Showing papers on "Mitoxantrone published in 2023"

An eco-friendly matrix-augmented fluorescence spectroscopic approach for the analysis of mitoxantrone, an oncogenic therapy; application to the dosage form and biological matrices.

Abstract: Mitoxantrone is a synthetic anthracenedione oncogenic therapy. It is often prescribed as an anticancer agent to manage a variety of cancers. A green, fast, and easy fluorimetric technique for the assay of Mitoxantrone (MXN) as a topoisomerase type II enzyme suppressor. An investigation of MXN's fluorescence behavior in various media and solvents constituted the basis for this new technique. Methanol was shown to enhance the intrinsic fluorescence considerably. After excitation at 610 nm, the highest fluorescence intensity was found at 675 nm. Various experimental parameters, such as media, solvents, and pH levels, were tested and adjusted. ICH guidelines were followed when validating procedures. It was possible to achieve linearity in the 0.02-1.50 μg ml-1 with the method. The sensitivity (in terms of LOD and LOQ) was 0.003 and 0.008 μg ml-1 , indicating low toxicity. As a result, the current technology has a remarkable recovery for detecting residues in diverse bodily fluids. Also, the quantum yield was estimated for the designed system. Finally, the method was rated by eco-scale scoring.

Red emission carbon dots for mitoxantrone detection

Abstract: Red-emitting carbon dots were designed for the first time as the fluorescent probe for the determination of mitoxantrone (MITX) anticancer drug in human serum based on the inner filter effect (IFE). With the increase of MITX concentration, the single emission fluorescence intensity of the red carbon dots (R-CDs) at 655 nm gradually decreased and the emission peak position red-shifted to 661 nm. The developed R-CDs detection probe was sensitive to MITX with a wide linear detection range of 0.096–30 µM and a low limit of detection (LOD) of 0.032 µM. Moreover, the proposed method had been successfully applied to the determination of MITX in human serum samples, showing exhibited good operability, low cost, and high accuracy.

Treatment of Patients with Multiple Sclerosis Transitioning Between Relapsing and Progressive Disease

Abstract: Multiple sclerosis (MS) is a chronic autoimmune demyelinating and neurodegenerative disease of the central nervous system with a wide variety of clinical phenotypes. In spite of the phenotypic classification of MS patients, current data provide evidence that diffuse neuroinflammation and neurodegeneration coexist in all MS forms, the latter gaining increasing clinical relevance in progressive phases. Given that the transition phase of relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS) is not well defined, and widely accepted criteria for SPMS are lacking, randomised controlled trials (RCTs) specifically designed for the transition phase have not been conducted. This review summarizes primary and secondary analyses and reports derived from phase III prospective clinical RCTs listed in PubMed of compounds authorised through the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of MS. The best data are available for interferon beta-1a (IFNb-1a) subcutaneous (s.c.), IFNb-1b s.c., mitoxantrone and siponimod, the latter being the most modern compound with likely the best risk-to-effect ratio. Moreover, there is a labels discrepancy for many disease-modifying treatments (DMTs) between the FDA and EMA, which have to be taken into consideration when opting for a specific DMT.

DNA Damage Inducer Mitoxantrone Amplifies Synergistic Mild‐Photothermal Chemotherapy for TNBC via Decreasing Heat Shock Protein 70 Expression

Abstract: Patients with triple‐negative breast cancer (TNBC) have the worst clinical outcomes when compared to other subtypes of breast cancer. Nanotechnology‐assisted photothermal therapy (PTT) opens new opportunities for precise cancer treatment. However, thermoresistance caused by PTT, as well as uncertainty in the physiological metabolism of existing phototherapeutic nanoformulations, severely limit their clinical applications. Herein, based on the clinically chemotherapeutic drug mitoxantrone (MTO), a multifunctional nanoplatform (MTO‐micelles) is developed to realize mutually synergistic mild‐photothermal chemotherapy. MTO with excellent near‐infrared absorption (≈669 nm) can function not only as a chemotherapeutic agent but also as a photothermal transduction agent with elevated photothermal conversion efficacy (ƞ = 54.62%). MTO‐micelles can accumulate at the tumor site through the enhanced permeability and retention effect. Following local near‐infrared irradiation, mild hyperthermia (<50 °C) assists MTO in binding tumor cell DNA, resulting in chemotherapeutic sensitization. In addition, downregulation of heat shock protein 70 (HSP70) expression due to enhanced DNA damage can in turn weaken tumor thermoresistance, boosting the efficacy of mild PTT. Both in vitro and in vivo studies indicate that MTO‐micelles possess excellent synergetic tumor inhibition effects. Therefore, the mild‐photothermal chemotherapy strategy based on MTO‐micelles has a promising prospect in the clinical transformation of TNBC treatment.

