Chronic Myeloid Leukemia Research Articles

Intensification of upfront chemotherapy for patients with myeloid blast phase CML: a single center experience.

Outcomes for patients with myeloid blast phase chronic myeloid leukemia (CML-MBP) are dismal, and no preferred chemotherapy regimen has been identified. Recent studies have suggested a higher response rate with administration of timed-sequenced regimens (TSR) (purine analog, high-dose cytarabine, anthracycline) in high-risk acute myeloid leukemia patients. We retrospectively evaluated outcomes of newly diagnosed CML-MBP patients consecutively treated at our institution with a TSR or standard-dose cytarabine and an anthracycline ("7 + 3") combined with a tyrosine-kinase inhibitor (TKI) between 2011 and 2023. Endpoints of interest included hematologic response, clinically significant cytogenetic response (CSCR) defined as achieving at least a minor cytogenetic response (Ph + metaphases 0%-≤65%) after induction therapy, event-free survival (EFS), and overall survival (OS). A total of 18 patients with CML-MBP were included of whom 9 (50%) received a TSR and 9 (50%) received "7 + 3". Hematologic response (55.6% vs. 55.6%) and CSCR (25% vs. 37.5%) were similar between TSR- and "7 + 3" treated patients. Twelve patients (66.7%) experienced at least one grade ≥ 3 non-hematologic, end-organ toxicity with 33.3% and 11.1% of TSR- and 7 + 3-treated patients, respectively, experiencing at least two. Our data suggests that intensification of upfront chemotherapy does not appear to improve treatment outcomes in CML-MBP patients however, further studies are warranted to confirm these findings involving a larger cohort.

Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR-ABL-Positive Leukemia.

SOS1 is an essential guanine nucleotide exchange factor for RAS that also plays a critical role in the activation of the small GTPase RAC mediated by BCR-ABL in leukemogenesis. Despite this, small molecule inhibitors targeting SOS1 have shown limited efficacy in clinical trials for KRAS mutant cancers, and their potential as a therapeutic approach for chronic myeloid leukemia (CML) remains largely unexplored. In this study, we developed a potent SOS1 PROTAC SIAIS562055, which was designed by connecting a CRBN ligand to an analogue of the SOS1 inhibitor BI-3406. SIAIS562055 exhibited sustained degradation of SOS1 and inhibition of downstream ERK pathways, resulting in superior anti-proliferative activity compared to small molecule inhibitors. SIAIS562055 also potentiated the activity of both KRAS inhibitors in KRAS-mutant cancers and ABL inhibitors in BCR-ABL+ CML. In KRAS-mutant xenografts, SIAIS562055 displayed promising antitumor potency as a monotherapy and enhanced ERK inhibition and tumor regression when combined with KRAS inhibitors, overcoming acquired resistance. In CML cells, SIAIS562055 promoted the active uptake of BCR-ABL inhibitors by upregulating the carnitine/organic cation transporter SLC22A4. SIAIS562055 and BCR-ABL inhibitors synergistically enhanced inhibition of ABL phosphorylation and downstream signaling, demonstrating robust antitumor activities in both mouse xenografts and primary CML patient samples. In summary, this study suggests that PROTAC-mediated SOS1 degradation represents an effective therapeutic strategy for treating not only KRAS-mutant cancers but also BCR-ABL-harboring leukemia.

The BIM deletion polymorphism potentiates the survival of leukemia stem and progenitor cells and impairs response to targeted therapies.

One sixth of human cancers harbor pathogenic germline variants, but few studies have established their functional contribution to cancer outcomes. Here, we developed a humanized mouse model harboring a common East Asian polymorphism, the BIM deletion polymorphism (BDP), which confers resistance to oncogenic kinase inhibitors through generation of non-apoptotic splice isoforms. However, despite its clear role in mediating bulk resistance in patients, the BDP's role in cancer stem and progenitor cells, which initiate disease and possess altered BCL-2 rheostats compared to differentiated tumor cells, remains unknown. To study the role of the BDP in leukemia initiation, we crossed the BDP mouse into a chronic myeloid leukemia (CML) model. We found that the BDP greatly enhanced the fitness of CML cells with a three-fold greater competitive advantage, leading to more aggressive disease. The BDP conferred almost complete resistance to cell death induced by imatinib in CML stem and progenitor cells (LSPCs). Using BH3 profiling, we identified a novel therapeutic vulnerability of BDP LSPCs to MCL-1 antagonists, which we confirmed in primary human LSPCs, and in vivo. Our findings demonstrate the impact of human polymorphisms on the survival of LSPCs and highlight their potential as companion diagnostics for tailored therapies.

