Kelley V. Foyil

Anti-CD30 Antibodies for Hodgkin Lymphoma

Treatment of refractory or relapsed classical Hodgkin lymphoma (HL) remains challenging, but targeted immunotherapy has recently emerged as a potential treatment option for these patients. Although first-generation monoclonal anti-CD30 antibodies proved disappointing, current efforts to modify anti-CD30 antibodies to improve binding of effector cells and enhance activity appears more promising, as does the development of novel antibody-drug conjugates (ADCs). ADCs offer the potential to deliver potent therapies with minimal toxicity. One highly active ADC, brentuximab vedotin (SGN-35), combines an anti-CD30 monoclonal antibody and the antitubulin agent monomethyl auristatin E. Initial phase 1 studies of brentuximab vedotin showed a 52% overall response rate in relapsed HL, with minimal toxicity. This article highlights the development of anti-CD30 antibodies and ADCs for relapsed or refractory classical HL.

Longterm Changes in Creatinine Clearance after Laparoscopic Renal Surgery

BACKGROUND Controversy exists about the impact of ischemia on renal function. We evaluated the creatinine clearance of patients having undergone laparoscopic renal extirpative and ablative surgery. STUDY DESIGN The records of patients undergoing laparoscopic procedures for renal masses from February 2000 to March 2004 were examined. Creatinine clearance (CrCl) for each patient was determined using the Cockcroft-Gault equation and ideal body weight. We compared CrCl changes of patients undergoing laparoscopic partial nephrectomy (without renal ischemia [LPN-none], with warm ischemia [LPN-warm], and with cold ischemia [LPN-cold]) with patients undergoing laparoscopic radical nephrectomy (LRN) and laparoscopic cryoablation. Patients predisposed to medical renal disease were substratified and evaluated. RESULTS All patients who underwent LRN or LPN-warm sustained a significant drop in CrCl on the first postoperative day, compared with patients who had LPN without ischemia or cryoablation (p < 0.01). The CrCl decrease correlated directly with warm ischemia time. Six months postoperatively, CrCl changes were no longer significant. Patients with medical renal disease risk factors were more likely to sustain longterm (1 year postoperatively) renal damage if they had renal ischemia, trending toward statistical significance. CONCLUSIONS Ischemia causes acute renal damage, which is apparently reversible in patients without evidence of medical renal disease. Patients with known medical renal disease have substantial longterm changes in renal function associated with unilateral renal ischemia. Considering the insensitivity of creatinine-based renal function metrics, only eliminating ischemic time will realize the goal of maximal nephron preservation, particularly in patients with preexisting medical renal disease.

Optical Mapping of the Human Atrioventricular Junction

Fluorescent optical mapping of cardiac electrophysiology in animal models has produced a wealth of information about the function of the cardiac pacemaking and conduction system. However, expanding optical mapping studies to the human conduction system will significantly increase our understanding of clinically relevant phenomena, such as atrioventricular nodal reentrant tachycardia, that are difficult to fully reproduce in animal models. In this report, we present the first instance of optical mapping data recorded from the human atrioventricular junction, revealing its dual pathway electrophysiology, which is the basis of atrioventricular nodal reentrant tachycardia. Explanted human hearts (n=2) were obtained at the time of cardiac transplantation and perfused with cardioplegic solution. The atrioventricular junction was cannulated, isolated from the rest of the heart, immobilized with the excitation-contraction uncoupler blebbistatin (10 μmol/L),1 and optically mapped using the voltage sensitive dye Di-4-ANEPPS and a 16×16 photodiode array. In the first heart, explanted because of idiopathic cardiomyopathy, successful perfusion of the His bundle and ventricular septum, but not the atrioventricular (AV) node, was achieved. In this preparation, a junctional rhythm of 55 bpm originated from the His bundle (Figure 1). Optical action potentials (OAPs) from the His displayed diastolic depolarization and a slow upstroke with the maximum derivative of the fluorescent signal dF/dtmax=2.8±0.5 U/s. Pacing the surrounding working ventricular myocardium produced a sharper upstroke (dF/dtmax=37±11, P <0.001 versus His OAPs) and longer action potential duration (APD) than the His (APD80: 315±23 ms in His versus 410±3ms in ventricle, P <0.001). The activation map of the His junctional rhythm demonstrated slow conduction (7 cm/s) transversely along the His bundle (Figure 1). These data provide the first optical recordings of the human His bundle. Figure 1. Junctional rhythm in the His bundle with schematic of the atrioventricular junction shown in the …

