Treatment Of Leukemia Research Articles

Complete Remission with Partial Hematological Recovery as a Palliative Endpoint for Treatment of Acute Myeloid Leukemia

Complete remission with partial hematological recovery (CRh) has been used as an efficacy endpoint in clinical trials of nonmyelosuppressive drugs for acute myeloid leukemia (AML). We conducted a pooled analysis to characterize the clinical outcomes for patients with AML who achieved CRh after treatment with ivosidenib, olutasidenib, enasidenib, or gilteritinib monotherapy in clinical trials used to support marketing applications. The study cohort included 841 adult patients treated at the recommended drug dosage; 64.6% were red blood cell or platelet transfusion dependent at study baseline. Correlations between disease response and outcomes were assessed by logistic regression modeling for categorical variables and by Cox proportional hazards modeling for time-to-event variables. In comparison to patients with no response (NR), those with CRh had a higher proportion with transfusion independence (TI) for at least 56 days (92.3% vs 22.3%, p < 0.0001) or TI for at least 112 days (63.5% vs 8.7%, p < 0.0001), a reduced risk over time for severe infection (HR 0.43, p = 0.0007) or severe bleeding (HR 0.17, p = 0.01), and a longer overall survival (OS) (HR 0.31, p < 0.0001). The effects were consistent across drugs. In comparison to patients with CR, the effect sizes for CRh were similar for TI-56 and for risk over time of infection or bleeding but less for TI-112 and OS. CRh is associated with clinical benefits consistent with clinically meaningful palliative effects for treatment of AML with nonmyelosuppressive drugs, although less robustly than for CR.

From niche to blockbuster: a greater role for allopurinol in maintenance treatment of acute lymphoblastic leukemia.

Not available.

Association between plasma imatinib levels and response to treatment of chronic myeloid leukemia in patients from Manaus, Brazil.

Imatinib mesylate (IM) is the drug of choice for the treatment of chronic myeloid leukemia (CML). However, despite most of the results obtained with this therapy being positive, some patients still present a suboptimal therapeutic response or still develop some type of resistance. Therefore, the aim of this study was to evaluate IM plasma levels in CML patients treated at a referral unit in Manaus and correlate them with variables that might interfere with these levels. Data from 52 patients were obtained through a standardized questionnaire containing clinical, sociodemographic, lifestyle, and use of other medication information, as well as an estimate of therapeutic adherence. Additionally, blood collection was performed to measure the plasma concentration of the drug using the HPLC-UV technique. Molecular studies were done to identify the presence of polymorphism in the ABCG2 C421A membrane transporter. Most patients were male with a mean age of 52 ± 12.3 years (95% CI 49.0-55.9). There was a high variation in drug concentrations in the range from 0 to 4694 ng/mL, with a mean of 1558.59 ± 989.79 ng/mL (95% CI 1283.0-1834.1). Approximately two-thirds of patients were classified in the drug-level range considered therapeutic, and there was a correlation between plasma concentration and higher molecular response. Additionally, most individuals had the normal genotype for the ABCG2 C421A polymorphism but further studies should be performed to reveal the role of this variable in the outcome of the disease in this population.

Oxidative Stress: An Intersection Between Radiation and Sulfur Mustard Lung Injury.

Nuclear and chemical weapons of mass destruction share both a tragic and beneficial legacy in mankind's history and health. The horrific health effects of ionizing radiation and mustard gas exposures unleashed during disasters, wars, and conflicts have been harnessed to treat human health maladies. Both agents of destruction have been transformed into therapies to treat a wide range of cancers. The discovery of therapeutic uses of radiation and sulfur mustard was largely due to observations by clinicians treating victims of radiation and sulfur mustard gas exposures. Clinicians identified vulnerability of leukocytes to these agents and repurposed their use in the treatment of leukemias and lymphomas. Given the overlap in therapeutic modalities, it goes to reason that there may be common mechanisms to target as protective strategies against their damaging effects. This commentary will highlight oxidative stress as a common mechanism shared by both radiation and sulfur mustard gas exposures and discuss potential therapies targeting oxidative stress as medical countermeasures against the devastating lung diseases wrought by these agents.

The Menin story in acute myeloid leukaemia-The road to success.

The treatment of acute myeloid leukaemia (AML) has changed fundamentally in the last decade with many new targeted therapies entering clinics. Some of the most interesting agents under development are Menin inhibitors which interfere with the interaction of Menin with wild-type (wt) KMT2A or a KMT2A-fusion protein and thereby downregulate the leukaemic gene expression (MEIS1, PBX3, HOX) in NPM1 mutant or KMT2A-rearranged leukaemia. Other HOX and MEIS1 expressing leukaemias may also be sensitive to Menin inhibition. Following the encouraging results as monotherapy in refractory and relapsed AML, the combination of Menin inhibitors with chemotherapeutic agents and other targeted drugs is being investigated clinically.

