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Marburg variant is a severe and fulminant pseudotumor form of multiple sclerosis (MS) with high morbidity and mortality rates. Because of its scarcity, it remains incompletely characterized and physicians' experiences will influence the treatment. We report the inflammatory explosive case of a 31-year-old woman presenting with rapid neurological degradation of histology proven Marburg's disease, successfully treated with early administration of Mitoxantrone (MITX). To our knowledge, it is the first case describing complete remission after MITX in a biopsy-proven condition.

Background Despite multiple reports of chemotherapy overdoses (ODs) in human and veterinary medicine, anthracycline ODs have been described infrequently. Hypothesis/Objectives Describe toxicities, treatments, and overall outcome after anthracycline OD in dogs. Animals Twelve mitoxantrone (MTX) and 4 doxorubicin (DOX) ODs were evaluated. Methods Multicenter retrospective analysis. The American College of Veterinary Internal Medicine oncology and internal medicine listservs were solicited for cases in which a chemotherapy OD occurred. Results Sixteen anthracycline cases were collected. Anthracycline ODs occurred because of an error in chemotherapy preparation (n = 9), or dose miscalculation (n = 7). The overall median OD was 1.9× (range, 1.4‐10×) the prescribed amount. Most ODs were identified immediately after drug administration (n = 11), and the majority of patients were hospitalized on supportive care (n = 11) for an average of 8 days (range, 3‐34 days). Adverse events after the OD included neutropenia (94%), thrombocytopenia (88%), anemia (63%), diarrhea (63%), anorexia (56%), vomiting (38%), lethargy (31%), and nausea (25%). Two patients did not survive the OD. High grade neutropenia was common and did not appear to be mitigated by the administration of filgrastim. Conclusions and Clinical Importance All patients received supportive care after identifying the OD and death was uncommon. Further evaluation is needed to determine ideal therapeutic guidelines anthracycline OD.

We investigated the efficiency of mitoxantrone (MIT) and high-dose cytarabine (Ara-C) chemotherapy followed by G-CSF and G-CSF/GM-CSF treatments for the mobilization of peripheral blood stem cells (PBSCs) in patients with leukemia and lymphoma. MIT was intravenously injected at 10 mg/(m2·d) for 2 to 3 days, followed by Ara-C injected intravenously at 2 g/m2 every 12 hours for 1 to 2 days. When white blood cell count recovered from the lowest value, 5 to 7.5 μg/ (kg·d) G-CSF was administered in 23 patients for 5 to 7 successive days. Another 27 patients received 3-5 μg/ (kg·d) G-CSF and 3-5μg/ (kg·d) GM-CSF. Autologous peripheral blood mononuclear cells were collected. Levels of CFU-GM and CD34+ cells were determined after unfreezing. The CD34+ cells and CFU-GM yields of 27 patients in G-CSF plus GM-CSF combination group [(8.79±3.11)×106/kg, (3.52±1.34)×105/kg, respectively] were significantly higher than those of patients receiving G-CSF alone (n=23) [(6.14±2.06)×106/kg, (2.03±1.06)×105/kg, respectively (P < 0.05)]. No obvious changes of T lymphocyte subsets in patients were observed when using G-CSF/GM-CSF, but levels of CD34+ cells increased gradually (P>0.05). The end-point separation blood volume was all above trebling TBV. No severe complications were observed during the mobilization and collection. Autologous PBSCT obtained quick hematopoietic reconstitution. In conclusion, MA chemotherapy combined with G-CSF alone and G-CSF/GM-CSF can safely and effectively mobilize autologous PBSCs, while G-CSF plus GM-CSF is superior to G-CSF alone. Large volume leukapheresis is an important method to enhance the production rate of stem cells and decrease harvesting time.

Purpose Curative intended treatment is challenging in patients with relapsed or refractory acute myeloid leukemia (r/r AML) and associated with a dismal prognosis for long-term survival. Despite novel treatment options, the majority of patients are treated with chemotherapy-based regimens. Although widely used, little data exist on the combination of fludarabine, cytarabine, granulocyte colony stimulating factor (FLAG) and mitoxantrone as salvage strategy for r/r AML. Materials and methods Sixty-six patients receiving Mito-FLAG for r/r AML treated at a German tertiary care center between 2009 and 2019 were analyzed with regard to response rates, survival and safety profile. Results Overall response rate was 75.8% with 56.1% of patients achieving complete remission (CR) and 19.7% partial remission (PR). After a median follow-up of 54 months, median overall survival (OS) was 13 months. Patients transitioned to allogeneic hematopoietic stem cell transplantation (alloHSCT) (75.8%) showed a significant improvement in OS with a median OS of 17 (95% CI 8.5–25.4) months vs 3 (95% CI 1.7–4.3) months (p Conclusion The Mito-FLAG salvage protocol represents an effective and feasible treatment regimen for r/r AML. Importantly, a high rate of transition to successful alloHSCT with the aim of long-term disease-free survival has been shown.

OBJECTIVES To assess calcium-phosphate parameters in SPMS patients treated with mitoxantrone (MTX). METHODS Thirty eight SPMS patients eligible for MTX therapy in the Department of Neurology in Zabrze, Poland were enrolled in a prospective study from March 2016 to November 2019. The parameters of serum calcium-phosphate metabolism and the neurological status according to the Expanded Disability Status Scale (EDSS) were assessed. In patients with hypovitaminosis D, vitamin D (VitD) supplementation was introduced (4000 IU/day for 1 month and later 2000 IU /day). RESULTS Most patients were women [57.89%]. The mean age [years] was 56.11 (±7.74). The median time from diagnosis to inclusion day (ID) was 7.50 [4.00-14.00] [years]. Due to VitD supplementation, an increase in serum VitD was observed during the study. 84.21% of patients presented with hypovitaminosis D before MTX treatment compared to 47.37% after treatment. Before MTX therapy, none of the patients underwent surgical repair of the fracture compared to 42.11% of patients after MTX treatment (p

INTRODUCTION The present case describes the treatment of a mucoepidermoid carcinoma in a 13-year-old female sterilized European domestic cat, using lung lobectomy and -accompanying mitoxantrone chemotherapy. Six, 14, 19 and 27 months after the initial treatment tomodensitometric and radiographic examinations showed no abnormalities. However, the cat had to be euthanized 27 months after the lung lobectomy due to a soft tissue sarcoma in the interscapular area.

Background: Canine lymphoma is one of the most frequently occurring malignant neoplasms in dogs. Anthracycline-based chemotherapy for the treatment of canine lymphoma is very effective; however, there is not enough evidence for the development of cardiac toxicity using several anthracyclines as chemotherapeutic agents. Case Description: An 8-year-old, castrated, mixed-breed dog was diagnosed with multicentric lymphoma and received multi-agent chemotherapy. Complete remission was achieved, but the patient had a relapse of lymphoma. After third-line chemotherapy with epirubicin, the patient was diagnosed with dilated cardiomyopathy. The total cumulative doses of doxorubicin, mitoxantrone, and epirubicin were 125, 8, and 125 mg/m2, respectively. Although the patient was treated with cardiac drugs and clinically stabilized, the patient had a relapse of lymphoma and died shortly after the diagnosis of cardiomyopathy. Conclusion: The patient was suspected to have anthracycline-induced cardiomyopathy. Further studies are required to establish prevention and management strategies for dogs receiving potentially cardiotoxic therapies, such as anthracyclines.

