A 36-year-old previously healthy woman presented to her primary medical doctor with fevers, night sweats, and back pain in January 2014. She was given a course of antibiotics with no improvement. Bloodwork demonstrated an elevated WBC to 17,000/mcL composed of 85% neutrophils and 4% lymphocytes, hemoglobin of 9.5 g/dL, and platelet count of 550,000/mcL. CT scan of the chest, abdomen, and pelvis revealed extensive lymphadenopathy in the chest and abdomen, as well as masses within her liver and spleen. A CT-guided biopsy of a retroperitoneal lymph node revealed classical Hodgkin lymphoma (cHL). PET scan confirmed stage IV disease with widespread lymphadenopathy and liver involvement, as well as multiple FDG-avid osseous lesions. She had 5 of the 7 International Prognostic Score (IPS) risk factors.

In February 2014, she initiated treatment with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), which was associated with marked improvement in her symptoms. PET scan after two cycles of ABVD showed resolution of FDG-avid lymphadenopathy and liver lesions, however, mild residual FDG-avidity associated with several osseous lesions was noted. She completed six cycles of ABVD, and end of treatment PET scan showed disease progression with recurrence of generalized FDG-avid lymphadenopathy, liver lesions, and osseous lesions. A repeat retroperitoneal lymph node biopsy confirmed refractory cHL. At this time, she had fatigue and pruritus, but no fevers or night sweats.

In September 2014, she received two cycles of ICE chemotherapy and achieved a complete response on PET. She subsequently underwent an autologous stem cell transplant (ASCT) conditioned with BEAM (carmustine, etoposide, cytarabine, melphalan). Unfortunately, 90 days after transplant, she developed pruritus and recurrent fevers; PET scan again showed widespread FDG-avid lymphadenopathy and liver lesions. A liver biopsy confirmed cHL.

Treatment options in the post-ASCT setting
At the time of relapse following ASCT, the patient was understandably disappointed. She was married with an 8-year-old daughter and had to spend considerable time away from her family while undergoing ICE chemotherapy and ASCT. She was fatigued due to cumulative effects of chemotherapy. She hoped for a treatment that would lead to long-term remission and was open to considering an allogeneic stem cell transplant (allo-SCT) if it would help her achieve that goal. She had no siblings; however, she was found to have one matched unrelated donor in the national registry. Brentuximab vedotin (BV) was recommended as her next treatment based upon its efficacy in the relapsed/refractory (rel/ref) setting. In addition, allo-SCT was determined to be a reasonable option for her given her young age, lack of comorbidities, and availability of a donor. She initiated treatment with BV in March 2015 with the plan to consider an allo-SCT, provided she achieved an adequate response.

Brentuximab vedotin for relapsed/refractory Hodgkin lymphoma
Before 2011, the prognosis for a patient who relapsed after ASCT was grim due to limited treatment options. The estimated median survival was only 25 months.1 With the approval of BV for rel/ref HL, the outcomes for these patients changed significantly; the median survival post-BV is estimated to be 91 months.2 BV is an anti-CD30 antibody conjugated to the anti-tubulin agent, monomethyl auristatin E (MMAE), which was approved for HL in August 2011 for patients who relapsed after ASCT or two multi-agent regimens. In the pivotal study leading to approval, 102 previously transplanted patients enrolled; 76% achieved objective responses and 36% achieved complete responses.3 The most common side effect observed with BV is peripheral neuropathy; it was observed in 55% of patients treated in the pivotal study. For the majority of patients, however, symptoms related to peripheral neuropathy improve or resolve with dose reduction or interruption.

Role of allogeneic stem cell transplant for relapsed/refractory cHL
Studies evaluating reduced-intensity allo-SCT for rel/ref cHL report progression-free survival rates ranging from 26% to 63% (Table 1).4-8 Improved outcomes are observed for patients with chemosensitive disease, particularly those in complete remission prior to transplant.8 In addition, retrospective studies suggest more favorable outcomes associated with haplo-identical transplants for rel/ref HL.4,5 With short follow-up, the outcomes for patients receiving BV followed by allo-SCT look encouraging. In a retrospective series published by Chen and colleagues, 1-year progression free survival (PFS) for 26 patients undergoing allo-SCT following BV was 92%.9 It will be important to see if these encouraging results are maintained with longer follow-up.

