Lin, Yi

AbstractSymptomatic hyperviscosity is a well‐established phenomenon in Waldenström macroglobulinemia (WM). Monoclonal IgM can variably impact intrinsic serum viscosity, leading to widely disparate symptomatic thresholds for development of hyperviscosity‐related symptoms. Data regarding the predictors of symptomatic hyperviscosity and outcomes related to this complication remain scarce and a recent study proposed that IgM >6000 mg/dL be considered a new criterion for initiating therapy in otherwise asymptomatic (smoldering) WM to pre‐empt hyperviscosity‐related injury. Herein, we attempt to identify predictors of the development of symptomatic hyperviscosity and its impact in patients with WM. Of 997 WM patients evaluated from January, 1996 through June, 2017, symptomatic hyperviscosity was observed in 130 (13%) patients. Overall survival (OS) of these 130 patients was similar to that of patients without symptomatic hyperviscosity (median: 11.5 vs 11.6 years; P = 0.63). On multivariate‐analysis, only viscosity >1.8 cp (risk ratio: 4.0, P = 0.02) assessed at the time of WM diagnosis was an independent predictor for the development of subsequent symptomatic hyperviscosity. Among patients with smoldering WM and IgM >6000 mg/dL at diagnosis (n = 13) who were managed expectantly, the median time‐to‐initial therapy was 6.9 years and only 15% developed hyperviscosity‐related symptoms subsequently. In summary, the occurrence of symptomatic hyperviscosity does not impact OS. Serum viscosity at diagnosis of WM, and not IgM concentration, represents the single most important independent predictor for development of subsequent hyperviscosity‐related symptoms. Patients with smoldering WM and high serum IgM can be safely observed in the absence of any indications per the Consensus recommendations to initiate WM‐directed therapy.

Abstract Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR T cell therapy approved by the US Food and Drug Administration for patients with relapsed or refractory large B cell lymphoma with ≥2 prior systemic therapies. Results from the primary analysis of ZUMA-1 demonstrated an objective response rate of 82%, with 54% complete responses (Neelapu & Locke et al. N Engl J Med. 2017). Grade ≥3 cytokine release syndrome and neurologic events occurred at 13% and 28%, respectively, and were generally reversible. Building on previous reports of CAR treatment-related tumor microenvironment (TME) changes (Galon et al. ASCO 2017. #3025), here, we examine associations between the pretreatment TME and clinical outcomes. Methods: Patients received axi-cel (target dose, 2.0 × 106 cells/kg) in phases 1 and 2 of ZUMA-1 (NCT02348216). Baseline tumor biopsy samples were analyzed by digital gene expression (NanoStringTM). Prespecified bioinformatics algorithm and cutoffs were applied to immune-mediated tumor regression genes (Immunosign®; Galon et al. Immunity. 2013), which included T cell-specific (effector T cell, Th1) genes, interferon pathway-related genes, chemokines, cytokines, and immune checkpoints. Expression analysis and scoring examined potential associations between TME features and response. A broader, hypothesis-generating analysis was performed using all PanCancer Immune Profiling Panel genes (770 genes) by NanoStringTM. Fisher's exact test and Wilcoxon signed rank test with multiple test correction by false discovery rate (Benjamini-Hochberg) were used. Results: Tumor samples from all immediate pre-treatment biopsy samples that passed quality control (6 nonresponders; 21 responders) were analyzed. Pretreatment TME Immunosign21 scores were elevated in responders vs nonresponders. Responses were seen in 18/20 patients (90%) with high and 3/7 patients (43%) with low Immunosign21 scores. Immune-related genes from the Immunosign21 or Pan Cancer profile that showed higher expression at baseline in responders included CTLA4, CD3γ, CD3ϵ, CD27, and ICOSL. Genes with lower expression in responders at baseline included MHC class II genes and cancer-testis antigens. Additional correlative analyses between TME characteristics and CAR T cell activity will be presented. Conclusions: Increased baseline expression of TME genes related to T cell activity, along with decreased expression of MHC class II and cancer testis antigens (CTAs), may be associated with a response to axi-cel. These findings should be validated in ongoing and subsequent studies. Citation Format: John M. Rossi, Jerome Galon, Sarah Turcan, Corinne Danan, Frederick L. Locke, Sattva S. Neelapu, David B. Miklos, Caron A. Jacobson, Lazaros J. Lekakis, Yi Lin, Armin Ghobadi, William Y. Go, Adrian Bot. Characteristics of the pretreatment tumor microenvironment may influence clinical response in patients with refractory large B cell lymphoma treated with axicabtagene ciloleucel (axi-cel) in the pivotal ZUMA-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-016.

AbstractDetection of myeloma progression (PD) relies on serial 24‐h urinary M protein measurements in patients without measurable serum M spike. We examined whether serial difference free light chain (dFLC) levels could be used as a surrogate for serial 24‐h urine M protein measurements in monitoring for PD in patients with baseline measurable urine M protein. We studied 122 patients who had serial measurement of urine M protein and serum FLC and had demonstrated PD. The median increase in dFLC with progression as defined by urine M spike was 110% (IQR: 55‐312) and median absolute increase was 74 mg/dL; while 89% of patients had dFLC increase ≥ 25%, 94% had absolute increase in dFLC > 10 mg/dL, and 98% met at least 1 of these 2 criteria at PD. In patients with baseline measurable serum FLC (n = 118), 89% had increase in dFLC ≥ 25%, 97% had dFLC increase of > 10 mg/dL, and 98% had 1 of the 2. We conclude that serial dFLC assessments can be used in place of serial 24‐h urine protein assessments during myeloma surveillance to monitor for PD. Once patients have an absolute increase in dFLC of >10 mg/dL from the nadir, a 24‐h urine collection can then be assessed to document PD as per the International Myeloma Working Group criteria.

Background: Heart involvement is the most important prognostic determinant in AL amyloidosis patients. Echocardiography is a cornerstone for the diagnosis and provides important prognostic information. Methods and Results: We studied 754 patients with AL amyloidosis who underwent echocardiographic assessment at the Mayo Clinic, including a Doppler-derived measurement of stroke volume (SV) within 30 days of their diagnosis to explore the prognostic role of echocardiographic variables in the context of a well-established soluble cardiac biomarker staging system. Reproducibility of SV, myocardial contraction fraction, and left ventricular strain was assessed in a separate, yet comparable, study cohort of 150 patients from the Pavia Amyloidosis Center. The echocardiographic measures most predictive for overall survival were SV index <33 mL/min, myocardial contraction fraction <34%, and cardiac index <2.4 L/min/m 2 with respective hazard ratios (95% confidence intervals) of 2.95 (2.37–3.66), 2.36 (1.96–2.85), and 2.32 (1.91–2.80). For the subset that had left ventricular strain performed, the prognostic cut point was −14% (hazard ratios, 2.70; 95% confidence intervals, 1.84–3.96). Each parameter was independent of systolic blood pressure, Mayo staging system (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and troponin), and ejection fraction on multivariable analysis. Simple predictive models for survival, including biomarker staging along with SV index or left ventricular strain, were generated. Conclusions: SV index prognostic performance was similar to left ventricular strain in predicting survival in AL amyloidosis, independently of biomarker staging. Because SV index is routinely calculated and widely available, it could serve as the preferred echocardiographic measure to predict outcomes in AL amyloidosis patients.