Brentuximab vedotin in combination with extended field radiotherapy as salvage treatment for primary refractory <scp>H</scp>odgkin lymphoma
Authors: Massimo Dozzo, Francesco Zaja, Stefano Volpetti, Alessandra Sperotto, Alessandro Magli, Renato Fanin
Journal: American Journal of Hematology (2014)

To the Editor: Hodgkin lymphoma (HL) is a B-cell derived lymphoid malignancy that accounts for about 10% of all lymphomas. Despite most of patients being cured by modern regimens of chemotherapy and radiotherapy (RT), nearly 20% show primary refractoriness or relapse after initial remission. In these cases second-line chemotherapy followed by autologous stem cell transplantation (ASCT) consolidation leads in nearly 50% of patients to a long lasting remission. For patients with HL relapsed/refractory (R/R) to more than two lines of therapy, there is no standard approach and prognosis is generally dismal. Therapeutic options include palliative chemotherapy, radiotherapy, and transplant procedures. More recently, Brentuximab Vedotin (BV), an anti-CD30 monoclonal antibody conjugated with Auristatin, showed therapeutic activity in 75% of patients with HL R/R to ASCT, with 35% complete response (CR) and median progression-free survival (PFS) of nearly 6 months 1. Limited data are available regarding the combination of BV with chemotherapeutic agents while, the combination of BV with RT has not been reported so far. A 45-year-old male, with no significant comorbidities, was referred at our Centre on August 2013 for onset of multiple lympho-adenopaties (size varying from 2 to 7 cm and involving bilateral the cervical area and the right axillary) associated with fever, night sweats, fatigue, mild cough, and mild skin itching. Total white blood cell count was 39 × 109/L (90% neutrophils, 4% lymphocytes), while hemoglobin and platelet count were 98 g/L and 635 × 109/L, respectively; erythrocyte sedimentation rate was 91 mm/hr. After lateral cervical lymphonode biopsy and standard staging, the patient was diagnosed to have a sclero-nodular, classic HL, stage IIIs (spleen) B. The patient was started on standard ABVD chemotherapy program (Dacarbazine, Bleomycin, Vinblastine, and Doxorubicin) with rapid resolution of systemic symptoms and lymphonodes disappearance. A CT-PET evaluation after two cycles showed a picture of response with FDG uptake lower than liver (Deauville Score 3). After the fourth planned ABVD course, the patient had evidence of supradiaphragmatic progression with recurrence of right supraclavicular, axilla, and mediastinal involvement. A lymphonode biopsy confirmed the initial diagnosis of scleronodular classic HL. The patient was treated in December 2013 and January 2014 with one course of IGEV (Vinorelbine, Ifosfamide, Metilprednisolone and Gemcitabine) and one course of DHAP chemotherapy (Dexamethasone, Cisplatin, Cytosine Arabinoside) each, with no response and further clinical and radiological evidence of rapid progression with reappearance of fever, itching, and lymphoadenopaties in all supradiaphragmatic areas with bulky right axillary involvement (12 cm × 10 cm). Based on the disease's status of chemoresistance, a haploidentical stem cell transplant (SCT) with the patient's sister was considered. To induce a pre-transplant condition of response, and because of the high level of aggressiveness of the disease with rapid lymphnodes enlargement, a combination treatment with BV and extended field (EF) RT was started. From February to April 2014 the patient received four administrations of BV (1.8 mg/kg) every 21 days with concomitant classical mantle field RT at a dose of 36 Gy in 20 fractions. Hematological toxicity experienced during the therapy was mild, with Grade 2 anemia only after course 1 and 2, and no neutropenia or thrombocytopenia. There were no infective complication or any other major adverse effects to BV or RT, and, in particular, no clinical or functional signs of pulmonary toxicity. The patient showed rapid resolution of the clinical symptoms and progressive and gradual decrease of the size of' the right axillary lymphoadenopathy. Pre-transplant restaging documented a partial response status (according to Cheson 2007) due to the persistence of a residual single right axillary lymphoadenopathy of 3 cm in size. This status of improvement allowed, in May 2014, to proceed with haplo-identical SCT with no major complications. At present, 6 months after the end of BV plus EF-RT and 5 months after SCT, the patient is in good clinical conditions and in a complete response status. Patients with R/R HL have a poor prognosis and no standard treatment has been established so far. Allogeneic SCT seems to be a suitable treatment option for patients with a pre-SCT response condition, with nearly 30–40% PFS. Due to the good safety profile, BV is frequently associated with other systemic therapies. In our patient, the association of BV with EF RT allowed the patient to receive subsequent consolidation treatment with haplo-identical SCT. Further studies investigating the combination of RT with BV in HL are warranted. Massimo Dozzo, Francesco Zaja,* Stefano Volpetti, Alessandra Sperotto,Alessandro Magli and Renato Fanin Clinica Ematologica, Centro Trapianti E Terapie Cellulari “Carlo Melzi”, DISM, Azienda Ospedaliera Universitaria S. Maria Misericordia, Udine, Italy