Reverted exhaustion phenotype of circulating lymphocytes as immune correlate of anti-PD1 first-line treatment in Hodgkin lymphoma

While classical Hodgkin lymphoma (HL) is highly susceptible to anti-programmed death protein 1 (PD1) antibodies, the exact modes of action remain controversial. To elucidate the circulating lymphocyte phenotype and systemic effects during anti-PD1 1st-line HL treatment we applied multicolor flow cytometry, FluoroSpot and NanoString to sequential samples of 81 HL patients from the NIVAHL trial (NCT03004833) compared to healthy controls. HL patients showed a decreased CD4 T-cell fraction, a higher percentage of effector-memory T cells and higher expression of activation markers at baseline. Strikingly, and in contrast to solid cancers, expression for 10 out of 16 analyzed co-inhibitory molecules on T cells (e.g., PD1, LAG3, Tim3) was higher in HL. Overall, we observed a sustained decrease of the exhausted T-cell phenotype during anti-PD1 treatment. FluoroSpot of 42.3% of patients revealed T-cell responses against ≥1 of five analyzed tumor-associated antigens. Importantly, these responses were more frequently observed in samples from patients with early excellent response to anti-PD1 therapy. In summary, an initially exhausted lymphocyte phenotype rapidly reverted during anti-PD1 1st-line treatment. The frequently observed IFN-y responses against shared tumor-associated antigens indicate T-cell-mediated cytotoxicity and could represent an important resource for immune monitoring and cellular therapy of HL

Consolidated aspects in the treatment of hodgkin lymphoma

Accounting for 15% of all lymphomas, Hodgkin lymphoma (HL) is a relatively rare disease but the most common malignancies among young adults. Over the last decades prognosis markedly improved with the refinement of evidence based therapies. Current risk-adapted therapies usually consist of polychemotherapies such as ABVD or BEACOPPesc and up to 90% of all patients may be considered cured after adequate first-line treatment. Due to this favorable development recent research focused on reduction of therapeutic intensity and more individualized approaches. Prognosis is worse in relapsed or refractory HL (rrHL), where high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) is associated with progression-free survival (PFS) of only 50%. Outcomes tend to be inferior in elderly patients or those ineligible for intensified therapies due to comorbidities. This review delineates the development of current standard approaches in firstline and rrHL treatment and summarizes key findings of recent large scale clinical trials. Innovative approaches including response-guided therapy or implementation of novel agents are covered in a separate article

Checkpoint Inhibition in Hodgkin Lymphoma - a Review

Physiological immune checkpoint pathways are important to regulate self-tolerance, limit immune reactions, and moderate autoimmunity. Various cancers are commonly exploiting these mechanisms to evade the host immune system by restraining a durable, efficient antitumor immune response. Immune checkpoints include, but are not limited to, the programmed death 1 (PD1) and the cytotoxic T-lymphocyte-associated protein-4 (CTLA4) axis, which are both druggable by monoclonal antibodies referred to as checkpoint inhibitors (CIs). To date, the anti-PD1 antibodies nivolumab and pembrolizumab are approved for relapsed or refractory classical Hodgkin lymphoma (cHL) due to high response rates with a favorable yet distinct safety profile, and other agents are under investigation. This review summarizes the available preclinical and clinical data including the toxicity and efficacy of different CIs in cHL. It also provides future perspectives based on ongoing clinical trials, potentially synergistic combinatory approaches, and their fit in the therapeutic landscape in cHL. (C) 2017 S. Karger GmbH, Freibur

Balancing risk and benefit in early-stage classical Hodgkin lymphoma

With defined chemotherapy and radiotherapy (RT) and risk-adapted treatment, early-stage classical Hodgkin lymphoma (HL) has become curable in a majority of patients. Hence, a major current goal is to reduce treatment-related toxicity while maintaining long-term disease control. Patients with early-stage favorable disease (ie, limited stage without risk factors [RFs]) are frequently treated with 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (2xABVD) followed by 20-Gy involved-field or involved-site RT (IF/ISRT). In patients with early-stage unfavorable disease (ie, limited stage with RFs), 4 cycles of chemotherapy are usually consolidated with 30-Gy IF/ISRT. Compared with 4xABVD, 2 cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (2xBEACOPP(escalated)) followed by 2xABVD improved 5-year progression-free survival (PFS), with similar 5-year overall survival. Recently, treatment strategies based on [F-18] fluorodeoxyglucose positron emission tomography (PET) response were evaluated. In early-stage unfavorable HL, a majority of patients achieved a negative interim PET after 2xABVD and an excellent outcome after 4xABVD, whereas in those with a positive interim PET, 2xBEACOPP(escalated) improved 5-year PFS. Furthermore, a PET-guided RT approach was evaluated to decrease long-term toxicity. Although both the RAPID and H10 trials reported poorer disease control without RT, PET-guided omission of RT can constitute a valid therapeutic option in patients with an increased risk of RT-associated toxicity (eg, because of sex, age, or disease localization). Implementation of drugs such as the anti-CD30 antibody-drug conjugate brentuximab vedotin or the anti-programmed death 1 antibodies nivolumab or pembrolizumab might allow further reduction of overall mortality and improve quality of life in affected patients

Complete remission of Loeffler's endocarditis with Imatinib in a myeloid and lymphoid neoplasm associated with eosinophilia

