Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL

PURPOSE CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. PATIENTS AND METHODS We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. RESULTS Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. CONCLUSION With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.

How biomarker patterns can be utilized to identify individuals with a high disease burden: a bioinformatics approach towards predictive, preventive, and personalized (3P) medicine

Prevalences of non-communicable diseases such as depression and a range of somatic diseases are continuously increasing requiring simple and inexpensive ways to identify high-risk individuals to target with predictive and preventive approaches. Using k-mean cluster analytics, in study 1, we identified biochemical clusters (based on C-reactive protein, interleukin-6, fibrinogen, cortisol, and creatinine) and examined their link to diseases. Analyses were conducted in a US American sample (from the Midlife in the US study, N = 1234) and validated in a Japanese sample (from the Midlife in Japan study, N = 378). In study 2, we investigated the link of the biochemical clusters from study 1 to childhood maltreatment (CM). The three identified biochemical clusters included one cluster (with high inflammatory signaling and low cortisol and creatinine concentrations) indicating the highest disease burden. This high-risk cluster also reported the highest CM exposure. The current study demonstrates how biomarkers can be utilized to identify individuals with a high disease burden and thus, may help to target these high-risk individuals with tailored prevention/intervention, towards personalized medicine. Furthermore, our findings raise the question whether the found biochemical clusters have predictive character, as a tool to identify high-risk individuals enabling targeted prevention. The finding that CM was mostly prevalent in the high-risk cluster provides first hints that the clusters could indeed have predictive character and highlight CM as a central disease susceptibility factor and possibly as a leverage point for disease prevention/intervention.

How Routinely Assessed Biomarkers Can Be Utilized To Identify Individuals With A High Disease Burden: A Bioinformatics Approach Towards Predictive, Preventive And Personalised (3P) Medicine

Prevalences of non-communicable diseases such as depression and a range of somatic diseases are continuously increasing requiring simple and inexpensive ways to identify high-risk individuals to target with predictive and preventive approaches. Using k-mean cluster analytics, in study 1, we identified biochemical clusters (based on C-reactive protein, interleukin-6, fibrinogen, cortisol, and creatinine) and examined their link to diseases. Analyses were conducted in a U.S. American sample (from Midlife in the United States study, N = 1,234) and validated in a Japanese sample (from Midlife in Japan study, N = 378). In study 2, we investigated the link of clusters to childhood maltreatment (CM). The three identified biochemical clusters included one cluster (with high inflammatory signaling and low cortisol and creatinine concentrations) indicating the highest disease burden. This high-risk cluster also reported the highest CM exposure. The current study demonstrates how biomarkers can be utilized to identify individuals with a high disease burden and thus, may help to target these high-risk individuals with tailored prevention/intervention, towards personalized medicine. Furthermore, our findings raise the question whether the found biochemical clusters have predictive character; as a tool to identify high-risk individuals enabling targeted prevention. The finding that CM was mostly prevalent in the high-risk cluster provides first hints that the clusters could indeed have predictive character and highlight CM as a central disease susceptibility factor and possibly as a leverage point for disease prevention/intervention.

1104 Plasma Circulating Cell-Free Messenger RNA as a Potential Biomarker of Melanoma

Introduction Blood-borne cell-free nucleic acids are increasingly emerging as significant non-invasive adjuncts to current methods of disease status evaluation in cancer patients. In this study, we sought to examine whether significant differences exist in the plasma transcriptomic profile of advanced melanoma patients with a high disease burden compared to patients with therapeutic response. Method Plasma circulating cell-free messenger ribonucleic acid (ccfmRNA) was extracted from twenty patients with stage IV melanoma receiving immunotherapy. Pathway focused gene expression analysis was performed. Patients were assessed with paired blood sample collection and CT scan assessments at baseline and at 3 months follow up. Response Evaluation Criteria in Solid Tumours (RECIST 1.1) was used for tumour burden estimation. Results In stage IV melanoma patients, CCL5, GZMB and MYD88 genes were significantly over-expressed (p &lt; 0.05 versus healthy controls). In patients with high disease burden or progressive disease, CCL18, CCR1, CCR4, CD274, CSF2, and GBP1 genes were significantly over-expressed (p &lt; 0.05 versus patients with therapeutic response). Finally, in stage IV melanoma patients with brain metastases, CCL18, CCR1, CCR4, CD274, CSF2, EGF, GBP1, and PTGS2 genes were significantly over-expressed (p &lt; 0.05, versus patients without brain metastasis). Conclusions Significant differences were observed in the plasma transcriptomic profile between the various melanoma patient groups, and we postulate that these differences may be exploited to identify novel therapeutic targets or biomarkers relevant to melanoma. CCL4 and CCL5 are prognostic in melanoma, both genes had significantly higher expressions in low disease burden patients compared to patients with a high disease burden.

Spasmodic Abdominal Pain and Other Gastrointestinal Symptoms in Pontocerebellar Hypoplasia Type 2

Introduction Pontocerebellar hypoplasia type 2 (PCH2) is a rare neurodevelopmental disease with a high disease burden. Besides neurological symptoms, somatic symptoms, such as gastroesophageal reflux (GERD) and failure to thrive, are major contributors to this burden. Methods We report three patients with genetically confirmed PCH2A and significant gastrointestinal (GI) symptoms. Results Apart from impaired swallowing and GERD, which are frequently reported in patients with PCH2, all three patients suffered from episodes of spasmodic abdominal pain and restlessness. In one severely affected patient, lack of intestinal alkaline phosphatase (IAP) is demonstrated. Conclusion GI symptoms are common in PCH2. We draw attention to episodes of spasmodic abdominal pain seriously, aggravating the condition of the patients, especially their movement disorder, and discuss the role of IAP.

O52 Plasma circulating cell-free messenger RNA as a potential biomarker of melanoma

Introduction Blood-borne cell-free nucleic acids are increasingly emerging as significant non-invasive adjuncts to current methods of disease status evaluation in cancer patients. In this study, we sought to examine whether significant differences exist in the plasma transcriptomic profile of advanced melanoma patients with a high disease burden compared to patients with therapeutic response. Method Plasma circulating cell-free messenger ribonucleic acid (ccfmRNA) was extracted from twenty patients with stage IV melanoma receiving immunotherapy. Pathway focused gene expression analysis was performed. Patients were assessed with paired blood sample collection and CT scan assessments at baseline and at 3 months follow up. Response Evaluation Criteria in Solid Tumours (RECIST 1.1) was used for tumour burden estimation. Result In stage IV melanoma patients, CCL5, GZMB and MYD88 genes were significantly over-expressed (P &lt; 0.05 versus healthy controls). In patients with high disease burden or progressive disease, CCL18, CCR1, CCR4, CD274, CSF2, and GBP1 genes were significantly over-expressed (P &lt; 0.05 versus patients with therapeutic response). Finally, in stage IV melanoma patients with brain metastases, CCL18, CCR1, CCR4, CD274, CSF2, EGF, GBP1, and PTGS2 genes were significantly over-expressed (P &lt; 0.05, versus patients without brain metastasis). Conclusion Significant differences were observed in the plasma transcriptomic profile between the various melanoma patient groups, and we postulate that these differences may be exploited to identify novel therapeutic targets or biomarkers relevant to melanoma. CCL4 and CCL5 are prognostic in melanoma, both genes had significantly higher expressions in low disease burden patients compared to patients with a high disease burden. Take-home Message CCL4 and CCL5 ccfmRNA transcripts are prognostic in melanoma. High expression of both genes is favourable in melanoma patients.