Patrick M. Reagan

Approach to Diagnosis and Treatment of Hypercalcemia in a Patient With Malignancy

Hypercalcemia is a common complication of malignancy and portends a worse prognosis. It causes a variety of symptoms in patients, which can range from confusion and polyuria to coma and death. There are 4 broad mechanistic categories to classify hypercalcemia of malignancy: local osteolysis secondary to metastatic cancer or multiple myeloma, excess parathyroid-related hormone, excess 1,25-dihydroxyvitamin D production, and ectopic parathyroid hormone production. Volume expansion with normal saline solution and treatment with intravenous bisphosphonates to decrease osteoclast-mediated bone destruction are effective initial therapies. Calcitonin, gallium nitrate, and corticosteroids can serve as adjunctive therapies. Denosumab is an attractive therapeutic option for refractory cases of hypercalcemia, although more data are required before this therapy can be recommended.

Chemosensory responses to CO2 in multiple brain stem nuclei determined using a voltage-sensitive dye in brain slices from rats.

We used epifluorescence microscopy and a voltage-sensitive dye, di-8-ANEPPS, to study changes in membrane potential during hypercapnia with or without synaptic blockade in chemosensory brain stem nuclei: the locus coeruleus (LC), the nucleus of the solitary tract, lateral paragigantocellularis nucleus, raphé pallidus, and raphé obscurus and, in putative nonchemosensitive nuclei, the gigantocellularis reticular nucleus and the spinotrigeminal nucleus. We studied the response to hypercapnia in LC cells to evaluate the performance characteristics of the voltage-sensitive dye. Hypercapnia depolarized many LC cells and the voltage responses to hypercapnia were diminished, but not eradicated, by synaptic blockade (there were intrinsically CO2-sensitive cells in the LC). The voltage response to hypercapnia was substantially diminished after inhibiting fast Na+ channels with tetrodotoxin. Thus action potential-related activity was responsible for most of the optical signal that we detected. We systematically examined CO2 sensitivity among cells in brain stem nuclei to test the hypothesis that CO2 sensitivity is a ubiquitous phenomenon, not restricted to nominally CO2 chemosensory nuclei. We found intrinsically CO2 sensitive neurons in all the nuclei that we examined; even the nonchemosensory nuclei had small numbers of intrinsically CO2 sensitive neurons. However, synaptic blockade significantly altered the distribution of CO2-sensitive cells in all of the nuclei so that the cellular response to CO2 in more intact preparations may be difficult to predict based on studies of intrinsic neuronal activity. Thus CO2-sensitive neurons are widely distributed in chemosensory and nonchemosensory nuclei and CO2 sensitivity is dependent on inhibitory and excitatory synaptic activity even within brain slices. Neuronal CO2 sensitivity important for the behavioral response to CO2 in intact animals will thus be determined as much by synaptic mechanisms and patterns of connectivity throughout the brain as by intrinsic CO2 sensitivity.

Follicular Lymphoma: First-Line Treatment Without Chemotherapy for Follicular Lymphoma

Opinion StatementThe optimal initial treatment of follicular lymphoma (FL) is not known, and initial management of patients varies considerably between providers and institutions. The assertion that patients with low tumor burden can be observed for a period of time is being challenged owing to the safety and tolerability of novel therapeutics and the movement of the field away from traditional chemotherapy agents. Single agent rituximab has become increasingly popular as initial management of patients with low tumor burden disease, and there is evidence that prolonged treatment with rituximab can improve progression-free survival (PFS) when compared to induction with rituximab or observation. Radioimmunotherapy (RIT) has similarly shown efficacy in low tumor burden disease. Novel agents such as lenalidomide, idelalisib, and ibrutinib are being studied in the first-line setting. Importantly, none of these strategies have demonstrated an improved overall survival in a randomized study versus observation. It is the opinion of the authors that endpoints such as PFS alone, while important, should not drive changes in management with limited resources. Composite endpoints including quality of life are more informative on the true impact of treatments on patients with follicular lymphoma. Providers should encourage all patients to be treated in the context of an appropriate clinical trial when possible. If a patient is not a clinical trial candidate, we typically treat patients with advanced stage and high tumor burden with chemoimmunotherapy. The decision to give maintenance rituximab is individualized to the patient, as there is no overall survival benefit. In patients with early stage disease, we favor consideration of radiation therapy if the patient is a candidate. Our initial recommendation to patients with advanced stage, low tumor burden disease, is close observation or “watch and wait.” We have observed that most patients become comfortable over time with an observation approach. If a patient is not comfortable with this recommendation, we will use single agent rituximab. If the patient responds to therapy, we do not recommend maintenance rituximab in low tumor burden disease but rather prefer a retreatment strategy or an extended schedule of four additional doses of rituximab.