Overcoming retinoic acid resistance in HER2-enriched breast cancers: role of MYC.

HER2-enriched (HER2+) breast cancers express high levels of the growth-promoting HER2 protein. Although these cancers are treated with the HER2-targeted drug, trastuzumab, resistance to treatment is common. Retinoic acid (RA) is an anti-cancer agent that has been successfully used for the treatment of leukemia and holds promise for the treatment of solid cancers, including breast cancer. The HER2 gene is frequently co-amplified with RARA, a key determinant of RA sensitivity in breast cancers. It seems surprising, therefore, that HER2+ breast cancers are refractory to RA treatment. Here, we show that MYC mediates RA resistance by suppressing the expression of cellular retinoic acid binding protein 2 (CRABP2), resulting in RARα inactivation. CRABP2 is an intracellular RA transporter that delivers RA to the nuclear receptor RARα for its activation. Our results indicate that response to RA is enhanced by MYC depletion in HER2+ breast cancer cells and that RA treatment enhances trastuzumab responsiveness. Our findings support the use of RA and trastuzumab for the treatment of subsets of patients with breast cancers that are HER2-RARα co-amplified and have low levels of MYC.

Fluocinolone intravitreal implant (Iluvien) for macular edema secondary to immune recovery uveitis in patient with acute myeloid leukemia

PurposeTo report the use of Fluocinolone intravitreal implant (Iluvien) for the treatment of persistent cystoid macular edema (CME) due to immune recovery uveitis syndrome in a patient with previous cytomegalovirus retinitis and acute myeloid leukemia.DesignCase report.MethodsThe clinical history of a patient who received an Iluvien implant in one eye for the treatment of cystoid macular edema due to immune recovery uveitis syndrome, previously treated with peribulbar Triamcinolone and intravitreal Dexamethasone injections, was reviewed.ResultsA 48-year-old woman presented with cystoid macular edema due to immune recovery uveitis syndrome. The patient had a history of cytomegalovirus retinitis 3.5 years prior, secondary to immunosuppressive treatment for an acute myeloid leukemia. Three periocular triamcinolone injections and two dexamethasone intravitreal implants were performed, but the edema recurred, so fluocinolone intravitreal implant was used, achieving a sustained control of the condition at one year of follow-up.ConclusionThe Fluocinolone intravitreal implant may be an effective treatment for persistent CME in patients with immune recovery uveitis syndrome.

Two chromatographic methods for determination of cytarabine and dexamethazone; two co-administered drugs for the treatment of leukemia: green analytical perspective

Two sensitive, straightforward and repeatable chromatographic techniques were developed for the determination of Cytarabine HCl and Dexamethazone in their pure form and spiked human plasma without prior separation. The drugs are used co-administered for the treatment of Leukemia, a certain type of blood cancer. Method (A) is an isocratic chromatographic HPLC method; separation was accomplished on C18 column using the eluting mixture of 6.9 g/L Monobasic Sodium Phosphate pH 3: methanol (70:30, v/v) and detection was at 275 nm. Concentrations were in the range of 0.2–15 μg/mL for both CYT and DEX. Method (B) is a HPTLC method in which separation was attained on HPTLC F254 plates using methanol: ethyl acetate: ammonia, (7.8:2:0.2, by volume) as eluting solvents and detection was at 275 nm. Concentrations were in the range of 0.1–4 μg/band for both CYT and DEX. The parameters for system suitability testing were evaluated to determine the effectiveness of the developed chromatographic procedures in terms of performance. The recently developed techniques were applied for the determination of the drugs under investigation in spiked human plasma. Validation parameters were examined in accordance with US-FDA criteria. All results were found to be within the acceptable ranges. To evaluate the greenness characters of the proposed methods to the environment; three greenness assessment tools including eco-scale assessments (ESA), green analytical procedure index (GAPI), and Analytical Greenness calculator (AGREE) were used. Acceptable and satisfying results that demonstrated the greenness characteristics of the suggested methods were attained.