Brentuximab vedotin for the treatment of CD30+ lymphomas

Brentuximab vedotin is a novel antibody-drug conjugate consisting of the anti-CD30 antibody cAC10 chemically conjugated to monomethylauristatin E, a potent antimicrotubule agent. Preliminary response rates of 75% in relapsed/refractory Hodgkins lymphoma and 87% in relapsed/refractory systemic anaplastic large-cell lymphoma were recently reported in large Phase II trials. Brentuximab vedotin is well tolerated with manageable side effects including peripheral sensory neuropathy. This antibody-drug conjugate is currently under investigation in numerous clinical trials, including in combination with front-line chemotherapy for high-risk Hodgkins lymphoma and in a placebo-controlled, Phase III trial for patients with Hodgkins lymphoma at high risk for residual disease following autologous stem cell transplant. The impressive response rates and limited toxicity of brentuximab vedotin are very promising for relapsed/refractory patients with few treatment options. In addition, the possibilities for incorporation into front-line therapies for both Hodgkins lymphoma and systemic anaplastic large-cell lymphoma are intriguing.

CD163 Immunohistochemistry Is Superior to CD68 in Predicting Outcome in Classical Hodgkin Lymphoma

OBJECTIVES In recent years, research has increasingly focused on the microenvironment of classical Hodgkin lymphoma (CHL) as a predictor of treatment outcome. The focus of this study was to assess the interobserver reproducibility in interpreting macrophage-associated immunohistochemistry (IHC) for CD68 and CD163 in a retrospective cohort of 88 patients with CHL. METHODS Staining results were correlated with clinical outcome in all patients and those with a high international prognostic score (IPS). RESULTS The intraclass correlation (ICC) for the five hematopathologists interpreting the IHC was stronger for CD163 (0.70) than for CD68 (0.50). Using a cutoff of 25% mean macrophage reactivity and including all patients, a statistically significant difference in overall survival (OS) was seen only for CD163 (P = .0006) and not for CD68 (P = .414). Patients with a mean CD163 reactivity of 25% or more had a median OS of 71 months vs 101 months for patients with less than 25% reactivity. CD163 retained statistical significance in multivariate analysis. In patients with advanced-stage CHL with high IPS, OS was also significantly worse for those with a mean CD163 reactivity of 25% or higher. CONCLUSIONS Our study confirms previous reports of a prognostic role of tumor-infiltrating macrophages in CHL, but only for CD163. Although most of the literature supports an increasing role of macrophage IHC as a predictor of clinical outcome, successful clinical translation will require a standardized method and reporting system.

Brentuximab vedotin and crizotinib in anaplastic large-cell lymphoma.

Abstract Systemic anaplastic large-cell lymphoma (ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. Anaplastic large-cell lymphoma cells express the surface antigen CD30, and more than half express the anaplastic lymphoma kinase (ALK) protein. These 2 proteins provide unique therapeutic targets in ALCL. Remission rates in ALCL with combination chemotherapy are approximately 80%, but relapse after first-line therapy is common. Brentuximab vedotin is a US Food and Drug Administration–approved, antibody-drug conjugate that combines an anti-CD30 antibody with monomethylauristatin E, a potent antimicrotubule agent. Response rates to brentuximab vedotin in patients with relapsed/refractory ALK+ and ALK− ALCL have exceeded 80% with frequent complete responses and a median duration of response greater than 1 year. Brentuximab vedotin in combination with chemotherapy is being explored as a first-line therapy in ALCL. Crizotinib is an inhibitor of ALK tyrosine kinase that has been approved for the treatment of ALK+ non–small cell lung cancer. Successful treatment of ALK+ ALCL with crizotinib has been reported in pediatric patients and small case series leading to ongoing trials in relapsed/refractory ALCL. Brentuximab vedotin and crizotinib represent major advances in the treatment of ALK+ and ALK− ALCL and will likely result in marked improvement in prognosis for this subset of aggressive lymphomas.

Rituximab is associated with improved survival in Burkitt lymphoma: a retrospective analysis from two US academic medical centers

Background: Burkitt lymphoma (BL) is a rare, highly aggressive B-cell malignancy treated most successfully with brief-duration, high-intensity chemotherapeutic regimens. The benefit of the addition of rituximab to these regimens remains uncertain. We sought to examine the effectiveness of chemotherapy with and without rituximab in patients with BL. Methods: This study is a retrospective cohort study of all adult patients with BL diagnosed and treated with modern, dose-intense chemotherapeutic regimens from 1998–2008 at two tertiary care institutions. All cases were confirmed by application of WHO 2008 criteria by hematopathologists. Medical records were reviewed for patient-, disease-, and treatment- related factors as well as treatment response and survival. Factors associated with survival were analyzed using Cox proportional hazards modeling. Results: A total of 35 patients were analyzed: 18 patients received rituximab with chemotherapy (R-chemo) and 17 received chemotherapy (chemo) alone. The median age was 42 (range 20–74 years); 57% were male; 71% had Ann Arbor Stage IV disease; 33% had central nervous system involvement; 78% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. R-chemo was associated with significantly longer overall survival (OS) than chemo alone (5-year OS 70% and 29%, respectively, p = 0.040). On multivariate regression analysis, poor performance status and central nervous system involvement were associated with poorer survival. Conclusions: The addition of rituximab to chemotherapy was associated with improved OS in patients with Burkitt lymphoma. Poor performance status and central nervous system involvement were prognostically significant on multivariate analysis.

