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Anti CD-19 chimeric antigen receptor T (CAR-T) cells demonstrate effective early anti-tumor response; however, impaired hematopoietic recovery is observed in about 30% of patients with prolonged cytopenia appearing as an unmet need for optimal treatment. All adult patients given commercially available anti CD-19 CAR-T for diffuse large B cell lymphoma (DLBCL) were screened at 21–28 days after CAR-T infusion for cytopenia. In case of severe persistent cytopenia, patients were given TPO receptor agonists. Initial dose of eltrombopag was 50 mg/day and gradually increased to a maximal dose of 150 mg/day. Romiplostim was given as subcutaneous injection once a week for 2 doses (125 mcg). Response was defined as transfusion independency along with resolution of severe neutropenia (ANC > 500 /microL) and/or platelets > 20,000/microL for three consecutive values on different days. TPO receptor agonists were tapered down when response was met. From May 2019 to December 2021, 93 patients were eligible (74%, tisagenlecleucel and 26%, axicabtagene ciloleucel). The median age was 69 (range, 19–85) years. Six patients (6.5%) (tisagenlecleucel, n = 4 or axicabtagene ciloleucel, n = 2) demonstrated prolonged severe cytopenia and were treated with TPO receptor agonists (eltrombopag, n = 4; romiplastim, n = 1, both drugs, n = 1). Median time from CAR-T infusion to initiation of TPO receptor agonist was 43 (range, 21–55) days. All patients were transfusion-dependent and were given daily GCSF prior to TPO receptor agonist administration. Response to TPO receptor agonists was seen in all 6 patients. Median time from TPO receptor agonist initiation to resolution of cytopenia was 22 (range, 8–124) days for Hb, 27 (range, 6–38) days for platelets, and 29 (range, 7–61) days for neutrophils. A complete resolution of all blood counts (ANC > 500 /microL and platelets > 20,000/microL and hemoglobin > 8 gr/dL) was seen in 5/6 patients. No toxicity was observed during the therapy course. This paper supports further investigation of TPO receptor agonists in the treatment of persistent cytopenia following CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Polatuzumab (Pola)-based regimens and chimeric antigen receptor T (CAR T) cells provide superior outcome compared to conventional chemoimmunotherapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Choosing between these strategies remains controversial. The efficacy of CAR T versus Pola-rituximab(R) /Pola-bendamustine(B)-R in R/R DLBCL patients after failing ≥2 lines of treatment was compared in a retrospective, 'real-world' study. Propensity score matching, for age, lymphoma category (de-novo/transformed), number of prior lines, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level, was applied to control for differences in patients' characteristics. Response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 82 patients, treated with CAR T (n=41) or Pola-based regimens (n=41), were included. No treatment-related deaths occurred with CAR T vs. 3 (7.3%) with Pola. The overall and complete response rates were 83% and 58% with CAR T vs. 66% and 44% with Pola-based-regimens (p=0.077 and p=0.18, respectively). At a median follow-up of 9 months (range 1-19.2) and 16 months (range 0.7-25.3) for the CAR T and Pola arm respectively, the median PFS has not been reached for CAR T vs. 5.6 months for Pola (95% CI 3.6-7.6, p=0.014). Median OS has not been reached for CAR T vs. 10.8 months (95% CI 2.2-19.4) for Pola (p=0.026). To conclude, in a real-world setting, treatment with CAR T achieved superior PFS and OS compared to Pola-based regimens in patients with R/R DLBCL. [ABSTRACT FROM AUTHOR]