Synthesis, design, and antiproliferative evaluation of 6-(N-Substituted-methyl)pyrazolo[3,4-d]pyrimidines as the potent anti-leukemia agents

Pyrazolopyrimidine derivatives, including pyrazolopyrimidines, 6-aminopyrazolopyrimidines, 6-[(formyloxy)methyl]pyrazolopyrimidines, 6-(hydroxymethyl)pyrazolopyrimidine, and 6-(aminomethyl)pyrazolopyrimidines have been successfully prepared and tested against NCI-H226, NPC-TW01, and Jurkat cancer cell lines. Among the tested pyrazolopyrimidine compounds, we found 6-aminopyrazolopyrimidines and 6-(aminomethyl)pyrazolopyrimidines with essential o-ClPh or p-ClPh substituted moieties on N-1 pyrazole ring exhibited the best IC50 inhibition activity for Jurkat cells. Furthermore, optimization of the SAR study on the C-6 position of pyrazolopyrimidine ring demonstrated that 6-(N-substituted-methyl)pyrazolopyrimidines 17b, 17d, and 19d possessed the significant IC50 inhibitory activity for the different leukemia cell lines, especially for Jurkat, K-562, and HL-60. On the other hand, further SAR inhibition and docking model studies revealed that compound 19d, which has a 3-(1H-imidazol-1-yl)propan-1-amino side-chain on the C-6 position, was able to form four hydrogen bonds with residues Ala226, Leu152, and Glu194 and specifically extended into the P1 pocket subsite with Aurora A, resulting in improved inhibitory activity almost similar to SNS-314. To explore the anti-cancer mechanism, compound 19d was measured by Western blot analysis in Jurkat T-cells, however, it showed non-responsibility to Aurora B. For the further structural modifications on the lateral chain of compound 19d, compounds 24 with longer lateral chain were designed and synthesized for testing leukemia cell lines. However, compounds 24 was significantly decrease inhibition potency against leukemia cell lines. Based on the in-vitro results, compounds 17b and 19d could be considered to be the best potential lead drug in our study for the development of new and effective therapies for leukemia treatment. On the other hand, the DHFR inhibition results indicated compound 19d possessed good inhibitory activity and better than the reported naphthalene derivative. Through further comparisons of the model superposition of three-dimensional (3D) conformations in DHFR, compound 19d presented a similar structural alignment to Methotrexate and the reported naphthalene derivative and led to similar drug-like functional relationships. As a results, compound 19d would be a potential DHFR inhibitor for anti-leukemia drug candidate.

Continuously improving outcome over time after second allogeneic stem cell transplantation in relapsed acute myeloid leukemia: an EBMT registry analysis of 1540 patients

Second allogeneic stem cell transplantation (alloSCT2) is among the most effective treatments for acute myeloid leukemia (AML) relapse after first alloSCT (alloSCT1). Long-term EBMT registry data were used to provide large scale, up-to-date outcome results and to identify factors for improved outcome. Among 1540 recipients of alloSCT2, increasing age, better disease control and performance status before alloSCT2, more use of alternative donors and higher conditioning intensity represented important trends over time. Between the first (2000–2004) and last (2015–2019) period, two-year overall and leukemia-free survival (OS/LFS) increased considerably (OS: 22.5–35%, LFS: 14.5–24.5%). Cumulative relapse incidence (RI) decreased from 64% to 50.7%, whereas graft-versus-host disease and non-relapse mortality (NRM) remained unchanged. In multivariable analysis, later period of alloSCT2 was associated with improved OS/LFS (HR = 0.47/0.53) and reduced RI (HR = 0.44). Beyond, remission duration, disease stage and patient performance score were factors for OS, LFS, RI, and NRM. Myeloablative conditioning for alloSCT2 decreased RI without increasing NRM, leading to improved OS/LFS. Haploidentical or unrelated donors and older age were associated with higher NRM and inferior OS. In summary, outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. The identified factors provide clues for the optimized implementation of alloSCT2.

Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to three months of imatinib therapy: final 5-year results from DASCERN.

Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%, P.

Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Recent advances on anti-HIV chimeric antigen receptor-T-cell treatment to provide sustained HIV remission.

