Imaging Biomarkers to Predict Outcomes in Patients With Large B-Cell Lymphoma With a Day 28 Partial Response by 18F-FDG PET/CT Imaging Following CAR-T Therapy.

BACKGROUND: CD19 directed CAR-T therapy for Large B-cell lymphoma (LBCL) has shown great therapeutic response in patients with relapsed/refractory disease with response rates of 60-80%. However, in patients with a partial response (PR) on initial day 28 post CAR-T therapy imaging, clinical uncertainty remains as half of these patients will ultimately have relapsed disease.   PATIENTS: In 24 patients receiving CD19 directed CAR-T therapy for relapsed/refractory LBCL achieving a PR on day 28, we utilize imaging biomarkers by 18F-FDG PET/CT imaging at pre CAR-T therapy baseline and day 28 to determine factors that may predict best overall response (B-OR), progression free survival (PFS), and overall survival (OS).   METHODS: Out of 75 patients receiving CAR-T therapy at a single institution, we retrospectively identified and reviewed 25 (33%) as achieving a PR on day 28. PR was defined using the 2014 Lugano classification system. All patients received standard of care CD19 directed CAR-T therapy with axicabtagene ciloleucel. Two independent nuclear medicine physicians measured baseline (pre-CAR-T therapy) and day 28 PET/CT SUVmax, SUVmean and TMV (cm3) of each lesion (node, organ or marrow uptake, if any) using ROVER software. All statistical tests were two-sided and conducted at the 0.05 level of significance. R version 1.3.1099 (R-studio) was used for statistical modeling.   CONCLUSION: We demonstrate that a higher day 28 SUVmax was significantly higher in those with a B-OR of PR and in our modeling, a lower day 28 SUVmax may predict favorable PFS and OS. Additionally, lower TMV, both at baseline and day 28, may also be predictive of longer PFS and OS, while lower TLG at baseline, but not day 28 is significantly associated with a B-OR of CR. While further study is warranted, these imaging biomarkers may allow for early identification of those with a day 28 PR at highest risk for relapse leading to early intervention to improve long term outcomes.

Combinatorial Efficacy and Toxicity of an Engineered Toxin Body MT-3724 with Gemcitabine and Oxaliplatin in Relapsed or Refractory Diffuse Large B Cell Lymphoma.

MT-3724 is an engineered direct-kill immunotoxin comprised of a CD20-specific scFv fused to a Shiga-like toxin subunit. In this phase IIa study, eight patients with relapsed diffuse large B-cell lymphoma were treated with MT-3724 combined with gemcitabine and oxaliplatin (GEMOX). The objective response rate was 85.7%, with a median duration of response of 2.2 months. The 12-month overall survival and progression-free survival were 71.4% and 28.6%, respectively. Two patients experienced grade 2 capillary leak syndrome (CLS). Combination therapy with MT-3724 and GEMOX demonstrated an early efficacy signal but was limited by the incidence of CLS.

Low utility of the H-Score and HLH-2004 criteria to identify patients with secondary hemophagocytic lymphohistiocytosis after CAR-T cell therapy for relapsed/refractory diffuse large B-Cell lymphoma.

Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation disorder. Use of chimeric antigen receptor T-cell therapy (CAR-T) is associated with cytokine release syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) and secondary HLH. However, application of HLH scoring systems (H-score, HLH-2004 criteria) are not validated in this setting. We analyzed the utility of applying the H-score and the HLH-2004 criteria to identify patients with possible HLH post-CAR-T for Relapsed/Refractory Diffuse Large B-cell Lymphoma. Only two of four patients with post CAR-T HLH met five or more of the diagnostic criteria for HLH by HLH 2004 criteria. In contrast all four post CAR-T HLH patients had a high H-score (>169); however, an additional ten patients that did not have HLH also had a high H-score. Thus, in this patient population, both scoring systems were demonstrated to have low prognostic significance in differentiating between high grade CRS and HLH.

The impact of bridging therapy prior to CD19-directed chimeric antigen receptor T-cell therapy in patients with large B-cell lymphoma.

In the relapsed/refractory setting for treatment of large B-cell lymphoma (LBCL), chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an effective treatment modality. Patients often have aggressive disease that requires prompt treatment in the form of bridging therapy (BT) for disease stabilisation while CAR-T cells are manufactured. Patients (n = 75) undergoing CAR-T therapy infusion for LBCL at our institution were identified. A total of 52 (69·3%) received BT and 23 (30·7%) received no BT (NBT). BT modalities included systemic BT (SBT) in 28 patients, radiation BT (RBT) in 14, and high-dose steroid BT (HDS) in 10. There was no difference in incidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome between BT and NBT (P = 0·18 and P = 0·53 respectively). Prolonged cytopenias at Day 180 were more common in BT than NBT (50% vs. 13·3%, P = 0·04). The SBT and RBT subgroups had more cytopenias at Day 180 compared to the HDS and NBT subgroups (58·3% and 57·1% vs. 20% and 13·3% respectively, P = 0·04). Disease response at last follow-up, progression-free survival and overall survival were similar between BT, NBT, and BT subgroups. In summary, BT can be safely considered in patients undergoing CAR-T therapy. However, those undergoing BT with SBT or RBT are at higher risk of prolonged cytopenias after CAR-T therapy.

