Antineoplastic Activity of Sodium Caseinate in a Cytarabine-Resistant Mouse Acute Myeloid Leukemia Cell Line.

BACKGROUND: Acute myeloid leukemia (AML) is a hematological neoplasm of rapid and progressive onset, and is the most common form of leukemia in adults. Chemoresistance to conventional treatments such as cytarabine (Ara-C) and daunorubicin is a main cause of relapse, recurrence, metastasis, and high mortality in AML patients. It is known that sodium caseinate (SC), a salt derived from casein, a milk protein, inhibits growth and induces apoptosis in acute myeloid leukemia cells but not in normal hematopoietic cells. However, it is unknown whether SC retains its antileukemic effect in cytarabine-resistant AML cell lines. OBJECTIVE: To evaluate the antineoplastic effect of SC in cytarabine-resistant leukemia models. METHODS: The SC inhibits the growth and induces apoptosis in parental WEHI-3 AML cells. Here, we generated two cytarabine-resistant sublines, WEHI-CR25 and WEHI-CR50, which exhibit 6- and 16-fold increased resistance to cytarabine, respectively, compared to the parental WEHI-3 cells. Thus, these sublines mimic a chemoresistant model. RESULTS: We demonstrate that WEHI-CR25 and WEHI-CR50 cells retain sensitivity to SC, similar to parental WEHI-3 cells. This sensitivity results in inhibited cell proliferation, induced apoptosis, and increased expression of ENT1 and dCK, molecules involved in the entry and metabolism of Ara-C, while decreasing MDR1 expression. Additionally, we observed that SC prolonged the survival of WEHI-CR50 tumor-bearing mice, despite their resistance to Ara-C. CONCLUSION: This is the first evidence that SC, a milk protein, may inhibit proliferation and induce apoptosis in cytarabine-resistant cells.

Enhancing Selectivity and Inhibitory Effects of Chemotherapy Drugs Against Myelogenous Leukemia Cells with Lippia alba Essential Oil Enriched in Citral.

Acute myelogenous leukemia (AML) is one of the most lethal cancers, lacking a definitive curative therapy due to essential constraints related to the toxicity and efficacy of conventional treatments. This study explores the co-adjuvant potential of Lippia alba essential oils (EO) for enhancing the effectiveness and selectivity of two chemotherapy agents (cytarabine and clofarabine) against AML cells. EO derived from L. alba citral chemotype were produced using optimized and standardized environmental and extraction protocols. Rational fractionation techniques were employed to yield bioactive terpene-enriched fractions, guided by relative chemical composition and cytotoxic analysis. Pharmacological interactions were established between these fractions and cytarabine and clofarabine. The study comprehensively evaluated the cytotoxic, genotoxic, oxidative stress, and cell death phenotypes induced by therapies across AML (DA-3ER/GM/EVI1+) cells. The fraction rich in citral (F2) exhibited synergistic pharmacological interactions with the studied chemotherapies, intensifying their selective cytotoxic, genotoxic, and pro-oxidant effects. This shift favored transitioning from necrosis to a programmed cell death phenotype (apoptotic). The F2-clofarabine combination demonstrated remarkable synergistic anti-leukemic performance while preserving cell integrity in healthy cells. The observed selective antiproliferative effects may be attributed to the potential dual prooxidant/antioxidant behavior of citral in L. alba EO.

Early Toxicity and Efficacy of Four Different Conditioning Regimens for Autologous Hematopoietic Cell Transplantation in Patients With Lymphoma: Impact of Drug Shortages in a Resource-Constrained Country.