PURPOSE The optimum number of treatment courses for younger patients with acute myeloid leukemia (AML) is uncertain. The United Kingdom National Cancer Research Institute AML17 trial randomly assigned patients who were not high risk to a total of three versus four courses. PATIENTS AND METHODS Patients received two induction courses based on daunorubicin and cytarabine (Ara-C), usually with gemtuzumab ozogamicin. Following remission, 1,017 patients were randomly assigned to a third course, MACE (amsacrine, Ara-C, and etoposide), plus a fourth course of MidAc (mitoxantrone and Ara-C) and following an amendment to one or two courses of high-dose Ara-C. Primary end points were cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS). Outcomes were correlated with patient characteristics, mutations, cytogenetics, induction treatments, and measurable residual disease (MRD) postinduction. RESULTS In logrank analyses, CIR and RFS at 5 years were improved in recipients of four courses (50% v 58%: hazard ratio [HR] 0.81 [0.69-0.97], P = .02 and 43% v 36%: HR 0.83 [0.71-0.98], P = .03, respectively). While OS was not significantly better (63% v 57%: HR 0.84 [0.69-1.03], P = .09), the noninferiority of three courses to four courses was not established. The impact on relapse was only significant when the fourth course was Ara-C. In exploratory analyses, although MRD impacted survival, a fourth course had no effect in either MRD-positive or MRD-negative patients. A fourth course was beneficial in patients who lacked a mutation of FLT3 or NPM1, had < 3 mutations in other genes, or had a presenting WBC of < 10 × 109 L−1. CONCLUSION Although a fourth course of high-dose Ara-C reduced CIR and improved RFS, it did not result in a significant OS benefit. Subsets including those with favorable cytogenetics, those lacking a mutation of FLT3 or NPM1, or those with < 3 other mutations may derive survival benefit.

Background Locoregional tumor control and prolonged survival for dogs with genitourinary carcinoma (CGUC) reportedly are achievable using treatment with radiotherapy (RT) with or without adjunctive chemotherapy and nonsteroidal anti‐inflammatory drugs (NSAIDs). Objectives To characterize event‐free and overall survival after treatment of CGUC using NSAIDs, mitoxantrone (MTX), and a standardized RT protocol (57 Gy in 20 fractions). Animals Fifty‐one client‐owned dogs treated between 2008 and 2017. Methods Dogs were retrospectively categorized into treatment groups: (a) first‐line concurrent chemoradiotherapy (≥1 dose of MTX started within 1 month of RT); (b) first‐line chemotherapy (MTX administered for >1 month before RT without tumor progression); (c) RT as a salvage procedure (MTX, surgery or both with subsequent locoregional tumor progression before RT). Treatment‐induced toxicoses, event‐free survival (EFS), and overall survival times (OSTs) were recorded. The influence of demographics, staging, and treatment‐related factors on survival was assessed using Cox proportional hazards modeling. Results Median EFS and OST for all dogs were 260 and 510 days with no significant differences among groups 1 (n = 39), 2 (n = 4), and 3 (n = 8). Both EFS and OST were shorter in dogs with moderate to severe clinical signs (P

Background Disease-modifying therapies (DMTs) for multiple sclerosis (MS) target immunity and have the potential to increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and alter its clinical course. We assessed these risks in patients with MS (PwMS). Objective The objective of this study was to describe the overall risk of coronavirus disease 2019 (COVID-19) infection, severe disease course, and potential population-level predictors of COVID-19 infection in PwMS, and to provide a context using a cohort of patients with systemic lupus erythematosus (SLE). In addition, the association of different MS DMTs with the incidence and clinical course of COVID-19 was evaluated. Safety data from the Biogen Global Safety Database are also presented on reported cases of COVID-19 in patients treated with Biogen MS therapies. Methods The IBM® Explorys electronic health record database of > 72,000,000 patients from US healthcare networks identified patients with MS or SLE, with and without polymerase chain reaction-confirmed COVID-19. COVID-19 cumulative incidence, hospitalization, and deaths among DMT classes were compared using logistic regression (adjusted for age, sex, body mass index, comorbidities, and race/ethnicity). As a secondary data source to assess safety data, COVID-19 reports for Biogen MS therapies were extracted and described from Biogen’s Global Safety Database. Results 30,478 PwMS with an open DMT prescription were identified within Explorys; 344 were COVID-19 positive. The most significant risk factors for acquiring COVID-19 were comorbidity score ≥ 1, body mass index ≥ 30, and Black/African ancestry. Similar risk factors were also identified for patients with SLE. Patients with MS were less likely to develop COVID-19 when treated with interferons (0.61%) and glatiramer acetate (0.51%), vs all other MS DMTs (both p < 0.001); anti-CD20 therapy was associated with the highest risk (3.45%; p < 0.0001). In the Biogen Global Safety Database, we identified 1217 patients who were COVID-19 positive treated with intramuscular interferon beta-1a, peginterferon beta-1a, natalizumab, dimethyl fumarate, diroximel fumarate, or fampridine. Conclusions Comorbidities, obesity, and Black/African ancestry, but not age, were associated with a higher risk of SARS-CoV-2 infection in PwMS. Interferons and glatiramer acetate were associated with a reduced COVID-19 risk, whereas anti-CD20 therapies were associated with an increased risk, within the treated MS cohort. COVID-19 safety reports for patients receiving Biogen MS therapies were consistent with the Explorys database and MS literature, illustrating the replicability and power of this approach. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00804-1.

Background The preferred salvage treatment for children with relapsed/refractory acute myeloid leukemia (R/R‐AML) remains unclear. The combination of cladribine/Ara‐C/granulocyte‐colony stimulating factor and mitoxantrone (CLAG‐M) shown promising results in adult R/R‐AML. We aim to investigate the efficacy and safety of CLAG‐M versus mitoxantrone/etoposide/cytarabine (MEC) or idarubicin/etoposide/cytarabine (IEC) in R/R‐AML children. Methods Fifty‐five R/R‐AML children were analyzed. The overall response rate (ORR), overall survival (OS), and progression‐free survival (PFS) at 3‐year were documented. Karyotype or mutations status were summarized as different risk groups. Results The ORR was achieved in 80% (16/20) and 51% (18/35) of patients after one‐cycle of CLAG‐M and MEC/IEC treatment (p, CLAG‐M regimen is a more valid option with similar adverse events as a salvage treatment for R/R‐AML in children when compared with conventional chemotherapy no matter in which risk group.

Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myelogenous leukemia (AML) and the mutation is associated with poor prognosis of patients. Two distinct types of activating mutations have been identified in AML samples. One is internal tandem duplications in the juxtamembrane domain (FLT3-ITD) and the other is point mutations in the tyrosine kinase domain (FLT3-TKD). Gilteritinib is a FLT3 inhibitor that inhibits both FLT3-ITD and FLT3-TKD. It was reported that differentiation of leukemic blasts accompanied by differentiation syndrome occurs in some patients treated with gilteritinib. However, information about the precise clinical course is limited, and appropriate management of differentiation syndrome has not been established. We report a case of relapsed AML with FLT3-ITD that was treated with gilteritinib. Analysis of the FLT3-ITD variant allele frequency (VAF) revealed that FLT3-ITD VAF was not decreased despite achievement of complete remission with incomplete hematologic recovery. Remarkable increases of monocytes and granulocytes accompanied by differentiation syndrome were observed at 6 months after the initiation of gilteritinib treatment. Intermittent chemotherapy with low-dose cytarabine and mitoxantrone was effective for reducing myelomonocytosis and resolving differentiation syndrome.

Purpose To investigate the effects of mitoxantrone and daunorubicin in induced chemotherapy on complete remission (CR), death during induction therapy, overall survival (OS), disease-free survival (DFS), and relapse in patients of all ages with acute myeloid leukemia (AML). Methods We searched published reports at the Medline, Embase, and Cochrane Databases as well as other databases from inception through July 2019. There was no restriction on date of publication or language (PROSPERO registration CRD42018095843). Results We enrolled 12 randomized controlled trials that included data of 4583 AML patients whose disease was untreated or relapsed/refractory, and compared the CR, death during induction therapy, DFS, and OS between mitoxantrone and daunorubicin. Mitoxantrone significantly increased the CR rate (relative risk = 1.07; 95% confidence interval [CI], 1.01, 1.14; P = .03) and DFS (hazard ratio = 0.87; 95% CI, 0.79, 0.96; P = .005) compared to daunorubicin. However, there was no significant difference in death during induction therapy (relative risk = 1.00; 95% CI, 0.81, 1.24; P = .99) and OS (hazard ratio = 0.94; 95% CI, 0.87, 1.01; P = .077) between the two drugs. Conclusion Although more studies are needed to compare mitoxantrone with higher-dose daunorubicin, the results showed that compared to daunorubicin, mitoxantrone can significantly improve CR and DFS in patients of all ages. These findings suggest that mitoxantrone may be a better choice than daunorubicin as an induction chemotherapy agent for AML patients, especially in developing countries.