Optimizing pegylated asparaginase use: An institutional guideline for dosing, monitoring, and management.

The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities. At the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, a standard of practice guideline was created to prevent and manage asparaginase-related adverse events. By sharing our long-term experience with asparaginase products and clinical management of asparaginase-induced toxicities, this article aims to improve patient safety and optimize treatment outcomes.

The Efficacy of Ketogenic Diet for Specific Genetic Mutation in Developmental and Epileptic Encephalopathy.

Objectives: Pathogenic mutations in developmental and epileptic encephalopathy (DEE) are increasingly being discovered. However, little has been known about effective targeted treatments for this rare disorder. Here, we assessed the efficacy of ketogenic diet (KD) according to the genes responsible for DEE. Methods: We retrospectively evaluated the data from 333 patients who underwent a targeted next-generation sequencing panel for DEE, 155 of whom had tried KD. Patients showing ≥90% seizure reduction from baseline were considered responders. The KD efficacy was examined at 3, 6, and 12 months after initiation. Patients were divided into those with an identified pathogenic mutation (n = 73) and those without (n = 82). The KD efficacy in patients with each identified pathogenic mutation was compared with that in patients without identified genetic mutations. Results: The responder rate to KD in the patients with identified pathogenic mutations (n = 73) was 52.1, 49.3, and 43.8% at 3, 6, and 12 months after initiation, respectively. Patients with mutations in SCN1A (n = 18, responder rate = 77.8%, p = 0.001), KCNQ2 (n = 6, responder rate = 83.3%, p = 0.022), STXBP1 (n = 4, responder rate = 100.0%, p = 0.015), and SCN2A (n = 3, responder rate = 100.0%, p = 0.041) showed significantly better responses to KD than patients without identified genetic mutations. Patients with CDKL5 encephalopathy (n = 10, responder rate = 0.0%, p = 0.031) showed significantly less-favorable responses to KD. Conclusions: The responder rate to KD remained consistent after KD in DEE patients with specific pathogenic mutations. KD is effective in patients with DEE with genetic etiology, especially in patients with SCN1A, KCNQ2, STXBP1, and SCN2A mutations, but is less effective in patients with CDKL5 mutations. Therefore, identifying the causative gene can help predict the efficacy of KD in patients with DEE.

Development of a hamster superovulation program and adverse effects of gonadotropins on microfilament formation during oocyte development.

OBJECTIVE: To establish a superovulation procedure for the golden hamster (Mesocricetus auratus) by elucidating gonadotropin effects on oocyte development. DESIGN: Randomized, prospective study. SETTING: University laboratory of embryology and gamete biotechnology. ANIMAL(S): Twelve- to 15-week-old female and sexually mature male hamsters. INTERVENTION(S): Different doses of pregnant mare serum gonadotropin (PMSG) were injected into female hamsters in metestrus, diestrus, or proestrus. The same dose of hCG was injected 56 hours later. MAIN OUTCOME MEASURE(S): Embryo development and oocyte morphology after treatment. RESULT(S): First, 10 IU or 15 IU each of PMSG and hCG was injected into 10 hamsters weighing <110 or 110-130 g, respectively. All hamsters were mated, but none delivered live young after injection. Second, the doses of 15 IU, 7.5 IU, 5 IU, or 0 IU of each gonadotropin were injected into each hamster (regardless of body weight, 5 per each group). Increasing numbers of embryos were retrieved as the dosage was increased (11.2 to 46.6 embryos per hamster), whereas the percentage of two-cell embryos at retrieval was significantly decreased (100% to 3%, P<.05). In subsequent culture, none developed to blastocysts after 15-IU injection, whereas 47%, 55%, and 70% of two-cell embryos developed after 7.5-IU, 5-IU, and 0-IU treatments, respectively. As a result, females injected with 5 IU yielded more blastocysts than did females without injection (67 vs. 39). The number of inner cell mass cells per blastocyst was greatly increased in the control groups compared with the 5-IU and 7.5-IU treatment groups (22 vs. 14.3-14.7 cells per blastocyst). Third, the ultrastructure of oocytes was examined after injecting 5 IU each of PMSG and hCG (regardless of body weight). Superovulation did not affect oocyte maturation, but different patterns in microfilament formation were detected after the treatment. CONCLUSION(S): Female hamsters can be superovulated effectively by injecting equal amounts of PMSG and hCG, 56 hours apart. However, embryo development was adversely affected in a dose-dependent manner at all doses of gonadotropins, and microfilament distribution was affected by such treatment.