High-dose therapy followed by autologous hematopoietic cell transplant (AHCT) remains a viable consolidation strategy for a subset of patients with relapsed or refractory (R/R) lymphomas. BEAM (carmustine, etoposide, cytarabine, and melphalan) is widely recognized as the predominant conditioning regimen due to its satisfactory efficacy and tolerability. Nevertheless, shortages of carmustine and melphalan have compelled clinicians to explore alternative conditioning regimens. The aim of this study was to compare the toxicity and transplant outcomes following BEAM, CBV (carmustine, etoposide, cyclophosphamide), BuMel (busulfan, melphalan), and BendaEAM (bendamustine, etoposide, cytarabine, melphalan). We retrospectively analyzed data from 213 patients (CBV 65, BuMel 42, BEAM 68, BendaEAM 38) with R/R lymphomas undergoing AHCT between 2014 and 2020. Multivariate models were employed to evaluate toxicity and transplant outcomes based on conditioning type. Among grade III to IV toxicities, oral mucositis was more frequently observed with BuMel (45%) and BendaEAM (24%) compared to BEAM (15%) and CVB (6%, P ≤ .001). Diarrhea was more common with BendaEAM (42%) and less frequent with BuMel (7%, P = .01). Acute kidney injury was only found after BendaEAM (11%). Febrile neutropenia and infectious complications were more frequent following BendaEAM. Frequencies of other treatment-related toxicities did not significantly differ according to conditioning type. BendaEAM (odds ratio [OR] 3.07, P = .014) and BuMel (OR 4.27, P = .002) were independently associated with higher grade III to IV toxicity up to D+100. However, there were no significant differences in relapse/progression, nonrelapse mortality, progression-free survival, or overall survival among the four regimens. BuMel and BendaEAM were associated with a higher rate of grade III to IV toxicity. Carmustine-based regimens appeared to be less toxic and safer; however, there were no significant differences in transplant outcomes. The utilization of alternative preparative regimens due to drug shortages may potentially lead to increased toxicity after AHCT for lymphoma.

Cisplatin as a Viable and Secure Alternative to Carmustine in BEAM-Based Conditioning for Autologous Hematopoietic Stem Cell Transplantation in Patients with Lymphoma.

BACKGROUND: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is a standard treatment for relapsed/refractory lymphoma patients. Yet, the widespread use of BEAM is hindered by carmustine accessibility. This study evaluates the efficacy and safety of PEAM (Cisplatin, Etoposide, Cytarabine, and Melphalan) versus BEAM in auto-HSCT for Hodgkin (HL) and non-Hodgkin lymphoma (NHL) patients. METHODS: We conducted a retrospective single-center study of adult lymphoma patients who received PEAM or BEAM pretransplant conditioning between January 2004 to December 2022, comparing efficacy and safety outcomes. RESULTS: Among 143 patients (median age of 33 years, 58% males), 55 had HL, and 88 had NHL. The overall response rate (ORR) was 86.7% for PEAM and 72.3% for BEAM, and the relapse rate (RR) was lower for PEAM than BEAM (22.9% vs 45.6%). Median time to relapse (TTR) and overall survival (OS) were not reached for either group. PEAM exhibited a shorter time to both neutrophil (NE) and platelet (PE) engraftment compared to BEAM (10 vs 12 days), with a more tolerable gastrointestinal (GI) toxicity profile. CONCLUSIONS: Both BEAM and PEAM showed similar outcomes, demonstrating comparable efficacy in terms of ORR, TTR, and OS for both HL and NHL patients. However, PEAM-conditioning was associated with a shorter time to engraftment and fewer GI adverse events.

Intake of oligoelements with cytarabine or etoposide alters dopamine levels and oxidative damage in rat brain.

Research on the relationships between oligoelements (OE) and the development of cancer or its prevention is a field that is gaining increasing relevance. The aim was to evaluate OE and their interactions with oncology treatments (cytarabine or etoposide) to determine the effects of this combination on biogenic amines and oxidative stress biomarkers in the brain regions of young Wistar rats. Dopamine (DA), 5-Hydroxyindoleacetic acid (5-Hiaa), Glutathione (Gsh), Tiobarbituric acid reactive substances (TBARS) and Ca+2, Mg+2 ATPase enzyme activity were measured in brain regions tissues using spectrophometric and fluorometric methods previously validated. The combination of oligoelements and cytarabine increased dopamine in the striatum but decreased it in cerebellum/medulla-oblongata, whereas the combination of oligoelements and etoposide reduced lipid peroxidation. These results suggest that supplementation with oligoelements modifies the effects of cytarabine and etoposide by redox pathways, and may become promising therapeutic targets in patients with cancer.

