Helen Ma

IMPORTANCE: Relapse prevention in recurrent depression is a significant public health problem, and antidepressants are the current first-line treatment approach. Identifying an equally efficacious nonpharmacological intervention would be an important development. OBJECTIVE: To conduct a meta-analysis on individual patient data to examine the efficacy of mindfulness-based cognitive therapy (MBCT) compared with usual care and other active treatments, including antidepressants, in treating those with recurrent depression. DATA SOURCES: English-language studies published or accepted for publication in peer-reviewed journals identified from EMBASE, PubMed/Medline, PsycINFO, Web of Science, Scopus, and the Cochrane Controlled Trials Register from the first available year to November 22, 2014. Searches were conducted from November 2010 to November 2014. STUDY SELECTION: Randomized trials of manualized MBCT for relapse prevention in recurrent depression in full or partial remission that compared MBCT with at least 1 non-MBCT treatment, including usual care. DATA EXTRACTION AND SYNTHESIS: This was an update to a previous meta-analysis. We screened 2555 new records after removing duplicates. Abstracts were screened for full-text extraction (S.S.) and checked by another researcher (T.D.). There were no disagreements. Of the original 2555 studies, 766 were evaluated against full study inclusion criteria, and we acquired full text for 8. Of these, 4 studies were excluded, and the remaining 4 were combined with the 6 studies identified from the previous meta-analysis, yielding 10 studies for qualitative synthesis. Full patient data were not available for 1 of these studies, resulting in 9 studies with individual patient data, which were included in the quantitative synthesis. RESULTS: Of the 1258 patients included, the mean (SD) age was 47.1 (11.9) years, and 944 (75.0%) were female. A 2-stage random effects approach showed that patients receiving MBCT had a reduced risk of depressive relapse within a 60-week follow-up period compared with those who did not receive MBCT (hazard ratio, 0.69; 95% CI, 0.58-0.82). Furthermore, comparisons with active treatments suggest a reduced risk of depressive relapse within a 60-week follow-up period (hazard ratio, 0.79; 95% CI, 0.64-0.97). Using a 1-stage approach, sociodemographic (ie, age, sex, education, and relationship status) and psychiatric (ie, age at onset and number of previous episodes of depression) variables showed no statistically significant interaction with MBCT treatment. However, there was some evidence to suggest that a greater severity of depressive symptoms prior to treatment was associated with a larger effect of MBCT compared with other treatments. CONCLUSIONS AND RELEVANCE: Mindfulness-based cognitive therapy appears efficacious as a treatment for relapse prevention for those with recurrent depression, particularly those with more pronounced residual symptoms. Recommendations are made concerning how future trials can address remaining uncertainties and improve the rigor of the field.

// Polina Matre 1, * , Juliana Velez 1, * , Rodrigo Jacamo 1 , Yuan Qi 2 , Xiaoping Su 2 , Tianyu Cai 1 , Steven M. Chan 3 , Alessia Lodi 4 , Shannon R. Sweeney 4 , Helen Ma 1 , Richard Eric Davis 5 , Natalia Baran 1 , Torsten Haferlach 6 , Xiaohua Su 7 , Elsa Renee Flores 7 , Doriann Gonzalez 1 , Sergej Konoplev 8 , Ismael Samudio 9 , Courtney DiNardo 1 , Ravi Majeti 3 , Aaron D. Schimmer 10 , Weiqun Li 11 , Taotao Wang 11 , Stefano Tiziani 4 , Marina Konopleva 1 1 Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA 4 Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA 5 Lymphoma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 CEO of MLL Munich Leukemia Laboratory, Munich, Germany 7 Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 8 Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 The Centre for Drug Research and Development Biologics, Vancouver, British Columbia, Canada 10 Medical Biophysics, Princess Margaret Hospital / Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada 11 Analytical Chemistry, Pharmacology, Spectroscopy, Calithera Biosciences, South San Francisco, CA, USA * These authors have contributed equally to this work Correspondence to: Marina Konopleva, email: mkonople@mdanderson.org Keywords: leukemia, metabolism, glutamine, microenvironment, differentiation therapy Received: June 08, 2016     Accepted: October 13, 2016     Published: October 27, 2016 ABSTRACT Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC). We analyzed mRNA expression of GLS1 splicing variants, GAC and KGA, in several large AML datasets and identified increased levels of expression in AML patients with complex cytogenetics and within specific molecular subsets. Inhibition of glutaminase by allosteric GLS inhibitor bis -2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide or by novel, potent, orally bioavailable GLS inhibitor CB-839 reduced intracellular glutamate levels and inhibited growth of AML cells. In cell lines and patient samples harboring IDH1/IDH2 (Isocitrate dehydrogenase 1 and 2) mutations, CB-839 reduced production of oncometabolite 2-hydroxyglutarate, inducing differentiation. These findings indicate potential utility of glutaminase inhibitors in AML therapy, which can inhibit cell growth, induce apoptosis and/or differentiation in specific leukemia subtypes.

Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.

Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance of RAS/MAPK activation, we found by single-cell DNA sequencing rapid clonal selection of RAS-mutated clones in AML patients treated with VEN-containing regimens. In summary, these findings establish RAS/MAPK/MCL-1 and mitochondrial fitness as key survival mechanisms of VEN-RE AML and provide the rationale for combinatorial strategies effectively targeting these pathways.