Effect of delayed cell infusion in patients with large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy.

Complications occurring after lymphodepleting chemotherapy (LDC) may delay chimeric antigen receptor (CAR) T-cell infusion. The effect of these delays on clinical outcomes is unclear. We performed a retrospective analysis of 240 patients with relapsed/refractory large B-cell lymphoma treated with standard-of-care axicabtagene ciloleucel (axi-cel) and identified 40 patients (16.7%) who had delay in axi-cel infusion. Of these, 85% had delay due to infection. At time of LDC initiation, patients with delayed infusion had lower absolute neutrophil count (p=0.006), lower platelets (p=0.004), lower hemoglobin (p5 days (4.6 vs. 8.2 months; p=0.036), but not 1 day (5.7 vs. 8.2 months; p=0.238). Following propensity score matching, patients with delayed infusion continued to have shorter median PFS (3.5 vs. 6.0 months; p=0.015). Levels of proinflammatory cytokines on day of infusion were significantly higher in patients with delayed infusion. Together, these findings suggest that delays in CAR T-cell administration after initiation of LDC are associated with inferior outcomes. Further studies are needed to guide strategies to improve efficacy in such patients.

Impact of cumulative dose of brentuximab vedotin on outcomes of frontline therapy for advanced-stage Hodgkin lymphoma.

In the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A + AVD) demonstrated superior efficacy compared with bleomycin + AVD for the treatment of advanced-stage classic Hodgkin lymphoma (cHL). However, there are minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 patients with stage III or IV cHL treated with frontline A + AVD from January 2010 to April 2022. Treatment consisted of up to 1.2 mg/kg of BV and standard dose AVD IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. At the time of treatment, the median patient age was 37 years, and a high-risk International Prognostic Score was observed in 46% of patients. Overall, 91% of patients received 6 cycles of AVD; 55% of patients did not receive the intended cumulative dose of BV (CDB); 28% of patients received two-thirds or less than the planned CDB. At a median follow-up time of 27.4 months (95% confidence interval [CI], 24.8-29), the median progression-free survival (PFS) was not reached, and the 12-month PFS was 90.3% (95% CI, 85.9-95.0). The impact of CDB on PFS was not significant (P = .15), nor was high CDB significantly associated with increased adverse events. In real-world experience, A + AVD is a highly effective treatment for patients with advanced-stage cHL, including for patients with prominent dose reductions of BV.

PD-L1+ macrophages are associated with favorable features in primary mediastinal (thymic) large B-cell lymphoma.

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a rare, aggressive subtype of non-Hodgkin lymphoma and has a complex inflammatory microenvironment. Although most patients can be cured with standard-of-care immunochemotherapy, patients who have disease relapse have an unfavorable prognosis. Pre-treatment prognostic biomarkers in PMBCL are needed. In this retrospective study, we analyzed the clinical features and outcomes of PMBCL patients and their association with immune cell subpopulations identified by multiplex immunofluorescence at initial diagnosis. Two different antibody panels were used to assess macrophages in tissue biopsy specimens collected before the initiation of induction therapy. Twelve PMBCL patients, including five patients who had disease relapse, were included in the analysis. At a median follow-up time of 32.2 months, the median progression-free and overall survival durations were not reached. Our findings suggest that a high density of PD-L1+ macrophages is associated with favorable features, such as early disease stage and the absence of B-symptoms, and indicate that a high percentage of PD-L1+ macrophages and high densities of CD30+PD-L1+ cells and CD30+ cells might be associated with a lower risk of relapse within 12 months of therapy initiation. Further studies are needed to develop a biomarker signature predictive of treatment response with therapeutic consequences for patients with newly diagnosed PMBCL.

Impact of conditioning chemotherapy on lymphocyte kinetics and outcomes in LBCL patients treated with CAR T-cell therapy.

Conditioning chemotherapy (CCT) has been shown to be essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy. Here, we determined whether the change in absolute lymphocyte count, referred to as delta lymphocyte index (DLIx), may serve as a surrogate marker for pharmacodynamic effects of CCT and whether it associated with germline genetic variants in patients with large B-cell lymphoma (LBCL). One-hundred and seventy-one patients were included, of which 86 (50%) received bridging therapy post-leukapheresis. Median DLIx was 0.5 × 109/L (range, 0.01-2.75 × 109/L) and was significantly higher in patients who achieved complete response (p = 0.04). On multivariate analysis, low DLIx was associated only with use of bridging therapy (odds ratio 0.4, 95% CI 0.2-0.8, p = 0.007). Low DLIx was independently associated with shorter progression-free (p = 0.02) and overall survival (p = 0.02). DLIx was associated with genetic variations related to drug metabolism and macrophage biology such as ABCB1, MISP and CPVL. The impact of CCT on lymphocyte count is affected by use of bridging therapy but change in lymphocyte count is independently associated with efficacy. Studies aimed at investigating macrophage biology in this setting may suggest strategies to increase the efficacy of CCT and improve outcomes.

