Jacob D. Soumerai

Patients in the lisocabtagene maraleucel (liso-cel) plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50 × 106 [dose level 1 (DL1)] or 100 × 106 [DL2] chimeric antigen receptor–positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n = 5; DL2, n = 51), median age was 64.5 years (range, 44-77), 98% had high-risk cytogenetics, and median number of prior therapies was 5 (range, 1-13). Median follow-up was 24.8 months (range, 3.1-51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31-60), and overall response rate was 86% (95% CI, 74-94). Median duration of response was not reached (NR; 95% CI, 28.7 to NR) for patients with CR/CRi. Median progression-free survival was 31.4 months (95% CI, 20.1 to NR). In DL1 plus DL2, the most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of the patients (grade 3, 4%; no grade 4/5), and neurological events were reported in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of the patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with R/R CLL/SLL with predictable and manageable safety. This trial was registered at www.clinicaltrials.gov as NCT03331198 and NCT03435796.

Triplet regimens induce high rates of undetectable measurable residual disease (MRD) at ≤10−4 (uMRD4) and appear to prolong progression-free survival (PFS) in treatment-naïve (TN) chronic lymphocytic leukemia (CLL), but the optimal treatment duration to minimize the risk of infections is unknown. In this phase 2 trial, we evaluated zanubrutinib, obinutuzumab, and venetoclax (BOVen) in TN CLL. Our MRD-driven study was designed to optimize treatment duration, balancing efficacy against toxicities associated with extended treatment exposure, and to evaluate zanubrutinib with venetoclax (Z+V) retreatment. With a median observation of 69 months and median treatment duration of 10 cycles, 96% achieved blood uMRD4, and 92% achieved uMRD4 in both blood and bone marrow (primary end point). BOVen was well-tolerated, with low rates of grade 3-4 neutropenia (25%) and infections (9.6%; no grade 5). Median MRD4-free survival was 34.1 months (95% confidence interval [CI], 23.1-50.5), and the 48-month PFS was 79.7% (95% CI, 68.6-92.5). ΔMRD400 (≥400-fold reduction in blood MRD [immunosequencing] at 4 months) identified patients with earlier bone marrow uMRD4 (6 vs 12 months, P< .001) and longer MRD4-free survival (50.5 vs 18.1 months, P< .001), despite shorter treatment duration (8 vs 13 months, P< .001). This manuscript also reports safety/efficacy of Z+V retreatment and pharmacokinetic and T-cell profiling studies. In summary, BOVen was well-tolerated and resulted in frequent uMRD4 and durable remissions in TN CLL with a short treatment duration (median, 10 months). ΔMRD400 is undergoing evaluation as a predictive biomarker to guide treatment duration in two prospective trials of venetoclax- and sonrotoclax-based triplets in TN CLL. This trial was registered at www.clinicaltrials.gov (#NCT03824483).

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) affect most patients receiving axicabtagene ciloleucel (axi-cel) for relapsed or refractory large B-cell lymphoma (LBCL). Based on pre-clinical data, we hypothesized that prophylactic IFN-γ blockade could prevent toxicity without impairing efficacy. We initiated an open-label phase 2 trial (NCT06550141) evaluating single-dose emapalumab one day before axi-cel. Here, we report the first two patients to caution against the pre-emptive emapalumab use prior axi-cel: Both developed treatment-refractory toxicities including high-grade ICANS and overlapping CRS-IEC-HS requiring multiple immunomodulatory agents. CAR T-cell expansion exceeded levels reported in ZUMA-1 and a standard-of-care axi-cel cohort at our institution. Despite therapeutic emapalumab and suppressed free IFN-γ, IL-2 and sIL-2R were markedly elevated, suggesting CRS was driven independent of IFN-γ. Both patients achieved complete responses, suggesting preserved efficacy. Given the unanticipated severity and refractoriness of toxicities, recruitment with this design was discontinued and the protocol was amended.