Successful sustained remission of HIV infection has been achieved after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation for treatment of leukemia in a small cohort of people living with HIV (PLWH). This breakthrough demonstrated that the goal of curing HIV was achievable. However, the high morbidity and mortality associated with bone marrow transplantation limits the routine application of this approach and provides a strong rationale for pursuing alternative strategies for sustained long-term antiretroviral therapy (ART)-free HIV remission. Notably, long-term immune-mediated control of HIV replication observed in elite controllers and posttreatment controllers suggests that potent HIV-specific immune responses could provide sustained ART-free remission in PLWH. The capacity of chimeric antigen receptor (CAR)-T cells engineered to target malignant cells to induce remission and cure in cancer patients made this an attractive approach to provide PLWH with a potent HIV-specific immune response. Here, we review the recent advances in the design and application of anti-HIV CAR-T-cell therapy to provide a functional HIV cure. HIV reservoirs are established days after infection and persist through clonal expansion of infected cells. The continuous interaction between latently infected cells and the immune system shapes the landscape of HIV latency and likely contributes to ART-free viral control in elite controllers. CAR-T cells can exhibit superior antiviral activity as compared with native HIV-specific T cells, particularly because they can be engineered to have multiple HIV specificities, resistance to HIV infection, dual costimulatory signaling, immune checkpoint inhibitors, stem cell derivation, CMV TCR coexpression, and tissue homing ligands. These modifications can significantly improve the capacities of anti-HIV CAR-T cells to prevent viral escape, resist HIV infection, and enhance cytotoxicity, persistence, and tissue penetration. Collectively, these novel modifications of anti-HIV CAR-T cell design have increased their capacity to control HIV infection. Anti-HIV CAR-T cells can be engineered to provide potent and sustained in-vitro and in-vivo antiviral function. The combination of anti-HIV CAR-T cells with other immunotherapeutics may contribute to long-term HIV remission in PLWH.

On the mechanism of wogonin against acute monocytic leukemia using network pharmacology and experimental validation

Wogonin is a natural flavone compound from the plant Scutellaria baicalensis, which has a variety of pharmacological activities such as anti-cancer, anti-virus, anti-inflammatory, and immune regulation. However, the potential mechanism of wogonin remains unknown. This study was to confirm the molecular mechanism of wogonin for acute monocytic leukemia treatment, known as AML-M5. The potential action targets between wogonin and acute monocytic leukemia were predicted from databases. The compound-target-pathway network and protein-protein interaction network (PPI) were constructed. The enrichment analysis of related targets and molecular docking were performed. The network pharmacological results of wogonin for AML-M5 treatment were verified using the THP-1 cell line. 71 target genes of wogonin associated with AML-M5 were found. The key genes TP53, SRC, AKT1, RELA, HSP90AA1, JUN, PIK3R1, and CCND1 were preliminarily found to be the potential central targets of wogonin for AML-M5 treatment. The PPI network analysis, GO analysis and KEGG pathway enrichment analysis demonstrated that the PI3K/AKT signaling pathway was the significant pathway in the wogonin for AML-M5 treatment. The antiproliferative effects of wogonin on THP-1 cells of AML-M5 presented a dose-dependent and time-dependent manner, inducing apoptosis, blocking the cell cycle at the G2/M phase, decreasing the expressions of CCND1, CDK2, and CyclinA2 mRNA, as well as AKT and p-AKT proteins. The mechanisms of wogonin on AML-M5 treatment may be associated with inhibiting cell proliferation and regulating the cell cycle via the PI3K/AKT signaling pathway.

Discovery of indole-2-one derivatives as BRD4 (BD1) selective inhibitors

Bromodomain protein 4 (BRD4) is a member of the BET family, and its overexpression is closely associated with the development of many tumors. Inhibition of BRD4 shows great therapeutic potential in anti-tumor, and pan-BRD4 inhibitors show adverse effects of dose limiting toxicity and thrombocytopenia in clinical trials. To improve clinical effects and reduce side effects, more efforts have focused on seeking selective inhibitors of BD1 or BD2. Herein, a series of indole-2-one derivatives were designed and synthesized through docking-guided optimization to find BRD4-BD1 selective inhibitors, and their BRD4 inhibitory and antiproliferation activities were evaluated. Among them, compound 21r had potent BRD4 inhibitory activity (the IC50 values of 41 nM and 313 nM in BD1 and BD2 domain), excellent anti-proliferation (the IC50 values of 4.64 ± 0.30 µM, 0.78 ± 0.03 µM, 5.57 ± 1.03 µM against HL-60, MV-4–11 and HT-29 cells), and displayed low toxicity against normal cell GES-1 cells. Further studies revealed that 21r inhibited proliferation by decreasing the expression of proto-oncogene c-Myc, blocking cell cycle in G0/G1 phase, and inducing apoptosis in MV-4–11 cells in a dose-dependent manner. All the results showed that compound 21r was a potent BRD4 inhibitor with BD1 selectivity, which had potential in treatment of leukemia.