Tratamiento de la recaída de pacientes pediátricos con leucemia linfoblástica aguda en la Argentina: resultados de un ensayo clínico y una cohorte prospectiva / Treatment of Relapse in Pediatric Patients with Acute Lymphoblastic Leukemia in Argentina: Results from a Clinical Trial and a Prospective Cohort

Introducción: desde 2002, el Grupo Argentino para el Tratamiento de la Leucemia Aguda (GATLA) implementa protocolos del grupo Berlín-Frankfurt-Münster (BFM) como tratamiento estándar de las recaídas de la leucemia linfoblástica aguda (LLA). En 2010, el BFM generó el protocolo IntReALL 10, que en la Argentina se implementó con las limitaciones propias de la región. Población y métodos: 180 pacientes menores de 18 años fueron tratados entre 2010 y 2015 por una LLA recaída de alto riesgo en la Argentina siguiendo un protocolo de recaída del BFM que comparó en forma abierta el tratamiento estándar con una terapéutica innovadora (experimental); esta incluyó el fármaco clofarabina. Se evaluaron 171 pacientes, de los cuales 78 pacientes fueron aleatorizados en forma centralizada (ensayo clínico) y 93 fueron asignados a una de las ramas según el criterio del grupo tratante (cohorte prospectiva). La cohorte donde la asignación del tratamiento no fue aleatorizada fue analizada realizando un ajuste por sexo, edad y por la presencia o no de síndrome de Down, cromosoma Philadelphia e inmunofenotipo T. Resultados: los pacientes que recibieron el tratamiento experimental tuvieron peores resultados (el doble de mortalidad a cinco años) que los que recibieron tratamiento estándar. Esta diferencia alcanzó significancia estadística tanto en el ensayo clínico (p=0,001) como en la cohorte prospectiva (p=0,0009). Conclusiones: nuestros resultados avalan continuar con la rama estándar de los protocolos tipo BFM para el tratamiento de las recaídas de la LLA y fueron concordantes con las conclusiones del grupo ALLIC-REC. (AU)

Introduction: since 2002, the Grupo Argentino para el Tratamiento de la Leucemia Aguda (GATLA) has been implementing protocols from the Berlin-Frankfurt-Münster (BFM) group as the standard treatment for relapses of acute lymphoblastic leukemia (ALL). In 2010, BFM developed the IntReALL 10 protocol, implemented in Argentina with the inherent limitations of the region. Population and Methods: we treated a total of 180 patients under 18 years of age between 2010 and 2015 for high-risk relapsed acute lymphoblastic leukemia (ALL) in Argentina following a BFM relapse protocol. This protocol openly compared standard treatment with an innovative (experimental) therapeutic approach that included Clofarabine. Out of these, 171 patients were assessable, with 78 patients being centrally randomized in a clinical trial, and 93 were assigned to one of the arms based on the treating group's criteria (prospective cohort). The cohort where the treatment assignment had not been randomized, was analyzed with adjustments for gender, age, and the presence or absence of Down Syndrome, Philadelphia Chromosome, and T-cell immunophenotype. Results: patients who received the experimental treatment had worse outcomes (double the five-year mortality) compared to those who received the standard treatment. This difference reached statistical significance in the clinical trial (p=0.001) and the prospective cohort (p=0.0009). Conclusions: our results support the continuation of the standard arm in BFM-type protocols for relapsed ALL treatment and were consistent with the conclusions of the ALLIC-REC group. (AU)

Degradation of cytostatics methotrexate and cytarabine through physico-chemical and advanced oxidative processes: influence of pH and combined processes on the treatment efficiency.

Environmental release of wastewater that contains cytostatic drugs can cause genotoxic impact, since these drugs act directly on the genetic material of aquatic organisms. Thus, the aim of this study was to evaluate the removal of the cytostatic drugs cytarabine (CTR) and methotrexate (MTX) using different physico-chemical methods individually (i.e. US, O3, H2O2 and UV) and combined (i.e. O3/US, US/H2O2, O3/H2O2 and O3/US/H2O2) under different pH conditions (4, 7 and 10). In the degradation tests, the efficiency of the methods applied was found to be dependent on the pH of the solution, with the degradation of CTR being better at pH 4 and MTX at pH 7 and pH 10. The US, H2O2 and US + H2O2 methods were the least efficient in degrading CTR and MTX under the pH conditions tested. The highest MTX degradation rate after 16 min of treatment at pH 7 was achieved by the O3 + H2O2 method (97.05% - C/C0 = 0.0295). For CTR, the highest degradation rate after 16 min of treatment was achieved by the O3 process (99.70% - C/C0 = 0.0030) at pH 4. In conclusion, most of the treatment methods tested for the degradation of CTR and MTX are effective. Notably, ozonolysis is an efficient process applied alone. Also, in combination with other methods (US + O3, O3 + H2O2 and O3 + H2O2 + US) it increases the degradation performance, showing a rapid removal rate of 70-94% in less than 4 min of treatment.

