinib-resistance mechanism represents an unexplored avenue to overcome TKI resistance in CML.

Survival With Bone Marrow Transplantation Versus Hydroxyurea or Interferon for Chronic Myelogenous Leukemia

AbstractHydroxyurea, interferon, and HLA-identical sibling bone marrow transplantation are common therapies for chronic myelogenous leukemia (CML) in chronic phase. Which is best is controversial. The purpose of this study was to compare survival of patients with CML receiving HLA-identical sibling transplants versus hydroxyurea or interferon. The transplant cohort included 548 recipients of HLA-identical sibling transplants, reported to the International Bone Marrow Transplant Registry. The nontransplant cohort included 196 patients receiving hydroxyurea (n = 121) or interferon (n = 75) on a randomized trial of the German CML Study Group. Survivals were compared using proportional hazards regression with fixed and time-dependent variables to adjust for patient differences and changing risks over time. For the first 18 months after diagnosis, mortality was higher in the transplant than the nontransplant cohort (relative risk [RR], 5.85; P < .0001). From 18 to 56 months, mortality was similar (RR, 0.80; P = .38). After 56 months, mortality was lower in the transplant cohort (RR, 0.16; P < .0001). Seven-year survival probabilities (95% confidence interval) were 58% (50% to 66%) with transplant and 32% (22% to 41%) with hydroxyurea or interferon. There was a significant survival advantage for hydroxyurea or interferon in the first 4 years after diagnosis and for transplants starting 5.5 years after diagnosis. For transplants done within 1 year of diagnosis, the survival advantage for transplantation began earlier. Survival advantage for transplants was greater and occurred earlier in patients with intermediate- and high-risk prognostic features than in those with low-risk features. This study confirms higher early mortality, but a long-term survival advantage for HLA-identical sibling transplants over hydroxyurea or interferon in CML.