Alison M. Schram

How I treat hemophagocytic lymphohistiocytosis in the adult patient

Hemophagocytic lymphohistiocytosis (HLH) is a devastating disorder of uncontrolled immune activation characterized by clinical and laboratory evidence of extreme inflammation. This syndrome can be caused by genetic mutations affecting cytotoxic function (familial HLH) or be secondary to infectious, rheumatologic, malignant, or metabolic conditions (acquired HLH). Prompt recognition is paramount and, without early treatment, this disorder is frequently fatal. Although HLH is well described in the pediatric population, less is known about the appropriate work-up and treatment in adults. Here, we review the clinical characteristics, diagnosis, and treatment of HLH in adults.

Marked hyperferritinemia does not predict for HLH in the adult population.

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of uncontrolled immune activation that has gained increasing attention during the last decade. The diagnosis of HLH is based on a constellation of clinical and laboratory abnormalities, including elevated serum ferritin levels. In the pediatric population, marked hyperferritinemia is specific for HLH. To determine what conditions are associated with profoundly elevated ferritin in the adult population, we performed a retrospective analysis in a large academic health care system. We identified 113 patients with serum ferritin levels higher than 50,000 µg/L. The most frequently observed conditions included renal failure, hepatocellular injury, infections, and hematologic malignancies. Our results suggest that marked hyperferritinemia can be seen in a variety of conditions and is not specific for HLH in adults.

Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years.

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of uncontrolled immune activation that has gained increasing attention over the past decade. Although classically known as a familial disorder of children caused by mutations that affect cytotoxic T‐cell function, an acquired form of HLH in adults is now widely recognized. This is often seen in the setting of malignancy, infection or rheumatological disorders. We performed a retrospective review across 3 tertiary care centres and identified 68 adults with HLH. The average age was 53 years (range 18–77 years) and 43 were male (63%). Underlying disorders included malignancy in 33 patients (49%), infection in 22 (33%), autoimmune disease in 19 (28%) and idiopathic HLH in 15 (22%). Patients were treated with disease‐specific therapy and immunomodulatory agents. After a median follow‐up of 32·2 months, 46 patients had died (69%). The median overall survival was 4 months (95% CI: 0·0–10·2 months). Patients with malignancy had a worse prognosis compared to those without (median survival 2·8 months versus 10·7 months, P = 0·007). HLH is a devastating disorder with a high mortality. Further research is needed to improve treatment and outcomes.

Genomic Heterogeneity Underlies Mixed Response to Tropomyosin Receptor Kinase Inhibition in Recurrent Glioma

Glioblastoma is the most common malignant primary brain tumor in adults. Despite aggressive initial treatment, recurrence is inevitable and almost always fatal. Treatment options for recurrent disease are limited and do not substantially improve survival. In recent years, the molecular characterization of gliomas has revealed recurrent somatic mutations, structural rearrangements, and epigenetic alterations. These genomic alterations have implications for prognosis and response to treatment. IDH1/2 mutations are associated with a more favorable prognosis among glioblastomas while tumors with MGMT promoter hypermethylation are more likely to respond to treatment with alkylating agents.1, 2 The pattern of genomic alterations can also provide insight into the tumor’s origin and evolution. For example, the presence of co-existent mutations in IDH1 and ATRX suggest a secondary glioma that has progressed from a lower-grade glioma.3–5 In addition to informing prognosis and diagnostic classification, some genomic alterations in glioma represent potential therapeutic targets. Specifically, recurrent alterations in one of several receptor tyrosine kinases (RTK) including EGFR, PDGFRA, MET, and FGFR1/2/3 have been observed in the majority of glioblastomas.6 Unfortunately, efforts to develop genomically targeted therapy for glioblastoma have been unsuccessful to date.7 It remains unknown the extent to which the lack of activity of targeted therapy may be attributed to so-called key alterations not representing true clonal drivers critical to tumor growth and progression, versus the simple inability of existing drugs to achieve therapeutic exposures within the central nervous system. In addition to these more common genomic alterations, less common fusions involving the kinase domain of tropomyosin receptor kinases (TRK A/B/C) encoded by genes NTRK1, NTRK2 and NTRK3 have also been identified in gliomas.8–11 In other cancer types, selective inhibition of these TRK fusions has resulted in remarkable efficacy.12 However, it remains unknown whether this therapeutic strategy is effective in primary brain tumors. Here we report the case of a young woman with recurrent glioblastoma treated with larotrectinib, a first-in-class, potent and highly selective TRK inhibitor. To our knowledge this is the first report of the use of a TRK inhibitor in a patient with a TRK fusion-positive glioblastoma.

