Months Of Maintenance Therapy Research Articles

The Strategy of the Management of Patients with Chronic Lymphocytic Leukemia in the Post-Induction Period Based on the Results of the Evaluation of Minimal Residual Disease

Background. Although inclusion in the treatment programs of new drugs (including new monoclonal antibodies and targeted therapies) allowed the majority of patients with chronic lymphocytic leukemia (CLL) to achieve remission (complete or partial) after combined therapy virtually all patients relapse, presumably due to the persistence of minimal residual disease (MRD). There is strong evidence that the achievement of a negative status for MRD is the single most important factor predictive of final outcome in patients with CLL treated with chemoimmunotherapy. So, at now, the urgent task is long-term preservation and the deepening of the response, if it is possible. Continuing to administer rituximab to patients who respond to rituximab-based induction is possible option. Currently, there is no consensus about the need for maintenance therapy (MT) for patients with CLL.Aim. To estimate the importance of maintenance therapy of rituximab in the treatment of patients with CLL.Methods. Since January 2014, 83 patients were included in the study. Male to female ratio - 1.3:1. We have used NCI revised guidelines (Hallek M., et al., 2008) for treatment initiation, assessment of response and MRD. Induction chemotherapy was conducted under the following programs: RB, RFC, R-CHOP. Evaluation of MRD was performed using 5-color flow cytometry of the bone marrow cells. For the study, we developed an algorithm of patient management in post-induction period on the basis of the results of MRD evaluation. Group 1 (n=23): patients with MRD-negative remissions who were under dynamic observation (without therapy) every 3 month with mandatory evaluation of MRD. Group 2 (n=60): patients with MRD-positive remissions who received MT of Rituximab 500 mg/m2 intravenously every 8 weeks for 2 years. Another 48 patients (Control group) with MRD-positive remissions did not receive MT. MT was began if MRD was detected in the patients from Group 1 within 1 year after the end of chemotherapy, they began maintenance therapy.Results. Median observation was 18.8 month (5 - 36). The increasing the depth of response (from partial to complete remission) was observed only in group of patients receiving MT - 11.7%. MRD was not detected after 6-12 months of MT in 21.7% (13/60) patients from Group 2.The frequency of relapses in Group 1 was 52.2% (12/23), in Group 2 - 33.3% (20/60), in Control group - 81.3%. Significant differences were detected between Group 1 and Control group (p=.01) and Group 2 and Control group (p˂.0001). Median progression-free survival was not reached in the rituximab maintenance group, in the Group 2 was 30.4 month (p˃.05) and in the Control group - 24.3 month (p=.02).MT was begun in the 5 patients from Group 1 because MRD was detected in the first year of observation, but the symptoms of progression disease were absent. After 12 months, 2 patients achieved MRD-negative status.Significant differences in the incidence of infectious complications between patients with MT and without of MT were not detected (p˃.05).Conclusion. The conducting of MT patients with CLL allows to achieve increasing the depth achieved remission (clinical and molecular) and increase the duration of its preservation. MT with rituximab may be a means of control over the minimal residual disease and the method of its eradication. The proposed algorithm need further testing to confirm the initial results. DisclosuresShuvaev:Fusion Pharma LLC: Consultancy.

Maintenance acne therapy: prophylactic efficacy of fixed combination of adapalene and benzoyl peroxide

Acne is a chronic disease and even reliable therapies do not completely ensure absence of relapses. Acne relapses have a negative psychological impact on patients, as they feel unable to control the disease and achieve complete and long-lasting recovery. Supportive therapy is necessary to prolong the remission of acne achieved with initial successful treatment and to minimize the risk of relapse. According to the literature sources, the most justified as a maintenance therapy is the use of topical retinoids, which have been shown to be effective in the prevention of exacerbations of acne. In the present study 54 patients were involved who after the active therapy used a fixed combination of adapalene 0.1% / BPO 2.5% as maintenance treatment. Only 1 patient (2.9%) with moderate acne and 2 patients (5.8%) with severe acne had a relapse within 6 months of maintenance therapy. The absence of adverse events during the course of treatment was recorded, as well as high adherence of patients to the treatment. During the period of post-treatment observation (6 months after maintenance therapy), among the patients without exacerbations during maintenance therapy, a relapse occurred in 2 (7.1%) patients of group 1 (n = 28) and 2 (8.7%) patients of group 2 (n = 23). The obtained data indicates that maintenance therapy with Effezel® gel can extend the achieved effectiveness of the treatment and prevent the development of relapses.

Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of Griffin after 12 Months of Maintenance Therapy

Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of Griffin after 12 Months of Maintenance Therapy

The Impact of Sorafenib on Phospho-FLT3 Inhibition and FLT3-ITD MRD after Chemotherapy: Correlative Studies from the Phase 2 Randomized Study of Sorafenib Versus Placebo in Combination with Intensive Chemotherapy in Previously Untreated Patients with FLT3-ITD Acute Myeloid Leukemia (ALLG AMLM16)

The Impact of Sorafenib on Phospho-FLT3 Inhibition and FLT3-ITD MRD after Chemotherapy: Correlative Studies from the Phase 2 Randomized Study of Sorafenib Versus Placebo in Combination with Intensive Chemotherapy in Previously Untreated Patients with FLT3-ITD Acute Myeloid Leukemia (ALLG AMLM16)

CYP2E1-DEPENDENT VARIATIONS IN HEPATOCYTES DAMAGE DURING TREATMENT OF TUBERCULOSIS

Relevance. Investigation of polymorphism in a locus of CYP2E1 as the prognostic factor of drug-induced hepatotoxicity at anti-TB therapy is significant due to the influence of CYP2E1 on drug metabolism.
 The objective of the investigation is to analyze the association of rs2070676 СYP2E1 gene polymorphism with drug-induced hepatotoxicity by means of the clinical-laboratory values of serum transaminases at anti-TB treatment.
 Materials and methods. The study involved 47 patients with drug-susceptible tuberculosis first time discovered. 58 healthy volunteers comprised a control group. Laboratory indices were determined in venous blood three times: before the treatment as baseline; in 2 months of intensive therapy (isoniazid, rifampicin, ethambutol, pyrazinamide), then in 4 months of maintenance therapy (isoniazid, rifampicin). Serum activities of enzymes ALT, AST, and GGT were measured by standard algorithm on automatic analyzer BS-300. Analysis of rs2070676 polymorphism of CYP2E1 gene was performed by polymerase chain reaction using standard PureLink® Genomic DNA Kit for Purification of Genomic DNA; Manufacturer of INVITROGEN (USA). For statistical processing, IBM SPSS Statistics 23 was applied.
 Results. Investigation of serum ALT and AST in patients with major genotype CYP2E1 (C/C) showed the lower baseline ALT and AST levels comparing to the control group, which might be caused by suppression of hepatocytes functions at the development of the disease. Anti-TB treatment caused an increase in ALT and AST levels comparing to the baseline in patients with major CYP2E1 (C/C) genotype. In the group with C/G polymorphism, the baseline ALT level didn’t differ much from the baseline of the control group; it showed a decrease after intensive therapy and returned back to the initial level at maintenance therapy. This might be related to the certain protective property of СYP2E1 gene polymorphism. The AST level was increased after intensive therapy (to a smaller extent than for the patients with major C/C genotype) and remained on the same level at maintenance therapy. A study of GGT showed a gradual increase regardless of genotype.
 Conclusion. According to the data of the experiment, the status of hepatocytes in patients with tuberculosis at baseline and during treatment was different depending on the CYP2E1 genotype. The results of the experiment indicate that the CYP2E1 gene polymorphism has a certain protecting role. It reduces the level of drug metabolites and hepatotoxicity which causes mitochondrial dysfunction.

Anxiolytic effects of acute and maintenance ketamine, as assessed by the Fear Questionnaire subscales and the Spielberger State Anxiety Rating Scale.

Ketamine has rapid anxiolytic effects in treatment-resistant obsessive compulsive, post-traumatic stress, generalised anxiety and social anxiety disorders. This study aimed to assess changes following acute and maintenance ketamine therapy on the Fear Questionnaire (FQ) subscales and the Spielberger State Anxiety Inventory (SSAI). This secondary analysis used data from a mixed open-label and double-blinded placebo-controlled study. A total of 24 patients received short-term ascending subcutaneous doses of ketamine and were then eligible to enter a 3-month maintenance phase of 1 mg/kg ketamine dosed once or twice weekly. FQ and SSAI data were analysed using mixed models to identify between-dose differences and to describe trends during maintenance. Acute ketamine dosing showed a rapid dose-related reduction in all three FQ subscales (agoraphobia, social phobia and blood-injury phobia) and in the SSAI. A progressive decrease in pre-dose rating-scale scores was evident during the 3 months of maintenance therapy. Ketamine demonstrated dose-related improvements in all FQ subscales and in the SSAI. Both scales appear to be suitable tools to assess the anxiolytic effects of ketamine in patients with treatment-resistant anxiety. Furthermore, ketamine appears to have broad, dose-related anti-phobic effects. These findings raise the possibility that ketamine may have therapeutic potential in the treatment of other phobic states, such as specific phobia.

Five-year follow-up of early intervention peanut oral immunotherapy

There is a clear need for long-term outcome and safety data amongst participants treated with oral immunotherapy (OIT). A recent meta-analysis of 12 peanut OIT trials showed that peanut OIT versus no OIT increased anaphylaxis risk.1 Furthermore, a retrospective review of 270 clinical allergy patients undergoing peanut OIT found 28 epinephrine-treated reactions occurring during maintenance therapy, 10 of which were beyond the first 6 months of maintenance therapy.2 An improved understanding of the net health benefits of OIT is especially critical given the recent Food and Drug Administration approval of Palforzia, which will likely greatly expand the use of peanut OIT.

