Laser-activable murine ferritin nanocage for chemo-photothermal therapy of colorectal cancer.

Chemotherapy, as a conventional strategy for tumor therapy, often leads to unsatisfied therapeutic effect due to the multi-drug resistance and the serious side effects. Herein, we genetically engineered a thermal-responsive murine Ferritin (mHFn) to specifically deliver mitoxantrone (MTO, a chemotherapeutic and photothermal agent) to tumor tissue for the chemotherapy and photothermal combined therapy of colorectal cancer, thanks to the high affinity of mHFn to transferrin receptor that highly expressed on tumor cells. The thermal-sensitive channels on mHFn allowed the effective encapsulation of MTO in vitro and the laser-controlled release of MTO in vivo. Upon irradiation with a 660 nm laser, the raised temperature triggered the opening of the thermal-sensitive channel in mHFn nanocage, resulting in the controlled and rapid release of MTO. Consequently, a significant amount of reactive oxygen species was generated, causing mitochondrial collapse and tumor cell death. The photothermal-sensitive controlled release, low systemic cytotoxicity, and excellent synergistic tumor eradication ability in vivo made mHFn@MTO a promising candidate for chemo-photothermal combination therapy against colorectal cancer.

Magnetically modified-mitoxantrone mesoporous organosilica drugs: an emergent multimodal nanochemotherapy for breast cancer.

BACKGROUND: Chemotherapy, the mainstay treatment for metastatic cancer, presents serious side effects due to off-target exposure. In addition to the negative impact on patients' quality of life, side effects limit the dose that can be administered and thus the efficacy of the drug. Encapsulation of chemotherapeutic drugs in nanocarriers is a promising strategy to mitigate these issues. However, avoiding premature drug release from the nanocarriers and selectively targeting the tumour remains a challenge. RESULTS: In this study, we present a pioneering method for drug integration into nanoparticles known as mesoporous organosilica drugs (MODs), a distinctive variant of periodic mesoporous organosilica nanoparticles (PMOs) in which the drug is an inherent component of the silica nanoparticle structure. This groundbreaking approach involves the chemical modification of drugs to produce bis-organosilane prodrugs, which act as silica precursors for MOD synthesis. Mitoxantrone (MTO), a drug used to treat metastatic breast cancer, was selected for the development of MTO@MOD nanomedicines, which demonstrated a significant reduction in breast cancer cell viability. Several MODs with different amounts of MTO were synthesised and found to be efficient nanoplatforms for the sustained delivery of MTO after biodegradation. In addition, Fe3O4 NPs were incorporated into the MODs to generate magnetic MODs to actively target the tumour and further enhance drug efficacy. Importantly, magnetic MTO@MODs underwent a Fenton reaction, which increased cancer cell death twofold compared to non-magnetic MODs. CONCLUSIONS: A new PMO-based material, MOD nanomedicines, was synthesised using the chemotherapeutic drug MTO as a silica precursor. MTO@MOD nanomedicines demonstrated their efficacy in significantly reducing the viability of breast cancer cells. In addition, we incorporated Fe3O4 into MODs to generate magnetic MODs for active tumour targeting and enhanced drug efficacy by ROS generation. These findings pave the way for the designing of silica-based multitherapeutic nanomedicines for cancer treatment with improved drug delivery, reduced side effects and enhanced efficacy.

Exploratory study on the efficacy of bortezomib combining mitoxantrone or CD22-CAR T therapy targeting CD19-negative relapse after CD19-CAR T cell therapy with a simpler cell-line-based model.

