Mark J. Fesler, MD
Hematologic Malignancy Specialist
Director of Bispecific Immunotherapy
St. Luke’s Center for Cancer Care
CLINICAL DILEMMA
A 19-year-old female patient was diagnosed with classical Hodgkin lymphoma (nodular sclerosis subtype, stage IIA unfavorable [bulky]) that initially presented with mediastinal and hilar masses. She was treated with six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). She achieved a complete remission (CR) on intermediate PET-CT after two cycles, so bleomycin was omitted after two cycles. Within three months of her first-line therapy, her disease relapsed. A new biopsy was performed and confirmed the earlier diagnosis. The patient then received two cycles of ICE (ifosfamide, carboplatin, and etoposide). A subsequent PET-CT showed that a fairly small hot spot with a Deauville score of 5 remained, and she was then switched to DHAP (dexamethasone, high-dose cytarabine, and cisplatin), but after two cycles there is progressive disease. What would be your approach? One option could be pembrolizumab, radiotherapy, and autologous hematopoietic cell transplantation (AHCT) if the disease is in remission; do you think this could be the most effective approach?
EXPERT OPINION
Unfortunately, this patient has highly chemo-refractory Hodgkin lymphoma (HL). I would recommend a repeat biopsy, if feasible, provided one has not been performed at any of the relapse or progression events outlined. Fortunately, there are additional options for this young patient that may lead to remission and possibly even cure.
Given that the patient is naïve to targeting CD30, an antigen widely expressed on Reed-Sternberg cells, and there is no indication of a debilitating neuropathy in the case presentation, I would include brentuximab vedotin (BV) as part of salvage treatment. Additionally, given the high single-agent efficacy and overall excellent tolerability of checkpoint inhibition in this disease, I would include a checkpoint inhibitor in combination with the BV. The choice of checkpoint inhibitor is less important than its addition to the regimen, so either pembrolizumab or nivolumab would be acceptable options, and both agents have similar data supporting their efficacy and tolerability.
As a first salvage treatment, the combination of nivolumab and BV demonstrated a higher response rate than the single agents did, and long-term disease control was impressive, with a 77% three-year progression-free survival.1 As a third salvage treatment, such as in this case, limited data exist. Colleagues in Belgium retrospectively analyzed patients with relapsed or refractory HL who had received a median of three prior lines of treatment (range = 2-5) and were intravenously treated with pembrolizumab 200 mg and BV 1.8mg/kg every three weeks with intent to consolidate with AHCT if PET-CT showed a Deauville score of 4 or less after two cycles, followed by 16 cycles of BV maintenance. With a median follow-up of 16.5 months, complete metabolic response was achieved in 80% of patients, and stem cell collection was successful in 100% (n=7) of patients, who underwent transplantation with BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning. With a median follow-up of 16.5 months, five of these seven patients remained without progression.2
It’s difficult to know for certain whether adding more conventional chemotherapy to the BV and checkpoint inhibitor combination would improve the response and outcome. However, there are some reports of partial or complete responses with standard chemotherapy combined with either BV or a checkpoint inhibitor following failure of the combination; so, should this combination fail to elicit a response, I would strongly consider adding gemcitabine or bendamustine to BV or a checkpoint inhibitor. The explanation for this is not fully clear, but there may be a change in the immunologic milieu in the wake of the combination regimen.
The role of AHCT, exactly what response would qualify a patient for the procedure, optimal pretransplant cycle number, and the optimal conditioning regimen are controversial subjects without clear data. Given the patient’s young age, it would be reasonable to consider an autologous transplant if the BV and checkpoint combination elicits at least stable disease.
The role of external beam irradiation is also controversial in a case such as this, but given the highly chemo-refractory disease, incorporation of this treatment modality into the preconditioning, conditioning, or post-transplantation phases should strongly be considered.
Finally, the role of maintenance systemic treatment, including the exact regimen and length of treatment post-transplant, is also controversial, but its use should be considered, particularly if the BV and checkpoint inhibitor elicit a response in the absence of severe neuropathy or autoimmune or inflammatory issues.
References
- Advani RH, Moskowitz AJ, Bartlett NL, et al. Brentuximab vedotin in combination with nivoumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. Blood. 2021;138(6):427-438.
- Massaro F, Meuleman N, Bron D, et al. Brentuximab vedotin and pembrolizumab combination in patients with relapsed/refractory Hodgkin lymphoma: a single-centre retrospective analysis. Cancers. 2022;14(4):982.
NEXT MONTH'S CLINICAL DILEMMA
A 41-year-old male has a ferritin of 804 μg/L and is homozygous for the HFE H63D gene mutation; a liver MRI is ordered to assess iron stores and the presence of a fatty liver. In the absence of a fatty liver and due to the concern for iron in the liver, would you recommend a phlebotomy for this patient? Though the likelihood may not be high, iron overload can occur with H63D. Would there be a concern of undertreatment if this patient does not receive a phlebotomy?
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