Synergy, Additivity and Antagonism between Esculetin and Six Commonly Used Chemotherapeutics in Various Malignant Melanoma Cell Lines—An Isobolographic Analysis

Abstract: (1) Malignant melanomas are dangerous skin cancers, and the treatment of melanomas with various cytostatic drugs often causes side effects and after their prolonged use resistance to these drugs appears. The aim of this study was to evaluate the anticancer effects of esculetin (a simple coumarin) and to assess pharmacodynamic interactions between esculetin and six commonly used cytostatic drugs (cisplatin, epirubicin, docetaxel, paclitaxel, mitoxantrone and vemurafenib) using an isobolographic analysis. (2) The experiments were carried out on four human malignant melanoma cell lines (FM55P, A375, FM55M2 and SK-MEL28). The effects of esculetin on viability, cell proliferation and cytotoxicity were verified in the range of concentrations of 2–200 μM. (3) Esculetin inhibited, in a dose-dependent manner, malignant melanoma cell viability and proliferation. The IC50 for esculetin ranged from 18.20 ± 2.93 to 120.64 ± 30.39 μM depending on the melanoma cell lines used. The combinations of esculetin with epirubicin and vemurafenib showed antagonistic interactions, the combinations of esculetin with cisplatin, docetaxel and paclitaxel showed additive interactions. For the combinations of esculetin with mitoxantrone, the isobolographic analysis displayed synergy. (4) In the treatment of malignant melanoma, esculetin should not be combined with epirubicin or vemurafenib, due to the reduction of their anticancer effects, while the synergistic interactions (esculetin + mitoxantrone) deserve a preclinical recommendation as a beneficial combination during anticancer therapy.

In vivo evaluation of Sono-chemo therapy via hollow gold nanoshells conjugated to mitoxantrone on breast cancer.

Abstract: Conventional methods of cancer treatment include surgery, chemotherapy, radiation therapy, and immunotherapy. Chemotherapy, as one of the main methods of cancer treatment, due to the lack of targeted distribution of the drug in tumor tissues, is not able to destroy cancer cells and also affects healthy tissues and causes serious side effects in patients. Sonodynamic therapy (SDT) is a promising strategy for non-invasive treatment of deep solid cancer tumors. In this study, for the first time, the sono-sensitive activity of mitoxantrone was investigated and then mitoxantrone (MTX) was conjugated to hollow gold nanostructure (HGN) to improve the efficiency of in vivo SDT.Firstly, after the synthesis of hollow gold nanoshells and the PEGylation process, conjugation of MTX was performed. Then, after evaluating the toxicity of the treatment groups in vitro, in order to perform an in vivo study, 56 male Balb/c mice that had been tumorized by subcutaneous injection of 4T1 cells were divided into eight groups of breast tumor model. Ultrasonic irradiation (US) conditions including intensity of 1.5 W/cm2 (with a frequency of 800 kHz, 5 min), MTX concentration of 2 μM, and HGN dose of 2.5 mg/kg (unit of animal weight) were used.The results show that administration of PEG-HGN-MTX caused a slight reduction in tumor size and growth compared with free MTX. Ultrasound also improved the therapeutic effect of the gold nanoshell in treated groups, and the HGN-PEG-MTX-US treated groups were able to significantly reduce and control tumor size and growth.The findings also show that MTX and HGN can be used as sonosensitizers in SDT. Also, HGN-PEG-MTX can act as a sono-chemotherapy agent for the combination of sonodynamic therapy and chemotherapy for in vivo breast tumors.