Target-negative relapse after CD19 chimeric antigen receptor engineered (CAR) T cell therapy for patients with B lineage acute lymphoblastic leukemia (B-ALL) presents limited treatment options with dismal outcomes. Although CD22-CAR T cells mediate similarly potent antineoplastic effects in patients with CD19dim or even CD19-negative relapse following CD19-directed immunotherapy, a high rate of relapse associated with diminished CD22 cell surface expression has also been observed. Therefore, it is unclear whether any other therapeutic options are available. Mitoxantrone has shown significant antineoplastic activity in patients with relapsed or refractory leukemia over the past decades, and in some cases, the addition of bortezomib to conventional chemotherapeutic agents has demonstrated improved response rates. However, whether this mitoxantrone and bortezomib combination therapy is effective for those patients who have relapsed B-ALL after receiving CD19-CAR T cell therapy remains to be elucidated. In this study, we established a cellular model system using a CD19-positive B-ALL cell line Nalm-6 to investigate the treatment options for CD19-negative relapsed B-ALL after CD19-CAR T cell therapy. In addition to CD22-CAR T therapy, we observed that the combination of bortezomib and mitoxantrone exhibited effective anti-leukemia activity in the CD19-negative Nalm-6 cell line by downregulating p-AKT and p-mTOR. These results suggest that this combination therapy is a possible option for target-negative refractory leukemia cells after CAR-T cell treatment.

Mitoxantrone alleviates hepatic steatosis induced by high-fat diet in broilers.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a common nutritional metabolic disease in poultry that seriously compromises the health of chickens and reduces the economic benefits of the industry. In this study, we investigated the therapeutic effect of mitoxantrone (MTX) on hepatic steatosis in broilers. We constructed a steatosis cell model in vitro by adding oleic acid and palmitic acid to chicken hepatocytes (LMH cells), to examine influence of MTX on fat deposition on LMH cells. To determine the effects of MTX on hepatic steatosis in broiler livers in vivo, broilers were fed a high-fat diet to establish a fatty liver model. Our data show that MTX reduced the triglyceride (TG) levels and total cholesterol levels in LMH cells. In the MAFLD chick model, MTX decreased mRNA abundance of hepatic-lipid-synthesis-related gene such as FASN and increased mRNA abundance of fatty-acid-ß-oxidation-related genes such as CPT1, PPARα, and reduced hepatic TG levels. MTX also reduced serum lipid and the percentage of abdominal fat. These results suggest that MTX improves hepatic steatosis in broilers as well as reduces circulating lipid levels and fat accumulation in broilers. Our work provides a promising therapeutic strategy for MAFLD and excessive fat accumulation in broiler chickens.

Ten-year follow-up after mitoxantrone induction for early highly active relapsing-remitting multiple sclerosis: An observational study of 100 consecutive patients.

BACKGROUND: Six monthly courses of mitoxantrone were approved in France in 2003 for patients with highly active multiple sclerosis (MS). OBJECTIVE: To report the 10-year clinical follow-up and safety of mitoxantrone as an induction drug followed by maintenance therapy in patients with early highly active relapsing-remitting MS (RRMS) and an Expanded Disability Status Scale (EDSS) score<4, 12months prior to mitoxantrone initiation. METHODS: In total, 100 consecutive patients with highly active RRMS from the Rennes EDMUS database received monthly mitoxantrone 20mg combined with methylprednisolone 1g for 3 (n=75) or 6months (n=25) followed by first-line disease-modifying drug (DMD). The 10-year clinical impact was studied through clinical activity, DMD exposure, and adverse events. RESULTS: Twenty-four percent were relapse-free over 10years and the mean annual number of relapses was 0.2 at 10years. The mean EDSS score remained significantly improved for up to 10years, changing from 3.5 at mitoxantrone initiation to 2.7 at 10years. The probability of disability worsening and improvement from mitoxantrone initiation to 10years were respectively 27% and 58%, and 13% converted to secondary progressive MS. Patients only remained untreated or treated with a first-line maintenance DMD for 6.5years in average. In our cohort, mitoxantrone was generally safe. No leukemia was observed and six patients developed neoplasms, including 4 solid cancers. CONCLUSION: Monthly mitoxantrone for 3 or 6months, followed by maintenance first-line treatment, may be an attractive therapeutic option for patients with early highly active RRMS, particularly in low-income countries.

A brief rituximab, bendamustine, mitoxantrone (R-BM) induction followed by rituximab consolidation in elderly patients with advanced follicular lymphoma: a phase II study by the Fondazione Italiana Linfomi (FIL).