Asciminib in Advanced-Line Treatment of Chronic Myeloid Leukemia.

Asciminib, a novel allosteric BCR::ABL1 inhibitor, targets the ABL1 myristoyl pocket to potentially reduce toxicity and enhance efficacy. It is approved for Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) in patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs) or those with the T315I mutation. This retrospective analysis evaluated patients with CML treated with asciminib under a managed-access program across eight Israeli centers from July 2019 to August 2022. We assessed treatment responses, toxicities, event-free survival (EFS), and overall survival (OS) using Kaplan-Meier methods. The study included 30 patients who had received a median of three prior TKIs, with 73% starting asciminib due to intolerance. After a median follow-up of 7.1 months, 85% of those without prior complete cytogenetic response (CCyR) achieved CCyR, and 60% previously not in major molecular response (MMR) attained MMR. Resistance was rare (10%), with no cardiovascular events reported despite high baseline comorbidity (73%). Median EFS was 47 months; median OS was not reached. Asciminib demonstrates significant efficacy and tolerability in heavily pretreated patients with CML-CP, with no new cardiovascular events observed. Further long-term studies are necessary to explore its full cardiovascular impact.

Estimation of miRNA-183 expression and TGF-β level in Chronic Myeloid Leukemia

Background: MicroRNA-183 and Transforming Growth Factor Beta (TGF-β) have emerged as significant players in the pathophysiology of Chronic Myeloid Leukemia (CML). Research indicates that miRNA-183 may play a role in the regulation of cell proliferation and apoptosis in CML cells, potentially influencing disease progression and response to therapy. Elevated levels of miRNA-183 have been associated with poor prognosis, suggesting it could serve as a biomarker for disease severity. Objective: In this study, we aimed to analyze the expression of miR-183 and TGF- β level and investigate the relationship between miR-183 and level of TGF- β in CML patients. Material and Methods: The study has been carried out on 60 Iraqi patients (37 males and 23 females at age range 17 - 69 year) with chronic myeloid leukemia at chronic phase, who are referred to the National Center of Hematology/ Mustansiriyah University, Baghdad during the period from January to November 2023. Twenty of them are newly diagnosed (T0), and the other 40 patients are under treatment with TKIs (T+), Thirty age and gender-matched healthy subjects were enrolled to act as control group. TGF-β level estimates by ELISA while micrRNA-183 detection using RT- PCR. Conclusion: The elevated levels of TGF-β and miRNA-183 in CML patients, coupled with their positive correlation.

Targeting STAT3, FOXO3a, and Pim-1 kinase by FDA-approved tyrosine kinase inhibitor-Radotinib: An in silico and in vitro approach.

Cancer, a multifactorial pathological condition, is primarily caused due to mutations in multiple genes. Hepatocellular carcinoma (HCC) is a form of primary liver cancer that is often diagnosed at the advanced stage. Current treatment strategies for advanced HCC involve systemic therapies which are often hindered due to the emergence of resistance and toxicity. Therefore, a multitarget approach might prove more effective in HCC treatment. The present study focuses on targeting signal transducer and activator of transcription 3 (STAT3), forkhead box class O3a (FOXO3a), and proviral integration site for Moloney murine leukemia virus-1 (Pim-1) kinase, using a Food and Drug Administration (FDA)-approved anticancer drug library. Two compounds, namely, radotinib and capmatinib, were identified as top compounds using molecular docking. Among the two compounds, radotinib exhibited significant binding values towards the targeted proteins and their heterodimers. Furthermore, in vitro experiments involving 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), live/dead, 4',6-diamidino-2-phenylindole, and clonogenic assays were performed to evaluate the effect of radotinib in human hepatoblastoma cell line/hepatocellular carcinoma cells. The gene expression data indicated reduced expression of FOXO3a and Pim-1, but no basal-level alteration of STAT3. The Western blot analysis assay showed that the phosphorylation level of STAT3 was significantly decreased upon radotinib treatment. Taken together, our findings suggest that radotinib, which is currently used in the treatment of chronic myeloid leukemia (CML), could be considered as a potential candidate for repurposing in the treatment of HCC.

