Bridging Radiation Rapidly and Effectively Cytoreduces High-Risk Relapsed/Refractory Aggressive B Cell Lymphomas Prior to Chimeric Antigen Receptor T Cell Therapy

Abstract

Greater tumor burden before CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy predicts lower complete response rate and shorter overall survival (OS) in patients with aggressive non-Hodgkin lymphoma (NHL). Recent patterns of failure studies have identified lesion characteristics, including size, standard uptake value (SUV), and extranodal location, as associated with post-CAR-T therapy failure. Here we analyzed the effect of bridging radiation-containing treatment (BRT) on pre-CAR-T therapy lesion- and patient-level characteristics and post-CAR-T therapy outcomes, including patterns of failure. Consecutive NHL patients who received radiation therapy from 30 days before leukapheresis until CAR T cell infusion were reviewed. Metabolic tumor volume (MTV) was contoured with a threshold SUV of 4. The first post-CAR-T therapy failures were categorized as preexisting/new/mixed with respect to pre-CAR-T therapy disease and in-field/marginal/distant with respect to BRT. Forty-one patients with diffuse large B cell lymphoma (DLBCL; n = 33), mantle cell lymphoma (n = 7), or Burkitt lymphoma (n = 1) were identified. BRT significantly improved established high-risk parameters of post-CAR-T therapy progression, including in-field median MTV (45.5 cc to .2 cc; P < .001), maximum SUV (18.1 to 4.4; P < .001), diameter (5.5 cm to 3.2 cm; P < .001), and lactate dehydrogenase (LDH; 312 to 232; P = .025). DLBCL patients with lower LDH levels post-BRT had improved progression-free survival (PFS; P = .001). In DLBCL, first failures were new in 7 of 19 patients, preexisting in 5 of 19, and mixed in 7 of 19; with respect to BRT, 4 of 19 were in-field and 4 of 19 were marginal. Post-CAR-T therapy survival was similar in patients with initially low MTV and those with newly low MTV post-BRT using a statistically determined threshold of 16 cc (PFS, 26 months versus 31 months; OS unreached for both). BRT produced significant cytoreductions in diameter, SUV, MTV, and LDH, all predictors of poor post-CAR-T therapy outcomes. Similar PFS and OS in patients with initially low MTV and those who achieved newly low MTV after BRT suggest that BRT may "convert" poor-risk patients to better risk. In the future, the response to BRT may allow for risk stratification and individualization of bridging strategies.

Keywords: Bridging; Chimeric antigen receptor T cell; Diffuse large B cell lymphoma; Lymphoma; Radiation.

Figure 1.

Quantification of cytoreduction at the overall patient level including irradiated and non-irradiated disease (All disease) and only within the BRT field (Irradiated disease) over the bridging period. Values before and after BRT for maximum diameter in centimeters (a), maximum SUV (b), metabolic tumor volume (c), and LDH (d) in all and irradiated disease. Crossbars indicate median value. Patients of any histology with post-BRT interim PET included for 1a/b/c (n = 32), all patients included for LDH analysis in 1d (n = 41).

Figure 2.

Change in MTV over the bridging period. Percent change in MTV in only irradiated (a) and all disease (b) as well as absolute change in MTV (c) over the bridging period for patients of any histology with a post-bridging radiation PET; n = 32

Figure 3.

Patient outcomes following CAR T infusion. Swimmer’s plot depicting patient courses from CAR T infusion for full study cohort; N = 41 (a). Progression free survival (b) and overall survival (c) in DLBCL patients (n = 33). Median PFS was 20 months (CI: 2.7–not reached) and median overall survival was not reached (CI: 27–not reached). Patterns of first failure in DLBCL patients with any post-CAR T progression (d); n = 19

Figure 4.

Outcomes by MTV and BRT comprehensiveness in DLBCL. Progression free (a) and overall survival (b) in DLBCL patients with interim PET post radiation (n = 25) stratified by post radiation MTV cut point of 16.4cc (top row). In the middle row patients were stratified as ‘Poor Risk’ (>16.4cc MTV on post-radiation PET), ‘Good Risk’ (≤16.4cc MTV on both pre- and post-radiation PETs) or ‘Converted Risk’ (>16.4cc MTV on pre-radiation PET and ≤16.4cc MTV on post-radiation PET). In the bottom row patients were stratified by extent of radiation: ‘Partial’ (<100% of total MTV irradiated) or Comprehensive (100% of total MTV irradiated). P values were not evaluable for three group Kaplan Meier or for overall survival stratified by radiation extent due to low number of events. (c) Three example patient cases illustrating Good Risk (top row), Converted Risk (middle row), and Poor Risk (bottom row). Of note, the Good Risk patient received comprehensive radiation while the Converted and Poor Risk patients received partial radiation. PD = progressive disease; PR = partial response, CMR = complete metabolic response, QD = daily, BID = twice a day; fx = fractions