SIRPα+ macrophages are increased in patients with FL who progress or relapse after frontline lenalidomide and rituximab.

Limited data exist regarding the outcome of patients with follicular lymphoma (FL) who relapse or progress after frontline lenalidomide and rituximab (R2). Moreover, mechanisms of resistance to R2 in FL remain unclear, with increased protumoral macrophages suspected as a major contributory culprit to this phenomenon. This retrospective study analyzed the outcome of patients with advanced-stage FL grade 1 to 3A who relapsed or progressed after frontline R2. A multiplex immunofluorescence macrophage panel, including CD47, CD14, CD68, CD115 (also known as colony-stimulating factor 1 receptor [CSF1R]), CD163, CD172a (also known as signal regulatory protein α [SIRPα]), and CD274 (also known as programmed cell death-ligand 1 [PDL1]), was used to stain tissue biopsy specimens collected before initiation of R2 and at the time of progression. Among 156 patients with advanced-stage FL treated with frontline R2, 33 (21%) relapsed or progressed and required second-line therapy, after a median of 33 months (range, 1-122 months). Second-line therapy was chemoimmunotherapy in 16 (48%) patients and other therapy in 17 (52%). The overall response rate was 78%, and complete response rate was 72%. Median progression-free survival was significantly longer in patients who received chemoimmunotherapy compared with other therapy (99 vs 25 months; P = .004). Three macrophage populations were significantly increased in tissue samples collected at progression compared with before frontline treatment: CD68+CD115+ (P = .02), CD68+CD115+CD172a+ (P = .02), and CD68+CD163+CD172a+ (P = .01). Chemoimmunotherapy is an effective treatment strategy for patients with FL who relapse after frontline R2. Therapies targeting specific macrophage populations may yield novel approaches for improving outcomes with frontline R2.

Pretreatment SUVmax may influence the clinical benefit of BR over R-CHOP in patients with previously untreated FL.

In 2 randomized phase 3 trials BR resulted in longer progression-free survival (PFS) than frontline R-CHOP in patients with indolent and mantle cell lymphoma. However, in subset analyses of follicular lymphoma (FL), the results were incongruent. We conducted a retrospective matched-pair analysis to compare the outcome of patients with advanced stage FL, receiving frontline BR (N = 73) or R-CHOP (N = 73), matched by age, gender, stage, and FL International Prognostic Index score. On multivariable analysis, baseline maximum standardized uptake value (SUVmax) >13 was associated with use of R-CHOP (p = .001). After a median follow-up of 69 months for the BR arm and 126 months for the R-CHOP arm, 5-year PFS was 80% and 70%, respectively (p = .07). After adjusting for SUVmax >13, the trend for better PFS in BR was not maintained. Prospective studies are needed to validate the role of pretreatment SUVmax as a stratification factor in future randomized therapeutic trials in FL.

Pre-treatment maximum standardized uptake value predicts outcome after frontline therapy in patients with advanced stage follicular lymphoma.

The impact of pre-treatment maximum standardized uptake value (SUVmax) on the outcome of follicular lymphoma (FL) following specific frontline regimens has not been explored. We performed a retrospective analysis of 346 patients with advanced stage follicular lymphoma (FL) without histological evidence of transformation, and analyzed the impact of SUVmax on outcome after frontline therapy. Fifty-two (15%) patients had a SUVmax >18, and a large lymph node ≥6 cm was the only factor associating with SUVmax >18 on multivariate analysis (odds ratio 2.7, 95% confidence interval [CI]: 1.3-5.3, P=0.006). The complete response rate was significantly lower among patients treated with non-anthracycline-based regimens if SUVmax was >18 (45% vs 92%, P<0.001), but not among patients treated with R-CHOP (P=1). SUVmax >18 was associated with significantly shorter progression-free survival among patients treated with non-anthracycline-based regimens (77 months vs. not reached, P=0.02), but not among patients treated with R-CHOP (P=0.73). SUVmax >18 associated with shorter overall survival (OS) both in patients treated with R-CHOP (8-year OS 70% vs. 90%, P=0.02) and non-anthracycline-based frontline regimens (8-year OS 50% vs 85%, P=0.001). In conclusion, pre-treatment PET scan has prognostic and predictive value in patients with advanced stage FL receiving frontline treatment.

