BackgroundDescribe a single-center real-world experience with comprehensive genomic profiling (CGP) to identify genotype directed therapy (GDT) options for patients with malignancies refractory to standard treatment options.MethodsPatients who had CGP by a CLIA-certified laboratory between November 2012 and December 2015 were included. The medical records were analyzed retrospectively after Institutional Review Board (IRB) approval. The treating oncologist made the decision to obtain the assay to provide potential therapeutic options. The objectives of this study were to determine the proportion of patients who benefited from GDT, and to identify barriers to receiving GDT.ResultsA total of 125 pediatric and adult patients with a histologically confirmed diagnosis of malignancy were included. Among these, 106 samples were from adult patients, and 19 samples were from pediatric patients. The median age was 54 years for adults. The majority had stage IV malignancy (53%) and were pretreated with 2–3 lines of therapy (45%). The median age was 8 years for pediatric patients. The majority had brain tumors (47%) and had received none or 1 line of therapy (58%) when the profiling was requested. A total of 111 (92%) patients had genomic alterations and were candidates for GDT either via on/off-label use or a clinical trial (phase 1 through 3). Fifteen patients (12%) received GDT based on these results including two patients who were referred for genomically matched phase 1 clinical trials. Three patients (2%) derived benefit from their GDT that ranged from 2 to 6 months of stable disease.ConclusionsCGP revealed potential treatment options in the majority of patients profiled. However, multiple barriers to therapy were identified, and only a small minority of the patients derived benefit from GDT.

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Breast cancer can metastasize at any time during its course, but timing of systemic relapse cannot be predicted by traditional TNM staging. Characteristics of distant recurrence within the first 3 years of diagnosis may identify a group of patients who could benefit from novel strategies to prevent systemic relapse. Of 1,089 patients with breast cancer treated at our institution between January 2007 and May 2011, we identified 76 with de novo metastases (on presentation) and 40 with systemic relapse after a median follow up of 2.2 years. Compared to relapse, de novo metastatic disease was more likely to be grade 1 or 2 (43.1 vs. 18.4 %, p = 0.032), estrogen receptor (ER) positive (69.7 vs. 47.5 %, p = 0.019), progesterone receptor (PgR) positive (56.6 vs. 32.5 %, p = 0.014), and HER2-positive (27.5 vs. 10.3 %, p = 0.035). In the 815 patients with stage I-III disease who were at risk of systemic relapse, univariate analyses were performed for age, tumor size, grade, ER, PgR, HER2, lymph nodes, and TNM stage. A multivariate Cox regression model was built using step-wise model selection and identified 4 covariates that were significantly associated with risk of early relapse: stage-III (p < 0.001), grade-III (p = 0.002), PgR-negative status (p = 0.014), and HER2-negative status (p = 0.033). A risk-score was developed based on the linear combination of these covariates and time-dependent predictive curves were used to evaluate the predictive accuracy of the proposed risk-score. The highest risk-score group had a 1, 2, and 3-year relapse probabilities of 11.5, 41.2, and 52.5 %, respectively. The corresponding 1, 2, and 3-year relapse probabilities for the overall population were 1.2, 4.4, and 6.3 %, respectively. Our proposed model can be used to select patients at high-risk of early relapse who could benefit from enrollment on clinical trials with novel therapies designed for this group.

Autoimmune hemolytic anemia (AIHA) occurs in CLL at some time during the course of the disease in up to 7-10% of patients. The acute onset of AIHA may occur unrelated to therapy but has also been linked to treatment with chemo­therapeutic agents including chlor­ambucil, benda­mustine and particu­larly purine nucleosides such as fludarabine. Although the mechanism is still not well understood, chemo­therapy-induced changes in regulatory T-cells have been proposed as a trigger for autoimmunity and clinical hemolysis. In contrast to these cytotoxic therapies, ibrutinib, an inhibitor of Bruton’s tyrosine kinase recently approved for the treatment of CLL, appears to have a different mechanism of action and thus far has not been associated with AIHA in published reports. However, we report here a patient with CLL and a history of prior AIHA, who developed a recurrence of acute hemolysis after the initiation of ibrutinib. The patient is a 67-year-old man diagnosed with CLL in 2002 and treated for progressive disease with a single cycle of bendamustine in 2009. Although the lymphocytosis resolved rapidly, the hemoglobin also decreased from 14 g/dL to 5.2 g/dL by 3 weeks after the start of therapy. Due to the onset of Coombs-positive AIHA, chemotherapy was dis­con­tinued. Hemolysis resolved with prednisone therapy and did not recur after a slow taper. The CLL then remained asymptomatic until 2012 when night sweats developed at a white blood cell (wbc) count of 95,000/µL. Benda­mustine was re-started and despite a negative Coombs test prior to treatment, Coombs-positive AIHA developed again with the hemoglobin falling from normal to 7.0 g/dL within 4 weeks. After stabilization with transfusions and steroids, an additional cycle of bendamustine plus rituximab was administered without further complications and the patient’s symptoms and lympho­cytosis resolved. After the discontinuation of prednisone, hemolysis did not recur clinically although the Coombs test remained 1+ positive through early 2014. By May 2014 the wbc count had increased to 144,000/µL with the onset of a mild anemia (Hgb 12.3 g/dL) and symptomatic night sweats. Due to the history of repeated chem­otherapy-associated AIHA, alter­native therapy with ibrutinib, which had not been associated with AIHA, was instituted at 420 mg daily. However, within 2 weeks the hemoglobin decreased to 7.0 g/dL while the wbc count increased to 300,000/µL. A reticulocyte count was 16%, total bilirubin 3.2 mg/dL, haptoglobin <10 mg/dL, and the Coombs test was reported 3+ positive for IgG. Prednisone was started at 1 mg/Kg daily and ibrutinib was held. After 10 days of steroid therapy, the hemoglobin improved to 10 g/dL and ibrutinib was restarted. Over the next month, the hemoglobin continued to increase to 12.7 g/dL and the wbc count gradually decreased to 44,000/µL with 24% neutrophils, a marked increase in the absolute neutrophil count as compared to pre-treatment. The patient currently continues on ibrutinib with a slow prednisone taper and is now asymptomatic. In summary, this case suggests that some CLL patients may experience the acute onset of AIHA after starting ibrutinib with a clinical course similar to cases reported after fludarabine and other agents. In addition, a response to steroid therapy may allow the successful resumption of ibrutinib treatment. The actual likelihood of acute hemolysis after ibrutinib therapy in CLL is unclear, but may have been much greater in this case than in CLL patients without prior episodes of AIHA or a positive Coombs test. However, a potential mechanism for the precipitation or accel­eration of auto­immunity is suggested by the recent report by Byrd and colleagues (Blood 2013; 122:2539-49) showing that ibrutinib inhibits interleukin-2-inducible kinase (ITK). This inhibition skewed the CD4 T-cell popul­a­tions isolated from treated CLL patients toward a Th1 profile, a regulatory T-cell subset previously reported to drive the early auto­antibody response in an animal model of AIHA (Blood 2009; 113:389-95). Disclosures No relevant conflicts of interest to declare.