Treatment for follicular lymphoma (FL) in the elderly is not well standardized. A phase II, multicentre, single arm trial was conducted in this setting with a brief chemoimmunotherapy regimen. Treatment consisted in four monthly courses of rituximab, bendamustine and mitoxantrone (R-BM) followed by 4 weekly rituximab as consolidation; rituximab maintenance was not applied because the drug was not licensed at the time of enrolment. The primary endpoint was the complete remission rate (CR). Seventy-six treatment-naive FL patients (aged 65-80 and a "FIT" score, according to the Comprehensive Geriatric Assessment) were enrolled. CR was documented in 59/76 patients (78%), partial remission in 12 (16%) and stable/progressive disease in five (6%) with an overall response rate in 71/76 (94%). Median follow-up was 44 months with 3-year progression-free-survival (PFS) and overall-survival of 67% and 92% respectively. Nine deaths occurred, three of progressive disease. The regimen was well tolerated and the most frequent severe toxicity was neutropenia (18% of the cycles). Bcl-2/IGH rearrangement was found in 40/75 (53%) of evaluated patients. R-BM was highly effective in clearing polymerase chain reaction-detectable disease: 29/31 (96%) evaluated patients converted to bcl-2/IGH negativity at the end of treatment. A brief R-BM regimen plus rituximab consolidation is effective and safe in "FIT" elderly, treatment-naïve, FL patients, inducing high CR and molecular remission rates with prolonged PFS.

Prognostic value of interim FDG PET-CT in patients older than 60 years with diffuse large B-cell lymphoma treated by PMitCEBO plus rituximab. Comparison between Deauville 5-point scale and International Harmonization Project criteria.

BACKGROUND: Advanced age is an independent poor prognostic factor of diffuse large B-cell lymphoma (DLBCL). PMitCEBO (mitoxantrone, cyclophosphamide, etoposide, vincristine, bleomycin, and prednisolone) is an alternative to the cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen to decrease side effects in elderly patients. Many studies have shown prognostic value of an interim FDG PET-CT to predict survival. A recent consensus (ICML, Lugano 2013) has suggested using the 5-point scale Deauville criteria instead of those of the International Harmonization Project (IHP) to visually assess the response on interim PET. The objective of this study was to evaluate the prognostic value of an interim FDG PET-CT in patients older than 60 with treated DLBCL and to compare IHP and 5-PS Deauville visual interpretation to predict survival. METHODS: Forty-eight patients (mean age 73.2±5.2 years) treated by R-PMitCEBO for DLBCL undergoing FDG PET-CT before and after 3 cycles of treatment were retrospectively included. Event-free survival and overall survival were determined by Kaplan-Meier method and compared with interim PET-CT results using IHP and 5-PS Deauville criteria. RESULTS: Interim PET results using 5-PS Deauville criteria were significantly correlated with EFS (P<0.0001) and OS (P=0.001) whereas they were moderately correlated with EFS (P=0.046) and not with OS (P=0.106) using IHP criteria. Two-year EFS and OS rates were 86.5% and 89.2%, respectively, for patients in 1-3 score group, and 27.3% and 36.4%, respectively, for patients in ≥4 score group using the Deauville criteria. CONCLUSIONS: Our results confirmed the prognostic value of an interim PET-CT in elderly patients with DLBCL and the better performance of the 5-PS Deauville criteria.

Boron phenyl alanine targeted ionic liquid decorated chitosan nanoparticles for mitoxantrone delivery to glioma cell line.