Outcomes and survival predictors of Latin American older adults with acute myeloid leukemia: Data from a single center

ABSTRACT Introduction: Acute myeloid leukemia (AML) is most commonly presented in older adults; however, it appears 10 years earlier in Latin American countries. Clinical evolution in older adults from this populations has not been characterized. We analyzed outcomes and survival predictors. Methods: Patients ≥ 55 years old diagnosed with AML at a hematology referral center from 2005 to 2020 receiving intensive chemotherapy (IC), low-dose cytarabine (LDAC) and best supportive care (BSC) were included. Survival analysis included the Kaplan-Meier and Cox models and the cumulative incidence of relapse (CIR). Results: Seventy-five adults were included and the overall survival (OS) was 4.87, 1.67 and 1.16 months, using IC, LDAC and BSC, respectively. The IC led to a higher OS (p < 0.001) and was a protective factor for early death, at a cost of more days spent hospitalized and more non-fatal treatment complications; non-significant differences were found between the LDAC and BSC. Eight (10.7%) patients underwent hematopoietic cell transplantation, with a higher OS (p = 0.013). Twenty (26.7%) patients achieved complete remission; 12 (60%) relapsed with a 6-month CIR of 57.9% in those < 70 years old vs. 86.5% in those ≥ 70 years old, p = 0.034. Multivariate analysis showed the white blood cell count (WBC) and IC had a significant impact on the patient survival, whereas chronological age and the Charlson comorbidity index (CCI) did not. Conclusion: AML in low-middle income countries demands a different approach; the IC improves survival, even with a high incidence of relapse, and should be offered as first-line treatment. Eligibility criteria should include WBC and a multidimensional evaluation. The age per se and the CCI should not be exclusion criteria to consider IC.

Older Adults With Newly Diagnosed AML: Hot Topics for the Practicing Clinician.

Over the past decade, our understanding of AML pathogenesis and pathophysiology has improved significantly with mutational profiling. This has led to translational advances in therapeutic options, as there have been 10 new US Food and Drug Administration (FDA) approvals for AML therapies since 2017, half of which target specific driver mutations in FLT3, IDH1, or IDH2. These new agents have expanded the therapeutic armamentarium for AML, particularly for patients who are considered ineligible for intensive chemotherapy with anthracycline- and cytarabine-containing regimens. These new treatment options are relevant because the median age at diagnosis is 68 years, and outcomes for patients older than 60 years have historically been dismal. However, the optimal approach to incorporating novel agents into frontline regimens remains a clinical challenge, particularly with regard to sequencing of therapies, considering the role of allogeneic hematopoietic stem cell transplantation and managing toxicities.

Optimizing outcomes in secondary AML.

Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with inferior outcomes. Conventional therapy with cytarabine-based chemotherapy has been the mainstay of care for the past 30 years with disappointing overall outcomes. Novel therapies, including liposomal cytarabine/daunorubicin, and venetoclax-based therapies have emerged as options in recent years based on studies showing improvement in outcomes over standard-of-care therapies. Despite these advances, mutations in TP53 are associated with inferior response to both therapies and represent an area of unmet clinical need. Novel strategies with immune-targeted therapies such as CD47 monoclonal antibodies appear active in early-phase studies, but randomized studies have yet to report outcomes leading to approval. Allogeneic transplant remains the only known curative therapy for many of these cases. Nonetheless, pretransplant high-risk molecular features of secondary AML are associated with inferior outcome despite transplantation. An optimal approach to secondary AML is yet to be determined.