Supplementary Figure 3 from Mitoxantrone Inhibits HIF-1α Expression in a Topoisomerase II–Independent Pathway

Abstract: <p>PDF file - 172K</p>

Tamoxifen resistance induction results in mitoxantrone resistance in MCF-7 breast cancer cells via upregulation of ABCG2 expression

Abstract: Abstract One of the important barriers in the treatment of breast cancer is the development of tamoxifen resistance. Different mechanisms underlying tamoxifen resistance were identified. In this thesis, we aimed to assess the effect of tamoxifen resistance induction on ABCG2 gene/protein expression level and function in the parent MCF-7 breast cancer cell line and its tamoxifen-resistant (MCF-7/TAMR) cell line. The ABCG2 mRNA and protein expression were compared in MCF-7 and its tamoxifen-resistant derivative MCF-7/TAMR cells using Real-time PCR and western blot methods, respectively. For investigating the effect of tamoxifen-induced resistance on cross-resistance to other chemotherapy drugs such as mitoxantrone (as a well-known ABCG2 substrate), an MTT assay was used. Flow cytometry was applied to compare ABCG2 pump function between two cell lines using mitoxantrone accumulation assay. ABCG2 mRNA expression was also analyzed in tamoxifen-sensitive (TAM-S) (N=9) and tamoxifen-resistant (TAM-R) (N=9) breast tumor tissues. Our results indicated that the levels of ABCG2 mRNA, protein, and activity were significantly higher in MCF-7/TAMR cells compared to tamoxifen sensitive cell line and mitoxantrone was less toxic in the resistant cell line. Data further discovered that tamoxifen-resistant cells with high ABCG2 activation had a poor response when given rescue mitoxantrone chemotherapy. ABCG2 was also upregulated in tissue samples obtained from tamoxifen-resistant ER+ breast cancer patients compared to tamoxifen-sensitive patients. Increased expression of the ABCG2 mRNA and protein is a phenomenon that occurs after the emergence of resistance to tamoxifen and can cause cross-resistance to mitoxantrone in MCF-7 breast cancer cells.

Supplementary Figure 1 from Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

Abstract: <p>PDF file - 883K, Patient disposition by treatment group. IP, investigational product; MP, mitoxantrone and prednisone. *Patient had a decrease in hemoglobin prior to administration of IP on day 1 of cycle 1. �Patient had delays to cycles prior to cycle 12.</p>

Supplementary Figure 6 from Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

Abstract: <p>PDF file - 28K, Kaplan-Meier plot of OS (A) and PFS (B) by tumor MET expression in all treatment arms combined.</p>

Data from Histone Deacetylase Inhibitors Induce a Very Broad, Pleiotropic Anticancer Drug Resistance Phenotype in Acute Myeloid Leukemia Cells by Modulation of Multiple ABC Transporter Genes

Abstract: <div>Abstract<p><b>Purpose:</b> Histone deacetylase inhibitors (HDACi) are being studied in clinical trials with the aim to induce cellular differentiation, growth arrest, and apoptosis of tumor cells. Recent reports suggest that the multidrug resistance-1 (<i>MDR1</i>) gene is regulated by epigenetic mechanisms. To investigate whether additional drug transporters are regulated by HDACi and how this affects cytotoxicity, acute myeloid leukemia (AML) cells were examined.</p><p><b>Experimental Design:</b> AML cells were cultured in the presence of phenylbutyrate, valproate, suberoylanilide hydroxamic acid, or trichostatin A and analyzed for drug transporter expression and function as well as sensitivity to anticancer drugs.</p><p><b>Results:</b><i>MDR1</i>, breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRP) 7 and 8 were induced in a dose- and time-dependent manner as shown by semiquantitative PCR. The pattern of gene induction was cell line specific. Phenylbutyrate induced P-glycoprotein and BCRP expression and the efflux of drugs as determined with labeled substrates. KG-1a cells treated with phenylbutyrate developed resistance to daunorubicin, mitoxantrone, etoposide, vinblastine, paclitaxel, topotecan, gemcitabine, and 5-fluorouracil; as a result drug-induced apoptosis was impaired. Chromatin immunoprecipitation revealed the hyperacetylation of histone proteins in the promoter regions of <i>MDR1</i>, BCRP, and MRP8 on valproate treatment. Furthermore, an alternative MRP8 promoter was induced by HDACi treatment.</p><p><b>Conclusions:</b> Exposure of AML cells to HDACi induces a drug resistance phenotype broader than the “classic multidrug resistance,” which might negatively affect treatment effectiveness.</p></div>

Supplementary Figure 2 from Combining Oncolytic HSV-1 with Immunogenic Cell Death-Inducing Drug Mitoxantrone Breaks Cancer Immune Tolerance and Improves Therapeutic Efficacy

Abstract: <p>PDF file - 463K, Supplementary figure 2. Percent survival and fold changes in tumor volume after treatment with KM100 and/or 1 microM MTX</p>