Purpose: The introduction of CD19-specific chimeric antigen receptor T-cell therapy (CAR-T) for treatment of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) gives hope to patients with otherwise dismal prognosis. Therapy outcomes, however, depend upon selection of patients and accurate early identification of non-responders. Patients treated with CAR-T usually undergo [18F]FDG PET-CT at time of decision (TD), time of CAR-T transfusion (TT), 1 month (M1), and 3 months (M3) post-therapy. The purpose of the current study was to identify the specific parameters that should be addressed when reporting PET-CT studies in the clinical setting of CAR-T therapy. Methods: A total of 138 PET-CT scans (30 TD, 42 TT, 44 M1, 22 M3) of 48 patients treated with CAR-T were included. SUVmax, TMTV, and TLG were calculated in all scans. Response was assessed using the Deauville scale and ΔSUVmax method. Overall survival (OS) was the primary endpoint. Median follow-up was 12.8 (IQR 6.4–16.0) months from CAR-T infusion. Results: In a univariate analysis, TD-SUVmax > 17.1 and TT-SUVmax > 12.1 were associated with shorter OS (Pv < 0.05). In a multivariate analysis, three factors were significantly associated with shorter OS: TD-SUVmax > 17.1 (HR 10.3; Pv < 0.01), LDH > 450 U/l (HR 7.7; Pv < 0.01), and ECOG score > 1 (HR 5.5; Pv = 0.04). Data from TD and TT PET-CT scans were not predictive of toxicity. On M1-PET-CT, patients with a Deauville score > 3 had significantly shorter OS (median 7.9 months, versus not reached, Pv < 0.01). ΔSUVmax ≤ 66% on M1-PET-CT predicted shorter OS when M1-SUVmax was compared to TD-SUVmax (Pv = 0.02) but not to TT-SUVmax (Pv = 0.38). Conclusion: Pre-treatment SUVmax may guide patient selection for CAR-T therapy. On M1-PET-CT, Deauville score and ΔSUVmax from TD may identify early therapy failure. These parameters are easy to obtain and should be included in the PET-CT report. [ABSTRACT FROM AUTHOR]

Purpose: Vaccine-associated hypermetabolic lymphadenopathy (VAHL) is frequently observed on [18F]FDG PET-CT following BNT162b2 administration. Recent data suggest a prominent B cell germinal-center (GC) response elicited by mRNA vaccines in draining lymph nodes. Thus, in this study we aimed to explore the correlation between VAHL and humoral immunity as reflected by post-vaccination serologic testing and by comparing the incidence of VAHL between lymphoma patients treated recently with B cell depleting therapy and those that were not. Methods: A total of 137 patients with hematologic malignancy that had post-vaccination [18F]FDG PET-CT were included (All-PET group), 86 received both vaccine doses before imaging (PET-2 group). Their VAHL status and grade on imaging were recorded. Among 102 lymphoma patients, 34 (33.3%) were treated during the year prior vaccination with anti-CD20 antibody containing therapy. A subgroup of 54 patients also underwent serologic testing 2–3 weeks after the booster dose, and their anti-spike titers were recorded and graded as well. Results: The overall incidence of VAHL in patients with hematologic malignancy was 31.4%. The 34 lymphoma patients treated during the year prior vaccination with anti-CD20 antibody containing therapy had significantly lower rates of VAHL comparted with all other lymphoma patients (8.8 versus 41.2% in all-PET patients, Pv < 0.01). VAHL rates were 10% in patients with negative serology, 31.3% in patients with low anti-spike titers, and 72.2% in patients with high anti-spike titers. The positive predictive values of VAHL were 90 and 93.3% in all-PET and PET-2 patients, respectively. A positive statistically significant correlation was found between VAHL and serology ranks in All-PET patients (rs = 0.530, Pv < 0.001), and stronger correlation was found in PET-2 patients (rs = 0.642, Pv < 0.001). Conclusion: VAHL on [18F]FDG PET-CT of patients with hematologic malignancy may reflect GC B cell proliferation and an effective humoral response elicited by BNT162b2 vaccine. [ABSTRACT FROM AUTHOR]

The article reports that A 23-year-old female with refractory diffuse large B-cell lymphoma was referred to chimeric antigen receptor T-cell (CAR-T) therapy (axicabtagene ciloleucel). Before infusion, FDG PET-CT (A) identified active supra-diaphragmatic nodal and hepatic disease (SUVmax 14.5). Nine days following infusion, enlarged cervical masses were palpated and the patient complained of worsening dyspnea.