Physiotherapy delivery systems-clinical and microbiological effectiveness in the treatment of chronic periodontitis

Relevance . Currently, the symbiotic microflora of the oral cavity plays an increasing role in the occurrence of periodontitis. Frequent use of modern medications for the treatment of patients with chronic generalized periodontitis is not the most effective therapy. One of the reasons for the low effectiveness of treatment can be considered long-term use of antibacterial drugs that lead to the development of dysbiosis in the oral cavity and immune imbalance. In order to improve the quality of periodontal treatment, dentists successfully use physical therapy. It is known that the diode laser has a high therapeutic efficiency, its use leads to a rapid subsiding of acute inflammatory phenomena, stimulation of reparative (recovery) processes, improvement of tissue microcirculation, normalization of the General immune system, and increased resistance (stability) of the body. Ozone generators used for dental treatment have a beneficial effect on periodontal tissues. Therapeutic ozone has: immunostimulating, bactericidal, fungicidal, anti-inflammatory, detoxifying and other properties. Purpose . The goal is to study the antibacterial effect of physiotherapy methods with local delivery of exposure agents. Materials and methods . We examined 80 patients with chronic generalized periodontitis of moderate severity, who, depending on the physiotherapy method used in the complex treatment of periodontitis, were divided into 2 groups of 40 people each: the first group used the Picasso led laser, and the second group used the Ozonedta device with combined local exposure to darsonvalization and ozone. The microbiological composition of periodontal pockets was determined before and after physical therapy. To isolate the aerobic microflora, we used the method of sector crops according to Gold (1965) with the calculation of the number of microorganisms in the obtained material. Anaerobes were identified by PCR using the «Multident» kit. The clinical effectiveness of the studied physiotherapy methods was evaluated 12 months after two courses of treatment (once every 6 months) using index indicators that characterize the state of periodontal tissues (PMA, CPI, Green-Vermillion, PPP, PDI, and the degree of gum recession). Results . After exposure to the Picasso diode laser, the number of aerobic microorganisms sown decreases, but not significantly. While the number of aerobic microorganisms significantly decreased after exposure to the «Ozonedta» device (P ≤ 0.001). The titer of the anaerobic microflora studied after exposure to the «Picasso» diode laser on the periodontal pocket changed in the direction of reducing the content of microorganisms by an average of 2 times, and after treatment with the ozone generator «Ozone DTA Generator» in the second group decreased by an average of 4.8 times. After 12 months of maintenance therapy, all clinical indices decreased significantly in both groups, especially the PMA index in the group where the «Ozonedta» device was used. Conclusion . Physiotherapy methods performed using the Picasso diode laser and the «Ozonedta» device for the treatment of periodontitis allow to obtain an antibacterial effect by non-drug local delivery of exposure agents in patients with chronic generalized periodontitis and significantly reduce the signs of inflammation in the periodontal tissues.

NUDT15 genetic variants are related to thiopurine-induced neutropenia in Thai children with acute lymphoblastic leukemia.

Aim: 6-Mercaptopurine (6MP) is key to the treatment of acute lymphoblastic leukemia (ALL) as part of maintenance therapy. NUDT15 was identified as a novel thiopurine regulator conferring 6MP sensitivity. The aim of this study was to evaluate the influence of NUDT15 variants on 6MP-induced neutropenia in Thai children with ALL.Materials& methodology: Genotyping of NUDT15 (c.415C>T; rs116855232) and c.36_37insGGAGTC; rs554405994) was performed by Sanger sequencing in 100 patients with ALL. Patients were classified into wild-type (group 1), heterozygous variant (group 2) and homozygous variant (group 3). Clinical and laboratory features during the first 6 months of maintenance therapy were investigated. Therapy-induced neutropenia was observed in 31 patients during the weeks 1-8 (early myelotoxicity), while therapy-induced neutropenia was observed in 47 patients during the weeks 9-24 (late myelotoxicity).Results: There were 85 wild-type patients, 14 heterozygous variant patients and one homozygous variant patient. NUDT15 variants were associated with neutropenia as compared with wild-type (odds ratio: 17.862; 95% CI: 4.198-75.992, padj=9.5×10-5). Multivariate analysis showed that the low-risk group was associated with neutropenia (p=0.014) in the first 8weeks of 6MP therapy. Group 2 and group 3 patients had significantly lower absolute neutrophil counts compared with group 1. The adjusted dose during the first 6months of maintenance therapy with NUDT15 genotype group 1, 2 and 3 were 50, 36.6 and 12.5mg/m2/day, respectively.Conclusion: Taken together, our results indicate NUDT15 variants may cause neutropenia, and the 6MP dosage should be considered in patients according to the NUDT15 variants to inform personalized 6MP therapy.

