Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion.

Prolonged cytopenias after chimeric antigen receptor (CAR) T cell therapy are a significant clinical problem and the underlying pathophysiology remains poorly understood. Here, we investigated how (CAR) T cell expansion dynamics and serum proteomics affect neutrophil recovery phenotypes after CD19-directed CAR T cell therapy. Survival favored patients with "intermittent" neutrophil recovery (e.g., recurrent neutrophil dips) compared to either "quick" or "aplastic" recovery. While intermittent patients displayed increased CAR T cell expansion, aplastic patients exhibited an unfavorable relationship between expansion and tumor burden. Proteomics of patient serum collected at baseline and in the first month after CAR-T therapy revealed higher markers of endothelial dysfunction, inflammatory cytokines, macrophage activation, and T cell suppression in the aplastic phenotype group. Prolonged neutrophil aplasia thus occurs in patients with systemic immune dysregulation at baseline with subsequently impaired CAR-T expansion and myeloid-related inflammatory changes. The association between neutrophil recovery and survival outcomes highlights critical interactions between host hematopoiesis and the immune state stimulated by CAR-T infusion.

The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL.

CD19-directed CAR T-cell therapy with brexucabtagene autoleucel (brexu-cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu-cel. Furthermore, we report associations between the baseline CAR-HEMATOTOX (HT) score and toxicity events, non-relapse mortality (NRM), and progression-free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HTlow (score 0-1) while 47 patients were HThigh (score ≥2). The HThigh cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1-year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HThigh patients experienced inferior 90-day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not-reached, p < .0001), and OS (median 26 months vs. not-reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu-cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.

Inferior Outcomes of EU Versus US Patients Treated With CD19 CAR-T for Relapsed/Refractory Large B-cell Lymphoma: Association With Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization, and CAR-T Product Use.

Real-world evidence suggests a trend toward inferior survival of patients receiving CD19 chimeric antigen receptor (CAR) T-cell therapy in Europe (EU) and with tisagenlecleucel. The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. In this multicenter retrospective observational study, we studied the patient-individual journey from CAR-T indication to infusion, baseline features, and survival outcomes in 374 patients treated with tisagenlecleucel (tisa-cel) or axicabtagene-ciloleucel (axi-cel) in EU and the United States (US). Compared with US patients, EU patients had prolonged indication-to-infusion intervals (66 versus 50 d; P < 0.001) and more commonly received intermediary therapies (holding and/or bridging therapy, 94% in EU versus 74% in US; P < 0.001). Baseline lactate dehydrogenase (LDH) (median 321 versus 271 U/L; P = 0.02) and ferritin levels (675 versus 425 ng/mL; P = 0.004) were significantly elevated in the EU cohort. Overall, we observed inferior survival in EU patients (median progression-free survival [PFS] 3.1 versus 9.2 months in US; P < 0.001) and with tisa-cel (3.2 versus 9.2 months with axi-cel; P < 0.001). On multivariate Lasso modeling, nonresponse to bridging, elevated ferritin, and increased C-reactive protein represented independent risks for treatment failure. Weighing these variables into a patient-individual risk balancer (high risk [HR] balancer), we found higher levels in EU versus US and tisa-cel versus axi-cel cohorts. Notably, superior PFS with axi-cel was exclusively evident in patients at low risk for progression (according to the HR balancer), but not in high-risk patients. These data demonstrate that inferior survival outcomes in EU patients are associated with longer time-to-infusion intervals, higher tumor burden/LDH levels, increased systemic inflammatory markers, and CAR-T product use.

Impact of Pre-transplant Induction Therapy on Outcomes of Patients Who Undergo Autologous Stem Cell Transplantation for Mantle Cell Lymphoma in First Complete Remission.

Mantle cell lymphoma is a rare subtype of non-Hodgkin's lymphoma with poor prognosis and continue to be challenging to treat. The choice of first line induction regimen remains a topic of debate due paucity of clinical trials. We retrospectively evaluated 66 patients diagnosed with mantle cell lymphoma who achieved first complete response after induction chemotherapy followed by autologous stem cell transplant. Treatment groups were divided into low-intensity versus high-intensity regimens. Our data showed the intensity of induction regimen does not impact posttransplant outcomes of mantle cell lymphoma who underwent autologous stem cell transplant in first complete response.

The role of CAR-T cell therapy as second line in diffuse large B-cell lymphoma.

