Predictive value of pre-infusion tumor growth rate for the occurrence and severity of CRS and ICANS in lymphoma under CAR T-cell therapy.

Chimeric antigen receptor T-cell therapy (CART) can be administered outpatient yet requires management of potential side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The pre-infusion tumor burden is associated with CRS, yet there is no data on the relevance of pre-infusion tumor growth rate (TGR). Our objective was to investigate TGR for the occurrence and severity of CRS and ICANS. Consecutive patients with available pre-baseline and baseline (BL) imaging before CART were included. TGR was determined as both absolute (abs) and percentage change (%) of Lugano criteria-based tumor burden in relation to days between exams. CRS and ICANS were graded according to ASTCT consensus criteria. Clinical metadata was collected including the international prognostic index (IPI), patient age, ECOG performance status, and LDH. Sixty-two patients were included (median age: 62 years, 40% female). The median pre-BL TGR [abs] and pre-BL TGR [%] was 7.5 mm2/d and 30.9%/d. Pre-BL TGR [abs] and pre-BL TGR [%] displayed a very weak positive correlation with the grade of CRS (r[abs] = 0.14 and r[%] = 0.13) and no correlation with ICANS (r[abs] = - 0.06 and r[%] = - 0.07). There was a weak positive correlation between grade of CRS and grade of ICANS (r = 0.35; p = 0.005) whereas there was no significant correlation of CRS or ICANS to any other of the examined parameters. The pre-infusion TGR before CART was weakly associated with the occurrence of CRS, but not the severity, whereas there were no significant differences in the prediction of ICANS. There was no added information when compared to pre-infusion tumor burden alone. Outpatient planning and toxicity management should not be influenced by the pre-infusion TGR.

Prognostic value of pre-infusion tumor growth rate for patients with lymphoma receiving chimeric antigen receptor T-cell therapy.

BACKGROUND AIMS: Chimeric antigen receptor T-cell therapy (CART) prolongs survival for patients with refractory or relapsed lymphoma, yet its efficacy is affected by the tumor burden. The relevance of tumor kinetics before infusion is unknown. We aimed to study the prognostic value of the pre-infusion tumor growth rate (TGRpre-BL) for progression-free (PFS) and overall survival (OS). METHODS: Consecutive patients with available pre-baseline (pre-BL) and baseline (BL) computed tomography or positron emission tomography/computed tomography scan before CART were included. TGR was determined as change of Lugano criteria-based tumor burden between pre-BL, BL and follow-up examinations (FU) in relation to days between imaging exams. Overall response rate (ORR), depth or response (DoR) and PFS were determined based on Lugano criteria. Multivariate regression analysis studied association of TGR with ORR and DoR. Proportional Cox regression analysis studied association of TGR with PFS and OS. RESULTS: In total, 62 patients met the inclusion criteria. The median TGRpre-BL was 7.5 mm2/d (interquartile range -14.6 mm2/d to 48.7 mm2/d); TGRpre-BL was positive (TGRpre-BL POS) in 58% of patients and negative (TGRpre-BL NEG, indicating tumor shrinkage) in 42% of patients. Patients who were TGRpre-BL POS had a 90-day (FU2) ORR of 62%, a DoR of -86% and a median PFS of 124 days. Patients who were TGRpre-BL NEG had a 90-day ORR of 44%, DoR of -47% and a median PFS of 105 days. ORR and DoR were not associated with slower TGR (P = 0.751, P = 0.198). Patients with an increase of TGR from pre-BL over BL to 30-day FU (FU1) ≥100% (TGRpre-BL-to-FU1≥100%) showed a significant association with shorter median PFS (31 days versus 343 days, P = 0.002) and shorter median OS after CART (93 days versus not reached, P < 0.001), compared with patients with TGRpre-BL-to-FU1<100%. CONCLUSIONS: In the context of CART, differences in pre-infusion tumor kinetics showed minor differences in ORR, DoR, PFS and OS, whereas the change of the TGR from pre-BL to 30-day FU significantly stratified PFS and OS. In this patient population of refractory or relapsed lymphomas, TGR is readily available based on pre-BL imaging, and its change throughout CART should be explored as a potential novel imaging biomarker of early response.