Recent advances in CAR-T cell therapy for acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a fatal and refractory haematologic cancer that primarily affects adults. It interferes with bone marrow cell proliferation. Patients have a 5 years survival rate of less than 30% despite the availability of several treatments, including chemotherapy, allogeneic haematopoietic stem cell transplantation (Allo-HSCT), and receptor antagonist drugs. Allo-HSCT is the mainstay of acute myeloid leukaemia treatment. Although it does work, there are severe side effects, such as graft-versus-host disease (GVHD). In recent years, chimeric antigen receptor (CAR)-T cell therapies have made significant progress in the treatment of cancer. These engineered T cells can locate and recognize tumour cells invivo and release a large number of effectors through immune action to effectively kill tumour cells. CAR-T cells are among the most effective cancer treatments because of this property. CAR-T cells have demonstrated positive therapeutic results in the treatment of acute myeloid leukaemia, according to numerous clinical investigations. This review highlights recent progress in new targets for AML immunotherapy, and the limitations, and difficulties of CAR-T therapy for AML.

Oxidative stress is two-sided in the treatment of acute myeloid leukemia.

Oxidative stress caused by elevated ROS, as a novel therapeutic mechanism, has been implicated in various tumors including AML. AML cells are chronically under oxidative stress, yet overreliance on ROS production makes tumor cells increasingly vulnerable to further damage. Reducing the cytotoxic effect of ROS on normal cells while killing leukemia stem cell (LSC) with high levels of reactive oxygen species is a new challenge for oxidative stress therapy in leukemia. By searching literature databases, we summarized recent relevant studies. The relationship of ROS on AML genes, signaling pathways, and transcription factors, and the correlation of ROS with AML bone marrow microenvironment and autophagy were summarized. In addition, we summarize the current status of research on ROS and AML therapeutics. Finally, we discuss the research progress on redox resistance in AML. This review discusses the evidence showing the link between redox reactions and the progression of AML and compiles the latest research findings that will facilitate future biological studies of redox effects associated with AML treatment. We believe that exploiting this unique oxidative stress property of AML cells may provide a new way to prevent relapse and drug resistance.

The dynamic changes of ghrelin and anandamide during the treatment of acute lymphoblastic leukemia in the pediatric population

The dynamic changes of ghrelin and anandamide during the treatment of acute lymphoblastic leukemia in the pediatric population

Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9-dependent AML.

The mainstay of acute myeloid leukemia (AML) treatment still relies on traditional chemotherapy, with a survival rate of approximately 30% for patients under 65 years of age and as low as 5% for those beyond. This unfavorable prognosis primarily stems from frequent relapses, resistance to chemotherapy, and limited approved targeted therapies for specific AML subtypes. Around 70% of all AML cases show overexpression of the transcription factor HOXA9, which is associated with a poor prognosis, increased chemoresistance, and higher relapse rates. However, direct targeting of HOXA9 in a clinical setting has not been achieved yet. The dysregulation caused by the leukemic HOXA9 transcription factor primarily results from its binding activity to DNA, leading to differentiation blockade. Our previous investigations have identified two HOXA9/DNA binding competitors, namely DB1055 and DB818. We assessed their antileukemic effects in comparison to HOXA9 knockdown or cytarabine treatment. Using human AML cell models, DB1055 and DB818 induced in vitro cell growth reduction, death, differentiation, and common transcriptomic deregulation but did not impact human CD34+ bone marrow cells. Furthermore, DB1055 and DB818 exhibited potent antileukemic activities in a human THP-1 AML in vivo model, leading to the differentiation of monocytes into macrophages. In vitro assays also demonstrated the efficacy of DB1055 and DB818 against AML blasts from patients, with DB1055 successfully reducing leukemia burden in patient-derived xenografts in NSG immunodeficient mice. Our findings indicate that inhibiting HOXA9/DNA interaction using DNA ligands may offer a novel differentiation therapy for the future treatment of AML patients dependent on HOXA9.

Malakoplakia: A rare cause of hematochezia in pediatric patients

AbstractMalakoplakia is a rare inflammatory condition characterized by impaired macrophages unable to completely digest and kill phagocytized bacteria, resulting in partially digested bacterial components accumulating within the phagolysosome. Malakoplakia typically presents in immunocompromised individuals due to underlying disease or to medication effects and is rarely diagnosed in the pediatric population. The urinary tract is the most commonly involved site, followed by the gastrointestinal (GI) tract, mainly affecting the descending colon, sigmoid colon, and rectum. Treatment focuses on the use of antibiotics that concentrate in macrophages such as quinolones and trimethoprim‐sulfamethoxazole as well as cholinergic agents such as bethanechol, which raise intracellular levels of cyclic guanosine monophosphate in macrophages to improve bactericidal activity. We report a rare case of GI tract malakoplakia in a pediatric patient undergoing treatment for leukemia.