Supplementary Figure 3 from Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

Abstract: <p>PDF file - 1076K, Kaplan-Meier plot of PFS by tumor MET subgroups in the combined rilotumumab and control arms (A) and forest plot of the biomarker effect of high versus low tumor MET expression on PFS within the combined rilotumumab and control arms (B). MP, mitoxantrone and prednisone; NA, not applicable.</p>

Preliminary results of gemcitabine, etoposide, mitoxantrone hydrochloride liposome and dexamethasone regimen for newly diagnosed early nuat or advanced stage enktl

Abstract: Introduction: Extra-nodal NK/T-cell lymphoma (ENKTL) is an aggressive disease common in Asia but rare in the West. More than two-thirds of persons have stage I/II disease of the upper aero-digestive tract (UAT), which have relatively superior prognosis. However, patient of early non-UAT (NUAT) or advanced stage show an aggressive clinical course with extremely poor prognosis and low survival rates. Mitoxantrone hydrochloride liposome has reported to have efficacy in relapsed/ refractory (R/R) ENKTL in a phase II clinical trial. Furthermore, patient of early NUAT or advanced stage always have hemophagocytic lymphohistiocytosis (HLH) at diagnosis. Therefore, etoposide and high dose dexamethasone were also important for these patients. Based on these facts, this study evaluates the efficacy and safety of the regimen of gemcitabine, etoposide, mitoxantrone hydrochloride liposome, and dexamethasone (P-GEMD) in patients of newly diagnosed early NUAT or advanced stage ENKTL. Methods: Patients diagnosed as ENKTL in early NUAT and advanced stage form 18‒80 years with ECOG of 0‒2 were eligible for enrollment. We planned a maximum of 6 cycles of P-GEMD regimens for patients. The P-GEMD regimen was administered intravenously every 3 weeks until disease progression (PD) or unacceptable toxicity as follows (Figure 1A): pegaspargase at 2500 IU/m2 d2; gemcitabine at 1000 mg/m2, d1; etoposide at 65 mg/m2, d2‒4; mitoxantrone hydrochloride liposome at 12 mg/m2, d1; dexamethasone at 40 mg/d, d1‒4. The primary endpoint is complete response rate (CRR). The second endpoint are overall response rate (ORR), duration of response (DOR) and 1-year overall survival (OS) and progression-free survival (PFS). Results: Five patients were preliminarily planned for P-GEMD regimens. Median age was 51y (range 44‒60 y). All the five patients were advanced stage with B symptoms. The median PINK and PINK-E score was 2 (range 2‒4) and 3 (range 3‒4), respectively. Two patients experienced HLH at diagnosis. All the five patients completed the induction of P-GEMD regimens with the median cycles of 6 (range 3‒6). Only 1 patient experienced PD while the other 4 patients were evaluated as CR by PET-CT. Therefore, the CRR is 80% (Figure 1B). Furthermore, the 4 patients with CR evaluated by PET-CT were all negatively for minimal residual disease (circulating tumor DNA) checked by next generation sequencing (NGS) while the ctDNA burden of patient with PD was positive (Figure 1C-G). There were 30 adverse events (AEs) recorded, of which 86.7% were grade 1 or 2. Hypo-fibrinogenemia, hypo-albuminemia and asparate transaminase increase were the most common grade 3 or 4 AEs (Figure 1H). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Chemotherapy, Combination Therapies No conflicts of interests pertinent to the abstract.

Supplemental methods from A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia

Abstract: <p>Supplemental methods</p>

[Therapeutic Strategies and Disease-Modifying Therapies for Multiple Sclerosis].

Abstract: Multiple sclerosis is an inflammatory demyelinating disease of unknown cause that affects the central nervous system. Although it was once deemed "incurable," many disease-modifying therapies have been introduced since the beginning of the 20th century; eight of these are now available in Japan. Treatment for multiple sclerosis is undergoing a significant shift from the safety-oriented "escalation strategy," in which the patient is initially administered medications with low risks of side effects but moderate efficacy, to a "personalized approach" based on individual prognostic factors followed by an "early top-down strategy" in which higher efficacy treatments are initiated first. Disease-modifying drugs for multiple sclerosis can be high- (fingolimod, ofatumumab, natalizumab) or moderate-efficacy (interferon beta, glatiramer acetate, dimethyl fumarate), and there are also disease-modifying therapies for secondary progressive multiple sclerosis (siponimod and ofatumumab). Approximately 20,000 Japanese patients have multiple sclerosis, and this number continues to increase. Many neurologists are expected to prescribe high-efficacy drugs in the future. The risk management of adverse events, particularly progressive multifocal leukoencephalopathy, is required to ensure that the importance of safety never be underestimated, even though treatment efficacy is the main focus.

