Up to 40% of patients with advanced Hodgkin lymphoma (HL) become refractory or relapsed after current standard chemotherapy, among which primary refractory HL confers a particularly poor outcome. With intensive salvage chemotherapy and autologous stem cell transplantation, the long-term remission rate for these patients was only 30%, but more selective treatments with higher therapeutic index are needed. We report the experience of using a new anti-CD30 immunotoxin, brentuximab vedotin, in salvage treatment of a 30-year-old woman with primary refractory Hodgkin lymphoma. The patient presented with SVC syndrome due to the bulky mediastinal tumor and was confirmed to have classical Hodgkin lymphoma, nodular sclerosis type, stage IIIA. The tumor responded to induction chemotherapy transiently, but local progression was noted during subsequent cycles of treatment. Salvage radiotherapy to the mediastinal tumor, obtained no remission but was followed by rapid in-field progression and then lung metastasis. She declined stem cell transplantation and received salvage brentuximab vedotin (BV) therapy, which induced dramatic shrinkage of tumor without significant side effects. Serial followup of PET/CT imaging confirmed a rapid and continuous complete remission for 12 months. Although durability of the remission needs further observation, this case illustrates the excellent efficacy of brentuximab vedotin in primary refractory Hodgkin lymphoma.
Despite recent improvement of therapy, the outcome of patients with refractory or relapsed Hodgkin lymphoma (RR-HL) remained compromised [
A thirty-year-old female patient presented with dyspnea due to SVC syndrome. Chest CT scan showed bulky tumors over the mediastinum and left supraclavicular fossa, with right internal jugular vein thrombosis and right side pleural effusion (Figure
Images showing Hodgkin lymphoma refractory to induction chemotherapy. (a) Chest computerized tomography (CT) demonstrates the superior mediastinal tumor at diagnosis. (b) Positron emission tomography/computerized tomography (PET/CT) reveals involvement of right supraclavicular, left lower neck, mediastinal, epicardial, and retroperitoneal lymph nodes at initial diagnosis. (c) PET/CT after 4 cycles of induction chemotherapy shows partial remission with a residual uptake at right anterior mediastinum. (d) PET/CT after completion of 6 cycles of chemotherapy reveals relapse of the mediastinal tumor.
Under diagnosis of classical Hodgkin lymphoma, stage IIIA, she received the standard induction chemotherapy with epirubicin, bleomycin, vinblastine, and dacarbazine (EBVD), with regression of neck tumors and SVC syndrome. After four cycles of chemotherapy, an interim PET/CT study showed partial remission with residual uptake over right anterior mediastinum (Figure
Salvage radiotherapy was commenced for the progressive mediastinal tumor. The PET/CT scan images and CT-simulation images were fused for contouring target volumes. The involved lymphoid regions constituted the gross tumor volume. Isodose curves confirmed that at least 95% of the prescribed dose was delivered to the planning target volume. A total of 36 Gy in 20 daily fractions, 5 fractions per week, was delivered with intensity-modulated radiotherapy techniques. The patient tolerated it well, but CT imaging showed no remission of the mediastinal tumor followed by early relapse (Figures
Mediastinal tumor refractory to salvage radiotherapy. (a) CT shows relapsed superior mediastinal tumor before radiotherapy. (b) CT reveals progression of the superior mediastinal tumor 2 months after completion of radiotherapy.
Due to immediate relapse after induction chemotherapy and no response to salvage radiotherapy, primary refractory HL was impressed. Salvage chemotherapy and ASCT was suggested, but the patient hesitated due to concerns about anticipated toxicities with high-dose chemotherapy and ASCT. Two months later, left neck tumor enlarged significantly, the PET/CT study revealed progressive mediastinal tumor with metastases to left lung, left axilla, and supraclavicular lymph nodes (Figure
Serial PET/CT images before and after brentuximab vedotin treatment. (a) Before treatment, showing mediastinal tumor progression, with metastases to left lung, left axillary, and supraclavicular lymph nodes. (b) Near-complete remission after 4 cycles of treatment, with a faint uptake over left lower neck. (c) Complete remission after 9 cycles of treatment.
Recognizing the efficacy and side-effect profile of brentuximab vedotin, she opted for the new treatment. After approval by the National Department of Health, the drug was imported via the named-patient-program (Millennium/Takeda). The treatment was commenced at the recommended dose (1.4 mg/m2) every 3 weeks. The neck tumor regressed dramatically with minimal toxicity. Follow-up PET/CT scans after 4 and 9 cycles of BV showed CR of the tumor (Figures
Optimal management of RR-HL is a difficult clinical challenge with three conventional options of salvage treatment: radiotherapy, chemotherapy, and stem cell transplantation.
For selected patients with confirmed local relapse, salvage radiotherapy is a very effective treatment modality with nearly 80% CR rate and 65% long-term local control in the GHSG report [
For patients with sensitive relapse, high-dose chemotherapy followed by ASCT is the current standard treatment based on two randomized phase III studies by the British National Lymphoma Investigation and the GHSG, reporting 3-year PFS around 50%. However, chemorefractory patients were underrepresented in these trials due to exclusion of most patients with rapid progression [
Among the adverse prognostic factors identified in patients with RR-HL, remission duration after initial treatment was particularly important. In a report of salvage chemotherapy for RR-HL by the NCI Italy, primary refractory HL has the poorest eight-year survival of 8% (versus 28% for early relapse and 54% for late relapse) [
Considering the observed tradeoff between efficacy and toxicities of intensified chemotherapy and the suboptimal outcome of ASCT in refractory cases, more selective drug with higher therapeutic index is clearly needed for the poor-risked HL. Brentuximab vedotin (SGN 35) is a chimeric anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent (monomethyl auristatin E; MMAE). After binding to cell-surface CD30, the MMAE is internalized, traffics to the lysosome, and then is released to disrupt microtubules, and to induce cell-cycle arrest and apoptosis. In the phase I dose escalation trial of 45 patients with relapsed/refractory CD30+ hematological malignancies, tumor regression was observed in 86% of cases [
The safety profiles for BV are favorable compared with conventional cytotoxic chemotherapy. More common side effects are usually mild and include cough, fatigue, pyrexia, nausea, and peripheral neuropathy. The most clinical relevant toxicity is peripheral neuropathy
Exciting reports about brentuximab vedotin are continuously emerging. In patients with post-ASCT relapse, a recent study confirmed the superior survival with BV than any other salvage treatments (median: 91.49 mo versus 27.99 mo,
Many researches are currently ongoing to explore the expanding roles of this new drug in management of HL and other CD30+ malignancies. However, the role of BV in salvage treatment of primary refractory HL is an under-explored area which needs further clinical studies. This case scenario shows good efficacy of BV in primary refractory HL and suggests the potential use in this poor-risk group. Hopefully, with optimal incorporation of BV into current treatment modalities, the survival of primary refractory and other poor-risk Hodgkin lymphoma will be further improved.
Brentuximab vedotin
Relapsed or refractory Hodgkin lymphoma
German Hodgkin Study Group
Progression-free survival
Overall survival
Autologous stem cell transplantation
Complete remission.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review.
The authors declare that they have no conflict of interests.
Hung-Bo Wu was responsible for clinical management of the patient and drafting of the paper. Shyh-An Yeh participated in patient management and drafting of the paper. Huei-Yung Chen carried out the PET/CT imaging, interpretation, and helped in preparation of the paper. All authors read and approved the final paper.