Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Is There Still a Role for Autologous Stem Cell Transplantation in the CAR T-Cell Era?

Recently, CD19-directed chimeric antigen receptor (CAR) T-cell therapies have revolutionized treatment strategies for diffuse large B-cell lymphoma (DLBCL). CAR T-cell therapy is increasingly used as a second-line therapy for patients with DLBCL with early relapse or refractoriness to initial chemoimmunotherapy and displaced high-dose chemotherapy, followed by autologous stem cell transplantation (ASCT) as the standard of care for these patients. However, patients with late relapse or chemosensitive disease still benefit from autologous stem cell transplantation. We will review practice-changing studies in early relapse (ZUMA-7 and TRANSFORM) under consideration of the negative BELINDA trial, with a focus on register data, comparing CAR T-cell therapy and ASCT for patients responding to salvage therapy.

Identification of clinical factors impacting outcome in patients undergoing autologous hematopoietic cell transplantation after BEAM and TEAM conditioning.

Organ dysfunction, including pulmonary function impairment, plays a key role in the choice of conditioning chemotherapy before autologous hematopoietic stem cell transplantation (auto-HSCT). Replacement of BCNU/carmustine as part of BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) conditioning protocol by thiotepa (TEAM) reduces pulmonary toxicity while maintaining efficacy. We retrospectively analyzed the association of clinical characteristics, comorbidities, and organ function with outcomes after conditioning with BEAM or TEAM. Three hundred ninety-six patients undergoing auto-HSCT (n = 333 with BEAM; n = 63 with TEAM) at our institution between 2008 and 2021 were included in this study. In the multivariate analysis, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, progressive disease (PD) before auto-HSCT, Karnofsky performance score (KPS) ≤ 80%, HCT-CI score ≥ 4, and cardiac disease before auto-HSCT were associated with decreased overall survival (OS) in patients treated with BEAM. In contrast, only PD before auto-HSCT was identified in patients treated with TEAM. Patients conditioned with BEAM and DLCOcSB ≤ 60% had higher non-relapse mortality, including pulmonary cause of death. In summary, we have identified clinical and pulmonary risk factors associated with worse outcomes in patients conditioned with BEAM compared to TEAM. Our data suggest TEAM conditioning as a valid alternative for patients with comorbidities, including pulmonary dysfunction and/or poorer performance scores, before auto-HSCT.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Colon and liver tissue damage detection using methylated SESN3 and PTK2B genes in circulating cell-free DNA in patients with acute graft-versus-host disease.

Cell-free DNA (cfDNA) has been investigated in acute graft-versus-host disease (aGvHD) following allogeneic cell transplantation (HSCT). Identifying the tissue of origin of cfDNA in patients with aGvHD is relevant particularly when a biopsy is not feasible. We investigate the cfDNA tissue of origin in patients with aGvHD using methylated gene biomarkers. Patients with liver, colon, or skin aGvHD (n = 28) were analyzed. Liver- and colon-derived cfDNA was measured using a colon- (SESN3) and liver (PTK2B)-specific methylation marker with digital droplet PCR. A statistically significant difference (p < 0.001) in PTK2B and SESN3 concentration was observed between patients with colon or liver GvHD and the control group. For SESN3 and PTK2B the area under the curve in the receiver-operating characteristic (ROC) space was 0.952 (95% CI, 0.888-1 p < 0.001) and 0.971 (95% CI, 0.964-1 p < 0.001), respectively. Thresholds to differentiate aGvHD from non-aGvHD in colon were 0 (sensitivity: 0.905; specificity: 0.989) and liver 1.5 (sensitivity: 0.928; specificity: 0.910). Clinical improvement of liver or colon aGvHD resulted in PTK2B and SESN3 reduced concentration. Whereas, in those patients without improvement the PTK2B and SESN3 level remained stable or increased. The PTK2B liver-specific marker and the SESN3 colon-specific marker and their longitudinal analysis might improve aGvHD detection.

Favourable outcomes of poor prognosis diffuse large B-cell lymphoma patients treated with dose-dense Rituximab, high-dose Methotrexate and six cycles of CHOP-14 compared to first-line autologous transplantation.