Leukocytosis and thrombocytosis after splenectomy: expected finding, infection, or something else: a case report

BackgroundLeukocytosis and thrombocytosis often follow splenectomy in blunt trauma patients, complicating the postoperative identification of infection. While the platelet count to white blood cell ratio provides diagnostic assistance to discern between expected laboratory alterations and infection, diagnoses such as leukemia are often overlooked.Case presentationA 53-year-old Hispanic male presented with abdominal pain, nausea, tachycardia, and focal peritonitis 4 days after being assaulted and struck multiple times in the abdomen. Initial white blood cell count was 38.4 × 109/L, platelet count was 691 × 109/L, and lipase was 55 U/L. Computed tomography abdomen/pelvis demonstrated a hematoma encasing the distal pancreas and abutting the stomach and colon. Emergent laparotomy revealed a nearly transected pancreas and devascularized colon, necessitating a distal pancreatectomy, splenectomy, and colonic resection with primary anastomosis. Postoperatively, he had a persistently elevated leukocytosis, thrombocytosis, segmented neutrophils, eosinophilia, and basophilia (peak at 70, 2293, 64, 1.1, and 1.2 × 109/L, respectively). Despite sepsis workup, including repeat computed tomography, no source was identified. Hematology/oncology was consulted for concern for hematologic etiology, with genetic testing and bone marrow biopsy performed. The diagnosis of breakpoint cluster–Abelson gene-positive chronic myeloid leukemia was made based on genetic tests, including polymerase chain reaction and fluorescence in situ hybridization analysis, which confirmed the presence of the Philadelphia chromosome. Bone marrow biopsy suggested a chronic phase. The patient was treated with hydroxyurea and transitioned to imatinib.ConclusionsThrombocytosis following splenectomy is a common complication and a plate count to white blood cell count ratio < 20 indicates infectious etiology. A significantly elevated white blood cell count (> 50 × 109/L) and thrombocytosis (> 2000 × 109/L) may suggest something more ominous, including chronic myeloid leukemia , particularly when elevated granulocyte counts are present. Chronic myeloid leukemia workup includes peripheral smear, bone marrow aspiration, and determination of Philadelphia chromosome. Post-splenectomy vaccines are still indicated within 14 days; however, the timing of immunization with cancer treatment must be considered. Tyrosine kinase inhibitors are the first-line therapy and benefits of pretreatment with hydroxyurea for cytoreduction remain under investigation. Additionally, tyrosine kinase inhibitors have been associated with gastrointestinal perforation and impaired wound healing, necessitating heightened attention in patients with a new bowel anastomosis.

Atypical chronic myeloid leukemia (CML) with ETV6-ABL1 mutation managed successfully with a third-generation TKI and hematopoietic stem cell transplant

Atypical chronic myeloid leukemia (CML) with ETV6-ABL1 mutation managed successfully with a third-generation TKI and hematopoietic stem cell transplant

Severe acute cutaneous only graft-versus-host disease after late relapse of chronic myeloid leukemia and ultraviolet B phototherapy.

Not available.

Ischemic stroke as a presenting feature of promyelocytic blast phase in chronic myeloid leukemia - an uncommon presentation: a case report and literature review in the post imatinib era.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm (MPN characterized by reciprocal translocation in the ABL1 and BCR region of chromosomes 9 and 22 respectively. Progression to the blast phase in chronic myeloid leukemia results in a poorer prognosis. It can be of either myeloid, lymphoid or a mixed lineage. Progression to the promyelocytic blast phase is very rare, and there are no evidence-based guidelines for its management. Thrombosis in CML is not well defined. Thrombosis can be seen in patients with acute promyelocytic leukemia (APL) with venous thrombosis (VTE) being more common than arterial thrombosis. Ischemic stroke as the presenting feature of blast phase progression in CML is extremely rare. We report a case of CML who presented to us with acute ischemic stroke and subsequently was diagnosed as CML transformed to the promyelocytic blast phase. She was successfully treated with dasatinib along with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).