Modification of Lugano criteria by pre-infusion tumor kinetics improves early survival prediction for patients with lymphoma under chimeric antigen receptor T-cell therapy.

BACKGROUND: Chimeric antigen receptor T-cell therapy (CART) is effective for patients with refractory or relapsed lymphoma with prolongation of survival. We aimed to improve the prediction of Lugano criteria for overall survival (OS) at 30-day follow-up (FU1) by including the pre-infusion tumor growth rate (TGRpre-BL) and its early change to 30-day FU1 imaging (TGRpost-BL). METHODS: Consecutive patients with pre-baseline (pre-BL), baseline (BL) and FU1 imaging with CT or positron emission tomography/CT before CART were included. TGR was defined as change of Lugano criteria-based tumor burden between pre-BL, BL and FU1 examinations in relation to days between imaging examinations. Overall response and progression-free survival were determined based on Lugano criteria. Proportional Cox regression analysis studied association of TGR with OS. For survival analysis, OS was analyzed using Kaplan-Meier survival curves. RESULTS: Fifty-nine out of 81 patients met the inclusion criteria. At 30-day FU1 8 patients (13.6%) had a complete response (CR), 25 patients (42.4%) a partial response (PR), 15 patients (25.4%) a stable disease (SD), and 11 patients (18.6%) a progressive disease (PD) according to CT-based Lugano criteria. The median TGRpre-BL was -0.6 mm2/day, 24.4 mm2/day, -5.1 mm2/day, and 18.6 mm2/day and the median TGRpost-BL was -16.7 mm2/day, -102.0 mm2/day, -19.8 mm2/day and 8.5 mm2/day in CR, PR, SD, and PD patients, respectively. PD patients could be subclassified into a cohort with an increase in TGR (7 of 11 patients (64%), PD TGRpre-to-post-BL INCR) and a cohort with a decrease in TGR (4 of 11 patients (36%), PD TGRpre-to-post-BL DECR) from pre-BL to post-BL. PD TGRpre-to-post-BL DECR patients exhibited similar OS to patients classified as SD, while PD TGRpre-to-post-BL INCR patients had significantly shorter OS (65 days vs 471 days, p<0.001). CONCLUSION: In the context of CART, the additional use of TGRpre-BL and its change to TGRpost-BL determined at 30-day FU1 showed better OS prognostication for patients with overall PD according to Lugano criteria. Therefore, this modification of the Lugano classification should be explored as a potential novel imaging biomarker of early response and should be validated prospectively in future studies.

Health-Related Physical Fitness and Arterial Stiffness in Childhood Cancer Survivors.

Introduction: Despite decreasing mortality in pediatric oncology as a result of standardized treatment protocols, the high number of functional and cardiovascular late sequelae due to anticarcinogenic therapy remains unchanged. The aim of this study was to further assess functional limitations in Health-related Physical Fitness (HRPF) and cardiovascular risk by means of markers of arterial stiffness in Childhood Cancer Survivors (CCS). Materials and Methods: Between March 2016 and August 2017 a total of 92 CCS (Age 12.5 ± 4.2 years, 43 girls) were recruited from their routine follow-up outpatient visit. HRPF was assessed using five Fitnessgram® tasks. Pulse Wave Velocity (PWV) along with peripheral and central blood pressure were assessed using oscillometric measurements performed by Mobil-O-Graph. Z-scores were used to compare the test results either to German reference values or to a recent healthy reference cohort. Results: In CCS, the HRPF was significantly reduced (z-score: -0.28 ± 1.01, p = 0.011) as compared to healthy peers. The peripheral Systolic Blood Pressure (pSBP) was significantly increased (z-score: 0.31 ± 1.11, p = 0.017) and the peripheral Diastolic Blood Pressure (pDBP) was decreased (z-score: -0.30 ± 1.25, p = 0.040), resulting in an increased pulse pressure. The PWV (p = 0.649) and cSBP (p = 0.408), were neither increased nor showed any association to HRPF. Discussion: CCS showed functional limitations in HRPF and an increased pulse pressure, which acts as an early onset parameter of arterial stiffness. Both a low HRPF and impaired hemodynamics are independent cardiovascular risk factors and needs to be taken into consideration in tertiary prevention of CCS.