Faculty Bibliography

Introduction: Natural Killer cells (NKC) play an important role in tumor immune-surveillance. AFM13 is a CD30/CD16A targeting high affinity bispecific tetravalent antibody that engages and activates NKC. This study evaluates AFM13 clinical and immunological activity. It examines the immunologic changes in the tumor and peripheral blood (PB) as a function of the dose and method of administration of AFM13 over time.
Method(s): Subjects with relapsed or refractory CD30 expressing lymphoma with cutaneous involvement were recruited into 3 cohorts: 1.5 mg/kg IV weekly, 7 mg/kg IV weekly and 7 mg/kg continuous intravenous infusion (CIVI) over 5 days weekly. Each cohort consisted of 3 patients. Subjects received 8 weeks of therapy each cycle. Response assessment was performed on week 11 of each cycle by mSWAT, photography, PET imaging and PB flow cytometry. A 2nd cycle was administered if there was no progression. Subjects underwent skin biopsies and PB immunologic studies as follows: pretreatment, day 5, week 4 and week 8 of therapy. Biopsies were analyzed and evaluated by a pathologist and IHC image analyzer. PB samples were analyzed by flow cytometry.
Result(s): Nine subjects were accrued. Age 37-79 years, 3 of 9 where white and 6 of 9 were men. The median number of prior therapies was 4 (1-11) and 2 patients had progressed on brentuximab vedotin. The disease etiologies, treatment emergent toxicities and response by cohort are presented in table 1. An objective response rate of 44% was observed in the study. In the PB, flow cytometry revealed a decrease in circulating NKC (CD56+ CD3-, CD56+ CD16+ and NKp46+) during therapy with post therapy recovery. The activation marker CD69 on NKC increased in responders (R) compared to non-responders (NR). Similarly, tumor biopsies in R showed increased infiltration and activation of CD56+ NKC as opposed to NR (Figure 1). NKC cytotoxicity through the expression of Granzyme B was seen in R vs NR. Flow quantitation of circulating CD4+ CD25+ T cells (Tregs) shows a decrease in R vs. NR.
Conclusion(s): AFM13 demonstrated a high ORR of 44 % among a population of heavily pretreated patients with a CD30 positive lymphoproliferative T-cell malignancy. AFM 13 exhibited activity post brentuximab vedotin failure. In addition, biological changes in NKC infiltration and activation in the PB and tissue biopsy correlate with response. This data is the first to demonstrate the therapeutic advantages of this bispecific, and the first to correlate changes in NKC as a function of dose and schedule

BACKGROUND:Primary plasmacytomas are localized proliferations of clonal plasma cells occurring in the absence of a systemic plasma cell dyscrasia such as multiple myeloma. Primary plasmacytomas most commonly manifest as solitary lesions of the bone or of the upper aerodigestive tract. Presentation in a lymph node is very uncommon and can often be initially mistaken for lymphoma. Because they are local phenomena, primary plasmacytomas are managed with local therapies such as radiation or, less commonly, excision. Multifocal presentations are rare and are often not amenable to local treatment modalities, thus requiring systemic therapies. Because of their rarity, standardized treatment guidelines are not established, and treatment paradigms borrow heavily from those employed in multiple myeloma. Multifocal presentation in lymph nodes is nearly unheard of with only seven such cases reported in the existing literature, only four of which were diffuse enough to require systemic therapy. Here we describe the most diffuse and widely distributed instance of primary lymph node plasmacytoma yet reported and present a description of its successful treatment with systemic therapy. CASE PRESENTATION/METHODS:A 71-year-old Asian man presented with progressive fatigue in the setting of diffuse hypermetabolic lymphadenopathy throughout his chest, abdomen, and pelvis. A diagnosis of lymphoma was initially suspected; however, a lymph node biopsy was consistent with plasmacytoma. A bone marrow biopsy was unremarkable, and no monoclonal protein was identified, establishing a diagnosis of primary extramedullary plasmacytomas of the lymph nodes. He was treated with a myeloma-like regimen consisting of four cycles of bortezomib/dexamethasone followed by two cycles of thalidomide/prednisone with improvement in symptoms and near complete resolution of prior hypermetabolic lymphadenopathy. He remains in remission over 18 months following completion of therapy. CONCLUSION/CONCLUSIONS:This case report and accompanying literature review highlight the exceedingly rare and easily misclassified entity of primary plasmacytoma of diffuse lymph nodes. Importantly, we demonstrate that this entity may be treated with, and demonstrate excellent response to, systemic therapies often employed in multiple myeloma.

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States alone. The hallmark of ALL is chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells. In adults, 75% of cases develop from precursors of the B-cell lineage, with the remainder of cases consisting of malignant T-cell precursors. Traditionally, risk stratification has been based on clinical factors such age, white blood cell count and response to chemotherapy; however, the identification of recurrent genetic alterations has helped refine individual prognosis and guide management. Despite advances in management, the backbone of therapy remains multi-agent chemotherapy with vincristine, corticosteroids and an anthracycline with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of ALL.