For approximately three decades, autologous hematopoietic cell transplantation (auto-HCT) has been the standard of care for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after frontline therapy. This approach is limited due to the intensity of chemotherapy and the proportion of patients who relapse after auto-HCT. Since the approval of anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy and novel agents, the treatment paradigm for DLBCL has changed remarkably. Anti-CD19 CAR-T therapy was first approved for relapsed DLBCL after two or more previous lines of therapy with long-lasting responses, with over 50% of patients still alive at 5-year follow-up. Here, we discuss recent randomized phase 3 clinical trials using axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel in the second-line therapy setting compared with the standard of care in transplant-eligible patients who have DLBCL R/R within 12 months of completing chemo-immunotherapy, potentially changing the treatment algorithm for DLBCL.

Mindfulness in Adolescent and Young Adult (AYA) Patients Undergoing Hematopoietic Stem Cell Transplantation (HSCT): A Qualitative Study.

Previous adolescent and young adult (AYA) research suggests patients undergoing hematopoietic stem cell transplantation (HSCT) experience severe physiological stress. The goal of this study was to identify unmet needs, interests, and preferences for mindfulness to inform the development of a mindfulness-based stress reduction intervention. Semi-structured interviews were conducted at three time points: prior to (n = 20), immediately after (n = 13), and three months post HSCT (n = 16) in the same AYA patients. Interviews assessed stress reduction strategies used, interest in mindfulness, and current quality of life. Three major thematic categories emerged from interview data across all time points: Concerns, Coping Strategies, and Mindfulness Activities. Prior to HSCT, two additional themes emerged including: Hope for the Future and Getting the Body Moving-Physical Activity. Most participants were not familiar with the term "mindfulness" prior to HSCT; but after being provided the definition of mindfulness, participants expressed interest in an online mindfulness-based intervention (e.g., ZOOM), stating: "I think it's necessary" and "It would definitely be useful". Participants suggested an intervention immediately following HSCT may decrease isolation concerns stating: "[in the hospital] You kind of feel like a hamster in a cage" and "you obviously have a lot of time to just be sitting by yourself in a hospital room". The results suggest that a mindfulness-based online intervention is of interest to AYA HSCT patients and may be beneficial in decreasing physiological stress and improving quality of life.

Grade 3-4 cytokine release syndrome is associated with poor survival in haploidentical peripheral blood stem cell transplantation.

The information on the impact of cytokine release syndrome (CRS) on haploidentical donor peripheral blood stem cell transplant (haploPBSCT) outcomes is limited. We retrospectively evaluated 98 patients who underwent haploPBSCT between June 2012 and June 2019 for the onset and severity of CRS per the ASTCT guidelines. The incidence of CRS was 93% (91/98). Outcomes were compared between grade 1-2 and 3-4 CRS. Eighty-one patients developed grade 1-2 CRS (89%) and 10 (11%) developed grade 3-4 CRS. Compared to grade 1-2 CRS, grade 3-4 CRS experienced adverse survival (73.7% vs. 30%, p<.001), inferior relapse-free survival (64.0% vs. 20%, p<.001), and higher non-relapse mortality (NRM) (16.4% vs. 60%, p<.001) at 1-year. Propensity score-based multivariable analyses revealed worse survival (HR 2.71, p=.04), and higher NRM (SHR 4.51, p=.006) with grade 3-4 CRS. Our study shows that grade 3-4 CRS was adversely associated with survival. Therefore, early identification and preventive strategies are warranted.

High Ki67 proliferation index but not cell-of-origin subtypes is associated with shorter overall survival in diffuse large B-cell lymphoma.

BACKGROUND: CD10, BCL6, and MUM1 are commonly used immunohistochemical stains for classifying diffuse large B-cell lymphoma (DLBCL), which is useful in predicting outcome. Conflicting reports of the prognostic value of other markers such as BCL2, CD23, and Ki67 proliferation index have been reported. Our objective was to correlate these immunostains and Hans classification with response to therapy and overall survival. MATERIALS AND METHODS: A retrospective study of patients diagnosed with DLBCL from 2008-2014 at a tertiary-care cancer hospital. The slides with the IHC stains were reviewed by two independent pathologists. The clinical outcomes--assessed independently--were response to therapy and overall survival. The treatment response evaluation was based on the new Lugano classification. Statistical analyses were conducted using the Fisher's exact test and Kaplan-Meier survival curves. Significance was set at P < 0.05. RESULTS: Forty-one patients were included in the study with a known Hans classification, available clinical data, and at least 5-year follow-up. CD10 immunostain was reported in all patients, whereas CD23 was the least reported in only four patients. No significant association was observed between CD10, BCL6, MUM1, BCL2, and both Response to therapy and overall survival. Owing to few cases reported CD23 immunostain, further analysis of association is not reported. High Ki67 proliferative index of >80% was statistically significantly associated with shorter overall survival and not statistically significant associated with no response to therapy. Hans classification subtypes were not predictive in regard to therapy response. CONCLUSION: High Ki67 expression (>80%) was associated with shorter overall survival in DLBCL. Hans classification subtypes were not predictive.