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare disease with a dismal prognosis compared to its systemic large B-cell lymphoma counterpart. Real world data are limited, when considering a uniform backbone treatment. Methods: A retrospective study of all adult patients treated sequentially with a high-dose methotrexate (HD MTX)-based regimen in a single tertiary medical center between 2003 and 2019. Results: The 2015–2019 period differed from its predecessor in that most patients were treated with an HD MTX-based polychemotherapy regimen as opposed to HD MTX monotherapy (81% vs. 13%, P <.001), rituximab was given as standard of care (100% vs. 56%, P <.01), and most induction-responsive patients received consolidation treatment (70% vs. 18%, P =.01). The median progression-free and overall survival (OS) for the entire cohort (n = 73, mean age 64 years) was 9.9 and 29.8 months, respectively. Patients diagnosed between 2015 and 2019 had superior OS (P =.03) compared to those treated earlier. An interim partial response (PR) state, documented after two cycles of chemotherapy, was associated with increased incidence of progression, with only 33% of those patients achieving end-of-induction complete response. Twenty-three percent of patients developed thrombotic events and 44% developed grade 3–4 infections. HD MTX-based polychemotherapy induction was associated with both increase in thrombotic and infection incidence. Conclusions: Contemporary HD MTX-based combination therapies suggestively improved the outcomes for PCNSL, but at a cost of increased incidence of toxicity. Patients who achieve an interim PR status are at a high risk for treatment failure. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL), a disease of mostly young patients, also peaks in the elderly. Despite the profound improvement in the outcome of young patients, in the elderly, 5-year progression-free survival (PFS) rates are under 70%. Interim PET-CT (iPET) is known to be highly predictive for PFS in young HL patients, but it has not been sufficiently validated in the elderly patient population. In this multi-center collaboration, all consecutive elderly patients (age ≥ 60) diagnosed with HL between 1998 and 2016 were retrospectively reviewed. Baseline characteristics, outcome measures, and iPET results, classified according to the Deauville score, were recorded and analyzed. We identified 78 elderly HL patients (median age 69) who underwent iPET. ABVD was the treatment regimen in 52 (67%) patients. Eighty-three percent of patients had iPET scores of 1-3 while 17% had scores of 4-5. Patients with iPET scores of 1-3 had 5-year PFS and OS rates of 72% and 82% compared with 25% and 45%, respectively, in patients with scores of 4-5 (p < 0.001). Our findings show that iPET is highly predictive of outcome in elderly HL patients and provide evidence that iPET-guided therapy in this patient population may be key to achieving superior treatment outcome. [ABSTRACT FROM AUTHOR]

High-dose therapy followed by autologous hematopoietic cell transplantation (HCT) prolongs overall survival in patients under 65 years old with relapsed aggressive lymphoma. We aimed to explore the toxicity and efficacy of HCT in patients over 65 years with aggressive lymphoma compared with younger patients. We compared the transplantation outcomes between patients ≥ 65 years (n = 58) and 55-64 years (n = 44) with chemosensitive aggressive lymphoma (DLBCL, MCL and TCL) that underwent HCT between 1999 and 2016 in the Tel-Aviv Medical Center. The median age was 68 (range, 65-74) and 61 (range, 55-64) years, respectively. There were no differences in the incidences of grade 3-4 mucositis, documented infections and pulmonary complications between the two groups. There was no difference in the incidences of secondary malignancies, relapse (p = .26), non-relapse mortality, (p = .77) and overall survival (p = .53). Multivariate analysis revealed that smoking was a risk factor for non-relapse mortality, while partial remission and > 2 lines of treatment prior HCT were associated with higher risk for relapse. Psycho-socioeconomic score was associated with prolonged hospitalization after HCT and recurrent hospitalizations. We conclude that patients ≥ 65 years old with aggressive lymphoma, compared to younger counterparts, have similar transplantation outcome. Improving habits and psychosocial factors may further improve outcomes in these patients. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) cells depend on their microenvironment for proliferation and survival. Ectonucleotidase CD39 has anti-inflammatory properties as it hydrolyzes proinflammatory extracellular ATP, generates anti-inflammatory adenosine, and also protects regulatory T cells from ATP-induced cell death. In this study, we investigated the clinical significance of CD39 expression on CD4 T cells in 62 patients with CLL as well as its compartmental regulation and explored the possible mechanisms for its induction. Compared to healthy individuals, CD4CD39 lymphocytes were increased in the peripheral blood of patients with CLL and correlated with the advanced stage of disease. CD4CD39 cells were also higher in patients with CLL, who needed therapeutic intervention, and in those who had unmutated immunoglobulin heavy chain variable region gene, were ZAP70 or had β2-microglobulin levels of >3 g/L. There were more CD4CD39 lymphocytes in the bone marrow compartment than in the peripheral blood, and in vitro studies showed that CD39 can be induced on CD4 cells by exposure to ATP or indirectly, following B cell receptor engagement. This may support the notion that the leukemic cells contribute to create an immune-subversive environment, and perhaps to a poorer prognosis. CD39 may also serve as a future target for the development of novel therapies with immune-modulating antitumor agents in CLL. [ABSTRACT FROM AUTHOR]

