Targeting the innate immune system in pediatric and adult AML.

While the introduction of T cell-based immunotherapies has improved outcomes in many cancer types, the development of immunotherapies for both adult and pediatric AML has been relatively slow and limited. In addition to the need to identify suitable target antigens, a better understanding of the immunosuppressive tumor microenvironment is necessary for the design of novel immunotherapy approaches. To date, most immune characterization studies in AML have focused on T cells, while innate immune lineages such as monocytes, granulocytes and natural killer (NK) cells, received less attention. In solid cancers, studies have shown that innate immune cells, such as macrophages, myeloid-derived suppressor cells and neutrophils are highly plastic and may differentiate into immunosuppressive cells depending on signals received in their microenvironment, while NK cells appear to be functionally impaired. Hence, an in-depth characterization of the innate immune compartment in the TME is urgently needed to guide the development of immunotherapeutic interventions for AML. In this review, we summarize the current knowledge on the innate immune compartment in AML, and we discuss how targeting its components may enhance T cell-based- and other immunotherapeutic approaches.

A multidimensional analysis reveals distinct immune phenotypes and tertiary lymphoid structure-like aggregates in the bone marrow of pediatric acute myeloid leukemia.

Because of the low mutational burden, children with acute myeloid leukemia (AML) are thought to have a 'cold' tumor microenvironment and consequently, a low likelihood of response to T cell-directed immunotherapies. Here, we provide a multidimensional overview of the tumor immune microenvironment in newly diagnosed pediatric AML. On a cohort level, we demonstrate wide variation in T cell infiltration with nearly one-third of cases harboring an immune-infiltrated bone marrow. These immune-infiltrated cases are characterized by a decreased abundance of M2-like macrophages, which we find to be associated with response to T cell-directed immunotherapy in adult AML. On an organizational level, we reveal the composition of spatially organized immune aggregates in pediatric AML, and show that in the adult setting such aggregates in post-treatment bone marrow and extramedullary sites associate with response to ipilimumab-based therapy. Altogether, our study provides immune correlates of response to T cell-directed immunotherapies and indicates starting points for further investigations into immunomodulatory mechanisms in AML.

Case Report: Immune dysregulation associated with long-lasting regression of a (pre)leukemic clone.

Regression of leukemia in the absence of disease-modifying therapy remains poorly understood, although immunological mechanisms are thought to play a role. Here, we present a unique case of a 17-year-old boy with immune dysregulation and long-lasting regression of a (pre)leukemic clone in the absence of disease-modifying therapy. Using molecular and immunological analyses, we identified bone marrow features associated with disease control and loss thereof. In addition, our case reveals that detection of certain fusion genes with hardly any blasts in the bone marrow may be indicative of an accompanying oncogenic fusion gene, with implications for disease surveillance- and management in future patients.

Treating CD33-Positive de novo Acute Myeloid Leukemia in Pediatric Patients: Focus on the Clinical Value of Gemtuzumab Ozogamicin.

Although survival in pediatric acute myeloid leukemia (AML) has increased considerably over the past decades, refractory disease and relapse rates remain high. Refractory and relapsed disease are difficult to treat, with overall survival rates less than 40-50%. Preventing relapse should, therefore, be one of the highest priorities. Current conventional chemotherapy regimens are hard to intensify due to associated toxic complications, hence more effective therapies that do not increase toxicity are needed. A promising targeted agent is the CD33-directed antibody-drug conjugate gemtuzumab ozogamicin (GO). Because CD33 is highly expressed on leukemic cells in the majority of AML patients, GO can be useful for a broad range of patients. Better relapse-free survival (RFS) after therapy including GO has been reported in several pediatric clinical trials; however, ambiguity about the clinical value of GO in newly diagnosed children remains. Treatment with GO in de novo AML patients aged ≥1 month, in combination with standard chemotherapy is approved in the United States, whereas in Europe, GO is only approved for newly diagnosed patients aged ≥15 years. In this review, we aimed to clarify the clinical value of GO for treatment of newly diagnosed pediatric AML patients. Based on current literature, GO seems to have additional value, in terms of RFS, and acceptable toxicity when used in addition to chemotherapy during initial treatment. Moreover, in KMT2A-rearranged patients, the clinical value of GO was even more evident. Also, we addressed predictors of response, being CD33 expression and SNPs, PgP-1 and Annexin A5. The near finalized intent-to-file clinical trial in the MyeChild consortium investigates whether fractionated dosing has additional value for pediatric AML, which may pave the way for a broader application of GO in pediatric AML.

Paving the Way for Immunotherapy in Pediatric Acute Myeloid Leukemia: Current Knowledge and the Way Forward.

Immunotherapeutic agents may be an attractive option to further improve outcomes and to reduce treatment-related toxicity for pediatric AML. While improvements in outcome have been observed with immunotherapy in many cancer types, immunotherapy development and implementation into patient care for both adult and pediatric AML has been hampered by an incomplete understanding of the bone marrow environment and a paucity of tumor-specific antigens. Since only a minority of patients respond in most immunotherapy trials across different cancer types, it will be crucial to understand which children with AML are likely to respond to or may benefit from immunotherapies. Immune cell profiling efforts hold promise to answer this question, as illustrated by the development of predictive scores in solid cancers. Such information on the number and phenotype of immune cells during current treatment regimens will be pivotal to generate hypotheses on how and when to intervene with immunotherapy in pediatric AML. In this review, we discuss the current understanding of the number and phenotype of immune cells in the bone marrow in pediatric AML, ongoing immunotherapy trials and how comprehensive immune profiling efforts may pave the way for successful clinical trials (and, ultimately, implementation into patient care).

Pilot Study of the Pharmacokinetics of Cefotaxime in Critically Ill Patients with Acute Kidney Injury Treated with Continuous Renal Replacement Therapy.

The objective of this study was to describe the pharmacokinetics of cefotaxime (CTX) in critically ill patients with acute kidney injury (AKI) when treated with continuous renal replacement therapy (CRRT) in the intensive care unit (ICU). This single-center prospective observational pilot study was performed among ICU-patients with AKI receiving ≥48 h concomitant CRRT and CTX. CTX was administered intravenously 1,000 mg (bolus) every 6 h for 4 days. CRRT was performed as continuous venovenous hemofiltration (CVVH). Plasma concentrations of CTX and its active metabolite desacetylcefotaxime (DAC) were measured during CVVH treatment. CTX plasma levels and patient data were used to construct concentration-time curves. By using this data, the duration of plasma levels above 4 mg/liter (four times the MIC) was calculated and analyzed. Twenty-seven patients were included. The median CTX peak level was 55 mg/liter (range, 19 to 98 mg/liter), the median CTX trough level was 12 mg/liter (range, 0.8 to 37 mg/liter), and the median DAC plasma level was 15 mg/liter (range, 1.5 to 48 mg/liter). Five patients (19%) had CTX plasma levels below 4 mg/liter at certain time points during treatment. In at least 83% of the time any patient was treated with CTX, the CTX plasma level stayed above 4 mg/liter. A dosing regimen of 1,000 mg of CTX given four times daily is likely to achieve adequate plasma levels in patients with AKI treated with CVVH. Dose reduction might be a risk for suboptimal treatment.