Advancing radioimmunotherapy and its future role in non-Hodgkin lymphoma

Radioimmunotherapy is an effective treatment modality with an acceptable toxicity profile in both indolent B-cell non-Hodgkin lymphoma and histologic transformation. Its ease of administration from a patients perspective sets it apart from chemoimmunotherapy regimens. It has demonstrated efficacy in a range of different treatment scenarios. Despite its promise as a treatment modality, radioimmunotherapy has been seldom used, and one of the previously available agents is now off the market. Radioimmunotherapy has shown impressive activity in both the relapsed and upfront settings in follicular lymphoma, histologic transformation, as consolidation after chemotherapy, and in conjunction with high-dose chemotherapy and autologous stem cell support. Future efforts should focus on its optimal employment in the upfront setting for follicular lymphoma as well as further investigation of the promising activity in histologic transformation.

In Situ Vaccination with a TLR9 Agonist and Local Low-Dose Radiation Induces Systemic Responses in Untreated Indolent Lymphoma

This multicenter phase I/II clinical trial evaluated intratumoral SD-101, a TLR9 agonist, and low-dose radiation in patients with untreated indolent lymphoma. Twenty-nine enrolled patients received 4 Gy of radiation followed by 5 weekly intratumoral injections of SD-101 at a single tumor site. No treatment-related grade 4 or serious adverse events occurred. Nearly all patients had tumor reduction at their treated site. More importantly, 24 patients had tumor reduction at their nontreated sites, with 5 patients achieving a partial response and one achieving a complete response. Treatment-related increases of CD8+ and CD4+ effector T cells and decreases of T follicular helper and T regulatory cells (Treg) were observed in the tumor microenvironment. Low pretreatment levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells were associated with favorable outcomes. Intratumoral SD-101 in combination with low-dose radiation is well tolerated and results in regression of both treated and untreated sites of disease.Significance: In situ vaccination with the TLR9 agonist SD-101, along with low-dose radiation, was safe and induced systemic responses in patients with indolent lymphoma. Low levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells in the tumor microenvironment predicted favorable response to treatment. Cancer Discov; 8(10); 1258-69. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195.

Abstract CT020: Immune signatures of cytokine release syndrome and neurologic events in a multicenter registrational trial (ZUMA-1) in subjects with refractory diffuse large B cell lymphoma treated with axicabtagene ciloleucel (KTE-C19)

Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy. ZUMA-1 is a multicenter registrational trial of axi-cel in patients with refractory, aggressive B-cell non-Hodgkin lymphoma. In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with a 76% objective response rate and 47% complete response. The incidence of Grade 3 and higher (Gr 3+) cytokine release syndrome (CRS) and neurologic events (NE) was 13% and 29%, respectively, in 93 patients with 1 month follow-up (Neelapu ASH 2016). We present novel immune signatures of Gr 3+ CRS and NE by analyzing the axi-cel-related biomarker profile in association with clinical outcomes. Methods: In this interim analysis of 62 patients, 44 serum analytes pre- and post-axi-cel treatment were measured via ELISA at multiple timepoints during the first month. The number of CAR+ cells in blood was determined by qPCR. Kinetics and association of these markers with CRS and NE were analyzed. The treatment-related profile was defined by analytes with at least double an increase over baseline in at least 50% of patients. These analytes were selected and evaluated for association with Gr 3+ CRS or NE. Immune signatures were determined based on p-values applied to peak or cumulative levels of analytes and adjusted for multiplicity (stepdown method). Results: Out of 44 analytes measured, 12 demonstrated an increase by double over baseline in at least 50% of patients. This axi-cel-related biomarker profile includes immune proliferative/modulating cytokines, pro-inflammatory cytokines, markers of myeloid activation, and chemokines. Markers with the highest median-fold increase were IFNγ (44x), IL-10 (31x), IL-6 (26x), IL-15 (20x), and GRZB (17x). These peaked within 7-14 days and generally returned to baseline within 1 month post-treatment. Within this panel of 12 analytes elevated post-axi-cel treatment, markers associated with Gr 3+ CRS (p Citation Format: Frederick L. Locke, John Rossi, Xiaodong Xue, Sattva S. Neelapu, Daniel H. Ryan, Armin Ghobadi, Lazaros J. Lekakis, David Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Patrick M. Reagan, Marika Sherman, Janice Nagatani, Xiao Zhang, Lynn Navale, William Y. Go, Jeff Wiezorek, Adrian Bot. Immune signatures of cytokine release syndrome and neurologic events in a multicenter registrational trial (ZUMA-1) in subjects with refractory diffuse large B cell lymphoma treated with axicabtagene ciloleucel (KTE-C19) [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 CT020. doi:10.1158/1538-7445.AM2017-CT020