BCAT1 contributes to the development of TKI-resistant CML.

Although most of chronic myeloid leukemia (CML) patients can be effectively treated by the tyrosine kinase inhibitors (TKIs), such as Imatinib, TKI-resistance still occurs in approximately 15-17% of cases. Although many studies indicate that branched chain amino acid (BCAA) metabolism may contribute to the TKI resistance in CML, the detailed mechanisms remains largely unknown. The cell proliferation, colony formation and in vivo transplantation were used to determined the functions of BCAT1 in leukemogenesis. Quantitative real-time PCR (RT-PCR), western blotting, RNA sequencing, BCAA stimulation in vitro were applied to characterize the underlying molecular mechanism that control the leukemogenic activity of BCAT1-knockdown cells. In this report, we revealed that branched chain amino acid transaminase 1 (BCAT1) is highly enriched in both mouse and human TKI-resistant CML cells. Leukemia was almost completely abrogated upon BCAT1 knockdown during transplantation in a BCR-ABLT315I-induced murine TKI-resistant CML model. Moreover, knockdown of BCAT1 led to a dramatic decrease in the proliferation of TKI-resistant human leukemia cell lines. BCAA/BCAT1 signaling enhanced the phosphorylation of CREB, which is required for maintenance of TKI-resistant CML cells. Importantly, blockade of BCAA/BCAT1 signaling efficiently inhibited leukemogenesis both in vivo and in vitro. These findings demonstrate the role of BCAA/BCAT1 signaling in cancer development and suggest that targeting BCAA/BCAT1 signaling is a potential strategy for interfering with TKI-resistant CML.

Targeting Oxidative Phosphorylation with a Novel Thiophene Carboxamide Increases the Efficacy of Imatinib against Leukemic Stem Cells in Chronic Myeloid Leukemia

Patients with chronic myeloid leukemia (CML) respond to tyrosine kinase inhibitors (TKIs); however, CML leukemic stem cells (LSCs) exhibit BCR::ABL kinase-independent growth and are insensitive to TKIs, leading to disease relapse. To prevent this, new therapies targeting CML-LSCs are needed. Rates of mitochondria-mediated oxidative phosphorylation (OXPHOS) in CD34+CML cells within the primitive CML cell population are higher than those in normal undifferentiated hematopoietic cells; therefore, the inhibition of OXPHOS in CML-LSCs may be a potential cure for CML. NK-128 (C33H61NO5S) is a structurally simplified analog of JCI-20679, the design of which was based on annonaceous acetogenins. NK-128 exhibits antitumor activity against glioblastoma and human colon cancer cells by inhibiting OXPHOS and activating AMP-activated protein kinase (AMPK). Here, we demonstrate that NK-128 effectively suppresses the growth of CML cell lines and that the combination of imatinib and NK-128 is more potent than either alone in a CML xenograft mouse model. We also found that NK-128 inhibits colony formation by CD34+ CML cells isolated from the bone marrow of untreated CML patients. Taken together, these findings suggest that targeting OXPHOS is a beneficial approach to eliminating CML-LSCs, and may improve the treatment of CML.

Assessment of Molecular Response to Treatment of Chronic Myeloid Leukemia at Kigali University Teaching Hospital of Kigali

