Jessica Hochberg

Tumor lysis syndrome: current perspective

Tumor lysis syndrome is characterized by a group of metabolic derangements caused by the rapid lysis of malignant cells. This condition can lead to acute renal failure and even death. The early recognition and treatment of metabolic abnormalities usually prevents the life threatening complications associated with tumor lysis syndrome. See related article on page 67.

Adolescent non-Hodgkin lymphoma and Hodgkin lymphoma: state of the science.

Lymphoma is the most common malignancy among adolescents, accounting for >25% of newly diagnosed cancers in the 15–19 year age group. Hodgkin lymphoma (HL) accounts for the majority (two‐thirds) of cases, while the remainder of patients have one of four subtypes of non‐Hodgkin lymphoma (NHL): diffuse large B‐cell lymphoma (DLBCL) including primary mediastinal B‐cell lymphoma (PMBL), Burkitt lymphoma (BL), lymphoblastic lymphoma (LL) or anaplastic large cell lymphoma (ALCL). Epidemiology, histology, treatment and outcome differ between HL and NHL, as well as among the various subtypes of NHL. Adolescent lymphoma is particularly interesting because it often shares features with both childhood and adult lymphoma. As medical oncologists and paediatric oncologists often follow divergent treatment plans, disagreements may arise between practitioners as to how best treat the adolescent group. Additional complicating factors associated with the adolescent years, such as lack of insurance, issues pertaining to body image, and concerns about fertility, can also hinder prompt, appropriate medical management. This review details the complexities associated with the diagnosis and treatment of adolescent lymphoma and updates the state of the science, with particular emphasis on epidemiology, diagnosis, and proper management of HL and the various subtypes of NHL.

Cardio-oncology issues among pediatric cancer and stem cell transplant survivors.

Improvements in the survival of children and adolescents diagnosed with cancer have resulted in a growing population of childhood, adolescent and adult cancer and stem cell transplant survivors. Approximately two thirds of these survivors will experience at least 1 late effect of their treatment, and about one third will experience a late effect that is severe or life threatening. Childhood cancer survivors are at high risk for development of severe cardiac disease, particularly after anthracycline and/or radiation exposure. Cardiotoxicity can present as early cardiac dysfunction during or shortly after therapy or as chronic impairment of cardiac function several years after treatment. Attempts to minimize serious adverse effects have included reduction of high-dose chemotherapy, particularly anthracycline dosing to <350 mg/m2, use of cardioprotective agents such as dexrazoxane and decreased radiation dosing and radiation fields. There have been no convincing data showing medical interventions that can reliably slow or reverse cardiotoxicity in treated patients, which therefore warrants further studies looking at the use of beta blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or newer agents either prior to or following the discovery of heart damage. Emphasis on the prevention of further damage is critical and can be accomplished through aggressive surveillance, including screening for lipid abnormalities, cardiac biomarkers such as troponins and B-type natriuretic peptides, hypertension, diabetes and obesity as well as the use of echocardiography and cardiac magnetic resonance imaging to identify abnormalities early in their course. Here, we provide an overview of the field of cardio-oncology to stimulate interest among cardiologists.

Safety of liposomal cytarabine CNS prophylaxis in children, adolescent and young adult hematopoietic stem cell transplant recipients with acute leukemia and non-Hodgkin lymphoma

Safety of liposomal cytarabine CNS prophylaxis in children, adolescent and young adult hematopoietic stem cell transplant recipients with acute leukemia and non-Hodgkin lymphoma

Ruxolitinib significantly enhances in vitro apoptosis in Hodgkin lymphoma and primary mediastinal B-cell lymphoma and survival in a lymphoma xenograft murine model

Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBL) share similar molecular features by gene expression profiling. Frequent gains of chromosome 9p exhibit higher Janus Kinase 2 (JAK2) transcript levels with increased JAK2 activity, suggesting aberrant activity of JAK2 and STAT pathways. This signaling pathway alteration may in part play an important role in the pathogenesis and/or chemoradiotherapy resistance in HL and PMBL. Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor, with activity against myeloproliferative neoplasms (MPNs) including those harboring the JAK2V617F mutation. We investigated the in vitro and in vivo efficacy of ruxolitinib and changes in downstream signaling pathways in HL and PMBL. We demonstrated that ruxolitinib significantly inhibited STAT signaling in both HL and PMBL with constitutively active JAK2 signaling. We also observed that ruxolitinib significantly induced in vitro anti-proliferative effects (p < 0.05) and increased programmed cell death (p < 0.05) against both HL and PMBL cells. Importantly, ruxolitinib significantly inhibited tumor progression by bioluminescence (p < 0.05) and significantly improved survival in HL (p = 0.0001) and PMBL (p < 0.0001) xenograft NSG mice. Taken altogether, these studies suggest that ruxolitinib may be a potential adjuvant targeted agent in the therapeutic approach in patients with high risk HL and PMBL.

The safety and efficacy of clofarabine in combination with high-dose cytarabine and total body irradiation myeloablative conditioning and allogeneic stem cell transplantation in children, adolescents, and young adults (CAYA) with poor-risk acute leukemia

Acute leukemias in children with CR3, refractory relapse, or induction failure (IF) have a poor prognosis. Clofarabine has single agent activity in relapsed leukemia and synergy with cytarabine. We sought to determine the safety and overall survival in a Phase I/II trial of conditioning with clofarabine (doses 40 – 52 mg/m2), cytarabine 1000 mg/m2, and 1200 cGy TBI followed by alloSCT in children, adolescents, and young adults with poor-risk leukemia. Thirty-seven patients; Age 12 years (1–22 years); ALL/AML: 34:3 (18 IF, 10 CR3, 13 refractory relapse); 15 related, 22 unrelated donors. Probabilities of neutrophil, platelet engraftment, acute GvHD, and chronic GvHD were 94%, 84%, 49%, and 30%, respectively. Probability of day 100 TRM was 8.1%. 2-year EFS (event free survival) and OS (overall survival) were 38.6% (CI95: 23–54%), and 41.3% (CI95: 25–57%). Multivariate analysis demonstrated overt disease at time of transplant (relative risk (RR) 3.65, CI95: 1.35–9.89, P = 0.011) and umbilical cord blood source (RR 2.17, CI95: 1.33–4.15, P = 0.019) to be predictors of worse EFS/OS. This novel myeloablative conditioning regimen followed by alloSCT is safe and well tolerated in CAYA with very poor-risk ALL or AML. Further investigation in CAYA with better risk ALL and AML undergoing alloSCT is warranted.

Abstract 2657: PD-L1 blockade enhances T cell cytotoxicity against primary mediastinal B cell lymphoma

