Class of 2017 Abstract / This project is related to the article that was later published, available at this link: https://doi.org/10.1016/j.critrevonc.2016.11.009 / Objectives: Brentuximab vedotin (BV) is an antibody-drug conjugate comprising a CD30-directed antibody conjugated to the microtubule-disrupting agent MMAE via a protease cleavable linker. BV is FDA approved for use in relapsed classical Hodgkin lymphoma and relapsed systemic Methods: primary study outcomes being objective response rate. PubMed (1946-2015), EMBASE (1947-2015), and Cochrane Central Register of Controlled Trials (1898-2015). Inclusion criteria included all studies and case reports of NHLs in which BV therapy was administered. Twenty-eight articles met these criteria. Results: Utilizing the twelve clinical subtypes, we found clinical evidence of BV and stratified the study populations into three groups: B-cell malignancies (group A), T-cell malignancies (group B), and non-B or non-T-cell hematological malignancies (group C). Across the group A malignancies, there were 87 patients. 48% experienced an objective response (OR). Across the group B malignancies, there were 274 patients. 74% experienced an OR. Across the group C malignancies, there were 9 patients. 44% experienced an OR. Conclusions: Our findings indicate that BV induces a variety of responses, largely positive and variable between NHL subtypes. With properly powered prospective studies, BV may prove to be a strong candidate in the treatment of CD30+ malignancies.

Hodgkin’s lymphoma (HL) is a disease that represents approximately 10% of lymphomas with bimodal age distribution. It is curable in approximately 75 percent of patients worldwide. ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) was originally developed for patients with disease resistant to MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), but subsequently became the gold standard initial chemotherapy for patients with HL. Anthracyclines remain as a backbone for combination regimens and in patients with systolic dysfunction MOPP regimen has been used as initial chemotherapy. In patients with relapsed or refractory HL, the goal of treatment should be to achieve long-term disease control and requires salvage regimens to reduce disease burden beforehand followed by autologous hematopoietic cell transplantation (HCT) in curative intent. There are no randomized trials that directly compare the various salvage regimens for relapsed HL. Brentuximab Vedontin (BV) and nivolumab are currently approved for the treatment of refractory disease in patients who have failed two or more first-line treatments or who have failed HCT. Little literature exists regarding the efficacy and overall survival of patients who receive BV with or without nivolumab for refractory disease in patients who are ineligible or refuse HCT. We report a case of a 24-year-old refractory nodular sclerosing Hodgkin’s disease with a lengthy progression-free survival on BV and Nivolumab and without HCT. The patient was diagnosed with stage IV HL due to bone marrow involvement and was started on the MOPP regimen due to an ejection fraction of 45-50% and given a history of transposition of great vessels. The first surveillance PET scan after 6 cycles of MOPP chemotherapy showed new hypermetabolic widespread adenopathy and new multifocal abnormal FDG uptake within the liver and spleen suggestive of early relapse. Salvage chemoimmunotherapy with RICE was then started with the intention to reduce the disease burden prior to HCT. Despite starting salvage chemoimmunotherapy, the patient’s liver function tests (LFT) continued to rise along with progressively worsening pancytopenia. Due to concern for refractoriness and worsening LFT’s, he was started on third-line single-agent nivolumab and showed tremendous response after 4 cycles. BV was added to nivolumab to further improve responses based on phase 2 data. Despite considerable efforts in counseling regarding smoking cessation, he continued to smoke and refused HCT. The patient received 4 cycles of Nivolumab every 2 weeks and then a combination of BV and Nivolumab for 17 cycles. Subsequently had progressive disease. Right, mandibular gingiva biopsy was consistent with high-grade large B cell lymphoma with concern for Richter's transformation from Hodgkin’s to non-Hodgkin’s lymphoma (NHL). He has received a course of radiation therapy to the involved facial area for symptom control and was later started on CEOP (vincristine, etoposide, cyclophosphamide, prednisone) regimen with intrathecal methotrexate. This case provides unique clinical data of durability results of a patient treated with BV in combination with nivolumab in relapsed or refractory HL patients who are ineligible or refuse HCT. Our patient likely had Richter's transformation of HL to the NHL, which has rarely been reported in the literature.

Sezary Syndrome (SS) is a rare leukemic variant of primary cutaneous T-cell lymphoma. Relapsed or refractory disease is generally considered incurable by conventional therapeutic approaches, although durable responses can be achieved with novel monoclonal antibodies. Allogeneic hematopoietic stem cell transplantation (alloHSCT) may have potential value by inducing graft vs-lymphoma (GvL) effects, but there is currently no consensus regarding the timing of alloHSCT or type of conditioning regimen. Here we present the case of a male patient who achieved a complete remission (CR) of primary refractory SS after non-myeloablative alloHSCT. Patient: Two years prior to HSCT, the patient had been refractory to CHOEP-based chemotherapy, interferon, extracorporeal photopheresis (ECP), and bexarotene. Directly prior to alloHSCT brentuximab-vedotin (BV) was applied resulting in a partial remission of the skin compartment and overall in a stable disease. Prior to HSCT, flow cytometry of the bone marrow and peripheral blood showed an infiltration with T-cells positive for CD5, CD4, low CD3, low CD2 and negative for CD7, CD38, HLA-DR and CD8. The trephine biopsy showed a 7% infiltration of SS cells. The CD4:CD8 ratio in peripheral blood (pb) was massively increased at 76.67, with 63.5% of white blood cells expressing a SS immune phenotype. The conditioning regimen included 30 mg/m2 fludarabine on days -5, -4 and -3 and total body irradiation with 2 Gy on day -1. Immunosuppression consisted of cyclosporine A from day-1 and mycophenolate mofetil from day 0. The patient received 6.55x106 CD34+ cells and 1.11x108 CD3+ cells/kg body weight. Bone marrow evaluation on day 28 still showed persistent SS cells by flow cytometry. After tapering immunosuppression until day 169, the CD4:CD8 ratio in pb normalized. CR was documented on day 169 after alloHSCT and is now ongoing for almost 3 years after alloHSCT. Conclusions: We confirm that an alloHSCT can be a curative option for refractory patients with SS. The achievement of a CR after tapering the immunosuppressive therapy indicates a significant role of the GvL effect. In present treatment algorithms for patients with SS, the timing of an alloHSCT and the intensity of conditioning should be further explored.