Abstract Introduction/Objective Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative neoplasm that gives proliferation advantage to the granulocytes, it is one of the commonest chronic hematological malignancies and it is a burden to the world especially Rwanda. Since the introduction of Tyrosine Kinase Inhibitors (TKIs) especially the first line Imatinib in 2001, the outcomes of CML have been much improved and currently, in developed world, the life expectancy of patients with CML is almost the same as general population. However, it is not the case in developing world especially Rwanda due to limitation on access of all TKIs. The aim of this study is to assess molecular response on Imatinib of patients with CML. Methods/Case Report This was a one arm open label prospective cohort study that recruited 31 patients with CML and on Imatinib for at least three months and followed for 11 months. The clinical features at diagnosis and recruitment were captured from the hospitals filing systems and investigator’s own assessment at the time of recruitment respectively. Information was filled to a well-structured questionnaire. Lab results at the time of diagnosis was obtained from laboratories reporting systems. Samples for full blood count and BCR-ABL1/ABL1 were withdrawn from the patients at the time of diagnosis and they were run at University Teaching Hospital of Kigali (CHUK). Data analysis was performed using Statistical Package for the Social Sciences (SPSS 28) and South Texas Art Therapy Association (STATA 15.0). Results (if a Case Study enter NA) Better response according to European LeukemiaNet (ELN) defined as optimal response was found among only 38.7% and resistance to imatinib defined by ELN as Failure and warning was found in 45.2% and 16.1% respectively. The eleven months survival rate was 93.5% in which it is 85.7% among those in treatment failure group. Late presentation showed by presence of very high White Blood Cells above 100x109/L and massive splenomegaly at diagnosis, and poor adherence to Imatinib according to Morsiky Medication Adherence Scale (MMAS-8) are associated with poor molecular response to Imatinib. Conclusion CML is a serious disease especially to those who suffer from it; on time diagnosis, access to all available lines of TKIs and better follow up are crucial for patients with CML to access the same life expectancy as general population as it is in developed world.

Case Series: Unveiling mass-forming neoplastic extramedullary hematopoiesis in chronic myeloid leukemia

Abstract Introduction/Objective Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by BCR::ABL1 fusion and predominantly granulocytic proliferation. Three main phases of disease have previously been recognized: chronic, accelerated and blast phase, though accelerated phase has become controversial. During the chronic phase, leukemic cells exist predominantly in the peripheral blood and bone marrow; however, during blast phase, blasts can proliferate in the blood, bone marrow, or extramedullary tissues. Methods/Case Report We present two instances of cutaneous extramedullary hematopoiesis associated with CML at our institution. Results (if a Case Study enter NA) Case 1: A 34-year-old man previously diagnosed with CML presented with painful pustules on his right thigh. Biopsy revealed an infiltration of primarily left-shifted granulocytes, along with scattered megakaryocytes, and rare erythroid precursors. Immunohistochemical studies were consistent with maturing extramedullary hematopoiesis, devoid of sheets or clusters of blasts. Peripheral blood analysis revealed marked neutrophilic leukocytosis with basophilia and eosinophilia. Bone marrow examination depicted left-shifted granulocytic hyperplasia, megakaryocytic hyperplasia, and fewer than 5% blasts. Case 2: A 40-year-old man presented with fatigue, night sweats, weight loss, hepatosplenomegaly and palpable nodules on his left arm and thighs. The biopsy of the thigh nodule uncovered leukemic cells at different developmental stages, along with eosinophils, erythroid precursors, and megakaryocytes. Immunohistochemical staining confirmed their presence, with only a few blasts observed. Blood and bone marrow tests showed leukocytosis with blasts less than 5%, indicating CML in the chronic phase. Molecular analysis confirmed BCR-ABL1 fusion. Conclusion Mass-forming neoplastic extramedullary hematopoiesis in the skin during chronic phase of CML is a feature that is not well-documented in the literature. This entity shows immature granulocytic precursors, but does not exhibit an increase in blasts and therefore should not be called leukemia cutis or myeloid sarcoma. It is important to raise awareness of this entity to prevent misinterpretation as myeloid sarcoma and subsequent unnecessarily aggressive therapy.