Neutropenic fever of unknown origin and disseminated granulomatous disease in a patient with acute lymphoblastic leukemia.

An 18-year-old male was admitted for his second induction chemotherapy treatment for an acute lymphoblastic leukaemia with cyclophosphamide, cytarabine, and mercaptopurine. He presented with high fever, abdominal pain, non-bloody diarrhoea, portal hypertension and leukopenia. Stool sample analysis, blood cultures and extensive work-up were negative. The only microbiologic evidence was the presence of cytomegalovirus DNA detected by PCR. A profound hypogammaglobulinemia was documented. Pathology material reported non-caseating granulomas in liver, bone marrow, duodenum and colon with negative cytomegalovirus immunostaining. What is your diagnosis?

Un varón de 18 años se internó para recibir el segundo ciclo de inducción por una leucemia linfoblástica aguda con ciclofosfamida, citarabina y mercaptopurina. Desarrolló fiebre alta, dolor abdominal, diarrea no sanguinolenta, hipertensión portal y leucopenia. El análisis de materia fecal, cultivos de sangre y una evaluación exhaustiva fueron negativas. La única evidencia microbiológica fue la detección de ADN de citomegalovirus en sangre por PCR. También se documentó una hipogamaglobulinemia profunda. El material de patología reportó granulomas no caseificantes en hígado, médula ósea, duodeno y colon con inmunohistoquímica negativa para citomegalovirus. ¿Cuál es su diagnóstico?

Long-term results of the treatment of adolescents and adults with acute lymphoblastic leukemia with a pediatric-inspired regimen delivered on an outpatient basis: A single institution experience.

The results of treatment of adolescents and adults with acute lymphoblastic leukemia (ALL) remain unsatisfactory. Pediatric-inspired treatments seem to be related with better outcomes. 126 adolescent and adult patients with ALL were treated in a 37-year period with a pediatric inspired combined chemotherapy (PICC) schedule, delivered on an outpatient basis and based on the St. Jude´s TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intrathecal therapy. 80 % of patients were able to receive the initial seven-week period of induction / consolidation fully as outpatients and 77 % achieved a complete remission. In adolescents and young adults (AYAs) the median probability of overall survival (OS) was 44 months, whereas the 5-year OS was 48 %. In adults, the median probability of OS was 24 months, and the 5-year OS was 32 %. Patients with T-cell ALL did significantly worse than those with a B cell phenotype (OS at 5 years 17 versus 40 %, respectively). These figures are better than those informed in our country employing more aggressive, in-hospital schedules such as the hyper-CVAD. We found that, in AYAs and adult patients with ALL, the use of an asparaginase-containing PICC delivered on an outpatient basis renders acceptable results, better than those obtained in similar socioeconomic circumstances employing adult-oriented schedules. Additional studies are needed to assess the usefulness of these PICC treatments in adult individuals with ALL treated in underprivileged circumstances, such as those prevailing in LMIC.

Novel inhibitor of hematopoietic cell kinase as a potential therapeutic agent for acute myeloid leukemia.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are characterized by risk of relapses, poor survival, unwanted side effects and high toxicity with the current therapies. In light of these facts, there are efforts to develop new drugs specific for deregulated molecules that participate in leukemia pathogenesis. Hematopoietic cell kinase (HCK), an Src kinase family member, is overexpressed on hematopoietic stem cells of MDS and de novo AML patients and involved in the oncogenic process. Thus, we investigated in vitro, ex vivo and in vivo effects of a novel chemical compound targeting HCK inhibition (iHCK-37), in combination with the most used drugs for the treatment of MDS and de novo AML, 5-Azacytidine and Cytarabine. Herein, the combination treatment with iHCK-37 and 5-Azacytidine or Cytarabine demonstrated additive effects against leukemia cells, compared to either drug alone. iHCK-37 plus 5-Azacytidine or Cytarabine treatment was able to reduce the activation of oncogenic pathways, MAPK/ERK and PI3K/AKT, leading to reduction of ERK and AKT phosphorylation, and increased BAX and decreased BCL-XL protein expression. Moreover, treatment with iHCK-37 reduced MDS and AML CD34-positive cell numbers inside a 3D-structure but did not affect normal CD34-positive cell numbers. In vivo analysis showed that leukemic mice treated with iHCK-37 had reduced ERK and AKT proteins phosphorylation levels and leukocyte numbers. In conclusion, the iHCK-37 inhibitor has anti-neoplastic activity in leukemia cells without altering apoptosis and survival rate of normal cells, suggesting on-target malignant cell killing activity as a single agent or in combination with 5-Azacytidine or Cytarabine.