The risk of central nervous system relapses in patients with peripheral T-cell lymphoma.

We performed a retrospective analysis to identify risk factors and survival outcome for central nervous system (CNS) relapse of peripheral T-cell lymphoma (PTCL) by histologic type. Records of 600 PTCL patients diagnosed between 1999 and 2014 were analyzed including PTCL not otherwise specified (PTCL-NOS, 174 patients), angoimmunoblastic T-cell lymphoma (AITL, 144), ALK+anaplastic large cell lymphoma (ALCL, 74), ALK-ALCL (103), extranodal NK-cell lymphoma (ENKL, 54), or others (51). With a median follow up of 57 months, 13 patients (4 PTCL-NOS, 1 AITL, 4 ALK+ALCL, 2 ALK-ALCL, 2 ENKL) experienced CNS relapse. One-year and 5-year cumulative incidence of CNS relapse were 1.5% (95%CI: 0.7-2.8%) and 2.1% (95%CI: 1.1-3.5%), respectively. The 5-year cumulative incidence of CNS relapse was 1.8% in PTCL-NOS, 0.7% in AITL, 5.4% in ALK+ALCL, 2.1% in ALK-ALCL and 3.7% in ENKL. Extranodal involvement >1 site was the only significant factor associated with higher chance of CNS relapse (HR: 4.9, 95%CI: 1.6-15.0, p = 0.005). Patients with ALK+ALCL who had extranodal involvement >1 (N = 19) had very high risk of CNS relapse with one year cumulative incidence of 17% (95%CI: 4%-37%), all occurring within six months after diagnosis. All patients with CNS relapse eventually died (median, 1.5 months; range, 0.1-10.1 months). CNS relapse in patients with PTCL is rare event but the risk varies by subtype. ALK+ALCL patients with extranodal involvement >1 site have a very high risk of early CNS relapse, and thus evaluation of CNS involvement at the time of diagnosis and possible CNS-directed prophylaxis may be considered.

The survival outcome of patients with relapsed/refractory peripheral T-cell lymphoma-not otherwise specified and angioimmunoblastic T-cell lymphoma.

Survival outcome of patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL-NOS (n = 180) or AITL (n = 141) between 1999 and 2015, were analysed. Failure-free survival (FFS) and overall survival (OS) were calculated from the time of first disease progression (FFS1, OS1), from second disease progression (FFS2, OS2) and from third progression (FFS3, OS3). With a median follow-up duration of 52 months, 240 patients (135 PTCL-NOS, 105 AITL) experienced progression/relapse. In patients with PTCL-NOS, the median durations of FFS1, FFS2 and FFS3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL, they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS1 and OS1 by the time of recurrence during this period (1999-2004, 2005-2009 and 2010-2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5-year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5-year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.

Double hit lymphoma: the MD Anderson Cancer Center clinical experience.

We report our experience with 129 cases of double hit lymphoma (DHL), defined as B-cell lymphoma with translocations and/or extra signals involving MYC plus BCL2 and/or BCL6. All cases were reviewed for histopathological classification. Median age was 62 years (range, 18-85), 84% of patients had advanced-stage disease, and 87% had an International Prognostic Index score ≥2. Fourteen patients (11%) had a history of low-grade follicular lymphoma. MYC translocation was present in 81%, and extra signals of MYC in 25% of patients. IGH-BCL2 translocation was present in 84% and extra signals of BCL2 in 12% of patients. Two-year event-free survival (EFS) rates in all patients and patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and R-HyperCVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine plus methotrexate) were 33%, 25%, 67% and 32%, respectively. In patients achieving complete response with initial therapy (n = 71), 2-year EFS rates in patients who did (n = 23) or did not (n = 48) receive frontline stem cell transplantation were 68% and 53%, respectively (P = 0·155). The cumulative incidence of central nervous system involvement was 13% at 3 years. Multivariate analysis identified performance status ≥2 and bone marrow involvement as independent adverse prognostic factors for EFS and OS. Further research is needed to identify predictive and/or targetable biological markers and novel therapeutic approaches for DHL patients.