Efficacy and Safety of Blinatumomab in Asian Adults with Relapsed/Refractory B-Precursor ALL

Introduction: Blinatumomab is a bispecific T-cell engager (BiTE®) targeted immuno-oncology therapy with dual specificity for cluster of differentiation (CD) 19 and CD3 that redirects the patient's CD3-positive cytotoxic T cells to lyse CD19-positive malignant cells. Global studies have evaluated blinatumomab in patients with advanced Philadelphia chromosome-negative relapsed/refractory acute lymphoblastic leukemia (Ph- R/R ALL). In the global phase 3 TOWER study, blinatumomab monotherapy vs standard-of-care chemotherapy resulted in a significantly higher rate of complete remission (CR)/CR with partial hematologic recovery of peripheral blood counts (CRh)/CR with incomplete hematologic recovery of peripheral blood counts (44% vs 25%; P < 0.001) and longer median overall survival (7.7 vs 4.0 months; P = 0.01) (Kantarjian H, et al. NEJM. 2017;376:836-47). There are limited data on the efficacy and safety of blinatumomab in Asian patients, whose immunologic genetic background may differ from other patient populations. Therefore, we conducted a patient-level pooled analysis of the efficacy and safety of blinatumomab in 45 Asian adult patients with Ph- R/R ALL-19 from the blinatumomab arm of TOWER (NCT02013167) and 26 from a phase 1b/2 study in Japanese adults (NCT02412306). Methods: Patients in both studies were ≥ 18 years old and had Ph- R/R ALL, > 5% blasts, Eastern Cooperative Oncology Group performance status 0-2, and no central nervous system pathology. Patients received a maximum of 2 cycles of induction blinatumomab for 4 weeks by continuous intravenous infusion (cycle 1/week 1: 9 μg/day; cycle 1/weeks 2-4: 28 μg/day; subsequent cycles: 28 μg/day) followed by 2 weeks of no blinatumomab (each 6-week cycle). Responders (≤ 5% bone marrow blasts within 2 induction cycles) received blinatumomab 28 μg/day up to a maximum of 5 induction/consolidation cycles. In TOWER, patients who continued morphologic remission received up to 12 months of maintenance therapy. Patients could undergo stem cell transplantation at any time following the first treatment cycle. Results: Of the 45 Asian patients enrolled (26 female; median [range] age, 43 [18-75] years; prior hematopoietic stem cell transplantation, 20 [44.4%]; ≥ 1 prior salvage therapy, 30 [66.7%]), 44 received at least 1 cycle of blinatumomab 9-28 μg/day. Responses in the first 12 weeks of treatment (CR/CRh and minimal residual disease response) are shown in the Table. The Kaplan-Meier (KM) median overall survival time was 11.9 (95% CI: 9.9-17.1) months, and the KM median relapse-free survival time was 8.9 (95% CI: 3.8-10.7) months; median overall survival in the blinatumomab arm of TOWER was 7.7 months. Forty-one (93.2%) patients had grade ≥ 3 treatment-emergent adverse events (TEAEs), and 5 (11.4%) had fatal AEs. Grade ≥ 3 events TEAEs of interest included neurologic events (4.5%), cytokine release syndrome (2.3%), cytopenias (6.8%), and infections (20.5%). Conclusions: The safety and efficacy of blinatumomab in Asian patients were comparable with previous global studies with similar disease response rates and a favorable safety profile with no new safety signals. Disclosures Kobayashi: Astellas Amgen BioPharma: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; SymBio: Consultancy. Iida:Chugai Pharmaceutical Co., Ltd.: Research Funding. Minami:Astellas: Research Funding; Bayer: Honoraria, Other: Clinical trial, Research Funding; Taiho: Honoraria, Other: Clinical trial, Research Funding; Taisho-Toyama: Research Funding; Takeda: Honoraria, Research Funding; CSL Behring: Research Funding; Genomic Health: Honoraria; Daiichi Sankyo: Other: Clinical trial, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Eizai: Honoraria, Research Funding; Janssen: Honoraria; Kowa: Honoraria; Kyowa-Kirin: Honoraria, Research Funding; Nihon Shinyaku: Research Funding; Eli Lilly: Honoraria, Research Funding; Merck Serono: Honoraria, Research Funding; MSD: Honoraria, Other: Clinical trial, Research Funding; Nippon Chemiphar: Honoraria, Research Funding; Ono Yakuhin: Honoraria, Other: Clinical trial, Research Funding; BMS: Honoraria, Other: Clinical trial, Research Funding; Celgene: Honoraria; AstraZeneca: Other: Clinical trial; Boehringer: Honoraria, Research Funding; Otsuka: Honoraria; Pfizer: Honoraria, Other: Clinical trial, Research Funding; Sanofi: Honoraria, Research Funding; Shire Japan: Honoraria; Abbvie: Honoraria; Nihon Medi-Physics: Honoraria; Asahi-Kaseo Pharma: Research Funding; Amgen Inc: Other: Clinical trial; Nihon Kayaku: Research Funding; Shionogi: Research Funding; Novartis: Honoraria, Other: Clinical trial; Chugai: Honoraria, Other: Clinical trial, Research Funding; Yakult: Research Funding; Teijin Pharma: Research Funding. Maeda:Mundipharma Co Ltd.: Honoraria; Kyowa Kirin Co. Ltd.: Honoraria; Astellas Pharma Inc.: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Yoon:Novartis: Consultancy, Honoraria; Yuhan Pharma: Research Funding; MSD: Consultancy; Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Janssen: Consultancy; Amgen: Consultancy, Honoraria. Tran:Amgen: Employment, Equity Ownership. Morris:Amgen: Employment, Equity Ownership. Franklin:Amgen: Employment, Equity Ownership. Chong:Amgen Asia Holding Limited: Employment, Equity Ownership. Kiyoi:Astellas Pharma Inc.: Honoraria, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; FUJIFILM Corporation: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Perseus Proteomics Inc.: Research Funding.