Phase II trial evaluating olaparib maintenance in patients with metastatic castration resistant prostate cancer (mCRPC) after docetaxel treatment, reaching partial or stable response: SOGUG-IMANOL study.

Abstract: 168 Background: Prostate cancer is the second most common cancer in men. A number of important systemic therapies have been developed to treat mCRPC and now comprise the current therapeutic landscape. Docetaxel became the first systemic therapy to improve survival in these men in a randomized study demonstrating superiority versus mitoxantrone (18.9 months versus 16.5, p=0,004). But, inexorably, after stopping, disease progresses. Methods: A prospective phase II trial was designed to test Olaparib maintenance efficacy, in terms of progression free survival (PFS), in patients with mCRPC with DNA-repair defects that have achieved partial or complete response after being treated with systemic therapy (at least six cycles of docetaxel). Results: 134 mCRPC patients were included since Feb-2018 to Nov-2020 and were tested for DDR alterations. 19.4% of patients had somatic mutations (30.8% BRCA2, 3.8% BRCA1, 19.2% ATM, 7.7% CHEK2, 7.7% PALB2). 53,8% received Olaparib maintenance treatment, with a median follow-up of 23.3 months. Median age was 73 years. Median basal PSA was 17 ng/dL. 100% were metastatic (14.3% de novo and 85.7% relapsed after primary treatment), 78.6% had bone metastasis, 35.7% visceral and 35.7% adenopathies. 42.9% had previous treatment with abiraterone and 35.7% with enzalutamide. 46.2% received at least 8 cycles of docetaxel. 7.1% achieved a partial response and 92.9% a disease stabilization. Response to Olaparib treatment was 14.3% partial response, 71.4% stabilization and 7.1% disease progression.14.3% had a PSA50 decrease. Median duration of response was 8.27 months. Median PFS was 10.1 months. Median PSA-PFS was 3.5 months. G3/4 adverse events were 21.4% asthenia,14.3% anemia and 7.1% neutropenia. Conclusions: Olaparib maintenance after at least six cycles of docetaxel shows promising activity in mCRPC with DDR alterations, with an acceptable toxicity profile. Our pathogenic mutations percentage (19,4%) is in line with previous publications. Clinical trial information: NCT03434158 .

Supplemental methods from A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia

Abstract: <p>Supplemental methods</p>

Supplementary Figure 1 from Combining Oncolytic HSV-1 with Immunogenic Cell Death-Inducing Drug Mitoxantrone Breaks Cancer Immune Tolerance and Improves Therapeutic Efficacy

Abstract: <p>PDF file - 205K, Supplementary figure 1. Addition of MTX does not enhance KM100 virus replication</p>

Data from XPO1 Inhibition using Selinexor Synergizes with Chemotherapy in Acute Myeloid Leukemia by Targeting DNA Repair and Restoring Topoisomerase IIα to the Nucleus

Abstract: <div>Abstract<p><b>Purpose:</b> Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore, we asked whether adding already established effective drugs such as topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML.</p><p><b>Experimental Design:</b> The efficacy of combinatorial drug treatment using Topo II inhibitors (idarubicin, daunorubicin, mitoxantrone, etoposide) and selinexor was evaluated in established cellular and animal models of AML.</p><p><b>Results:</b> Concomitant treatment with selinexor and Topo II inhibitors resulted in therapeutic synergy in AML cell lines and patient samples. Using a xenograft MV4-11 AML mouse model, we show that treatment with selinexor and idarubicin significantly prolongs survival of leukemic mice compared with each single therapy.</p><p><b>Conclusions:</b> Aberrant nuclear export and cytoplasmic localization of Topo IIα has been identified as one of the mechanisms leading to drug resistance in cancer. Here, we show that in a subset of patients with AML that express cytoplasmic Topo IIα, selinexor treatment results in nuclear retention of Topo IIα protein, resulting in increased sensitivity to idarubicin. Selinexor treatment of AML cells resulted in a c-MYC–dependent reduction of DNA damage repair genes (<i>Rad51</i> and <i>Chk1</i>) mRNA and protein expression and subsequent inhibition of homologous recombination repair and increased sensitivity to Topo II inhibitors. The preclinical data reported here support further clinical studies using selinexor and Topo II inhibitors in combination to treat AML. <i>Clin Cancer Res; 22(24); 6142–52. ©2016 AACR</i>.</p></div>