Background/aim The objectives of this study were to evaluate systemic inflammation using different sclerosing agents and to estimate the prediction of systemic inflammation for the efficacy of pleurodesis. Patients and methods Ninety-six patients with recurrent and symptomatic malignant pleural effusion were enrolled in this retrospective study. We used serum C-reactive protein (CRP) levels, serum leukocyte counts and neutrophil-to-lymphocyte ratios (NLRs) as parameters of systemic inflammatory reactions. Evaluations of these parameters were performed before and 24 h after pleurodesis. Results Pleurodesis was successful in 81 (84.4%) patients. The non-graded talc induced the highest changes in serum CRP levels, total white blood cell and neutrophil counts compared to other agents, while mitoxantrone induced the lowest. Graded talc and bleomycin induced the same levels of changes in serum CRP levels and serum leukocyte counts. The change in serum NLR was the same for all agent groups. Logistic regression confirmed that a change in serum CRP levels [odds ratio (OR)=0.92, p=0.002] and previous chemotherapy (OR=3.31, p=0.012) were independent predictors of pleurodesis efficacy. Conclusion Pleurodesis agents induced a systemic inflammatory response at different levels. The change in serum CRP levels could be useful for predicting the success of pleurodesis.

We conducted a prospective study to evaluate the efficacy and safety of cladribine, cytarabine, mitoxantrone, and granulocyte colony-stimulating factor (CLAG-M) regimen combined with busulfan and cyclophosphamide (BuCy) as new intensive conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of relapsed/refractory acute myeloid leukemia (AML). 24 patients were enrolled. The median follow-up was 15.2 months (range 1.9-67.0 months). Except for one patient who died before graft infusion, the evaluable 23 patients (96%) achieved complete remission (CR). The two-year overall survival (OS) rate and leukemia-free survival (LFS) rate were 61.4% and 59.4%, respectively. The non-relapse mortality (NRM) was 9.1%. Univariate analysis revealed that the myeloid blast phase of chronic myelomonocytic leukemia (CMML), an EVI1 mutated, blood blasts ≥20% at transplant, and extramedullary disease were risk factors for LFS.

Canine malignant mesothelioma (CMM) is a rare and aggressive tumour associated with a poor prognosis. Limited information is available regarding effective treatment options and prognostic factors. The purpose of this retrospective case series was to describe the clinical presentation, treatment and survival in a cohort of dogs with this disease and to investigate possible prognostic factors. Thirty-four dogs were included. Tachypnoea and dyspnoea due to pleural effusion were the most common presenting clinical signs. Twenty-two dogs had a subcutaneous access port placed and 25 dogs were treated with intracavitary and/or intravenous chemotherapy. The main protocols used were single-agent 5-FU (n = 14) and carboplatin single-agent or alternated with mitoxantrone (n = 10). The overall response rate (defined as more than 25% reduction in effusion volume) to chemotherapy treatment was 37% after 3-weeks and 24% after 15-weeks. The median survival time (MST) for all dogs was 195 days (95% CI 53-324). MST was 234 days for dogs receiving chemotherapy and 29 days for dogs not receiving chemotherapy. The 1-year survival rate was 22% for all dogs. Treatment with chemotherapy was the only significant prognostic factor associated with survival (p = 0.001). Further studies are needed to determine the optimal treatment approach for malignant mesothelioma in dogs. Nevertheless, effusion recurrence should be expected and the prognosis for these patients in the long-term is poor. This article is protected by copyright. All rights reserved.

Oncogenic activation of the mTOR signaling pathway occurs frequently in tumor cells and contributes to the devastating features of cancer, including breast cancer. mTOR inhibitors rapalogs are promising anticancer agents in clinical trials; however, rapalogs resistance remains an unresolved clinical challenge. Therefore, understanding the mechanisms by which cells become resistant to rapalogs may guide the development of successful mTOR-targeted cancer therapy. In this study, we found that eEF-2K, which is overexpressed in cancer cells and is required for survival of stressed cells, was involved in the negative-feedback activation of Akt and cytoprotective autophagy induction in breast cancer cells in response to mTOR inhibitors. Therefore, disruption of eEF-2K simultaneously abrogates the two critical resistance signaling pathways, sensitizing breast cancer cells to rapalogs. Importantly, we identified mitoxantrone, an admitted anticancer drug for a wide range of tumors, as a potential inhibitor of eEF-2K via a structure-based virtual screening strategy. We further demonstrated that mitoxantrone binds to eEF-2K and inhibits its activity, and the combination treatment of mitoxantrone and mTOR inhibitor resulted in significant synergistic cytotoxicity in breast cancer. In conclusion, we report that eEF-2K contributes to the activation of resistance signaling pathways of mTOR inhibitor, suggesting a novel strategy to enhance mTOR-targeted cancer therapy through combining mitoxantrone, an eEF-2K inhibitor.

Standard post-remission therapy for adult patients with high-risk acute lymphoblastic leukemia (ALL) is allogeneic hematopoietic cell transplantation (allo-HCT). However, 20-30% of patients treated with allo-HCT subsequently relapse, and their long-term survival outcomes are very poor even after the next allo-HCT. The poor survival outcomes reported by previous studies have mainly been due to low complete remission (CR) rates and high mortality from conventional salvage chemo-regimens, such as mitoxantrone plus etoposide plus cytarabine (MEC) or fludarabine plus cytarabine plus idarubicin (FLA-Ida). However, several novel agents with proven high remission rates and a good measurable residual disease response can now be administered. The representative novel agents recently introduced are blinatumomab (anti-CD19 bispecific T-cell engager) and inotuzumab ozogamicin (anti-CD22 antibody- calicheamicin conjugate). In South Korea, blinatumomab has been used since October 2016 and inotuzumab ozogamicin has been in use since October 2019 under coverage by the national insurance system. Studies on blinatumomab in Korea showed that this drug is effective when used as an early salvage line, even in patients who relapse after an initial allo-HCT. However, a previous study revealed that relapsed patients with a short CR duration of < 12 months post-HCT show a poor response to blinatumomab compared to patients with a longer CR duration. Also, some early relapsed cases with active acute graft-versus-host disease (GVHD) show aggravated GVHD with the use of blinatumomab. No real-world data are available in Korea for inotuzumab, but previous trials have reported a good CR and proceeding rates to allo-HCT comparable to blinatumomab. We have experienced hepatotoxicity including venoocclusive disease in post-HCT relapsed patients treated with inotuzumab. (Korean J Med 2020;95:320-324)

Acute myeloid leukemia (AML) is a hematopoietic stem cell malignancy and the most common type of leukemia, with the 5-year relative survival rate of 19% in Europe. Chronic myeloid leukemia (CML) is a slowly progressive clonal malignant disease, and a myeloproliferative disorder which is derived from biphasic hematopoietic stem cells but driven by progenitor cells. AML following CML is common, which can be caused by an antecedent myeloid malignancy, leukemogenic therapy, or without an identifiable prodrome or exposure to cytotoxic agents. However, the case of secondary chronic myeloid leukemia following acute myeloid leukemia treated with autologous hematopoietic stem cell transplantation is rare.Here we report a unique case of secondary CML after AML treated by chemotherapy and autologous peripheral blood stem cell transplantation. The 34-year-old male was diagnosed with AML subtype M5b according to clinical features in 2011. The patient was treated with the MAE program (mitoxantrone, cytosine arabinoside, etoposide) for two courses, followed by the IAE program (idarubicin, cytosine arabinoside, etoposide) and cytosine arabinoside for consolidation chemotherapy. An autologous hematopoietic stem cell transplantation with prophylactic intrathecal methotrexate cytarabine and dexamethasone was initiated.Subsequently, the patient achieved complete remission in 2012. After 4 years, the patient presented with leukocyte elevation of more than 4 months, and then was diagnosed with secondary CML. Based on this diagnosis, and with respect to the patient's severely compromised overall condition, tyrosine kinase inhibitors (TKI) therapy was conducted in 2016. The patient achieved, and continue to be in, complete remission.The case expands the understanding of secondary CML and emphasizes the importance of oncological vigilance in patients with secondary CML after AML therapy.