Validation of AML-score in Older Adults Receiving CPX-351 Intensive Induction Chemotherapy for Treatment of Secondary Acute Myeloid Leukemia.

INTRODUCTION/BACKGROUND: The AML-Score has been validated in patients receiving traditional induction chemotherapies but not CPX-351. We conducted a retrospective analysis to evaluate, among patients with secondary acute myeloid leukemia who received intensive induction with CPX-351, if the AML-Score associates with (1) complete remission (CR) and (2) early mortality (EM) within 60 days of induction. MATERIALS AND METHODS: We abstracted demographic and clinical data from consecutive patients receiving CPX-351 at Sidney Kimmel Cancer Center at Thomas Jefferson University Hospital between September 2017 and November 2020. We used descriptive statistics and receiver operating curves to evaluate the relationship between AML-Score and rates of CR and EM. RESULTS: In total, 40 patients were included. 27 (67.5%) were male, 27 (67.5%) were white, 36 (90.0%) were not Hispanic or Latino, and 29 (72.5%) were aged ≥60 years. Twenty-seven patients (67.5%) had a CR, and 4 (10%) experienced EM. Observed rates of CR and EM generally increased with increasing predicted risk. The area under the curve was 0.75 (95% CI 0.60-0.90) for CR and 0.82 (95% CI 0.68-0.96) for EM. CONCLUSION: The AML-Score tool trends in the correct direction for predicting CR and EM, and thus may facilitate oncologist prognostication and treatment planning for patients receiving CPX-351. However, its clinical utility is limited by its underestimation of the risk of CR and overestimation of the risk of EM. Further validation in a larger cohort is needed to calculate accurate point estimates of CR and EM risk in this population.

Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review.

Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation. Approximately 60% of AML patients respond favorably to these treatments and go into complete remission; however, most eventually relapse, develop refractory disease or chemoresistance, and do not survive for more than five years. Therefore, drug resistance that initially occurs in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) has become the main obstacle to AML treatment. In this work, the main molecules responsible for generating chemoresistance to Ara-C in AML are discussed, as well as some of the newer strategies to overcome it, such as the inclusion of molecules that can induce synergistic cytotoxicity with Ara-C (MNKI-8e, emodin, metformin and niclosamide), subtoxic concentrations of chemotherapy (PD0332991), and potently antineoplastic treatments that do not damage nonmalignant cells (heteronemin or hydroxyurea + azidothymidine).

LOPH and D-MHC in the treatment of FeLV associated acute leukemia in a cat

Background: Bone marrow primary malignancies are denominated leukemias, classified as myeloid or lymphoid, according to the cell lineage, and acute or chronic, according to the cell´s state of maturation. In cats, acute lymphoid leukemiais the most common form, especially in regions endemic for feline leukemia virus and / or feline immunodeficiency virus.A new treatment protocol for lymphomas, called LOPH, was described for animals with FeLV persistent viremia. Thisstudy aimed to report a case of a cat presenting with FeLV associated acute leukemia and treated with the LOPH protocol,and, in the rescue phase, a modification of the D-MAC protocol, denominated D-MHC.Case: A 4-year-old mixed breed intact queen was attended due to lethargy and inappetence. The patient did not present anyrelevant abnormalities in the clinical exam and complementary exams were performed including complete blood count,biochemical profile, SNAP Feline Triple Test, chest radiographs and abdominal ultrasound. Imaging tests and biochemicalvalues were unremarkable, but the patient presented a reagent result for FeLV and severe leukocytosis due to lymphocytosis. The morphological evaluation of the blood smear revealed the presence of blasts, in a concentration greater than 20%of the nucleated cells, which allowed the characterization of a leukemic state, probably lymphoid. First-line treatmentwas based on the LOPH protocol, including Lomustine, Vincristine, Prednisolone and Doxorubicin, in four-week cycles.Nevertheless, during the third cycle, 66 days after the institution of this protocol, the patient presented a febrile conditionalong with marked leukocytosis due to lymphocytosis, confirming leukemia recurrence. A rescue attempt was performedwith a modification of the D-MAC protocol, originally consisting of the combination of dexamethasone, melphalan, actinomycin-D and cytarabine, but with replacement of actinomycin-D by doxorubicin, and therefore denominated D-MHC....(AU)