Abstract LB-103: Landscape of somatic ERBB2 Mutations: Findings from AACR GENIE and comparison to ongoing ERBB2 mutant basket study

Background: AACR GENIE is an international data-sharing project that aggregates clinical-grade cancer genomic data. As a demonstration of utility, we evaluated the landscape of ERBB2 mutations in the first 18,486 patients included in this registry and compared it to the first 100 patients enrolled in an ongoing international Phase 2 SUMMIT ‘basket’ study of the pan-HER inhibitor neratinib in ERBB2 mutant solid tumors (NCT01953926). Results: ERBB2 mutations were identified in 2.8% (519/18,486) of patients in the GENIE cohort and observed at all participating centers. In total, there were 482 missense, 66 indels, 19 truncating mutations, and 14 structural variants. A total of 263 unique missense mutations were observed including 12 at previously identified hotspots which accounted for 69.2% of all missense mutations. 35 unique cancer types were represented. The tumor types with the highest proportion of ERBB2 mutations were bladder (12.8%, 82/641), breast (3.9%, 87/2230), colorectal (3.3%, 70/2102), and NSCLC (3%, 90/3006). Among patients with copy number data available (91%) 11% had concurrent ERBB2 amplification, most often in breast cancer. The most frequently observed alterations in ERBB2, adjusted for differing exon coverage between panels, was S310F/Y in 0.46% of the GENIE cohort (12.6% of samples with ERBB2 alterations), Y772_A775dup in 0.21% (6.9%), R678Q in 0.17% (4.5%), L755S in 0.16% (5.2%), V777L in 0.12% (3.8%), and V842I in 0.09% (3.1%). The distribution of specific ERBB2 variants differed significantly by tumor type with exon 20 insertions being most common in NSCLC (44.4%, 40/90), L755S (18.9%, 11/92) in breast, S310F/Y (26.9%, 28/104) in bladder, and V842I (13.9%, 10/72) in colorectal cancer. Structural variants included intragenic deletions (n=4) and fusions involving various partners including GRB7 (n=2), and one each of C1orf87, PPIL6, HEXIM2, THRA, ASIC2, BCA3, WIPF2. The frequencies of ERBB2 mutant cancer types observed in the GENIE cohort were generally comparable to those enrolled to the neratinib basket study including NSCLC (17 vs 22%, respectively), breast (16.4 vs 24%), bladder (15.5 vs 14%), colorectal (13.2 vs 17%), and endometrial (4.2 vs 6%). At the variant level, S310F/Y was less prevalent in GENIE compared to the neratinib study (12.6 vs 24%) while all other mutations were generally similar including L755S (5.2 vs 9%), R678Q (4.5 vs 2%), Y772_A775dup (6.9 vs 13%), V777L (3.8 vs 9%), and V842I (3.1 vs 6%). Conclusion: GENIE confirms that a diversity of ERBB2 mutations are prevalent across a variety of tumor types in patients with advanced cancer. The genomic landscape of ERBB2 mutations was largely similar in the population based GENIE cohort and the neratinib SUMMIT study, providing the first direct evidence that basket study enrollment accurately reflects the true landscape of the target alteration. Citation Format: Alison Schram, Helen H. Won, Fabrice Andre, Monica Arnedos, Funda Meric - Bernstam, Philippe L. Bedard, Kenna R. Shaw, Hugo Horlings, Christine Micheel, Ben Ho Park, Grace Mann, Alshad S. Lalani, Lillian Smyth, David B. Solit, Deborah Schrag, Mia A. Levy, Barrett J. Rollins, Mark Routbort, Charles L. Sawyers, Eva Lepisto, Michael F. Berger, David M. Hyman, on behalf of the AACR Project GENIE Consortium. Landscape of somatic ERBB2 Mutations: Findings from AACR GENIE and comparison to ongoing ERBB2 mutant basket study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-103. doi:10.1158/1538-7445.AM2017-LB-103

Picking the Right Patient for Human Epidermal Growth Factor Receptor 3-Targeted Therapy in Platinum-Resistant Ovarian Cancer.