In this phase 1/2 study we evaluated duvelisib plus venetoclax in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and Richter transformation (RT). Venetoclax was added after 1 week of duvelisib. After 1 year of therapy, patients with a complete response (CR) and undetectable minimal residual disease (uMRD) could discontinue therapy; patients with detectable MRD continued venetoclax monotherapy until 2 separate occasions of uMRD. Thirty five patients with CLL/SLL and 9 with RT enrolled. Among patients with CLL, 77% had unmutated immunoglobulin heavy chain variable region, 46% had TP53 aberrancy, and patients had a median of 2 prior therapies, including 60% with prior Bruton tyrosine kinase inhibitor. In phase 1 the maximum tolerated dose was not reached, and the recommended phase 2 dose was 25mg twice daily duvelisib plus 400mg daily venetoclax. 91% of patients experienced ≥grade 3 neutropenia, with febrile neutropenia in 6%. Common nonhematologic toxicities were diarrhea (63%, 14% ≥grade 3) and elevated aspartate aminotransferase (51%, 9% ≥grade 3). The best CR and overall response rates were 60% and 91%, respectively. At cycle 13, peripheral blood and bone marrow uMRD at 10−4 were 43% and 40%, respectively. The median progression-free survival (PFS) for patients with CLL/SLL was 46 months, and the 3-year PFS was 67% (95% confidence interval, 0.51-0.86). Four patients with RS achieved a response (3 CRs). Overall, duvelisib plus venetoclax was active in R/R CLL/SLL and RT, although serious adverse events occurred, including immune-mediated toxicities. This trial was registered at www.clinicaltrials.gov as NCT03534323.

Synchronous systemic and de novo secondary central nervous system (CNS) large B-cell lymphoma (LBCL) is an aggressive clinical entity with a historically poor prognosis. Given the rarity of this presentation, prospective studies are limited, and treatment paradigms and outcomes are extrapolated from small, heterogenous retrospective studies. We performed a retrospective study with extended follow-up for 63 consecutive patients with previously untreated synchronous systemic and de novo secondary CNS LBCLs presenting to 2 institutions over 21 years. Most patients had diffuse LBCL (73%) and were treated with an average of 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) intercalated with high-dose IV methotrexate (R-CHOP-M). The overall response rate was 84% (75% complete). With a median follow-up of 8.1 years, the median progression-free survival (PFS) was 1.2 years, and the 6-year PFS rate was 37%. The median overall survival (OS) was 7.9 years, and the 6-year OS rate was 52%. Normal lactate dehydrogenase (LDH), low International Prognostic Index (IPI) score, and brain parenchymal-only CNS disease were associated with improved PFS, whereas normal LDH and parenchymal disease were associated with OS. The 25% of patients who underwent consolidation with high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) had superior PFS and OS than patients who did not receive a transplant, with particular benefit in those with IPI score of ≥3. This study demonstrates that a proportion of patients presenting with secondary CNS involvement are cured with upfront chemoimmunotherapy with or without HDC/ASCT and helps identify prognostically favorable subgroups, which can guide counseling of patients with this rare, high-risk clinical presentation.

Tumor inflammation-associated neurotoxicity (TIAN) was recently proposed as a unique complication of immunotherapy in patients with brain tumor. Here, we report a first comprehensive characterization of TIAN in patients with central nervous system (CNS) lymphoma (CNSL) treated with CD19-directed chimeric antigen receptor (CD19-CAR) T cells. TIAN occurred in 10 of 56 (17.9%) patients with CNSL, with clinical onset at a median 3.5 days (range, 1-9) after CD19-CAR T-cell infusion. It was less frequently associated with cytokine release syndrome (60% vs 100%; P = .009) than immune effector cell–associated neurotoxicity syndrome (ICANS). Although symptoms were usually transient and fully reversible, TIAN was associated with a fatal outcome in 1 patient. Larger CNS tumor volume at baseline allowed the identification of patients at risk for TIAN (area under the curve, 0.847; P = .002). Maximizing Youden J statistics, a discriminatory tumor volume threshold of >3.4 cm3 was determined, which carried 87.5% sensitivity and 80.5% specificity. TIAN correlated with higher overall response rates to CD19-CAR T cells (90% vs 52%; P = .036) and improved progression-free survival (hazard ratio, 0.22; 95% confidence interval, 0.07-0.61; P = .006) on multivariate Cox proportional hazard regression. Postmortem histopathological evaluation of a TIAN lesion revealed a dense macrophage population with central necrosis and peripheral reactive gliosis, accompanied by loss of white matter and intracytoplasmic myelin in foamy macrophages. Collectively, our work supports TIAN as a localized on-tumor, on-target neurotoxicity syndrome, closely related to preexisting CNSL lesions and distinct from ICANS. CNS tumor volume at baseline may allow to identify patients at risk and may guide management.