Endotoxin stimulation of the immune system produces marked alterations in memory functioning. However, molecular links between this cognitive response and infection-responding neurotransmission pathways are still unknown. The cytokine and memory responses of volunteers injected with 0.8 ng/kg Salmonella endotoxin were compared with changes in plasma levels and integrity of the stress-induced acetylcholinesterase variant, AChE-R. Vascular endothelial cells were found to express AChE-R messenger RNA and protein both in healthy and inflamed human tissues. Plasma AChE activity was reduced after endotoxin treatment, but not placebo treatment, parallel to the decline in cortisol after the endotoxin-induced peak and inversely to the accumulation of a C-terminal immunopositive AChE-R peptide of 36 amino acid residues. AChE-R cleavage coincided with significant endotoxin-induced improvement in working memory and impairment in declarative memory. By 3 h posttreatment, working memory improvement was negatively correlated with AChE-R cleavage, which showed association to proinflammatory cytokine levels. By 9 h posttreatment, declarative memory impairment was negatively correlated with AChE-R cleavage and positively correlated with the suppressed AChE activity. Endotoxin-induced peripheral cholinergic stress responses are hence associated with greater impairment in declarative memory and lower improvement in working memory, pointing at AChE-R as a surrogate marker of psychoneuroimmunological stress. [ABSTRACT FROM AUTHOR]

To study the regulation of acetylcholinesterase (AChE) gene expression in human brain tumors, 3′ splice variants of AChE mRNA and potentially relevant transcription factor mRNAs were labeled in primary astrocytomas and melanomas. AChE-S and AChE-R mRNA, as well as Runx1/AML1 mRNA accumulated in astrocytomas in correlation with tumor aggressiveness, but neither HNF3β nor c-fos mRNA was observed in melanoma and astrocytomas. Immunohistochemistry demonstrated nuclear Runx1/AML1 and cellular AChE-S and AChE-R in melanomas, however, only AChE-S, and not the secreted AChE-R variant, was retained in astrocyte tumor cells. Runx1/AML1 revealed weak linkage with ACHE promoter sequences, yet enhanced ACHE gene expression in co-transfected COS1 cells. The p300 co-activator and the ACHE promoter's distal enhancer facilitated this effect, which was independent of much of the Runx1/AML1 trans-activation domain. Surprisingly, GASP, a fusion product of green fluorescence protein (GFP) and ASP67, a peptide composed of the 67 C-terminal amino acid residues of AChE-S, localized to COS1 cell nuclei. However, GARP, the corresponding fusion product of GFP with a peptide having the 51 C-terminal residues of AChE-E or GFP alone, remained cytoplasmic. Runx1/AML1 exhibited improved nuclear retention in GASP-expressing COS1 cells, suggesting modulated nuclear localization processes. Together, these findings reveal brain tumor-specific regulation of both expression and cellular retention of variant ACHE gene products.Oncogene (2002) 21, 8428–8441. doi:10.1038/sj.onc.1205945 [ABSTRACT FROM AUTHOR]