Surgical cytoreduction followed by platinum-based chemotherapy has been the standard first-line treatment of patients with high-risk early-stage and advanced epithelial ovarian cancer for nearly two decades. Although the majority of women with advanced disease will respond to combined platinum/taxane therapy, most will ultimately experience recurrence and eventually die as a result of their ovarian cancer. Platinum-refractory and -resistant disease is defined as progression on first-line chemotherapy or within 6 months of platinum completion, respectively. These patients are treated with nonplatinum chemotherapy; however, anticipated response rates are low. Despite the urgent need for more effective treatments, few new agents have demonstrated sufficient efficacy to warrant approval by the Food and Drug Administration (FDA) in the last 10 years. In 2014, the Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer (AURELIA) trial established that the addition of bevacizumab to nonplatinum chemotherapy increases progression-free survival (PFS) from 3.4 to 6.7 months, leading to FDA approval. In 2015, Kaufman et al showed that olaparib achieved a 31% response rate in heavily pretreated women with germline BRCA1/2mutations, also leading to FDA approval in germline BRCA1/2 carriers. Despite this recent progress, there remains a significant unmet need for improved therapies in platinum-resistant and -refractory ovarian cancer. In the article that accompanies this editorial, Liu et al report the results of a 233-patient open-label, randomized phase II trial of once-weekly paclitaxel with or without the human epidermal growth factor receptor 3 (HER3) antibody, seribantumab, in platinumresistant/refractory epithelial ovarian cancer. Patients were randomly assigned 2:1 in favor of seribantumab and enrolled without prospective biomarker selection or stratification. Unfortunately, the study did not reach its primary end point, showing no difference in PFS between the two arms (3.8 months with the combination compared with 3.7 months with paclitaxel alone). Despite this disappointing result, the study fortunately mandated the collection of both archival and fresh tumor biopsies, and these were used to conduct an extensive retrospective biomarker analysis to determine if a subset of patients may have benefited from the addition of seribantumab. By evaluating multiple biomarkers relevant to the mechanism of action of seribantumab, Liu et al identified a tumor-based bivariate signature defined by high heregulin (HRG, also named neuregulin 1), the ligand of HER3, and low human epidermal growth factor receptor 2 (HER2) that was predictive of seribantumab benefit. Specifically, in the 38% of evaluable patients who were biomarker positive, the median PFS was 5.7 months with the combination compared with 3.5 months with paclitaxel alone. In addition to being predictive of benefit to seribantumab, this signature seemed to be prognostic in the paclitaxel monotherapy arm, with biomarker-positive patients experiencing more rapid disease progression (PFS, 3.5 months v 5.4 months). Together, these observations suggest that seribantumab overcomes the negative prognosis associatedwith highHRG and lowHER2 levels in platinum-resistant/ refractory ovarian cancer. Distressingly, the biomarker-negative patients did worse when exposed to seribantumab, although the mechanism underlying this apparent harm is not understood. HER3, the protein encoded by ErbB3, is a member of the human epidermal growth factor (EGFR) family and the only one that lacks catalytic kinase function. Instead, HER3 mediates its effects on signaling through heterodimerizationwith, and allosteric activation of, other EGFR family members, leading to downstream activation of the phosphatidylinositol 3-kinase/AKT pathway. Pertuzumab, an anti-HER2 monoclonal antibody, is believed to act by preventing dimerization with HER3 and has been approved for treatment of HER2-positive breast cancer, further credentialing HER3 as a therapeutic target in cancer. In ovarian cancer, HER3 is highly expressed in a subset of patients and is associated with a worse prognosis. Autocrine signaling loops between HER3 and its ligand, HRG, promote growth in patient-derived ovarian cancer models and cell lines. Treatment of ovarian cancer cell lines with certain chemotherapies increases activation of HER3, suggesting HER3 may be one of several mechanisms responsible for chemotherapy resistance in ovarian cancer. Seribantumab is a fully humanized monoclonal antibody that blocks binding of HRG to HER3 and has been shown to cause tumor growth arrest in ovarian cancer xenograph models. In tumors with high HRG expression, seribantumab is believed to block ligand-dependent activation of HER2/HER3 dimers. Conversely, high levels of HER2, leading to a greater presence of HER2/HER3 dimers, may mitigate therapeutic benefit by promoting ligand-independent signaling. Thus, the findings by Liu et al that the combination of high HRG and low HER2 levels were associated with benefit to seribantumab is consistent