Unexpected Presentations of Histiocytic Disorders as Mass Lesions in the Central Nervous System and Spine

Abstract Introduction/Objective A number of neoplastic and non-neoplastic hematolymphoid lesions can involve the CNS and spine. The majority are lymphomas, but some are rare lesions that mimic primary neoplasms clinically, radiologically, and even pathologically. Here, we present our experience of such cases. Methods/Case Report Pathology archives were searched, and five cases representing different challenges were identified to review clinical, radiological, and pathologic features. Case 1. 31-year-old female presented with vision changes and hearing loss and numerous supratentorial extra-axial masses, suspicious for meningiomatosis. Extensive lymphoplasmacytic infiltrate was seen at Intraoperative consult (IOC). Final diagnosis was Rosai-Dorfman disease with features of IgG4 related disease. Case 2. 31-year-old female with Chronic myeloid leukemia (CML), which progressed to AML presented with a right frontal brain mass. IOC displayed atypical hematolymphoid infiltrate. Final diagnosis was myeloid sarcoma. Case 3. 29-year-old male presented with a T10 vertebral lesion. IOC showed hypercellular tissue with atypia and was deferred. Subsequently, histiocytic sarcoma was diagnosed. Case 4. 22-year- old male presented with a T3-T4 intradural, extramedullary mass radiologically thought to be a meningioma. No IOC was requested. Final diagnosis was juvenile xanthogranuloma. Case 5. 36-year-old male presented with a C7-T1 dura-based mass. IOC revealed granulomatous inflammation, eventually resulting in a diagnosis of non-necrotizing granulomatous inflammation, suggesting sarcoidosis. Results (if a Case Study enter NA) NA Conclusion These cases highlight the importance of incorporating all clinical and radiological findings into pathologic evaluation, while being alert for mimickers and pitfalls. Both practicing general surgical pathologists and neuropathologists should remain alert to such unexpected and unusual cases especially at the time of IOC and initiate appropriate work-up with expedited diagnostic protocols such as intraoperative cultures, flow cytometry, and cytogenetics, as the differential diagnosis is broad with inflammatory, infectious, and neoplastic possibilities, presenting a variety of challenges.

Myeloid neoplasm with concurrent BCR::ABL1 translocation, and JAK2 and SF3B1 co-mutations with severe fibrosis: a case report

Abstract Introduction/Objective Myeloproliferative neoplasms (MPNs) arise from hematopoietic stem cells with somatically altered tyrosine kinase signaling. Classification of MPNs is based on hematologic, histopathologic and molecular characteristics including the presence of BCR::ABL1 and JAK2 V617F. Methods/Case Report We present a 72-year-old male with a myeloid neoplasm and severe fibrosis, with concurrent BCR::ABL1 translocation, and co-mutations in JAK2 and SF3B1. Initially, the patient was diagnosed with anemia, thrombocytosis and folic acid deficiency and was prescribed supplemental folic acid. At follow up, normocytic anemia and thrombocytosis were seen. Bone marrow biopsy showed overtly fibrotic marrow with maturing trilineage hematopoiesis, markedly increased megakaryopoiesis and ring sideroblasts. Chromosome analysis and sequential GTG-fluorescence in situ hybridization (FISH) of metaphases using the dual-fusion three color probe BCR/ABL1- ASS1 revealed abnormal results. A t(9;22)(q34;q11.2) was detected along with an atypical FISH signal pattern with a single BCR::ABL1 fusion on the derivative chromosome 22 instead of the typical two fusions, resulting in loss of one BCR::ABL1 fusion signal including loss of the ASS1 on the derivative chromosome 9. Next-generation sequencing (NGS) analysis detected double driver mutations, JAK2 p. Val617Phe and SF3B1 p. Lys700Glu in the patient. JAK2 V617F mutation was further confirmed by real-time quantitative PCR (qPCR) with variant allele frequencies of 39.7%. Additionally, the patient was positive for BCR::ABL1 p190 fusion transcript (10%). The presence of JAK2 and SF3B1 co-mutations along with ring sideroblasts and the patient’s clinical presentation suggests the diagnosis of myelodysplastic/myeloproliferative neoplasm with thrombocytosis and SF3B1 mutation. Results (if a Case Study enter NA) NA Conclusion Although, the detection of t(9;22) by chromosome analysis is a diagnostic feature of chronic myeloid leukemia (CML), our case adds to the limited information on co-existence of BCR::ABL1 and JAK2 V617F with SF3B1 mutations in severe fibrosis. The frequency of co-occurrence, the temporal order of acquisition and clonal relationship of these alterations is poorly understood, and it is also unclear for this case since there is no prior bone marrow biopsy or diagnostic work up. Literature search of these rare cases show that some patients with similar findings progress to myelofibrosis as in this patient. It is possible that the presence of two mutated tyrosine kinase genes accelerates disease progression.

