Summary Background Gemtuzumab Ozogamicin (GO) was the first example of antibody directed chemotherapy in cancer and developed for Acute Myeloid Leukaemia. Its role has been unclear. Five randomised trials where it was combined with standard induction chemotherapy in adults have produced different results. In an effort to clarify the level of benefit, if any, and in which patients outcomes might be improved, an individual patient data meta-analysis of these 5 trials has been undertaken. Methods All randomised trials of GO in adults (age >15), given in conjunction with the first course of intensive induction chemotherapy for AML (excluding APL) were identified. In a collaboration between the groups involved, source data concerning demographics, treatment was requested in May 2013 and collected in 3325 randomised patients (median age 58). All trials were centrally randomised and open-label, with survival as primary endpoint. Analyses are presented by standard techniques, and within standardised risk groups Results Remission rates were not increased, but by significantly reducing the risk of relapse overall survival at 5 years was improved irrespective of patient age (30.7% vs 34.6%; HR 0.90 (95% CI 0.82-0.98), p=0.01). The survival benefit was particularly clear in those with favourable cytogenetics (55.2% vs 76.3%; HR0.47 (0.31-0.73), p=0.0005), but also observed in intermediate risk patients (34.1% vs 39.4%; HR 0.84 (0.75-0.95), p=0.007) Patients with adverse karyotype did not benefit overall or within any trial. Dose levels of 3mg/m2 were associated with less toxicity and equal efficacy. Interpretation GO can be safely added to conventional induction therapy. For patients who do not have adverse cytogenetics there is a significant survival benefit. These data suggest that the use of GO should be re-evaluated and the license status of GO may need to be reviewed. Role of funding source There was no funder for this meta-analysis.

These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.

IntroductionCirculating monocytes are precursors that can differentiate into a variety of tissue-resident macrophages (M⌽s) or dendritic cells (DCs), and even osteoclasts. 1 M⌽s exhibit a variety of activities, some of which are in opposition (ie, proinflammatory versus anti-inflammatory, immunostimulatory versus immunosuppressive, and tissue destructive versus reconstructive). 1 The functional heterogeneity of M⌽s depends, at least in part, on the local microenvironment. 2,3 In analogy with the Th1/Th2 dichotomy of T-cell responses, M⌽s exposed to IFN␥ or IL-4 have been referred to as M1s or M2s (also called alternatively activated M⌽s), respectively. 4 M1s produce IL-12 and TNF␣ and are potent killers of microorganisms (especially intracellular pathogens) and tumor cells. M2s produce IL-10 but not IL-12, scavenge debris, tune inflammatory responses, and promote humoral immunity and tissue repair. 5 The detection in cancer patients of tumor-specific T cells that kill ex vivo autologous tumor cells demonstrates that numerous tumor-cell types are potentially immunogenic. However, spontaneous clearance of established tumors by immune mechanisms is rare and active antitumor immunotherapy usually has poor clinical efficacy. 6 It is now largely documented that established tumors propagate conditions that favor their immune escape. 6 Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) accumulate at tumor sites and maintain immune tolerance that contributes to defeating tumor immunity. 6,7 TAMs are far more abundant than Tregs and, in various solid tumors, constitute the major components of the leukocyte infiltrate. In most cases, especially breast, prostate, cervical, and ovarian cancers, TAM density is correlated with poor prognosis. [8][9][10] Strong evidence suggests that TAMs also promote cancer progression and metastasis. 8,11,12 TAMs are polarized M2 cells with potent immunosuppressive functions. They have poor antigen-presenting capacity, prevent T-cell activation, and may contribute to suppressing DC functions. 4,13,14 They also promote the recruitment of Tregs and Th2 cells (through CC chemokine ligand 17 [CCL17] and CCL22 secretion) and naive T cells (through CCL18). Naive T-cell activation, in an environment dominated by immature DCs and TAMs, is likely to induce anergy. 10,15 In addition, TAM production of growth and angiogenic factors (ie, vascular endothelial growth factor [VEGF] and platelet-derived endothelial cell growth factor [PDGF]), proteases (ie, matrix metalloproteinase 9 [MMP9]), and chemokines (eg, CCL2) favors tumor-cell proliferation, angiogenesis, dissolution of connective tissues, and metastasis. 8,12,14,16 The origin of TAMs has mostly been studied in mice in terms of precursor recruitment, survival, and proliferation. TAMs derive from circulating monocytes that are recruited into tumors by chemotactic factors, such as monocyte-colony-stimulating factor Submitted February 19, 2007; accepted August 29, 2007. Prepublished online as Blood First Edition paper, September 11, 2...

Key Points• Glutamine removal and knockdown of the glutamine transporter SLC1A5 have antileukemic activity in AML.• The glutaminase activity of L-asparaginase inhibits mTORC1 and protein synthesis and induces a strong autophagy in AML.Cancer cells require nutrients and energy to adapt to increased biosynthetic activity, and protein synthesis inhibition downstream of mammalian target of rapamycin complex 1 (mTORC1) has shown promise as a possible therapy for acute myeloid leukemia (AML). Glutamine contributes to leucine import into cells, which controls the amino acid/Rag/mTORC1 signaling pathway. We show in our current study that glutamine removal inhibits mTORC1 and induces apoptosis in AML cells. The knockdown of the SLC1A5 high-affinity transporter for glutamine induces apoptosis and inhibits tumor formation in a mouse AML xenotransplantation model. L-asparaginase (L-ase) is an anticancer agent also harboring glutaminase activity. We show that L-ases from both Escherichia coli and Erwinia chrysanthemi profoundly inhibit mTORC1 and protein synthesis and that this inhibition correlates with their glutaminase activity levels and produces a strong apoptotic response in primary AML cells. We further show that L-ases upregulate glutamine synthase (GS) expression in leukemic cells and that a GS knockdown enhances L-ase-induced apoptosis in some AML cells. Finally, we observe a strong autophagic process upon L-ase treatment. These results suggest that L-ase anticancer activity and glutamine uptake inhibition are promising new therapeutic strategies for AML. (Blood. 2013;122(20):3521-3532)