The optimal therapeutic approach for young diffuse large B-cell lymphoma (DLBCL) patients with high-intermediate and high-risk age-adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10-year single-centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R-CHOP-21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first-line high-dose chemotherapy with autologous stem-cell support (HDCT-ASCT), resulting in 2-year progression-free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP-14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose-dense rituximab and high-dose methotrexate resulting in promising overall response- (93·3%) and complete remission (90%) rates and sustained survival (2-year PFS and OS: 93·3%). In an intention-to-treat analysis, 2-year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P = 0·009) and OS (69·7% vs. 93·3%, HR 4·95, P = 0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox-regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83-35·9, P = 0·006) and OS (HR 5·86, 95% CI 1·28-26·8, P = 0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor-prognosis DLBCL patients appears superior after early therapy intensification.

Platelet-derived MIF: a novel platelet chemokine with distinct recruitment properties.

OBJECTIVE: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine with chemokine-like functions that plays a role in several inflammatory diseases including atherosclerosis. We recently demonstrated that in addition to macrophages and endothelial cells, platelets are a source of MIF. However, the functional relevance of platelet-derived MIF and differences to other platelet chemokines are unclear. Here, we sought to define the secretion pattern of platelet MIF and to characterize its functional profile in comparison with known atherogenic platelet chemokines. METHODS AND RESULTS: Applying ELISA, we show that MIF is released from thrombin-stimulated platelets after 2 h, whereas CXCL12 and CXCL4 are secreted within minutes. Applied to platelets, MIF, unlike CXCL12, did not enhance platelet activation as analyzed by platelet aggregation, CD62P exposure and chemokine secretion studies. In contrast, both MIF and CXCL12 attenuated ADP-induced calcium transients in platelets. Transmigration and monocyte flow adhesion assays toward conditioned platelet supernatants together with MIF antibody blockade or supernatants from Mif(-/-) mice suggested that platelet-derived MIF has a stronger chemotactic activity than CXCL12 at its respective optimal secretion interval, and showed that platelet MIF substantially contributes to monocyte adhesion on endothelial layers. Moreover, MIF was found to delay clot retraction. CONCLUSIONS: We demonstrate that MIF differs from other platelet-derived chemokines by delayed secretion kinetics and by a distinct autocrine/paracrine modulation potential. Importantly, MIF was found to be a major platelet-derived chemotactic recruitment factor with clot-modulating properties and therefore might be relevant in inflammatory diseases such as atherosclerosis.

High postoperative blood levels of macrophage migration inhibitory factor are associated with less organ dysfunction in patients after cardiac surgery.

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that exerts protective effects during myocardial ischemia/reperfusion injury. We hypothesized that elevated MIF levels in the early postoperative time course might be inversely associated with postoperative organ dysfunction as assessed by the simplified acute physiology score (SAPS) II and sequential organ failure assessment (SOFA) score in patients after cardiac surgery. A total of 52 cardiac surgical patients (mean age [± SD] 67 ± 10 years; EuroScore: 7) were enrolled in this monocenter, prospective observational study. Serum levels of MIF and clinical data were obtained after induction of anesthesia, at admission to the intensive care unit (ICU), 4 h after admission and at the first and second postoperative day. To characterize the magnitude of MIF release, we compared blood levels of samples from cardiac surgical patients with those obtained from healthy volunteers. We assessed patient outcomes using the SAPS II at postoperative d 1 and SOFA score for the first 3 d of the eventual ICU stay. Compared to healthy volunteers, patients had already exhibited elevated MIF levels prior to surgery (64 ± 50 versus 13 ± 17 ng/mL; p < 0.05). At admission to the ICU, MIF levels reached peak values (107 ± 95 ng/mL; p < 0.01 versus baseline) that decreased throughout the observation period and had already reached preoperative values 4 h later. Postoperative MIF values were inversely correlated with SAPS II and SOFA scores during the early postoperative stay. Moreover, MIF values on postoperative d 1 were related to the calculated cardiac power index (r = 0.420, p < 0.05). Elevated postoperative MIF levels are inversely correlated with organ dysfunction in patients after cardiac surgery.