Nanotechnology has revolutionized drug delivery in cancer treatment. In this study, novel efficient pH-responsive boron phenylalanine (BPA) targeted nanoparticles (NPs) based on ionic liquid modified chitosan have been introduced for selective mitoxantrone (MTO) delivery to the U87MG glioma cells. Urocanic acid (UA) and imidazolium (Im) based ionic liquids were used for structural modification simultaneously. The NPs were prepared by ionic gelation and fully characterized; the pH-responding and swelling index of NPs were studied carefully. The drug release was studied at a pH of 5.5 in comparison to the neutral state. Also, the cytotoxicity of loaded NPs was evaluated on U87MG glial cells, and cellular uptake was studied. The NPs were smaller than 250 nm, with a spherical pattern and acceptable uniformity with a zeta potential around +20 mV. The loading efficacy was about 85%, and most of the loaded MTO released at a pH of 5.5 after 48 h with a swelling-controlled mechanism. The NPs showed a relatively lower IC50 than the free MTO, and the BPA-targeted NPs have lower IC50 and better cellular uptake than non-targeted NPs in U87MG cells. More studies on this promising formula are on the way, and the results will be published soon.

MEC (mitoxantrone, etoposide, and cytarabine) induces complete remission and is an effective bridge to transplant in acute myeloid leukemia.

INTRODUCTION: Clinical response and chemosensitivity of relapse or refractory AML patients were evaluated after rescue and bridge-to-transplant MEC (mitoxantrone, etoposide, and cytarabine) regimen. METHODS AND PATIENTS: Fifty-five consecutive AML patients were treated with MEC from 2009 to 2018. Chemosensitivity was evaluated by WT1 quantification. RESULTS: 27/55 patients (49.1%) had AML resistant to induction and 28/55 patients (50.9%) had AML relapse. 25/55 patients (45.5%) achieved a CR after one course of MEC, and 12 patients (21.8%) achieved WT1 negativity. In 12 patients, a second MEC was administered. Four out of 12 patients improved significantly their response with the 2nd MEC. MEC was an effective bridge to transplant, 32/55 patients (58.2%) received an allogenic stem cell transplant. Median overall survival (OS) from MEC was 455 days (95% CI 307-602 days.); patient with WT1 negative CR had the best OS (P<.000). CONCLUSION: WT1 is a useful marker of chemosensitivity after MEC as rescue and bridge-to-transplant therapy.

A multi-institutional comparison of mitoxantrone, etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia.

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.

Biphasic Increases of Cell Surface Calreticulin Following Treatment with Mitoxantrone.

Calreticulin (CRT) and calnexin (CNX), homologous major chaperones in the endoplasmic reticulum (ER), are known to translocate to the cell surface in response to chemotherapeutic agents, such as mitoxantrone (MIT), and cellular stresses, including apoptosis. Cell surface CRT (ecto-CRT) is relevant to the phagocytic uptake of cancer cells and dying cells, and pre-apoptotic exposure of CRT has been reported to result in enhanced immunogenicity of dying tumor cells, serving as a damage-associated molecular pattern (DAMP). In this study, HT-29 cells were treated with MIT to induce ER stress, and ecto-CRT and cell surface CNX were quantified by flow cytometry in the absence or presence of caspase inhibitors, a calpain inhibitor, or a scavenger of reactive oxygen species. The biphasic (early transient and late sustained) increase of ecto-CRT on HT-29 cells was observed after treatment with MIT. We confirmed that the early increase in ecto-CRT after 4 h of MIT treatment was not related to apoptosis, whereas the increase of ecto-CRT, as well as that of cell-surface CNX, during the later stage of treatment was caspase dependent and related to apoptosis. In addition, our results suggested that the early peak of ecto-CRT was mediated by activation of caspase 8 by ER stress. Thus, the physiological significance of the late increases in cell-surface CRT and/or CNX might be considered an "eat-me signal" for the removal of dead cells by phagocytosis, while the early increase in ecto-CRT caused by ER stress might enhance the immunogenicity of stressed tumor cells.

Is there a new place for mitoxantrone in the treatment of multiple sclerosis?

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.

Elucidating the expression and function of Numbl during cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma (MM).

BACKGROUND: Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin ß1 and its sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development. METHODS: Development of an adhesion model of established MM cell lines and detection of Numbl and Integrinß1 expression by Western Blot analysis. The interaction between Numbl and Integrinß1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis. RESULTS: Our preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin ß1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin ß1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin ß1 promotes the formation of CAM-DR in MM cells. CONCLUSIONS: Our findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells.

