Emily Curran

Phase II Study of the Oral MEK Inhibitor Selumetinib in Advanced Acute Myelogenous Leukemia: A University of Chicago Phase II Consortium Trial

Purpose: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown. Experimental Design: Selumetinib is an oral small-molecule inhibitor of MAP–ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal—regulated kinase (ERK) and mTOR phosphorylation. Results: Common drug-related toxicities were grade 1–2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027). Conclusions: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials. Clin Cancer Res; 20(2); 490–8. ©2013 AACR.

How I treat acute lymphoblastic leukemia in older adolescents and young adults

At the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. Although the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease-free survival rates of 60% to 70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and the availability of disease-specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients.

Gender affects survival for medulloblastoma only in older children and adults: A study from the surveillance epidemiology and end results registry

Males have a higher incidence of medulloblastoma (MB) than females, but the effect of gender on survival is unclear. Studies have yielded conflicting results, possibly due to small sample sizes or differences in how researchers defined MB. We aimed to determine the effect of gender on survival in MB using a large data set and strict criteria for defining MB.

Survival and selected outcomes of older adults with locally advanced head/neck cancer treated with chemoradiation therapy

OBJECTIVES Chemoradiation therapy (CRT) remains a potentially curative treatment in patients with locally advanced head/neck cancer (LA-HNC). However, survival and other outcomes in older patients with head/neck cancer receiving chemoradiotherapy are not well established. This study was performed to elucidate selected outcomes in this patient population. MATERIALS AND METHODS Retrospective study of LA-HNC patients ≥ 70 years of age who had received 5-fluorouracil-hydoxyurea-based CRT with a minimum of 3 years of follow up after therapy initiation was performed. Pre-treatment patient- and cancer-related characteristics were recorded. Survival data in addition to gastrostomy tube utilization, swallowing function, and hematologic toxicity were captured. RESULTS Eighty-nine patients treated between 1997 and 2009 were eligible for analysis (median age, 76 years; range, 70-94; male, 61%; ECOG PS, 0-1 43%; stage IVA/B, 71%). 86 were evaluable for survival analysis. 5-year overall and event-free survival were both at 32% with a median follow-up time of 39.2 months. The majority (86.5%) were able to complete all planned treatment cycles. A significant proportion of patients, however, required gastrostomy tube during CRT (62%) and developed aspiration during swallowing evaluation post-treatment (44%). Several patients required hospice (9%) or skilled nursing facility (13%) referrals during treatment. CONCLUSION Select older adults with LA-HNC can still experience long-term benefits despite 5-year survival rates lower than those historically reported in younger patients undergoing identical CRT regimens although potentially at higher risk for acute toxicities. Assessment and selection of those who can tolerate more intense combined-modality strategies and their long-term outcomes merit further larger, prospective studies.

Phosphoinositide 3-kinase inhibitors in lymphoma.

Purpose of review The phosphoinositide 3-kinase (PI3K) pathway, with downstream targets including Akt and mammalian target of rapamycin, has been implicated in numerous human cancers, including hematologic malignancies and lymphomas. The development and refinement of PI3K inhibitors directed toward this pathway show promising clinical efficacy. This review will discuss the emerging body of clinical data in lymphoid malignancies and present future directions for research utilizing these inhibitors. Recent findings The PI3K&dgr; inhibitor, idelalisib, has been most widely studied in lymphoma, and has shown promising results both as a single agent and in combination with other therapies. IPI-145, a dual inhibitor of PI3K&dgr; and PI3K&ggr;, has also shown efficacy and several clinical trials are underway. Other PI3K inhibitors are in active development, with several entering early phase clinical trials. Summary The PI3K pathway appears to be important in lymphoma and targeting this pathway shows promising clinical efficacy.

Medulloblastoma incidence has not changed over time: a CBTRUS study.

Earlier studies have reported changes in the incidence of medulloblastoma (MB) but have conflicted, likely because of small sample size or misclassification of MB with primitive neuroectodermal tumor (PNET). The incidence of MB and PNET from 1985 to 2002 was determined from the Central Brain Tumor Registry of the United States, a large population-based cancer registry, using strict histologic and site codes. No statistically significant change in MB incidence was observed over the last 2 decades, but there was an increase in MB and PNET combined.

Targeting the Innate Immune System as Immunotherapy for Acute Myeloid Leukemia

Because of its disseminated nature and lack of tumor-draining lymph nodes, acute myeloid leukemia (AML) likely employs unique immune evasion strategies as compared to solid malignancies. Targeting these unique mechanisms may result in improved immunotherapeutic approaches. Emerging data suggest that a specific dendritic cell (DC) subset, CD8α DCs, may be responsible for mediating tolerance in AML and thus targeting the innate immune system may be of benefit in this disease. Promising immune targets include the toll-like receptors, calreticulin/CD47, the stimulator of interferon genes pathway, and signal transducer and activator of transcription 3 (STAT3). However, it is becoming clear that compensatory mechanisms may limit the efficacy of these agents alone and thus rationale combinations of immunotherapies are warranted. This review discusses the potential immune evasion strategies in AML, as well as discussion of the promising innate immune targets, both alone and in combination, for this disease.