An evaluation of monthly maintenance therapy among patients receiving intravesical combination gemcitabine/docetaxel for nonmuscle-invasive bladder cancer

PurposeTo report our experience with sequential maintenance intravesical gemcitabine/docetaxel (GEM/DOCE) for patients with nonmuscle-invasive bladder cancer. Materials and methodsFifty-nine patients who received full GEM/DOCE for nonmuscle-invasive bladder cancer between 2013 and 2018, per the protocol adapted from University of Iowa, were identified and characterized. Patients were treated with 6 weekly instillations of GEM/DOCE and subsequent monthly maintenance installations for those with no evidence of disease at the first surveillance. Student's t test and χ2 test were used to compare continuous and categorical variables as appropriate. For survival analyses, Kaplan-Meier (KM) curves were created to assess disease-free survival (DFS). Overall comparisons of KM survival analysis were conducted using the Wilcoxon test. ResultsAmong all patients, median follow-up was 24 months. Sixty-six percent of patients received ≥2 intravesical induction therapies prior to receiving GEM/DOCE. Thirty-one patients (63%) failed ≥2 induction courses of Bacillus Calmette-Guérin (BCG) before receiving GEM/DOCE. Overall DFS was 49% at 1 year and 29% at 2 years. For patients who failed ≥1 induction courses of BCG, overall DFS was 48% at 1 year and 32% at 2 years. GEM/DOCE appears to be effective for therapy naïve and patients who have failed previous intravesical therapies (P = 0.39). There were 41 (69.5%) patients who had no evidence of disease at the first surveillance and were eligible for maintenance therapy. Among these patients, 24 were managed with observation alone and 17 with monthly maintenance. Median follow-up for observed patients was 36 months and 26 months for patients with maintenance. DFS at 1 year was 42% for observed patients and 81% for patients receiving maintenance (P = 0.04). DFS at 2 years was 32% for observed patients and 59% for patients receiving maintenance therapy (P = 0.45). For maintenance eligible patients who received ≥1 induction courses of BCG, DFS was 42% for observed patients and 81% for patients receiving maintenance therapy at 1 year and 34% for observed patients and 59% for patients receiving maintenance therapy at 2 years. Pathologic stage at recurrence was similar between observed patients and those receiving maintenance (P = 0.83). KM analyses showed greater DFS for patients receiving maintenance therapy compared to observed patients (P = 0.04). ConclusionPatients who demonstrate initial complete response to GEM/DOCE may benefit from maintenance GEM/DOCE.

High prognostic value of measurable residual disease detection by flow cytometry in chronic lymphocytic leukemia patients treated with front-line fludarabine, cyclophosphamide, and rituximab, followed by three years of rituximab maintenance.

It has been postulated that monitoring measurable residual disease (MRD) could be used as a surrogate marker of progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients after treatment with immunochemotherapy regimens. In this study, we analyzed the outcome of 84 patients at 3 years of follow-up after first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) induction followed by 36 months of rituximab maintenance thearpy. MRD was assessed by a quantitative four-color flow cytometry panel with a sensitivity level of 10−4. Eighty out of 84 evaluable patients (95.2%) achieved at least a partial response or better at the end of induction. After clinical evaluation, 74 patients went into rituximab maintenance and the primary endpoint was assessed in the final analysis at 3 years of follow-up. Bone marrow (BM) MRD analysis was performed after the last planned induction course and every 6 months in cases with detectable residual disease during the 36 months of maintenance therapy. Thirty-seven patients (44%) did not have detectable residual disease in the BM prior to maintenance therapy. Interestingly, 29 patients with detectable residual disease in the BM after induction no longer had detectable disease in the BM following maintenance therapy. After a median followup of 6.30 years, the median overall survival (OS) and PFS had not been reached in patients with either undetectable or detectable residual disease in the BM, who had achieved a complete response at the time of starting maintenance therapy. Interestingly, univariate analysis showed that after rituximab maintenance OS was not affected by IGHV status (mutated vs. unmutated OS: 85.7% alive at 7.2 years vs. 79.6% alive at 7.3 years, respectively). As per protocol, 15 patients (17.8%), who achieved a complete response and undetectable peripheral blood and BM residual disease after four courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete two additional courses of rituximab and continue with maintenance therapy for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full six cycles of the induction regimen. These data show that, compared to historic controls, patients treated with FCR followed by rituximab maintenance have high-quality responses with fewer relapses and improved OS. The tolerability of this regime is favorable. Furthermore, attaining an early undetectable residual disease status could shorten the duration of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of BM MRD after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with CLL undergoing rituximab maintenance and could be a valuable tool to identify patients at high risk of relapse, influencing further treatment strategies. This trial is registered with EudraCT n. 2007-002733-36 and ClinicalTrials.gov Identifier: NCT00545714.