Background: Primary Mediastinal B cell Lymphoma (PMBL) represents 2-4% of Non-Hodgkin Lymphomas (NHL) in adolescents and young adults (AYA) (Gerrard/Cairo et al., Blood, 2013). Disease progression, relapse and long-term toxicity remain a concern for patients treated on current chemo-immunotherapy and mediastinal radiotherapy. Alternative therapeutic regimens are urgently needed, especially in patients without an early response to therapy. Programmed Death 1 (PD-1) is a negative co-stimulatory receptor critical for suppression of T-cell activation, with binding of PD-1 and Programmed Death Ligand 1 (PD-L1) resulting in T cell exhaustion (Postow/Wolchok et al., J Clin Oncol, 2015). Gain in 9p associated with amplification of PD-L1 has been reported in up to 60% of PMBL specimens, leading to overexpression of PD-L1 and potential immune cell evasion of PMBL (Rosenwald/Staudt et al., J Exp Med, 2003; Twa/Steidl et al., Blood, 2014). Blockade of PD-1/PD-L1 interaction, therefore, constitute a potentially promising alternative for treatment of resistant PMBL. Objective: In the current study, we sought to investigate whether PD-L1 blockade enhances T cell responses in PD-L1 expressing PMBL. Methods: PD-L1 expression on Karpas 1106p PMBL treated with or without IFN γ was investigated by western blotting and flow cytometry analyses. T cells were isolated from human PBMC followed by activation and expansion using anti-CD2, anti-CD3 and anti-CD28 Biotinylated MACSiBead particles. T cell activation was confirmed by CD25 and CD69 expression using flow cytometry. Activated T cells were incubated with or without anti-PD-L1 (Clone 6E11, Genentech) at a dose of 10 ug/ml together with Karpas 1106p cells treated with or without IFN γ. Cell proliferation was assessed with MTS assays after incubation for 24 hours. Results: We demonstrated that Karpas 1106p cells express a low level of PD-L1. However, following IFN γ treatment (48 hours) there was a significant increase in PD-L1 expression. Anti-PD-L1 had no significant effect on T cell mediated inhibition of cell proliferation in Karpas 1106p cells with low PD-L1 expression. However, anti-PD-L1 and T cell treatment significantly inhibited cell proliferation in IFN γ treated Karpas 1106p cells when compared to T cell treatment alone (32±18% vs. 3±3% at E:T=5:1, p=0.048). Conclusion: PD-L1 blockade enhances T cell cytotoxicity against PMBL, which is dependent on PD-L1 expression level on PMBL cells. Future in-vivo NSG xenograft studies are ongoing. Citation Format: Tishi Shah, Wen Luo, Aradhana Awasthi, Janet Ayello, Jessica Hochberg, Mitchell Cairo. PD-L1 blockade enhances T cell cytotoxicity against primary mediastinal B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2657. doi:10.1158/1538-7445.AM2017-2657

75. Development of an LMP-Specific T Cell Bank for Third Party Use as a Curative Strategy Post-Transplant Lymphoproliferative Disease After Solid Organ Transplant

EBV-associated tumors in the immune deficient host express type II and III latency antigens including latent membrane protein 1 (LMP1) and LMP2, which can serve as potential targets for immunotherapy. Several studies have documented the safety and efficacy of LMP-specific T cells for patients with EBV-associated malignancies, but clinical applications may be limited by the time to generate LMP-specific T cell products as well as the availability of an appropriate donor source. We hypothesize that the administration of “off the shelf” third party LMP-specific cytotoxic lymphocytes (LMP-CTLs) will rapidly restore EBV-specific T-cell immunity and prevent relapse in patients with post-transplant lymphoproliferative disease PTLD post solid organ transplant (SOT). To develop the third party T cell bank, we manufactured healthy donor-derived LMP-specific T cells from eligible donors with a wide range of HLA types in our good manufacturing practices (GMP) facility. This T-cell bank is for several clinical trials including a proposed multicenter Childrens Oncology Group (COG) trial (ANHL1522) for patients with PTLD after SOT. Currently, 15 LMP-specific T-cell products have been manufactured from healthy donors and released for third-party use using autologous monocytes and lymphoblastoid cell lines (LCL), transduced with an adenoviral vector expressing ΔLMP1 and LMP2. T-cell products were active against LMP2 (mean:172 SFU/1×10^5 cells; range:13-655), LMP1 (33; 1-322), and LCL (87; 0-424) as determined by IFN-γ ELISPOT assay. Epitope mapping of LMP-specific T cells using IFN-γ ELISPOT assay demonstrates that these products recognize a broad epitope repertoire within LMP1 and LMP2. At the time of cryopreservation, the T-cell products comprised a mean of 45% CD8+ T-cells, 35% CD4+ T-cells, and 9% NK cells. No B cells or monocytes were detected in the final products. Thus far, one patient with NK/T cell non-Hodgkin Lymphoma received third party LMP-specific T cells achieving a very good partial response. No infusion-related toxicities were observed, and LMP-specific T cells were detectable post-infusion. Thus, third party LMP-specific T cells appear to be a safe and promising therapeutic modality for patients with EBV-associated lymphomas, and a third party bank will make this therapeutic more readily available to patients with PTLD post-SOT.