Mechanisms of Immune Tolerance in Leukemia and Lymphoma

The mechanisms through which immune responses are generated against solid cancers are well characterized and knowledge of the immune evasion pathways exploited by these malignancies has grown considerably. However, for hematological cancers, which develop and disseminate quite differently than solid tumors, the pathways that regulate immune activation or tolerance are less clear. Growing evidence suggests that, while numerous immune escape pathways are shared between hematological and solid malignancies, several unique pathways are exploited by leukemia and lymphoma. Below we discuss immune evasion mechanisms in leukemia and lymphoma, highlighting key differences from solid tumors. A more complete characterization of the mechanisms of immune tolerance in hematological malignancies is critical to inform the development of future immunotherapeutic approaches.

Activation of the STING pathway enhances immunity and improves survival in a murine myeloid leukemia model

Type I interferon (IFN) production by innate immune cells is critical to prime spontaneous T cell responses against solid tumors. Emerging pre-clinical data suggests that tumor-derived DNA induces potent IFN-β production by activating a cytosolic DNA sensing receptor called STING (Stimulator of Interferon Genes), ultimately resulting in tumor antigen-specific T cell priming and in some cases, tumor rejection. However, because of their disseminated growth pattern, hematological malignancies, such as acute myeloid leukemia (AML), may not release sufficient quantities of DNA during cell death to activate the STING pathway in innate immune cells, which contributes to the T cell tolerance observed in these hosts. Thus, we hypothesized that STING pathway activation would promote a host type I IFN response sufficient to facilitate leukemia-specific T cell priming and immune-mediated control of AML progression. Murine C1498 AML cells expressing the model SIY antigen (C1498.SIY) were inoculated intravenously into syngeneic C57BL/6 mice which then received a single dose of the murine STING agonist, DMXAA (5,6-dimethylxanthenone-4-acetic acid), or vehicle control 5 days later. DMXAA induced potent IFN-β production by C57BL/6 spleen cells (90-fold induction over vehicle control). STING pathway activation via DMXAA treatment of C1498.SIY-bearing animals resulted in a massive expansion (10-fold over vehicle control) of endogenous SIY antigen-specific T cells as analyzed by SIY/Kb pentamer staining and flow cytometry. Intracellular cytokine staining of SIY-peptide restimulated spleen cells from DMXAA-treated animals revealed that the expanded SIY-specific CD8+ T cells produced high-levels of IFN-γ. This enhanced immune response also translated to a benefit in survival. After C1498.SIY AML cell-challenge, 80% of DMXAA-treated mice survived long-term, while controls succumbed to AML within approximately 3-4 weeks, as expected. DMXAA-treated mice surviving a primary C1498.SIY cell challenge also rejected a secondary challenge with parental C1498 cells (SIY-negative), suggesting DMXAA-induced STING activation led to potent immunological memory against native C1498-expressed antigens. DMXAA treatment of mice following a systemic challenge with parental C1498 cells also led to significantly enhanced survival compared to control-treated animals. This effect was T and/or B cell-dependent, as DMXAA treatment of leukemia-bearing RAG-/- mice had no effect on survival. Collectively, these data suggest that DMXAA-mediated activation of the STING pathway enhances adaptive immunity to AML, culminating in prolonged survival and even disease cure. Human STING agonists are currently in development and, if STING pathway activation demonstrates efficacy in additional pre-clinical leukemia models, it may be of interest to target this pathway in AML patients.

Diagnostic evaluation of RNA sequencing for the detection of genetic abnormalities associated with Ph-like acute lymphoblastic leukemia (ALL).

Abstract Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a molecular subtype of high-risk B-cell ALL characterized by formation of abnormal gene fusions involving tyrosine kinase (TK) and cytokine receptor genes and activation of TK signaling. Because of the diversity of associated genetic changes, the detection of Ph-like ALL cases currently requires multiple cytogenetic and molecular assays; thus, our goal was to develop a consolidated workflow for detecting genetic abnormalities in Ph-like ALL. We found that total and targeted RNA sequencing (RNAseq)-based approach allowed the detection of abnormal fusion transcripts (EBF1-PDGFRB, P2RY8-CRLF2, RCSD1-ABL1, and RCSD1-ABL2). The bioinformatics algorithm accurately detected the fusion transcripts without prior input about possible events. Additionally, we showed that RNAseq analysis enabled evaluation for disease-associated sequence variants in expressed transcripts. While total RNAseq can be a second tier approach allowing discovery of novel genetic alterations, the targeted RNAseq workflow offers a clinically applicable method for the detection of fusion transcripts.