Health-Related Quality of Life in Transplant Ineligible Newly Diagnosed Multiple Myeloma Patients Treated with Either Thalidomide or Lenalidomide-Based Regimen Until Progression (HOVON-87/NMSG18 Study): A Prospective, Open-Label, Multicenter, Randomized, Phase 3 Study

Background: The overall survival of patients with Multiple Myeloma has improved due to effective, often continuous, therapy. However, knowledge on the impact of long term treatment on health-related quality of life (HRQoL) is limited. Methods: The HOVON87/NMSG18 study was a prospective, randomized, phase 3 study of newly diagnosed transplant ineligible multiple myeloma patients, comparing melphalan-prednisolone in combination with thalidomide or lenalidomide, followed by thalidomide or lenalidomide maintenance therapy (MPT-T or MPR-R). The EORTC QLQ-C30 and MY20 questionnaires were completed by patients at baseline, after 3 and 9 induction cycles and after 6 and 12 months of maintenance therapy. Linear mixed models and minimal important differences were used for between and within treatment arm HRQoL evaluation. Findings: 596 of 637 eligible patients participated in HRQoL reporting. Patients in both arms reported clinical relevant improvement in global QoL, future perspective, role and emotional functioning and the summary score, and less fatigue and pain, in general occurring after 6 to 12 months of maintenance only and independent of WHO performance at baseline. MPR-R treated patients reported clinically relevant worsening of diarrhoea and MPT-T treated patients reported a higher incidence of neuropathy. Patients who remained on lenalidomide maintenance therapy for at least 3 months reported clinically meaningful improvement in global QoL, role functioning and the summary score over time, without any clinical meaningful deteriorations. In contrast, patients on thalidomide reported clinically relevant worsening of peripheral neuropathy. Interpretation: Treatment with both thalidomide- and lenalidomide-based regimens improved HRQoL, in general reaching clinical relevance during maintenance therapy only. Clinical relevant diarrhea was reported by lenaldiomide-treated and clinical relevant PNP by thalidomide-treated patients. Trial Registration Number: The study was registered at www.trialregister.nl NTR1630. Funding Statement: Dutch Cancer Society KWF VU-2008 4246, Celgene Declaration of Interests: AW reports that the study was supported by Celgene and receives honoraria Takeda and grant from Amgen. MH reports compensation for work related to the study from NTNU Department of Cancer Research and Molecular Medicine and receives grant from Celgene Aps. MS receives personal fees from Celgene, Amgen, Janssen and Takeda. SZ receives research funding from Celgene, Janssen, Takeda and Amgen and serves on advisory board for Celgene, Janssen, Takeda and Amgen. LKN has received grants from Celgene, Janssen, Amgen and Takeda, during the conduct of the study. NA receives research funding from Celgene, Janssen, Takeda and Amgen. PS receives grants from Takeda, Karyopharma, and grants and personal fees from Celgene, Janssen-Cilag. M-DL has received personal fees from Celgene. U-HM has received lecture honoraria from Amgen, Takeda, Janssen, Mundipharma, Oncopeptides and serves on advisory board for Amgen. NvdD receives grants from Celgene, Janssen pharmaceuticals, Novatis, Amgen and BMS and serves at the advisory board for Celgene, Janssen pharmaceuticals, Novartis, Amgen, Takeda, BMS, Bayer, Servier. All other authors declare no conflicting interest. Ethics Approval Statement: The study protocol was approved by the Ethics Committee and conducted in accordance with the ethical principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines. The authors obtained written informed consent from all participants.

Efficacy and safety of oral immunotherapy for peanut allergy: a pilot study in Singaporean children.