History and clinical findings A 53-year-old male presented with massive pruritus, whole-body exanthema, generalized muscle pain, and exercise dyspnoea NYHA II. Findings and Diagnosis Further hematologic examination lead to diagnosis of myeloid and lymphoid neoplasia with eosinophilia (MLN-EO) with FIPL1L1-PDGFRA fusion gene. An echocardiographic examination revealed a thrombus in the right ventricle. Magnetic resonance imaging (MRI) showed an extensive intracavitary thrombus extending from the apex to the right ventricular outflow tract. Therapy and course Oral anticoagulation with phenprocoumon and a targeted therapy with imatinib were initiated. Follow-up at 11- and 23-months revealed diminishing of the thrombus. Further follow-up did not show any complications. Conclusions In summary, Loeffler's endocarditis caused by a myeloid and lymphoid neoplasm associated with eosinophilia and abnormalities of FIP1L1-PDGFRA rearrangement could be treated successfully with oral anticoagulation therapy and the tyrosine-kinase inhibitor imatinib

Current and future immunotherapeutic approaches in Hodgkin lymphoma

Hodgkin lymphoma (HL) has become a highly curable malignancy even in advanced stages when treated adequately. However, relapsed or refractory disease and treatment-related toxicity constitute a significant clinical challenge. Innovative approaches are thus needed to improve treatment of these mainly young patients. In HL lesions, very few malignant Hodgkin and Reed-Sternberg (HRS) cells are embedded in an immunosuppressive microenvironment of reactive cells. Novel approaches such as bispecific antibodies, antibody-drug conjugates, immune-checkpoint inhibitors or adoptive cellular therapies are currently being investigated with promising results in relapsed or refractory patients. Encouraging response rates and a favorable toxicity profile have recently been reported in early phase clinical trials with antibodies blocking the programed-death receptor 1 (PD1). This review will summarize the current clinical knowledge on mechanism, safety and efficacy of the different agents and discuss potential future strategies, which are partly already investigated within clinical trials

Toxicities of novel therapies for hematologic malignancies

Introduction: Over the last decade targeted therapies have transformed the treatment landscape for hematologic malignancies with >70 new or extended approvals by the FDA since 2010. Since many of these drugs are registered for multiple entities and >1/3 were approved in the last two years, treatment options in hematology are rapidly expanding. Despite the justified excitement around the often previously unseen emerging therapeutic potential, distinct side-effect profiles require vigilance and adequate management by patients and caregivers. Areas covered: This review provides a summary of the unique toxicity profiles of therapies for hematologic malignancies during the last decade with a focus on clinical implications and applicability. Due to the already wide implementation in common practice or an immense potential thereof selected treatments such as immune checkpoint inhibitors, various monoclonal antibodies, tyrosine kinase inhibitors and CAR T-cell therapies are discussed in detail. Challenges and potential strategies to assess and manage real-world toxicity after drug approval are addressed. Expert opinion: The rapidly expanding therapeutic landscape of hematologic malignancies comes with a broad spectrum of side effects which are distinct from conventional hematotoxicity and require alertness

Relapsed or refractory classical Hodgkin's lymphoma. Novel therapeutic approaches

Classical Hodgkin's lymphoma is highly curable with risk-adapted first-line therapy. Despite a reduction of potential therapy-associated short-term and long-term toxicities, treatment of patients with relapsed or primary refractory disease (r/r HL) remains a clinical challenge. This review summarizes the currently available data regarding safety and efficacy of different therapeutic approaches in r/r HL and provides recommendations for specific clinical situations. Up to 50% of patients eligible for intensified therapies achieve long-term remission after high-dose chemotherapy and autologous stem cell transplantation (ASCT); however, multiple relapsed, refractory, elderly or frail patients until recently had an unfavorable prognosis with mostly palliative therapy. The anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) constitutes a highly effective and tolerable therapeutic option with some durable complete remissions. Accordingly, BV has been approved for r/r HL after ASCT or two prior therapies. More recently, two checkpoint inhibitors, i.aEuroe., the anti-PD1 antibodies nivolumab and pembrolizumab were also investigated in heavily pretreated r/r HL patients. Both drugs were very well tolerated and resulted in high response rates with long-lasting remission. Nivolumab and pembrolizumab were recently approved for r/r HL after prior treatment with BV. In addition, other targeted drugs, such as AFM13, everolimus, panobinostat, mocetinostat as well as agents, such as lenalidomide or bendamustine showed activity in intensively pretreated r/r HL patients

Prognostic factors in Hodgkin lymphoma

During the last decades, the prognosis of Hodgkin lymphoma (HL) has been improved significantly with the introduction of effective chemotherapy and the implementation of risk-adapted treatment approaches. Identification of reliable risk factors is crucial to guide treatment over the course of disease. Both clinical and biological factors have been implicated in the prognosis of HL and are often used in prognostic scores to discriminate risk groups. To prevent under- or overtreatment, patients are usually assigned to one of the three widely established risk groups for first-line treatment, based solely on clinical risk factors. To further individualize therapeutic approaches, functional imaging with positron emission tomography (PET) is becoming more widely implemented and precisely investigated within clinical trials. Biological prognostic factors have been widely evaluated but are still not a part of standard prognostication. This review will discuss the currently established factors and risk models at first diagnosis and in the setting of relapsed/refractory disease and also focus on biological factors and PET, summarizing current standards and future perspectives. (C) 2016 Elsevier Inc. All rights reserved