R-FND (rituximab, fludarabine, mitoxantrone, and dexamethasone) can induce molecular remissions in indolent lymphoma. The addition of 90yttrium ibritumomab tiuxetan (90YIT) radioimmunotherapy following first-line induction treatment in patients with advanced follicular lymphoma (FL) may improve remission rates. We now report 10-year follow-up results from our sequential treatment approach with an abbreviated regimen of R-FND followed by 90YIT consolidation and rituximab maintenance. Forty-nine patients were enrolled; 47 received treatment. Patients had high-risk (FLIPI score ≥3) FL of grade 1-3A and stage III/IV with adequate hematologic function. Following R-FND, the complete and partial response rates were 91% and 8.5%, respectively. After 90YIT consolidation, the CR rate increased to 97%. The 10-year PFS rate was 49%. The most common non-hematologic, grade 3 or 4 adverse events were fatigue, dyspnea, and myalgia. Five developed myelodysplastic syndrome (MDS). This treatment approach is most appropriate in FLIPI-based high-risk patients whose outlook with standard therapy is inadequate.

Cardiac diseases in the growing population of childhood cancer survivors are of major concern. Cardiotoxicity as a consequence of anthracyclines and chest radiotherapy continues to be relevant in the modern treatment era. Mitoxantrone has emerged as an important treatment-related risk factor and evidence on traditional cardiovascular risk factors in childhood cancer survivors is accumulating. International surveillance guidelines have been developed with the aim to detect and manage cardiac diseases early and prevent symptomatic disease. There is growing interest in risk prediction models to individualize prevention and surveillance. This State-of-the-Art Review summarizes literature from a systematic PubMed search focused on cardiac diseases after treatment for childhood cancer. Here, we discuss the prevalence, risk factors, prevention, risk prediction, and surveillance of cardiac diseases in survivors of childhood cancer.

The outbreak of novel coronavirus (COVID-19), which began from Wuhan City, Hubei, China, and declared as a Public Health Emergency of International Concern by World Health Organization (WHO) on 30th January 2020. The present study describes how the available drug candidates can be used as a potential SARS-CoV-2 Mpro inhibitor by molecular docking and molecular dynamic simulation studies. Drug repurposing strategy is applied by using the library of antiviral and FDA approved drugs retrieved from the Selleckchem Inc. (Houston, TX, http://www.selleckchem.com) and DrugBank database respectively. Computational methods like molecular docking and molecular dynamics simulation were used. The molecular docking calculations were performed using LeadIT FlexX software. The molecular dynamics simulations of 100 ns were performed to study conformational stability for all complex systems. Mitoxantrone and Leucovorin from FDA approved drug library and Birinapant and Dynasore from anti-viral drug libraries interact with SARS-CoV-2 Mpro at higher efficiency as a result of the improved steric and hydrophobic environment in the binding cavity to make stable complex. Also, the molecular dynamics simulations of 100 ns revealed the mean RMSD value of 2.25 Å for all the complex systems. This shows that lead compounds bound tightly within the Mpro cavity and thus having conformational stability. Glutamic acid (Glu166) of Mpro is a key residue to hold and form a stable complex of reported lead compounds by forming hydrogen bonds and salt bridge. Our findings suggest that Mitoxantrone, Leucovorin, Birinapant, and Dynasore represents potential inhibitors of SARS-CoV-2 Mpro., GRAPHICAL ABSTRACT

INTRODUCTION Mixed-phenotype acute leukemia (MPAL) accounts for 1.2% to 5% of acute leukemia across age groups with intermediate prognosis. We evaluated clinicoepidemiological profiles and outcomes of MPAL. METHODS Records of children younger than 15 years of age with acute leukemia from January 2010 to December 2016 were reviewed on the basis of the MPAL WHO 2008 criteria. Treatment was uniform with a modified MCP-841 protocol. Descriptive analysis tools were used. Outcomes were measured by the Kaplan-Meier method on MedCalc, version 14.8.1. RESULTS Among 3830 children with acute leukemia in the study period, 2892 received treatment from our center, of whom 24 (0.83%) had MPAL, median age 9 years, with a male:female ratio of 3:1, and median white blood cell of 13.4×10/L. Common immunophenotypes were B/myeloid-12 (50%), T/myeloid-9 (37.5%), and B/T-lymphoid-3 (12.5%). Some B/myeloid cases had abnormal cytogenetics. Seventeen patients were evaluable for outcome. Sixteen patients underwent postinduction bone marrow and 13 (81%) achieved morphologic remission. Thirteen patients underwent flow cytometry-based minimal residual disease evaluation; 9 (69%) were

A substantial segment of patients with acute myeloid leukemia (AML) will relapse following an initial response to induction therapy or will prove to be primary refractory. High-dose cytarabine and mitoxantrone (HiDAC/MITO) is an established salvage therapy for these patients. We studied all adult patients with relapsed/refractory (R/R) AML who were treated with HiDAC/MITO in our center between the years 2008-2017. To determine whether responding patients harbored a unique molecular signature, we performed targeted next-generation sequencing (NGS) on a subset of patients. The study cohort consisted of 172 patients with a median age of 54 years (range 18–77). The composite complete remission rate was 58%; 11 patients (6%) died during salvage therapy. Median survival was 11.4 months with a 1-year survival rate of 48%. In multivariate analysis favorable risk cytogenetics [Odds ratio (OR)=0.34, confidence interval (CI) 95%, 0.17–0.68; P = 0.002], and de-novo AML (OR = 0.4, CI 95%, 0.16–0.98; P = 0.047) were independently associated with a favorable response. Patients who attained a complete remission had a median survival of 43.7 months compared with 5.2 months for refractory patients (p < 0.0001). Neither the FLT3-ITD and NPM1 mutational status nor the indication for salvage therapy significantly impacted on the response to HiDAC/MITO salvage. NGS analysis identified 20 different mutations across the myeloid gene spectrum with a distinct TP53 signature detected in non-responding patients. HiDAC/MITO is an effective salvage regimen in R/R AML, however patients with adverse cytogenetics or secondary disease may not benefit as much from this approach.

Clofarabine is active in refractory/relapsed acute myeloid leukemia (AML). In this phase 2 study, we treated 18‐ to 65‐year‐old AML patients refractory to first‐line 3 + 7 daunorubicin/cytarabine induction or relapsing after 3 + 7 induction and high‐dose cytarabine consolidation, with clofarabine (30 mg/m2/d, Days 1‐5), cytarabine (750 mg/m2/d, Days 1‐5), and mitoxantrone (12 mg/m2/d, Days 3‐5) (CLAM). Patients achieving remission received up to two consolidation cycles of 50% CLAM, with eligible cases bridged to allogeneic hematopoietic stem cell transplantation (allo‐HSCT). The mutational profile of a 69‐gene panel was evaluated. Twenty‐six men and 26 women at a median age of 46 (22‐65) years were treated. The overall response rate after the first cycle of CLAM was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematologic recovery, CRi: 21.2%). Twenty‐two CR/CRi patients underwent allo‐HSCT. The 2‐year overall survival (OS), relapse‐free survival (RFS), and event‐free survival (EFS) were 65.8%, 45.7%, and 40.2%, respectively. Multivariate analyses showed that superior OS was associated with CR after CLAM (P = .005) and allo‐HSCT (P = .005), and superior RFS and EFS were associated with allo‐HSCT (P, Fifty‐two patients with relapsed/refractory acute myeloid leukemia (AML) were treated with clofarabine, cytarabine, and mitoxantrone. The overall response rate (ORR) was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematological recovery, CRi: 21.2%), with 22 CR/CRi patients undergoing allogeneic hematopoietic stem cell transplantation (allo‐HSCT), while in CR; resulting in a 2‐year OS of 84.3% in CR patients and 90% in patients receiving allo‐HSCT. Clofarabine, cytarabine, and mitoxantrone resulted in high ORR and was safe in refractory/relapsed AML.