T-cell lymphomas are rare and aggressive malignancies associated with poor outcome, often because of the development of resistance in the lymphoma against chemotherapy as well as intolerance in patients to the established and toxic chemotherapy regimens. In this review article, we discuss the epidemiology, pathophysiology, current standard of care, and future treatments of common types of T-cell lymphomas, including adult T-cell leukemia/lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, aggressive NK/T-cell lymphoma, and cutaneous T-cell lymphoma.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with an incidence of over 20 000 cases per year in the United States alone. Large chromosomal translocations as well as mutations in the genes involved in hematopoietic proliferation and differentiation result in the accumulation of poorly differentiated myeloid cells. AML is a highly heterogeneous disease; although cases can be stratified into favorable, intermediate and adverse-risk groups based on their cytogenetic profile, prognosis within these categories varies widely. The identification of recurrent genetic mutations, such as FLT3-ITD, NMP1 and CEBPA, has helped refine individual prognosis and guide management. Despite advances in supportive care, the backbone of therapy remains a combination of cytarabine- and anthracycline-based regimens with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens, and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of AML.

Multiple myeloma (MM) is a disease that affects plasma cells and can lead to devastating clinical features such as anemia, lytic bone lesions, hypercalcemia, and renal disease. An enhanced understanding of MM disease mechanisms has led to new more targeted treatments. There is now a plethora of treatments available for MM. In this review article, our aim is to discuss many of the novel agents that are being studied or have recently been approved for the treatment of MM. These agents include the following: immunomodulators (pomalidomide), proteasome inhibitors (carfilzomib, marizomib, ixazomib, oprozomib), alkylating agents (bendamustine), AKT inhibitors (afuresertib), BTK inhibitors (ibrutinib), CDK inhibitors (dinaciclib), histone deacetylase inhibitors (panobinostat, rocilinostat, vorinostat), IL-6 inhibitors (siltuximab), kinesin spindle protein inhibitors (filanesib), monoclonal antibodies (daratumumab, elotuzumab, indatuximab, SAR650984), and phosphoinositide 3-kinase (PI3K) inhibitors.

Increased production of mitochondrial-derived reactive oxygen species (ROS) is characteristic of a metabolic shift observed during malignant transformation. While the exact sources and roles of ROS in tumorigenesis remain to be defined, it has become clear that maintaining redox balance is critical for cancer cell proliferation and survival, and as such may represent a vulnerability that can be exploited therapeutically. STAT3, a latent cytosolic transcription factor activated by diverse cytokines and growth factors, has been shown to exhibit an additional, non-transcriptional function in mitochondria, including modulation of electron transport chain activity. In particular, malignant transformation by Ras oncogenes exploits mitochondrial STAT3 functions. We used mass-spectrometry based metabolomics profiling to explore the biochemical basis for the STAT3-dependence of Ras transformation. We identified the gamma-glutamyl cycle, the production of glutathione, and the regulation of ROS as a mitochondrial-STAT3 dependent pathway in Ras-transformed cells. Experimental inhibition of key enzymes in the glutathione cycle resulted in depletion of glutathione, accumulation of ROS, oxidative DNA damage, and cell death in an oncogenic Ras and mitochondrial-STAT3 dependent manner. These data uncover a synthetic lethal interaction involving glutathione production and mitochondrial ROS regulation in Ras-transformed cells that is governed by mitochondrial STAT3 and might be exploited therapeutically.

Half of a century ago, physicians managing chronic lymphocytic leukemia (CLL) recognized some of its presenting features such as lymphocytosis, lymphadenopathy, and splenomegaly. Subsequently, an enhanced understanding of the disease mechanisms involved in CLL led to new, more targeted treatments. There is now a plethora of treatments available for CLL. In this review article we discuss in detail several of the novel agents that are being studied or approved for the treatment of CLL including: phosphatidylinositol 3-kinase inhibitors (idelalisib and IPI-145), Bruton tyrosine kinase inhibitors (ibrutinib), B cell lymphoma 2 inhibitors (ABT-263 and ABT-199), new anti-CD20 monoclonal antibodies (obinutuzumab), cyclin-dependent kinase inhibitors (flavopiridol and dinaciclib), immunomodulators (lenalidomide) and chimeric antigen receptor T-cell therapy.

Peripheral T-cell lymphomas are a heterogeneous group of aggressive diseases associated with poor outcome. The current aim in peripheral T-cell lymphoma is to enhance the understanding of the disease, in order to aid the development of more effective treatments. There has been a plethora of targeted treatments available for T-cell lymphomas. In this review article, we will present an overview of some of these novel agents, including the antifolate (pralatrexate), histone deacetylase inhibitors (vorinostat, belinostat and romidepsin), proteasome inhibitors (bortezomib and carfilzomib), mTOR inhibitors (temsirolimus and everolimus), monoclonal antibodies (alemtuzumab, brentuximab vedotin, zanolimumab, anti-CXCR4 and anti-CCR4), immunomodulatory agent (lenalidomide), nucleoside analogs (gemcitabine, clofarabine, forodesine and pentostatin), and fusion toxin (denileukin diftitox)