Cervical Lymphadenopathy as Sole Presentation in a Case of Chronic Myeloid Leukemia at the Outset

Cervical Lymphadenopathy as Sole Presentation in a Case of Chronic Myeloid Leukemia at the Outset

Olverembatinib treatment in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

Olverembatinib is a novel orally administered third-generation tyrosine kinase inhibitor (TKI) with definitive responses in T315I-mutant chronic myeloid leukemia (CML) patients. However, its value in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remained unclarified. In this multiple-center study, 20 patients with de novo Ph + ALL were treated with olverembatinib-based regimens as frontline therapy. All patients acquired complete remission (CR) after induction. 85% of patients achieved complete molecular response (CMR) within three months, contributed mainly by the addition of blinatumomab. A total of 45% of patients experienced mild hematological treatment-related adverse events (TRAEs). Olverembatinib-based treatment led to promising outcomes in de novo Ph + ALL patients but warranted further studies to investigate the best-combined strategy.

BETULINIC ACID ACTS IN SYNERGISM WITH IMATINIB MESYLATE TRIGGERING APOPTOSIS IN MDR LEUKEMIA CELLS.

Chronic myeloid leukemia (CML) is a myeloproliferative disease, characterized by the presence of the oncogene BCR-ABL. Imatinib mesylate (IMA) is the first line treatment for CML, and some treatment resistance has been reported. Natural products are rich sources of bioactive compounds with biological effects, opening a possibility to alter cell susceptibility to drugs such as imatinib. Herein, we evaluated the interference of betulinic acid and ursolic acid in glycoprotein P (P-gp) activity and the possible synergistic effect when associated with IMA by the Chou-Talalay method. Ursolic acid presented an IC50 of 14,0µM and 19,6 µM for K562 and Lucena 1, respectively, whilst betulinic acid presented an IC50 of 8.6 μM and 12.5μM, for these cell lines. Evaluation of the combination of terpenoids and imatinib mesylate revealed that ursolic acid or betulinic acid acts in synergism with IMA, as indicated by the combination indexes (CI<1). Analysis of annexin V labelling demonstrated that combination of IMA with betulinic acid enhances the inhibition on cell proliferation via apoptosis pathway, with caspases 3/7 activation after 24 hours of treatment, and inhibition of the STAT5/Survivin pathway, decreasing cell viability. The combination of natural products and IMA on a multidrug-resistant leukemia cell line is a promising strategy for CML treatment.

Heterocyclic Compounds as Bcr-Abl Tyrosine Kinase Inhibitors Against Chronic Myeloid Leukemia

Abstract: Despite significant progress in oncology therapeutics, cancer remains a leading cause of mortality worldwide. Chronic myeloid leukemia, which accounts for 15% of all adult leukemia cases, is characterized by chromosomal abnormalities involving the fusion of the Bcr and Abl genes to form the Bcr-Abl oncogene. Current drug treatment of the disease involves the use of Bcr-Abl tyrosine kinase inhibitors belonging to the first, second, and third generations. However, the toxicity and resistance associated with the use of imatinib, a first-generation Bcr-Abl inhibitor, in cases where the T315I mutation exists, necessitates the need for new tyrosine kinase inhibitors. This review focuses on recent synthetic compounds that exhibit potential as inhibitors of the Bcr-Abl protein which could be utilized in chemotherapy. Herein, we evaluated and summarized 36 studies published in the last few years that reported on newly synthesized and biologically evaluated novel small molecules with different heterocyclic scaffolds as Bcr-Abl tyrosine kinase inhibitors. The intricacy of the structure of newly synthesized compounds and the fact that each compound contains more than one scaffold makes it difficult to infer the potentially active core or scaffold. However, investigating different combined scaffolds enhances the chance of successfully developing novel drug candidates. Overall, the information provided in this review can be beneficial to researchers with an interest in chronic myeloid leukemia and tyrosine kinase inhibitors.