Aim of the study. To compare the clinical and neuroradiological efficacy of mitoxantrone (MTX) in various forms of multiple sclerosis (MS), to ascertain whether there is a new place for the drug in the treatment regimen of the disease, as well as to determine its safety profile. Clinical rationale for the study. Due to the increasing availability of new immunomodulatory therapies in multiple sclerosis (MS), there is a strong need to re-identify clinical variants and stages of the disease in which mitoxantrone (MTX) can be the most effective form of treatment. Materials and methods. This was a retrospective, non-randomised, observational study evaluating a cohort of 100 MS patients (36 relapsing-remitting – RRMS, 36 secondary progressive – SPMS, and 28 primary progressive – PPMS). 59% of the RRMS patients had discontinued immunomodulatory therapies (IMTs) within the two years preceding MTX infusion. Patients’ disability levels, based on the Kurtzke Expanded Disability Status Scale (EDSS) as well as haematological and echocardiographic parameters, were assessed at baseline and before every infusion. Magnetic resonance imaging (MRI) were performed at entry and after termination of treatment. Results. We observed a decrease in the median EDSS score from 4.0 at baseline to 3.5 at the end of MTX infusion in the RRMS subgroup, an increase from 4.5 to 5.25 in the PPMS subgroup, and a stable value of 5 points in the SPMS subgroup (p < 0.0001). During the treatment period, 97% of patients with initial RRMS were free of exacerbations. The baseline EDSS in the RRMS subgroup, as well as the ineffectiveness of previous IMTs, suggested the beginning of conversion to SPMS. We found an 86% decrease in the proportion of patients with gadolinium-enhancing lesions on MRI after MTX infusions. There were no lifethreatening adverse events of MTX during the period of evaluation. Conclusions and clinical implications. Mitoxantrone can be considered as a valuable therapeutic option for patients who are on the borderline of RRMS and SPMS.

Introduction Mitoxantrone is a chemotherapeutic agent approved for various diseases. The literature has been conflicting in classifying mitoxantrone as a vesicant or irritant. Case report We report a patient who had an extravasation of mitoxantrone. Mitoxantrone was administered in 50 ml normal saline. After mitoxantrone was completely infused, the site appeared edematous and the blue color of mitoxantrone developed beneath the skin. The patient reported pain. Management and outcome: The extravasation was treated with dexrazoxane and cold compresses. The pain improved each day. However, blistering developed five weeks later and the patient ultimately required surgical intervention for debridement and grafting. Discussion Extravasation events are rare and there are few controlled studies. Because of the similarities in chemical structures and mechanism of actions between mitoxantrone and anthracyclines, mitoxantrone extravasation is often treated similar to anthracyclines. Mitoxantrone's classification is unclear, as some literature classifies it as a vesicant and others as an irritant. Our case supports the categorization of mitoxantrone as a vesicant.

Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials were used to test the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients. The bone marrow samples were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts. We found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies.

Background Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML. Methods Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7. Results There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion. Conclusions The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777). Lay summary The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.

Pancreatic cancer (PC) represents an intriguing topic for researchers. To date, the prognosis of metastasized PC is poor with just 7% of patients exceeding a five-year survival period. Thus, molecular modifications of existing drugs should be developed to change the course of the disease. Our previously generated nanocages of Mitoxantrone (MIT) encapsulated in human H-chain Ferritin (HFt), designated as HFt-MP-PASE-MIT, has shown excellent tumor distribution and extended serum half-life meriting further investigation for PC treatment. Thus, in this study, we used the same nano-formulation to test its cytotoxicity using both in vitro and in vivo assays. Interestingly, both encapsulated and free-MIT drugs demonstrated similar killing capabilities on PaCa44 cell line. Conversely, in vivo assessment in a subcutaneous PaCa44 tumor model of PC demonstrated a remarkable capability for encapsulated MIT to control tumor growth and improve mouse survival with a median survival rate of 65 vs. 33 days for loaded and free-MIT, respectively. Interestingly, throughout the course of mice treatment, MIT encapsulation did not present any adverse side effects as confirmed by histological analysis of various murine tissue organs and body mass weights. Our results are promising and pave the way to effective PC targeted chemotherapy using our HFt nanodelivery platforms.

Oral squamous cell carcinoma (OSCC) is the most common malignant epithelial neoplasm and anatomical subtype of head and neck squamous cell carcinoma (HNSCC) with an average 5-year survival rate of less than 50%. To improve the survival rate of OSCC, the discovery of novel anti-cancer drugs is urgently needed. In the present study, we performed metanalysis of 5 gene expression datasets (GSE23558, GSE25099, GSE30784, GSE37991 and TCGA-OSCC) that resulted in 1851 statistically significant DEGs in OSCC. The DEGs were involved in key biological pathways that drive the progression of OSCC. A comprehensive protein-protein interaction (PPI) network was constructed from the DEGs and the top protein clusters (modules) were extracted in Cytoscape. The DEGs from the top modules were searched for antineoplastic agents using L1000CDS2 server. The search resulted in a total of 37 perturbing agents from which 12 well-characterized antineoplastic agents were selected. The selected 12 antineoplastic agents namely Teniposide, Palbociclib, Etoposide, Fedratinib, Tivozanib, Afatinib, Vemurafenib, Mitoxantrone, Idamycin, Canertinib, Dovitinib and Selumetinib. These drugs showed interactions with the over expressed hub genes that regulate cellular proliferation and growth in OSCC progression. These identified antineoplastic agents are candidates for their potential role in treating OSCC.

In Asia, including Taiwan, malignant tumors such as Hepatocellular carcinoma (HCC) one of the liver cancer is the most diagnosed subtype. Magnetic resonance imaging (MRI) has been a typical diagnostic method for accurately diagnosing HCC. When it is difficult to demonstrate non-enhanced MRI of tumors, radiologists can use contrast agents (such as Gd3+, Fe3O4, or FePt) for T1-weighted and T2-weighted imaging remain in the liver for a long time to facilitate diagnosis via MRI. However, it is sometimes difficult for T2-weighted imaging to detect small tumor lesions because the liver tissue may absorb iron ions. This makes early cancer detection a challenging goal. This challenge has prompted current research to create novel nanocomposites for enhancing the noise-to-signal ratio of MRI. To develop a method that can more efficiently diagnose and simultaneously treat HCC during MRI examination, we designed a functionalized montmorillonite (MMT) material with a porous structure to benefit related drugs, such as mitoxantrone (MIT) delivery or as a carrier for the FePt nanoparticles (FePt NPs) to introduce cancer therapy. Multifunctional FePt@MMT can simultaneously visualize HCC by enhancing MRI signals, treating various diseases, and being used as an inducer of magnetic fluid hyperthermia (MFH). After loading the drug MIT, FePt@MMT-MIT provides both MFH treatment and chemotherapy in one nanosystem. These results ultimately prove that functionalized FePt@MMT-MIT could be integrated as a versatile drugs delivery system by combining with MRI, chemotheraeutic drugs, and magnetic guide targeting. Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-01052-7.