While a subset of patients with rel/ref HL appear to be cured with allo-SCT, its associated toxicity and variable outcomes makes the decision to refer to this treatment difficult. Furthermore, follow-up from the pivotal BV study suggests that long-term remission following ASCT failure may be possible without allo-SCT. In fact, after 5-year follow-up, 9 of the 33 patients who achieved CR with BV remain in remission without further therapy.10 This suggests that BV monotherapy following ASCT failure can be curative; however, at least half of the patients who received BV monotherapy in lieu of allo-SCT developed disease progression, indicating that it is still reasonable to consider referral to transplant. Overall, despite long-term remissions observed in a small subset of patients receiving BV alone, allo-SCT continues to be an important, potentially curative option for patients following ASCT failure.

Follow-up for our patient
Initiation of BV was associated with resolution of B symptoms, but her pruritus persisted; repeat PET scan after 3 cycles showed a mixed response. She had improvement in many of her abnormal lymph nodes; however, her PET scan showed additional new liver lesions. Various treatment options were discussed, including gemcitabine-based therapy and other agents active in rel/ref HL (Table 2). Based upon the emerging data regarding checkpoint inhibitors in HL, she enrolled in the phase II study for nivolumab, which was open at our institution at the time.

Checkpoint inhibitors in Hodgkin lymphoma
Immune checkpoint pathways, such as programmed death-1 (PD-1), down-regulate T cell activation, and thereby prevent autoimmunity and excessive immune responses; unfortunately, this can also reduce anti-tumor immunity. PD-1 is expressed on activated T cells and when engaged by one of its ligands, PD-L1 or PD-L2, activates a signaling cascade that leads to T-cell suppression.11 Hodgkin Reed-Sternberg cells almost always express PD-L1, either through amplification of the 9p24.1 chromosome or through induced expression by EBV-related transcription factors.12-14 Consequently, anti-PD-1 monoclonal antibodies have significant activity in rel/ref HL. In initial phase I studies, nivolumab and pembrolizumab induced responses in 87% and 66% of rel/ref HL patients, respectively.15,16 In a larger phase II study with nivolumab, the overall response rate was 66% among 80 patients enrolled. As a result, nivolumab was FDA approved in May 2016 for the treatment of rel/ref HL after failure of ASCT and BV. A confirmatory phase II study with pembrolizumab is underway as well. While typically well-tolerated, nivolumab and pembrolizumab can cause immune-related side effects, including hyper- or hypothyroidism, pneumonitis, colitis, hepatitis, rash, adrenal insufficiency, or hypophysitis. Hematology/oncology providers should know the signs and symptoms to monitor for, as they may be unfamiliar with immune-mediated adverse events, given the differences between these and side effects more common with traditional chemotherapy. 

Follow-up for our patient
Our patient initiated nivolumab in May 2015. Her pruritus resolved and energy improved. Re-staging after 12 weeks of treatment revealed a partial response. One year after initiation of nivolumab, she remains on treatment with a partial response. She has no HL-related symptoms and aside from mild dry eyes, she has experienced no side effects from nivolumab.

Role of allogeneic stem cell transplant following anti-PD-1 therapy
At this point, there is limited experience with allo-SCT following treatment with checkpoint inhibitors. In a recent report of 19 patients who underwent allo-SCT following anti-PD-1 therapy, the 1-year overall survival (OS) rate was 78%; however, four early treatment-related deaths were observed, three from acute graft verse host disease and one from veno-occlusive disease.17 Although the series is small, this raises concern for a higher rate of early toxicity than expected. Currently, allo-SCT following anti-PD-1 is done with significant caution and further studies are needed to establish the optimal timing and management for patients pursuing allo-SCT following anti-PD-1 therapy.

Our patient: conclusion
After discussions regarding the pros and cons of allo-SCT, our patient decided to continue on treatment with nivolumab and not pursue transplant. Both pembrolizumab and nivolumab have been associated with ongoing responses beyond one year of treatment, therefore it is reasonable to expect continued response for our patient. She will hold off on pursuing transplant until there is more experience with optimizing transplant following anti-PD-1 therapy. If she develops disease progression or toxicity on nivolumab, transplant will be re-considered after achieving response to additional therapy. For now, she feels fortunate to feel well and to enjoy quality time with her family.