Immunomodulatory Effect of Green Tea Treatment in Combination with Low-dose Chemotherapy in Elderly Acute Myeloid Leukemia Patients with Myelodysplasia-related Changes.

Green tea (GT) treatment was evaluated for its effect on the immune and antineoplastic response of elderly acute myeloid leukemia patients with myelodysplasia-related changes (AML-MRC) who are ineligible for aggressive chemotherapy and bone marrow transplants. The eligible patients enrolled in the study (n = 10) received oral doses of GT extract (1000 mg/day) alone or combined with low-dose cytarabine chemotherapy for at least 6 months and/or until progression. Bone marrow (BM) and peripheral blood (PB) were evaluated monthly. Median survival was increased as compared to the control cohort, though not statistically different. Interestingly, improvements in the immunological profile of patients were found. After 30 days, an activated and cytotoxic phenotype was detected: GT increased total and naïve/effector CD8+ T cells, perforin+/granzyme B+ natural killer cells, monocytes, and classical monocytes with increased reactive oxygen species (ROS) production. A reduction in the immunosuppressive profile was also observed: GT reduced TGF-ß and IL-4 expression, and decreased regulatory T cell and CXCR4+ regulatory T cell frequencies. ROS levels and CXCR4 expression were reduced in bone marrow CD34+ cells, as well as nuclear factor erythroid 2-related factor 2 (NRF2) and hypoxia-inducible factor 1α (HIF-1α) expression in biopsies. Immune modulation induced by GT appears to occur, regardless of tumor burden, as soon as 30 days after intake and is maintained for up to 180 days, even in the presence of low-dose chemotherapy. This pilot study highlights that GT extracts are safe and could improve the immune system of elderly AML-MRC patients.

The pterocarpanquinone LQB­118 compound induces apoptosis of cytarabine­resistant acute myeloid leukemia cells.

Acute myeloid leukemia (AML) is a complex hematological disorder characterized by blockage of differentiation and high proliferation rates of myeloid progenitors. Anthracycline and cytarabine­based therapy has remained the standard treatment for AML over the last four decades. Although this treatment strategy has increased survival rates, patients often develop resistance to these drugs. Despite efforts to understand the mechanisms underlying cytarabine resistance, there have been few advances in the field. The present study developed an in vitro AML cell line model resistant to cytarabine (HL­60R), and identified chromosomal aberrations by karyotype evaluation and potential molecular mechanisms underlying chemoresistance. Cytarabine decreased cell viability, as determined by MTT assay, and induced cell death and cell cycle arrest in the parental HL­60 cell line, as revealed by Annexin V/propidium iodide (PI) staining and PI DNA incorporation, respectively, whereas no change was observed in the HL­60R cell line. In addition, the HL­60R cell line exhibited a higher tumorigenic capacity in vivo compared with the parental cell line. Notably, no reduction in tumor volume was detected in mice treated with cytarabine and inoculated with HL­60R cells. In addition, western blotting revealed that the protein expression levels of Bcl­2, X­linked inhibitor of apoptosis protein (XIAP) and c­Myc were upregulated in HL­60R cells compared with those in HL­60 cells, along with predominant nuclear localization of the p50 and p65 subunits of NF­κB in HL­60R cells. Furthermore, the antitumor effect of LQB­118 pterocarpanquinone was investigated; this compound induced apoptosis, a reduction in cell viability and a decrease in XIAP expression in cytarabine­resistant cells. Taken together, these data indicated that acquired cytarabine resistance in AML was a multifactorial process, involving chromosomal aberrations, and differential expression of apoptosis and cell proliferation signaling pathways. Furthermore, LQB­118 could be a potential alternative therapeutic approach to treat cytarabine­resistant leukemia cells.