BACKGROUND: High-risk pediatric acute myeloid leukemia confers a poor prognosis, and alternative strategies are needed to improve outcomes. We hypothesized that intensifying induction on the AAML1031 clinical trial would improve outcomes compared to the predecessor trial AAML0531. METHODS: Patients on AAML0531 received cytarabine (1600 mg/m(2))/daunorubicin (150 mg/m(2))/etoposide (ADE) for induction II and patients on AAML1031 received mitoxantrone (48 mg/m(2))/cytarabine (8000 mg/m(2)) (MA). Stem cell transplant (SCT) conditioning included busulfan/cyclophosphamide on AAML0531, whereas AAML1031 used busulfan/fludarabine and liberalized donor eligibility. Patients were included in this analysis if they met high-risk criteria common to the two trials by cytogenics or poor disease response after induction I ADE. RESULTS: MA provided no benefit over ADE at: induction II response (complete response [CR]: 64% vs. 62%, p = .87; measurable residual disease [MRD]+: 57% vs. 46%, p = .34); or intensification I response (CR: 79% vs. 94%, p = .27; MRD+: 27% vs. 20%, p = 1.0). When considered with altered SCT approach, MA did not improve 5-year disease-free survival (24% ± 9% vs. 18% ± 15%, p = .63) or 5-year overall survival (35% ± 10% vs. 38% ± 18%, p = .66). MA was associated with slower neutrophil recovery (median 34 vs. 27 days, p = .007) and platelet recovery (median 29 vs. 24.5 days, p = .04) and longer hospital stay (32 vs. 28 days, p = .01) during induction II. CONCLUSION: Intensification of induction II did not improve treatment response or survival, but did increase toxicity and resource utilization. Alternative strategies are urgently needed to improve outcomes for pediatric patients with high-risk acute myeloid leukemia (trials registered at clinicaltrials.gov NCT01371981, NCT00372593).

Immunotherapy holds great promise for patients undergoing tumor treatment. However, the clinical effect of immunotherapy is limited because of tumor immunogenicity and its immunosuppressive microenvironment. Herein, the metal-organic framework (MIL-100) loaded with chemotherapeutic agent mitoxantrone (MTO) was combined with photothermal-chemotherapy for enhancing immunogenic cell death. MIL-100 loaded with MTO and hyaluronic acid as nanoparticles (MMH NPs) yielded an NP with two therapeutic properties (photothermal and chemotherapy) with dual imaging modes (photoacoustic and thermal). When MMH NPs were coinjected with an anti-OX40 antibody in colorectal cancer, the highest antitumor efficacy and a robust immune effect were achieved. This work provides a novel combined therapeutic strategy, which will hold great promise in future tumor therapy.

BACKGROUND: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease.OBJECTIVE: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue.METHODS: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map.RESULTS: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons.CONCLUSION: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.

Breast cancer is the leading cause of cancer-related deaths among women worldwide. The conventional chemotherapeutic regimens used in the treatment of this disease often lead to severe side-effects and reduced efficacy. In this study, a novel drug delivery system for the chemotherapeutic drug mitoxantrone (Mito) was developed using solid lipid nanoparticles (SLN). The production of the SLN was carried out using an organic-solvent-free, low-cost method and optimized using a Box-Behnken design. SLN presented adequate size for cancer-related applications, more than 90% of EE% and remained stable for at least 6 months. A much higher drug release was obtained at acidic pH (mimicking the endosomal compartment) than plasmatic pH, highlighting the potential of the nanosystem for tumor drug delivery. Additionally, SLN were non-hemolytic and cytocompatible, even at high concentrations of lipid. A significantly higher anti-cancer efficacy was obtained for Mito-loaded SLN comparing to the free drug at different concentrations in MCF-7 2D models. Finally, the nanoformulation was evaluated in heterotypic breast cancer spheroids showing capacity to penetrate the tridimensional structure and ability to induce a high anti-tumoral effect, similarly to the free drug. Overall, these results support that the developed SLN are effective Mito nanocarriers for the treatment of breast cancer.

Objectives Physical function is one of the core domains to be measured in all trials in psoriatic arthritis (PsA). We aimed to evaluate two instruments for physical function in PsA: The Health Assessment Questionnaire-disability index (HAQ-DI) and the physical functioning subscale of the Medical Outcome Survey Short-Form 36 items (SF-36 PF). Methods We followed guidelines set out by the OMERACT Filter 2.1. A working group was formed to evaluate each instrument for domain match and feasibility to reach consensus. Two systematic literature reviews (SLRs) were conducted to identify the relevant articles supporting measurement properties of both instruments. Five additional measurement properties were appraised: construct validity, test-retest reliability, longitudinal construct validity, clinical trial discrimination, and threshold of meaning. New evidence was synthesized to fill the gap. Data were presented to the OMERACT technical advisory group (TAG) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) community for endorsement. Results The results for seven measurement properties for HAQ-DI and SF-36 PF were presented in Summary of Measurement Property (SOMP) tables. The working group proposed “Provisional Endorsement” for both instruments. The body of evidence was approved by the OMERACT TAG. In two Delphi exercises among GRAPPA members, HAQ-DI received 93.9% and 97.5% endorsement votes, while that for SF-36 PF were 86.7% and 77.3%. Conclusion Both HAQ-DI and SF-36 PF were provisionally endorsed for the measurement of physical function in PsA trials, using the OMERACT Filter 2.1.

In this systematic review and network meta-analysis (NMA), we aimed to assess the benefits and harms of third-line (L3) treatments in randomized controlled trials (RCTs) of patients with metastatic castration-resistant prostate cancer (mCRPC). Two reviewers searched for publications from 1 January 2006 to 30 June 2021. The review analyzed seven RCTs that included 3958 patients and eight treatments. Treatment with prostate-specific membrane antigen (PSMA)-based radioligand therapy (PRLT) resulted in a 1.3-times-higher rate of median PSA decline ≥50% than treatment with abiraterone, enzalutamide, mitoxantrone, or cabazitaxel (p = 0.00001). The likelihood was 97.6% for PRLT to bring about the best PSA response, out of the examined treatments. PRLT resulted in a 1.1-times-higher six-month rate of median radiographic progression-free survival. Treatment with PRLT in the VISION trial resulted in 1.05-times-higher twelve-month median overall survival than L3 treatment with cabazitaxel in other RCTs. PRLT more often resulted in severe thrombocytopenia and less often in severe leukopenia than did cabazitaxel. In conclusion, for patients with mCRPC, L3 treatment with PRLT is highly effective and safe.

SummaryPurpose. This trial aimed to evaluate the efficacy and safety of mitoxantrone hydrochloride liposome injection (Lipo-MIT) in advanced breast cancer (ABC). Methods. In this randomized, open-label, active-controlled, single-center, phase II clinical trial, eligible patients were randomized in a ratio of 1:1 to receive Lipo-MIT or mitoxantrone hydrochloride injection (MIT) intravenously. The primary endpoint was objective response rate (ORR). The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and safety outcomes. Results. Sixty patients were randomized to receive Lipo-MIT or MIT. The ORR was 13.3% (95% confidence interval (CI): 3.8–30.7%) for Lipo-MIT and 6.7% (95% CI: 0.8–22.1%) for MIT. The DCR was 50% (95% CI: 31.3–68.7%) with Lipo-MIT vs. 30% (95% CI: 14.7–49.4%) with MIT. The median PFS was 1.92 months (95% CI: 1.75–3.61) for Lipo-MIT and 1.85 months (95% CI: 1.75–2.02) for MIT. The most common toxicity was myelosuppression. Lipo-MIT resulted in an incidence of 86.7% of leukopenia and 80.0% of neutropenia, which was marginally superior to MIT (96.7% and 96.7%, respectively). Lipo-MIT showed a lower incidence of cardiovascular events (13.3% vs. 20.0%) and increased cardiac troponin T (3.3% vs. 36.7%); but higher incidence of anemia (76.7% vs. 46.7%), skin hyperpigmentation (66.7% vs. 3.3%), and fever (23.3% vs. 10.0%) than MIT. Conclusions The clinical benefit parameters of Lipo-MIT and MIT were comparable. Lipo-MIT provided a different toxicity profile, which might be associated with the altered distribution of the drug. Additional study is needed to elucidate the potential benefit of Lipo-MIT in ABC. Clinical trial registration. This study is registered with ClinicalTrials.gov (No. NCT02596373) on Nov 4, 2015.