BackgroundPeanut allergy is an increasing problem in Singapore and strict avoidance is difficult as peanut is ubiquitous in Asian cuisine.ObjectiveWe aimed to assess the efficacy and safety of peanut oral immunotherapy (OIT) in children with obvious peanut allergy in Singapore.MethodsThis was an open-label study of peanut OIT in children living in Singapore, with 2 weekly dose escalation until final maintenance dose of 3,000 mg of peanut protein and a maintenance phase of 12 months. An oral food challenge was performed at 6 months to assess for desensitisation and at 4 weeks after discontinuation of OIT having completed 12 months of maintenance therapy to assess for possible sustained unresponsiveness. The adverse events were monitored using the symptom diaries.ResultsNine subjects were started on OIT, with 7 managing to complete maintenance phase of therapy. Of these 7, all were able to tolerate at least 3,000 mg of peanut protein by 6 months of maintenance therapy, showing that the OIT was effective. Of these 7, 3 patients complied with the 4-week abstinence period after completion of OIT before another peanut challenge; 2 of the 3 subjects showed a significant decrease from the initial ability to tolerate 3,000 mg of peanut protein. Side effects were mainly gastrointestinal in nature and were more common during the updosing phase than the maintenance phase. No episodes of anaphylaxis were observed in this study.ConclusionPeanut OIT seemed to be effective and safe in our cohort of Singaporean children.

Objective and subjective sinonasal and pulmonary outcomes in aspirin desensitization therapy: A prospective cohort study

ObjectiveAspirin exacerbated respiratory disease (AERD) patients are challenging to manage with sinonasal and pulmonary symptoms refractory to maximal medical and surgical therapies. Our objective was to comprehensively examine objective and validated, disease-specific subjective sinonasal and pulmonary outcomes of aspirin (ASA) desensitization therapy in this patient population. MethodsProspective cohort study at an academic tertiary center. AERD patients with a history of chronic rhinosinusitis with nasal polyposis (CRSwNP), prior diagnosis of asthma, and a history of ASA sensitivity were eligible for inclusion. Patients underwent ASA desensitization using an established institutional protocol and continued on a 650mg twice daily maintenance dose. Baseline Sinonasal Outcome Test (SNOT-22) and Asthma Control Questionnaire (ACQ) responses, acoustic rhinometry, peak flow readings, and endoscopic scoring of nasal polyps were recorded prior to desensitization and after 6months of maintenance therapy. ResultsTwelve patients were recruited for participation and underwent desensitization. Eight patients continued maintenance therapy and follow up at 6months. Prior to desensitization, patients reported bothersome sinonasal symptoms with a median SNOT-22 score of 30.0±34.5 (interquartile range (IQR)). There was significant improvement after 6months of maintenance therapy to a median SNOT-22 score of 18.5±17.3 (p=0.025, Wilcoxon signed rank test). Acoustic rhinometry, endoscopic scores, ACQ and forced expiratory volume values remained stable at 6months. ConclusionsAERD patients may benefit from ASA desensitization with subjective sinonasal symptom improvement at 6months and stable asthma and objective sinonasal measures. Further discussion is needed in the otolaryngology community regarding ASA desensitization in AERD management.

Monitoring of FLT3 Phosphorylation and FLT3 Ligand Levels in Patients with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) Treated with Midostaurin within the AMLSG 16-10 Trial of the German-Austrian Study Group

Monitoring of FLT3 Phosphorylation and FLT3 Ligand Levels in Patients with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) Treated with Midostaurin within the AMLSG 16-10 Trial of the German-Austrian Study Group

Systematic literature review on patterns of pharmacological treatment and adherence among patients with bipolar disorder type I in the USA.

BackgroundBipolar disorder type I (BD-I) is a chronic condition characterized by mania episodes followed by syndromic recovery periods, usually permeated by depressive symptoma-tology and recurring acute manic episodes. It requires long-term pharmacological treatment; thus, it is critical to understand the patterns of drug therapy use and medication compliance to better plan health care policies and needs. This systematic literature review aims to study these data among patients with BD-I in the USA, focusing on medications to treat mania.MethodsArticles published in the last 10 years to October 2016 were searched on MEDLINE and Embase. Studies on patterns of drug therapy, concordance of prescription with clinical practice guidelines, and adherence and persistence with pharmacological treatments for BD-I in the USA under observational conditions, with focus on treatments for mania, were selected.ResultsTreatment prevalence for BD-I is low in the USA, with the most current study showing a 46% 12-month rate. There is a lack of studies addressing the use of long-acting injectable (LAI) antipsychotics. Second-generation antipsychotics (SGAs) have been used by nearly all patients receiving oral antipsychotics since the 2000s. However, 30%–60% of individuals with BD do not receive appropriate treatment, and adherence to oral therapies is poor, with medication possession ratios ≥80% seen in only approximately 60% of patients. For persistence rates, results suggest that treatment duration is short for a condition with recommendation for at least 6 months of maintenance therapy. Literature indicates that LAI SGAs may be related to better adherence and persistence.ConclusionThere is a need for studies addressing specifically patterns of therapy and adherence to pharmacological treatment in BD-I patients in the USA to better understand the value of current standards, and an urgent need to improve the rates of adherence and persistence to BD-I pharmacotherapy and to increase the understanding of LAI SGAs’ potential to address this issue.