Pixantrone beyond monotherapy: a review.

Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL.

Cerebrospinal fluid NCAM levels are modulated by disease-modifying therapies.

BACKGROUND: Little is known about what leads to recovery between relapses in multiple sclerosis (MS), particularly following treatment. In the past, it has been demonstrated that soluble neural cell adhesion molecule (sNCAM), a putative biomarker of neuroplasticity, increased following steroid treatment in the Cerebrospinal fluid (CSF) of MS subjects undergoing acute relapses. Taking this a step further, we have evaluated the effect of disease-modifying treatment (DMTs) on CSF sNCAM levels in various subtypes of MS. METHODS: We measured CSF sNCAM levels at baseline and after 12-24 months of DMT in 69 patients, 49 relapsing-remitting MS (RRMS), 20 progressive MS(PMS), and 24 healthy controls (HC) using an in-house ELISA. Of this, 31 patients had received natalizumab, 17 mitoxantrone, and 21 fingolimod. Changes in disability were measured using EDSS and disease severity by MSSS. In conjunction, CSF NfL levels were also measured. RESULTS: At baseline, the mean sNCAM level was 268.7 ng/mL (SD: 109 ng/mL) in MS patients compared with 340.6 ng/ml (SD: 139 ng/mL) in HC, and PMS had significantly lower sNCAM (239.2 ng/mL, SD: 123.0, P = 0.019) compared to RRMS (269.4, SD: 127.4, P = 0.043). After natalizumab and mitoxantrone treatments, we observed an increase in mean sNCAM. However, in the fingolimod-treated group, mean sNCAM decreased. There was no correlation found with EDSS or MSSS, or NfL levels as a whole. CONCLUSIONS: Cerebrospinal fluid sNCAM levels were found to be lower in MS than in HC and the lowest sNCAM levels were found in PMS. Following natalizumab and mitoxantrone treatments, we observed an elevation in sNCAM levels, an effect that was not observed following fingolimod treatment. These changes, however, did not appear to correlate with disability in the short-term or NfL levels.

Mitoxantrone-melphalan conditioning regimen for autologous stem cell transplantation in relapsed/refractory lymphoma

Background/aim: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for patients with relapsed/refractory Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL). In this study, we report the outcome of the mitoxantrone-melphalan conditioning regimen for lymphoma. Materials and methods: The study group included 53 patients who were relapsed/refractory HL (n = 14) and NHL (n = 39) and received mitoxantrone and melphalan followed by ASCT. The transplant regimen consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) followed by peripheral blood stem cell infusion (PBSC). Results: Prior to high-dose chemotherapy, 37.7% of the patients were in complete remission (CR) and 45.3% were in partial remission (PR), and 17% had stable or progressive disease. After high-dose chemotherapy and PBSC, 44 out of 51 patients achieved CR (86.2%). CR was achieved in 24 out of 33 patients (72.7%) who were transplanted in a marginally active phase of the disease. At a median followup of 25.4 months (1.8­131.3 months) after ASCT, 13 patients relapsed/ progressed and 8 patients died. The estimated 2-year overall survival (OS) was 81.9%, and event-free survival (EFS) was 59.3%. Conclusion: High-dose chemotherapy followed by ASCT is an effective conditioning regimen in relapsed/refractory lymphoma patients who are undergoing ASCT.

Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition.

Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.

Clinical follow-up of 411 patients with relapsing and progressive multiple sclerosis 10 years after discontinuing mitoxantrone treatment: a real-life cohort study.