Objective.Due to no existing data, we aimed to derive evidence to support test-retest reliability for the Health Assessment Questionnaire–Disability Index (HAQ-DI) and 36-item Short Form Health Survey physical functioning domain (SF-36 PF) in psoriatic arthritis (PsA).Methods.We identified datasets that collected relevant data for test-retest reliability for HAQ-DI and SF-36 PF, and evaluated them using Outcome Measures in Rheumatology (OMERACT) Filter 2.1 methodology. We calculated intraclass correlation coefficients (ICC) as a measure of test-retest reliability. We then conducted a quality assessment and evaluated the adequacy of test-retest reliability performance.Results.Two datasets were identified for HAQ-DI and 1 for SF-36 PF in PsA. The quality of the datasets was good. The ICCs for HAQ-DI were good and excellent in study 1 (0.90, 95% CI 0.79–0.95) and study 2 (0.94, 95% CI 0.89–0.97). The ICC for SF-36 PF was excellent (0.96, 95% CI 0.92–0.98). The performance of test-retest reliability for both instruments was judged to be adequate.Conclusion.The new data derived support good and reasonable test-retest reliability for HAQ-DI and SF-36 PF in PsA.

Background: Rituximab (RTX), a CD20 depleting agent, is a frequently used off-label treatment for multiple sclerosis (MS), while mitoxantrone (MTX) is approved, albeit rarely used for active relapsing MS (RMS). However, observational data comparing RTX and MTX effectiveness and safety are scarce. Objective: We aimed to compare effectiveness and safety of MTX and RTX in patients with active RMS. Methods: From combined retrospective clinical data of three MS centers, we selected patients who had received at least one infusion of RTX or MTX and had at least a 6-month clinical follow-up available. Treatment groups were compared by propensity score (PS)-adjusted regression and inverse PS-weighted generalized estimated equation models regarding disability progression, relapse activity, and adverse events (AEs). Results: We included 292 RMS patients (mean age 41.8 years, 71.6% female) who received RTX (119 patients, mean age 36.8 years, 74.8% female) or MTX (173 patients mean age 45.3 years, 69.4% female). Using both PS methods, we did not find a significant effect favoring RTX or MTX treatment regarding the probability of disability worsening or relapse occurrence. However, RTX treatment was associated with a significantly lower probability of severe AEs and AEs. Conclusions: RTX shows comparable effectiveness but a favorable safety profile compared with MTX in active RMS.

Background: Antigen-specific tolerance in auto-immune diseases is the goal for effective treatment with minimal side-effects. Whilst this is achievable in animal models, notably via intravenous delivery of the model-specific autoantigen following transient CD4 T cell depletion, specific multiple sclerosis autoantigens remain unproven. However, anti-drug antibodies to human therapeutic proteins represent a model human autoimmune condition, which may be used to examine immune-tolerance induction. Some people with MS (PwMS) on interferon-beta1a (IFNβ1a) develop neutralizing antibodies to IFNβ1a that do not disappear in repeated tests over years. Methods: One PwMS was recruited, as part of a planned phase IIa trial (n = 15), who had developed neutralizing antibodies to subcutaneous IFNβ1a. Mitoxantrone (12 mg/m2) was administered as a lymphocyte depleting agent followed by four days of (88 μg/day + three 132 μg/day) intravenous IFNβ1a. Subcutaneous IFNβ1a three times a week was maintained during follow-up. IFNβ1a neutralizing antibody responses in serum were measured during treatment and three-monthly for 12 months. Findings: One participant was recruited and, within 6 months of tolerization, the neutralizing antibodies were undetectable. The tolerization treatment was well tolerated. However, the study was terminated after the first enrolment, on ethical grounds, as treatment alternatives became available and the potential risks of mitoxantrone use increased. Interpretation: The data suggest that it may be possible to induce antigen-specific tolerance by providing tolerogenic antigen following transient immune depletion. Further studies are warranted. Funding: The study was supported by an unrestricted research grant from Merck-Serono.

Background: Alvocidib is an investigational cyclin-dependent kinase-9 (CDK9) inhibitor that can suppress RNA polymerase II-mediated transcription of genes implicated in leukemia cell survival, including myeloid leukemia cell-1 (MCL-1). MCL-1 is an anti-apoptotic BCL-2 family member that is a key mediator of apoptosis in AML. Alvocidib combined in a timed-sequential regimen with cytarabine and mitoxantrone (ACM) has shown clinical activity in newly diagnosed and relapsed/refractory (R/R) AML through Phase I and II clinical trials. Analysis of bone marrow samples from newly diagnosed AML patients (pts) treated with ACM showed an association of complete remission (CR) with MCL-1 dependence by a BH3 profiling biomarker assay. Zella 201 was initiated based on the hypothesis that ACM may have preferential clinical activity in pts with MCL-1 dependence. We report the findings from an exploratory cohort of newly diagnosed high-risk (NDHR) AML pts with MCL-1 dependence treated with ACM. Methods: Zella 201 is a biomarker-driven Phase II study of ACM in R/R AML patients with MCL-1 dependence. Stage 1 included a cohort of R/R AML pts with various levels of MCL-1 dependence and an exploratory cohort of NDHR AML with MCL-1 dependence >40%, as determined by a BH3 profiling assay. Eligibility criteria for the NDHR cohort included pts 18-65 years with high-risk AML defined as one of the following: A) treatment-related AML, B) AML from preexisting MDS/MPN, C) adverse-risk by ELN 2017 criteria. Induction therapy consisted of alvocidib 30 mg/m2 as a 30 minute IV bolus followed by 60 mg/m2 over 4 hours on Days (D) 1-3, cytarabine 667 mg/m2/D by continuous IV infusion D6-8, and mitoxantrone 40 mg/m2 IV on D9. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permitted in responders. The primary endpoint was CR/CRi. Key secondary endpoints were overall survival (OS), relapse-free survival (RFS), overall response rate and safety. Results: Thirteen NDHR pts were treated and evaluable in this cohort (Table 1). One pt received alvocidib on days 1-3 and withdrew from the study on day 6 due to grade 4 diarrhea, cytokine release syndrome, and acute kidney injury. This pt was excluded from the efficacy analysis. Median MCL-1 score was 56% (Range: 42-70%). This cohort was influenced by the following poor risk categories: secondary AML (n= 9; 69%), adverse-risk by ELN (n=8; 62%) and TP53 mutations (n=6; 46%). The most common ≥Grade 3 treatment-emergent non-hematologic AEs (n=14) were diarrhea (29%); TLS, hypocalcemia, sepsis, hypotension (21%), pneumonia, colitis, hyperglycemia, anorectal infection, dyspnea, and left ventricular dysfunction (all 14%). Overall, CR/CRi was 62% with 7 (54%) pts responding following 1 cycle of therapy and another pt achieving CR after a second cycle. Two of six pts with TP53 mutation achieved CR. Although all pts included in this cohort were determined to be MCL-1 dependent, there was no association of CR with increasing MCL-1 dependence. Six (46%) pts went on to an allogeneic stem cell transplant (SCT). Sixty-day mortality was 0%. Median follow-up, OS, and RFS were 8.0, 8.5, and 6.1 months, respectively. Five of 8 (68%) CR/CRi pts have relapsed, and 10 pts (77%) have expired to date. The three pts still alive all received a post-study SCT. Conclusion: ACM has clinical activity in a limited cohort of NDHR AML pts with MCL-1 dependence scores >40% in a biomarker assay. Despite observed CR rates, duration of CR was modest and overall outcomes were poor. These results are comparable to historical controls with conventional chemotherapy regimens given the high-risk subset (62% of pts had adverse-risk and 46% had TP53 mutations). Further study is warranted to better define subgroups of ND AML pts who may benefit from alvocidib-containing induction regimens. Disclosures Zeidner: AsystBio Laboratories: Consultancy; AROG: Research Funding; Forty-Seven: Other: Travel Reimbursement, Research Funding; Merck: Research Funding; Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Daiichi Sankyo: Honoraria; Genentech: Honoraria; Pfizer: Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Reimbursement, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Other: Independent Review Committee; Agios: Honoraria. Lee:Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bayer: Research Funding; AbbVie: Research Funding; Celgene: Consultancy. Fine:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Wang:Bristol Meyers Squibb (Celgene): Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Pfizer: Speakers Bureau; Genentech: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy. Bhatt:Incyte: Consultancy, Research Funding; Oncoceutics: Other; National Marrow Donor Program: Research Funding; Jazz: Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding. Kolibaba:Verastem: Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Compass Oncology: Ended employment in the past 24 months; Seattle Genetics: Research Funding; Atara Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma Oncology, Inc.: Consultancy, Other: Travel, Accommodations, Expenses Paid; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; McKesson Life Sciences: Consultancy; Cell Therapeutics: Research Funding; Pharmacyclics: Research Funding. Anthony:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment; Exact Sciences: Consultancy. Bearss:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background Primary refractory acute myeloid leukemia (AML) is associated with dismal prognosis. No standard treatment options are available, and it remains an unmet clinical need. Here, we report a case of a tandem allogeneic hematopoietic stem cell transplantation (allo-HSCT) performed in a patient who did not achieve remission after 2 courses of induction chemotherapy. Methods Case report The treatment was approved by the Bioethical Commission of the Medical University of Warsaw and was performed in accordance with the Declaration of Helsinki. The patient gave informed consent. Results A 41-year-old woman was diagnosed with AML, high cytogenetic risk, with concomitant skin and central nervous system involvement, bone marrow necrosis, and hemophagocytic lymphohistiocytosis. She received “3+7” induction and HAM (cytarabine, mitoxantrone) reinduction, after which she did not achieve remission and hematopoietic recovery. Tandem allo-HSCT was performed from the same HLA-identical brother---the first after reduced intensity conditioning (cladribine, cytarabine, mitoxantrone, melphalan) and the second after myeloablative conditioning (BuCy--busulphan, cyclophosphamide). The patient obtained complete remission after the first allo-HSCT and remains disease-free after the second for 5 years Conclusion Tandem allo-HSCT may be a treatment option for primary refractory AML.