Complications Associated with Dose-Adjusted EPOCH-Rituximab Therapy for Non-Hodgkin Lymphoma.

Introduction: Certain aggressive non‐Hodgkin lymphoma subtypes are increasingly being treated with infusional DA‐EPOCH‐R (dose‐adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), which requires a central venous catheter. This study aims to identify the rates and predictors of line‐associated complications (LACs) associated with DA‐EPOCH‐R therapy in NHL. Patients and Methods: We retrospectively identified all patients treated with DA‐EPOCH‐R at our institution between March 2011 and July 2016. We also identified a concurrent cohort of patients with diffuse large B‐cell lymphoma treated with R‐CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Results: Forty‐three patients received DA‐EPOCH‐R during the study period; 17 (39.5%; 95% confidence interval, 0.25‐0.56) patients experienced at least 1 LAC (including venous thromboembolism, chemotherapy extravasation, and line‐associated infection). Forty‐four patients received R‐CHOP during the study period; 8 (18.2%; 95% confidence interval, 0.08‐0.32) patients experienced at least 1 complication. Compared with the R‐CHOP cohort, patients treated with DA‐EPOCH‐R experienced a significantly higher rate of these complications (P = .03). In the DA‐EPOCH‐R cohort, grade 3 toxicity was seen in 41% (7/17). In univariate analysis, body mass index ≥ 35 kg/m2 and using a peripherally inserted central catheter line were significantly associated with an increased risk of venous thromboembolism (P = .04 and P = .02, respectively). Conclusions: Forty percent of patients receiving DA‐EPOCH‐R therapy developed LACs, almost one‐half of whom experienced grade 3 toxicities. The complication rate was significantly greater in patients undergoing therapy with DA‐EPOCH‐R compared with those undergoing R‐CHOP therapy. Clinicians need to balance these risks when selecting therapy. Future studies are needed to evaluate prophylactic anticoagulation strategies in this population.

Poor survival with high-dose chemotherapy and autologous stem cell support in double-hit and double-expressor B-cell lymphomas

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease both in biology and clinical behavior. Approximately two thirds of patients achieve prolonged disease free survival and cure after induction with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemoimmunotherapy (1). Much of the research in the field has been devoted to characterizing the biology of those with progressive disease or who ultimately relapse. Aberrations of MYC , BCL2 and BCL6 have been implicated in a proportion of these cases and include both translocations involving these genes as well as abnormal protein expression of MYC and BCL2. In recognition of the unique clinical behavior of translocations involving MYC , BCL2 and BCL6 , a provisional entity of high grade B-cell lymphoma (HGBL) with rearrangements of MYC and BCL2 and/or BCL6 has been included in the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms (2). These have been referred to as double-hit lymphomas (DHL), or in the case of DLBCL with co-expression of MYC and BCL2, double-expressor lymphomas (DEL).