BACKGROUND AND PURPOSE: Mitoxantrone (MITOX) has been used to treat patients with aggressive multiple sclerosis (MS) for decades. We aimed to describe the effectiveness and adverse events over 10 years post-MITOX in patients with relapsing and progressive MS from an exhaustive real-life database. METHODS: Data from patients who received MITOX before 1 January 2006 were collected from the MS Lorraine registry. Expanded Disability Status Scale (EDSS) scores and annual relapse rates (ARRs) year by year during follow-up and the year prior to MITOX were compared. Time to the first relapse and a 1-point increase in EDSS score were used in Cox multivariate models to find associations with potential predictive factors. RESULTS: A total of 411 patients were included. The ARR for the 155 relapsing patients had decreased from 2.0 (SD 1.20) the year before treatment to 0.3 (SD 0.31) by year 10 (P < 0.0001). The EDSS score increased from 2.8 (SD 1.44) to 4.8 (SD 1.90) by year 10 (P < 0.0001). A high ARR at MITOX initiation was associated with a longer time to a 1-point increase in EDSS score (hazard ratio, 0.81; 95% confidence interval, 0.67-0.99; P = 0.04). The EDSS score in 256 progressive patients increased from 5.0 (SD 1.33) to 6.5 (SD 1.26) by year 10 (P < 0.0001). We identified four cases of acute myeloid leukemias. CONCLUSIONS: Patients with the most active forms of MS are the most likely to benefit from MITOX in the long term.

Pregnancy planning and outcomes in patients with multiple sclerosis after mitoxantrone therapy: a monocentre assessment.

BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) have many pregnancy-related doubts and fears. Careful counselling is thus important. Mitoxantrone (MITO) is used in patients with aggressive MS and may affect reproductive capacity. The aim of this study was to investigate pregnancy planning and outcomes in patients with MS treated with MITO, both before and after the treatment. METHODS: Patients with MS previously treated with MITO were recruited. Clinical, demographic and treatment data were recorded. A questionnaire regarding the planning and outcomes of all pregnancies was administered. Parametric and non-parametric tests were performed using SPSS 22 software. RESULTS: A total of 238 patients (female/male, 158/80) were included; 106 subjects planned a pregnancy before MITO and 40 after MITO. Of these, respectively, 102 (97%) and 35 (85%) resulted in conception, 19 (19%) and 7 (18%) in miscarriage, 6 (6%) and 1 (3%) in abortion and 98 (96%) and 32 (91%) were full-term pregnancies. A total of 96 patients (40%) planned a pregnancy only before MITO (and not after), whereas 30 (13%) planned a pregnancy only after MITO (and not before) (P < 0.01). A total of 103 patients did not plan a pregnancy before MITO and 198 did not plan a pregnancy after MITO. The reasons included lack of interest or a partner, fear of MS and infertility. All of the babies born were healthy until the end of follow-up. CONCLUSIONS: Mitoxantrone does not affect the ability to conceive or pregnancy outcomes. We found no differences in pregnancies, abortions or miscarriages before and after MITO. The tendency to plan pregnancies decreased significantly after MITO. Our findings may be useful for improving the quality of life of patients and the approach taken by neurologists.

[Mitoxantrone, etoposide, and cytarabine combination therapy for acute myeloid leukemia patients failing to achieve a complete remission after induction chemotherapy: a single-center experience].

Optimal salvage chemotherapy has not been established for patients with acute myeloid leukemia (AML) who fail to attain complete remission (CR) after one course of induction chemotherapy. This retrospective study aimed to assess the efficacy and safety of an MEC (mitoxantrone, 6 mg/m2, 1-3 days; etoposide, 80 mg/m2, 1-6 days; cytarabine, 1 g/m2, 1-6 days) regimen in patients with AML who failed to attain CR after one course of induction chemotherapy. Twenty-four patients were included in this study (median age, 58 years; range, 28-79 years). After one course of MEC, 11 patients (45.8%) attained CR. Febrile neutropenia was observed in all patients, and acute infection was observed in 7 patients (29.2%). However, no therapy-related death occurred. All patients eligible for transplantation and who attained CR after MEC salvage chemotherapy underwent allogeneic hematopoietic stem cell transplantation. The MEC regimen exhibited a good response rate with tolerable adverse events. Therefore, the MEC regimen can be safely used as a salvage treatment for patients with AML who failed to attain CR after one course of induction chemotherapy.