Devimistat (CPI-613®) is an intravenously administered, novel lipoate analog that inhibits two key tricarboxcylic acid (TCA) cycle enzymes, pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes (KGDH). These complexes control TCA cycle entry of glucose and glutamine-derived carbons, respectively. Acute myeloid leukemia (AML) cells upregulate the TCA cycle in response to DNA damaging agents and treatment with devimistat increases sensitivity to them. A Phase I study of devimistat in combination with cytarabine and mitoxantrone produced a complete remission rate of 50% in patients with relapsed or refractory AML. In the combined Phase I/II experience, older patients with R/R AML treated with 2000 mg/m2 of devimistat had a 52% complete remission/complete remission with incomplete hematologic recovery rate and a median survival of 12.4 months. This report outlines the rationale and design of the ARMADA 2000 study, a Phase III clinical trial of devimistat in combination with high dose cytarabine and mitoxantrone compared with high dose cytarabine and mitoxantrone alone for older patients (≥60 years of age) with relapsed or refractory AML. Clinical trial registration: NCT#03504410

Background Current chemotherapy for acute myeloid leukemia (AML) mainly involves cytotoxic agents such as doxorubicin (DNR), mitoxantrone (Mito) or 2‐aminopurine‐6‐thiol (6‐TG). However, because these agents are relatively ineffective, discovering other more effective drugs for AML treatment would be valuable. Methods The in vitro antitumor effect of lenvatinib on AML cells was examined using the colorimetric MTT assay for assessing cell metabolic activity. AML cells mixed with Poloxamer 407 were injected into nude mice to form subcutaneous tumors. Tumor‐bearing mice received lenvatinib by oral administration. The antitumor effect of lenvatinib was established by measuring tumor volumes and weights. Results Lenvatinib inhibited the growth of AML cells in a dose‐dependent manner. We used AML cells to establish subcutaneous tumor tissues by mixing the cell suspension with Poloxamer 407. Poloxamer 407 alone did not influence the subcutaneous growth of AML cells. Treatment of lenvatinib inhibited in vivo tumor growth of AML cells. Conclusion The multiple‐kinase inhibitor lenvatinib inhibits the in vitro proliferation of AML cells, and restricts the in vivo growth of AML tumors.

Many conventional chemotherapies have indicated side effects due to a lack of treatment specificity and are thus not suitable for long-term usage. Natural health products are well-tolerated and safe for consumption, and some have pharmaceutical uses particularly for their anticancer effects. We have previously reported the anticancer efficacy of dandelion (Taraxacum officinale) root and lemongrass (Cymbopogon citratus) extracts. However, their efficacy on prostate cancer and their interactions with standard chemotherapeutics have not been studied to determine if they will be suitable for adjuvant therapies. If successful, these extracts could potentially be used in conjunction with chemotherapeutics to minimize the risk of drug-related toxicity and enhance the efficacy of the treatment. We have demonstrated that both dandelion root extract (DRE) and lemongrass extract (LGE) exhibit selective anticancer activity. Importantly, DRE and LGE addition to the chemotherapeutics taxol and mitoxantrone was determined to enhance the induction of apoptosis when compared to individual chemotherapy treatment alone. Further, DRE and LGE were able to significantly reduce the tumour burden in prostate cancer xenograft models when administered orally, while also being well-tolerated. Thus, the implementation of these well-tolerated extracts in adjuvant therapies could be a selective and efficacious approach to prostate cancer treatment.

Purpose: The prognosis of patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) remains poor, and novel therapies are needed. The proteasome pathway represents a potential therapeutic target. A phase I trial of the second-generation proteasome inhibitor ixazomib in combination with MEC (mitoxantrone, etoposide, and cytarabine) was conducted in patients with R/R AML. Patients and Methods: Dose escalation of ixazomib was performed using a standard 3 × 3 design. Gene-expression profiling was performed on pretreatment and posttreatment bone marrow or blood samples. Results: The maximum tolerated dose of ixazomib in combination with MEC was 1.0 mg. The dose limiting toxicity was thrombocytopenia. Despite a poor risk population, the response rate [complete remission (CR)/CR with incomplete count recovery (CRi)] was encouraging at 53%. Gene-expression analysis identified two genes, IFI30 (γ-interferon inducible lysosomal thiol reductase) and RORα (retinoic orphan receptor A), which were significantly differentially expressed between responding and resistant patients and could classify CR. Conclusions: These results are encouraging, but a randomized trial is needed to address whether the addition of ixazomib to MEC improves outcome. Gene-expression profiling also helped us identify predictors of response and potentially novel therapeutic targets.

Objective: This study entails the structure-based design of type II inhibitors of human topoisomerase, by some notable anticancer compounds registered in the National Cancer Institute (NCI). The study aims to identify a series of more potent Top II inhibitors but are resistant to biochemical interaction with BRCA1 enzyme responsible for identifying and removing damaged cells resulting from a mutagenic response and finally subjecting the identified lead compound in the design of more active drug candidates. Methods: The structure-based drug design technique employed was molecular docking and the ICM pro software was used in both the preparation of the receptor and the docking process. The results were presented in both 2-dimensional and 3-dimensional views to best capture the binding poses as well as their interaction with the amino acids present in the binding pockets. Results: The result of our molecular docking study showed that Rubidazone and other ligands such as DAUNORUBICIN, m-AMSA, BISANTRENE HCl and MITOXANTRONE with binding score for topoisomerase given as −32.894–2.7452, −26.231, −25.022 and −25.843 respectively, were the best topoisomerase II inhibitors. VP-16 was selected as the lead compound, which was then utilized in designing new and improving topoisomerase II inhibitors by introducing one or more secondary functional groups containing heteroatoms. Conclusion: Our findings suggested that the presence of π- π, π -sigma and π-alkyl interactions of all the strategies with the receptor were primarily responsible for its firm ternary complex with topoisomerase o-DNA complex. Keywords: Topoisomerase II inhibitors, Etoposide, Intercalation, Pi-alkyl interaction