Current treatment of double hit and double expressor lymphoma

A 60-year-old female presented with abdominal pain and distension. Following computed tomography scans of the abdomen and pelvis, she was taken urgently to the operating room, with the belief that she had appendicitis with perforation. At laparotomy, the findings were consistent with an ovarian carcinoma; there was extensive infiltration of the ovary, bowel, and omental deposits. Cytoreductive surgery was performed including total abdominal hysterectomy and bilateral salpingo-oophorectomy. The final pathology, however, revealed infiltration with medium-sized atypical lymphoid cells positive for CD20, CD10, MYC, BLC2, and BCL6 by immunohistochemistry. MYC and BCL2 translocations were identified by fluorescence in situ hybridization consistent with a diagnosis of high-grade B-cell lymphoma with rearrangements of MYC and BCL2 With the current data available, what is the optimal treatment of this patient?

HIGH-RISK PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA ARE NOT ENROLLED ON CLINICAL TRIALS

taneous occurrence of DLBCL and FL (DLBCL/FL) in the same lymph node (LN). These pts are treated as DLBCL. The outcome of these pts was not described yet, and these pts are usually excluded from DLBCL and FL trials. Methods: Data of newly diagnosed pts have been prospectively collected in the Lymphoma Project NiHiL since 1999. Altogether, 201 DLBCL/FL pts diagnosed in 2002 to Jan 2016 were confirmed by histopathological review. The percentage of DLBCL and FL components was established. The clinical characteristics, treatment and outcome were analysed. Two comparator groups were selected, the DLBCL patients of GC subtype (Hans algorithm) (n 304, dg 2005 to Jan 2016) and FL pts (n 1420, dg 2005 to Jan2016), both groups treated by Rituximab (R) chemo. Outcome of these subgroups was compared by logrank test. Results: Out of 201 DLBCL/FL pts, grade of FL part was evaluated as G1‐G3A in 87 (43.3%), G3B in 89 (44.3%) and G3 without specification in 25 (12.4%). The proportion of DLBCL component was ≥50% in 105 pts (55.9%). The median age was 61 years (29 to 97) and male/female ratio 1.12/1. The IPI score was low and lowintermed (LI) vs highintermed (HI) and high in 58.7% vs 41.3% resp. The FLIPI score was good, intermed and high in 33.0%, 21.0% and 46.0% resp. R was used in 181 pts (87.9%), CHOP in 166 (82.6%) and other chemo in 35 (17.4%) pts. The OS and PFS probability at 5 years was 77.2% and 66.4% resp. with median follow‐up 5.6 year. The DLBCL GC comparator group had median age 64.5 years (19 to 88), HI and high risk IPI was found in 47.8% pts. The FL comparator group had median age 59 years (27 to 90); FLIPI good, intermed and high risk score were in 22.2%, 29.3% and 48.5% resp. The cohorts were not different from the DLBCL/FL group in terms of patients characteristic. The 5‐year OS probability for DLBCL/FL1‐3A, DLBCL/FL3B, DLBCL GC and FL cohorts were 76.1%, 81.8%, 79.9% and 86.5% resp. (p = 0.001; Figure 1). The 5‐year PFS probability for DLBCL/FL1‐3A, DLBCL/ FL3B, DLBCL GC and FL cohorts were 63.3%, 71.8%, 71.6% and 62.8% resp. (p = 0.14). FL had statistically better outcome for OS. RM was used in 20 pts, in both subgroups DLBCL/FL1‐3A (n 10) as well as DLBCL/FL3B (n 8) and DLBCL/FL 3 (n 2). When compared to pts without RM, there was identified a trend for better PFS in RM cohort with 5‐year PFS 89.5% vs cohort w/o RM with 5‐year PFS 74.4% (p = 0.15; Figure 2). Forty‐six relapses in DLBCL/FL pts were observed, 19 pts with histological verification of relapse. Out of these, 7 pts (36.8%) relapsed as DLBCL, 6 (32.0%) as FL, 5 pts (10.8%) as DLBCL/FL and 1 pts into B NHL. Conclusions: Our analysis shows that DLBCL/FL behaves as GC DLBCL with the same OS probability. RM for patients with DLBCL/ FL G1‐G3A might improve the outcome, but more data are needed. Supported by grant of Ministry of Health of the Czech Republic MZ VES 16‐31092A.