Fusion status in patients with lymph node-positive (N1) alveolar rhabdomyosarcoma is a powerful predictor of prognosis: Experience of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

Alveolar rhabdomyosarcoma (aRMS) with lymph node involvement (N1 classification) accounts for up to 10% of all cases of RMS. The prognosis is poor, and is comparable to that of distant metastatic disease. In the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS2005 protocol, patients with a histologic diagnosis of aRMS/N1 received intensified chemotherapy with systematic locoregional treatment. Patients with aRMS/N1 were enrolled prospectively after primary surgery/biopsy and fusion status was assessed in tumor samples. All patients received 9 cycles of induction chemotherapy and 6 months of maintenance therapy. Local treatment included radiotherapy to the primary site and lymph nodes with or without secondary surgical resection. A total of 103 patients were enrolled. The clinical characteristics of the patients were predominantly unfavorable: 90% had macroscopic residual disease after initial surgery/biopsy, 63% had locally invasive tumors, 77% had a tumor measuring >5 cm, and 81% had disease at unfavorable sites. Fusion genes involving forkhead box protein O1 (FOXO1) were detected in 56 of 84 patients. Events occurred in 52 patients: 43 developed disease recurrence, 7 had disease that was refractory to treatment, and 2 patients developed second neoplasms. On univariate analysis, unfavorable disease site, tumor invasiveness, Intergroup Rhabdomyosarcoma Study group III, and fusion-positive status correlated with worse prognosis. The 5-year event-free survival rate of patients with fusion-positive tumors was 43% compared with 74% in patients with fusion-negative tumors (P = .01). On multivariate analysis, fusion positivity and tumor invasiveness proved to be unfavorable prognostic markers. Fusion status and tumor invasiveness appear to have a strong impact on prognosis in patients with aRMS/N1. Fusion status will be used to stratify these patients in the next EpSSG RMS study, and treatment will be intensified in patients with fusion-positive tumors. Cancer 2018. © 2018 American Cancer Society.

Early Nutrition Intervention Attenuates Weight Gain for Pediatric Acute Lymphoblastic Leukemia Patients in Maintenance Therapy.

Obesity following treatment of pediatric acute lymphoblastic leukemia (ALL) has become a significant long-term concern. Excessive weight gain often occurs during treatment, particularly during induction and the first 6 months of maintenance therapy, and it may be potentially modifiable. This retrospective study aimed to evaluate the impact of an early, 3-visit nutrition intervention on weight gain during maintenance therapy in ALL patients. Medical records of the intervention group were compared with historical controls who were treated on the same ALL treatment protocols during an earlier time period. Anthropometrics were collected throughout intensive therapy and at every monthly visit during the first 12 months of maintenance therapy. In total, 67 patients were evaluated (33 in the intervention group and 34 in the control group). After controlling for significant predictors of body mass index (BMI) z-scores in maintenance therapy-including higher BMI at diagnosis and weight gain throughout intensive therapy-the intervention group demonstrated more controlled weight gain during maintenance therapy (P<0.0001). A 3-visit nutrition intervention was effective in attenuating weight gain trends during ALL maintenance therapy.

Chlormethine Hydrochloride is Not Inferior to Tacrolimus in Treating Steroid-Resistant Nephrotic Syndrome

Background/Aims: The present study aimed to explore the equivalence of CHL and tacrolimus (TAC), despite reports regarding the efficacy and safety of TAC in treating SRNS patients. Methods: A retrospective cohort study of CHL or TAC treatment was performed by collecting the medical records of SRNS patients with a pathological classification of focal segmental glomurular sclerosis (FSGS) or membranous nephropathy (MN) from December 2008 to December 2014 in a 3A grade hospital in southern China. The treatment regimen includes 6 months of induction therapy and a subsequent 6 to 30 months of maintenance therapy, which were evaluated by the scheduled follow-up and the detection of proteinuria and serum creatinine levels. The treatment outcomes were classified as complete remission, partial remission or no remission. Results: In a total of 146 SRNS patients, CHL treatment showed a higher proportion of complete remission (27.8% vs 14.9%) or partial remission (52.8% vs 37.8%) compared to TAC treatment (P < 0.10) at the stage of induction therapy. The CHL treatment of SRNS patients with FSGS showed better efficacy than treatment of the TAC group, but the difference of efficacy in the pathological type of MN between CHL and TAC group was not significant (P > 0.10). During maintenance therapy, the difference between the CHL and TAC groups was not significant in the SRNS patients with FSGS or MN (P > 0.10). In addition, the difference of adverse effects between CHL and TAC group was not significant (P > 0.10), although there was a slightly higher proportion of nausea and vomiting in the CHL group. Conclusion: The non-inferior efficacy of CHL treatment on the SRNS patients with FSGS or MN compared to TAC treatment, which highlighted CHL can be considered to be alternative treatment for SRNS patients in the clinical setting.