Supplementary Figure Legend from Combining Oncolytic HSV-1 with Immunogenic Cell Death-Inducing Drug Mitoxantrone Breaks Cancer Immune Tolerance and Improves Therapeutic Efficacy

Abstract: <p>PDF file - 75K</p>

Supplementary Figure 1 from Combining Oncolytic HSV-1 with Immunogenic Cell Death-Inducing Drug Mitoxantrone Breaks Cancer Immune Tolerance and Improves Therapeutic Efficacy

Abstract: <p>PDF file - 205K, Supplementary figure 1. Addition of MTX does not enhance KM100 virus replication</p>

Sequential salvage chemotherapy and lintuzumab-Ac225 results in deep responses and prolonged survival in adverse risk relapsed/refractory AML and in AML patients that received prior venetoclax therapy.

Abstract: e19030 Background: Lintuzumab-Ac225 is a humanized CD33 antibody conjugated to an alpha emitting isotope, Ac225, delivering high energy radiation to CD33 expressing AML blasts. Preclinical studies indicate Lintuzumab-Ac225 also depletes the anti-apoptotic protein MCL-1, which is a known resistance factor in BCL2-inhibitor (venetoclax (Ven)) exposed patients (pts). We performed a Phase I study where Lintuzumab-Ac225 was administered after salvage chemotherapy, and this study demonstrated safety and encouraging response rates in R/R AML. Herein, we report results of high-risk patients who enrolled to this study. Methods: R/R AML pts deemed fit, and with CD33 expression on >25% of blasts were enrolled onto a Phase I study, Lintuzumab-Ac225 in Combination with Cladribine + Cytarabine + Filgrastim + Mitoxantrone (CLAG-M). Induction consisted of G-CSF, 300mcg/d on D1-6, cladribine 5mg/m2 on D2-6, cytarabine 2g/m2 on D2-6, and mitoxantrone 10mg/m2 on D2-4. Lintuzumab-Ac225 was administered once on D8 ±1 day. The trial enrolled to 4 cohorts, with Lintuzumab-Ac225 at doses ranging from 0.25 uCi/kg to 1.0 uCi/kg. We defined high-risk pts as those who met ELN 2019 criteria for adverse risk disease, or pts who received a Ven combination prior to trial enrollment. Response is descriptively reported, and KM estimator was used to report overall survival (OS). Results: 19 pts on trial met high-risk criteria. Of these, 16 pts had ELN adverse risk disease, a TP53 mutation was detected in 75% (n=12) of pts. Median age was 65 yrs, pts received a median 2 lines of prior therapy, including prior allo-HCT in 58% (n=11), and prior Ven combination in 68% (n=13) of pts. In high-risk pts, 42% (n=8) of pts achieved CRc (CR+CRi), 16% (n=3) achieved MLFS, for an overall response rate (ORR) of 58%. Among evaluable pts achieving CRc, 71% achieved flow MRD negativity. Median OS was 7.4 months. Table reports results in select subgroups. Prior to treatment initiation, 7 pts were deemed eligible for first HCT. 4 (57%) were successfully able to bridge to HCT. Median survival among transplanted pts was 28 months. Post-HCT, one pt died due to GVHD, one due to relapse. Conclusions: CLAG-M in combination with Lintuzumab-Ac225 yielded significantly better clinical outcomes in high-risk populations, particularly in pts previously treated with Ven combinations (median OS 13.8 mo.) and in pts with TP53 mutations (median OS 7.3 mo.), for which recent studies have reported a survival of 4 months or less. The results support further advance in late-stage clinical development of Lintuzumab-Ac225 in combination with CLAG-M in R/R AML, especially in high-risk pts. Clinical trial information: NCT03441048 . [Table: see text]

Data from A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia

Abstract: <div>Abstract<p><b>Purpose:</b> CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.</p><p><b>Experimental Design:</b> The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.</p><p><b>Results:</b> Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.</p><p><b>Conclusions:</b> The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. <i>Clin Cancer Res; 24(9); 2060–73. ©2018 AACR</i>.</p></div>