Pulmonary vein isolation and the Cox maze procedure only partially denervate the atrium.

OBJECTIVES The effects of ablation lines on myocardial innervation and response to autonomic stimuli are unclear. This study examined the effects of radiofrequency ablation on atrial autonomic innervation and compared pulmonary vein isolation and the biatrial Cox maze procedure. METHODS In 12 acute canines right and left vagosympathetic trunks and right and left stellate ganglia were isolated. Each nerve was stimulated before bipolar ablation, after pulmonary vein isolation, and after the Cox maze procedure. Nadolol (n = 6) and atropine (n = 6) were administered to block sympathetic and parasympathetic responses, respectively. Changes in heart rate and atrioventricular interval were compared. Changes in QRST area relative to an isoelectric baseline (index of local innervation) were calculated. RESULTS Sympathetic stimulation of each nerve and parasympathetic stimulation of the vagosympathetic trunks caused significant changes in heart rate and atrioventricular interval. After pulmonary vein isolation, the effect of 33% of the nerves on heart rate changes was eliminated. The Cox maze procedure eliminated right stellate sympathetic effects on heart rate. Fifty percent of the nerves caused heart rate changes after the Cox maze procedure. There was no significant effect of either lesion set on atrioventricular interval changes. Stimulation of 50% of nerves after pulmonary vein isolation produced local area changes significantly different from control area. After the Cox maze procedure, a different 50% of the nerves produced local changes different from those seen after pulmonary vein isolation. CONCLUSIONS Surgical ablation procedures disrupted innervation, affecting heart rate but not atrioventricular interval. Autonomic innervation affecting the atria was changed by pulmonary vein isolation and additionally by the Cox maze procedure. Residual autonomic effects were present even after the complete Cox maze procedure.

Expression of TIA1 and PAX5 in Classical Hodgkin Lymphoma at Initial Diagnosis May Predict Clinical Outcome.

Although the expression of T-cell antigens and proteins associated with tumor-infiltrating T-lymphocytes (TILs), regulatory T cells (T-regs), and B-cell development have been evaluated in classical Hodgkin lymphoma (cHL), few studies correlate these proteins’ expression patterns with clinical outcome. The purpose of this study was to evaluate proteins expressed in the Reed-Sternberg cells (RSCs) and TILs of cHLs at initial diagnosis to determine their prognostic significance. The expression of 12 proteins in RSCs and TILs from 88 diagnostic cHL biopsies was quantitated and correlated to overall survival (OS) and progression-free survival (PFS). CD2, CD3, CD4, CD5, CD7, CD25, PD1, TIA1, MUM1, and ZAP70 expression in RSCs did not correlate with OS or PFS, nor did programmed death 1 (PD1) expression in TILs. High numbers of TIA1-positive TILs (≥50%) correlated with OS (P=0.027), but not PFS (P=0.993) in univariate analysis. Expression of CD2, CD3, CD4, CD5, and/or TIA1 (6%) in RSCs was associated with lymphocyte-rich/mixed-cellularity subtype (P=0.032). High International Prognostic Score (IPS; P=0.036), and high stage (P=0.046) were independent predictors of worse PFS in univariate analysis. Low IPS (P=0.003) and nodular sclerosing subtype (P=0.022) were associated with better OS in univariate analysis. Only the IPS predicted OS in multivariate (P=0.009) analysis. High TIA1+ TILs correlated with worse clinical outcomes for cHLs, as did PAX5-RSCs (P=0.024), although only 2/74 cases were shown to be negative for this marker, suggesting that the tumor microenvironment and a transcription factor crucial for B-cell development are critical biological determinants of the disease course.

Solid, Low-Attenuation Splenic Lesions on Computed Tomography in Patients With Indolent Lymphoma Often Signal Transformation: A Series of Ten Patients

Introduction Transformation to aggressive large-cell lymphoma occurs in nearly 30% of patients with indolent lymphoma, most commonly in those with a follicular histologic type. Typically, transformation is considered when there is rapid growth of a lymph node, involvement of an unusual extranodal site, elevated lactate dehydrogenase (LDH) levels, hypercalcemia, or the presence of B symptoms (fever, night sweats, weight loss). However, up to 20% of patients with follicular lymphoma (not transformed) will present with B symptoms and/or elevated LDH levels. Patients may lso present with unusual radiographic findings, such as solid, ow-attenuation lesions in the spleen. Herein we report our instiutional experience with patients with indolent lymphoma preenting with solid low-attenuation splenic lesions.