Pro Discusses Options for Patients With Advanced-Stage Hodgkin Lymphoma

Barbara Pro, MD

Barbara Pro, MD

Barbara Pro, MD, spoke with a group of physicians during aTargeted Oncologylive case-based peer perspectives discussion about the diagnosis, prognosis, and treatment of patients with Hodgkin lymphoma. Pro, a professor of medicine, Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, explained the treatment options based on the case of a young woman with classic Hodgkin lymphoma.

CASE

A 22-year-old woman presented with right cervical nodes developing over several months. She was initially evaluated by her obstetrician-gynecologist, who recommended observation.

The patient subsequently developed neck pain while drinking wine. She was referred for lymph node biopsy, whichindicated classical Hodgkin lymphoma.

She had no prior medical or surgical history, her only medication was oral contraception, and she had no drug allergies. She had no smoking history and only occasional ethanol; she was a division 1 swimmer. Her maternal grandfather had squamous cell cancer, her maternal grandmother had melanoma, and her aunt had breast cancer; her 2 siblings were both healthy.

Her laboratory values were notable for: white blood cells, 19.8 × 10⁹/L (85% polymorphonuclear leukocytes); hemoglobin, 12.0 g/dL; platelets, 571 × 10⁹/L; erythrocyte sedimentation rate, 30 mm/h; creatinine, 0.76 mg/dl; albumin, 4.2 g/dl; and HIV/hepatitis status was negative.

She had a PET/CT scan which showed intrathoracic adenopathy; right cervical, 2.3 × 1.9 (standardized uptake value[SUV], 9.3); left cervical: 2.2 × 1.8 (SUV, 8.8); anterior mediastinum, 4.8 × 2.9 (SUV, 21.3); right axillary: 2.8 × 2.8 (SUV, 12.2); spleen, SUV 2.9 with normal size; diffuse uptake in the axial skeleton (SUVs, 4.9-5.5); and mediastinum SUV 1.8/liver 2.4.

She was diagnosed with nodular sclerosis classic Hodgkin lymphoma. Per immunohistochemistry (IHC), the Hodgkin cells expressed CD30, CD15, and PAX5 (weak) and were negative for CD3, CD20, and CD45.

TARGETED ONCOLOGY:How do you choose which lymph node to biopsy?

Pro:If you do the PET scan before the biopsy, I usually try to go after the lymph node that tested highest in activity. If the highest SUV is 6 in some areas and 10 in other areas, I will go after the 10-SUV lymph nodes. Sometimes it’s not possible because, say, the highest activity is in the mediastinum, [so] I do not want to do an open biopsy. Instead, I will go after the lymph node that’s palpable in the leg.If you don’t have the PET scan, [use] whatever is accessible, because it’s easier on the patient. Now, if the biopsy comes back as inconclusive, then I think you have a real problem, and you have to decide which lymph node to [biopsy] after that. But typically, if you have lymph nodes in the neck, it is Hodgkin lymphoma. A biopsy of the cervical node is sufficient most of the time.

TARGETED ONCOLOGY:What does the IHC tell you about this patient?

Pro:We will have to assume this patient has stage IV disease, and she undergoes a lymph node biopsy. The diagnosis is classic Hodgkin lymphoma, and you can see how the markers are classic. The 2 markers that are important for making the diagnosis of Hodgkin lymphoma are CD15 and CD30, but the pathologist will do a panel to make sure there are no other problems. CD20 here is negative, CD3 is a marker for T cells, and the CD45 is the lymphocyte antigen. Usually, this is the panel that the pathologist will do: an antigen for T cells to allow a CT scan to look at CD20, CD19 for B-cells, and CD30 and CD15 for Hodgkin lymphoma. But usually the morphology of Hodgkin lymphoma is unique.

The pathologist will have some clues about the differential diagnosis.

TARGETED ONCOLOGY:What is the prognosis for this patient?

Pro:In advanced-stage Hodgkin lymphoma, there are a number of important factors, including leukocytosis, lymphopenia, and the presence of anemia. This patient does not carry a high [international prognostic] score [IPS]; it is a score of 2 because of the stage and the leukocytosis. We don’t know if she’s lymphopenic; she’s not that anemic, and the albumin is fine. With an IPS score of 2, [her chance of] survival at 5 years is still over 80%.

TARGETED ONCOLOGY:Do you calculate the IPS score of all patients with advanced stage Hodgkin lymphoma?

Pro:I do, because at least before the [introduction of the] newest therapies that are available, in patients who were fit and young with an IPS score of 5 or higher, the 5-year overall survival [OS] was about 50%; so, significantly lower. In the past, I’ve used escalated BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone] for patients who I think can tolerate it. Advanced-stage disease is rare, but I do try to calculate it, at least to have an idea about the prognosis.

TARGETED ONCOLOGY:What are the systemic options in the front line for this patient?

Pro:Historically, we have had ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine] as the most common chemotherapy regimen used in North America, [including] Canada; but in Europe, the German [Hodgkin Study] Group established that escalated BEACOPP is perhaps more effective in advanced-stage Hodgkin lymphoma.¹It’s a tough regimen to give even in young patients. Sometimes, I used it at the beginning of therapy and then de-escalated [the dose]. Markable studies throughout the years have established ABVD to be as effective as other regimens and less toxic in this patient population.

TARGETED ONCOLOGY:What factors would you consider when selecting a treatment for this patient?

Pro:Performance status and the presence of other comorbidities will help guide our therapy, but [this] young patient is healthy—she’s a swimmer—so I don’t see any problem in using a more aggressive approach.

I have not used radiation therapy in a long time in Hodgkin lymphoma. I probably was one of the first who tried to [reduce] radiation therapy as much as I could because of the long-term toxicity that is associated with the use of a combined modality in a patient population that is so young. Here we are not dealing with bulky disease in the mediastinal. I think the largest lymph node was 4.9 cm in a 22-year-old patient. If you radiate the mediastinum, the axilla, and the neck, you are going to have problems with your thyroid, you are going to have cardiac consequences, and you are going to have lung problems. I weigh all these factors, and, in advanced-stage Hodgkin lymphoma, that is probably less of an issue. It is more of an issue in early-stage Hodgkin lymphoma.

TARGETED ONCOLOGY:How do you counsel patients like this one about the effects of therapy on fertility?

Pro:We have them meet with our fertility team. With ABVD, the infertility risk is low. Most of my patients will go [with] collection because they’re afraid. This is a patient with advanced-stage disease; there is still a risk of not achieving completion in frontline therapy and having to undergo stem cell transplantation, so I will better advise them. These days it’s so much easier. [Now] you delay the start of treatment by just 2 weeks for them to harvest their eggs. It’s an easy procedure these days, so I’d recommend it, especially to patients with advanced-stage Hodgkin lymphoma. I think it should be recommended.

CASE (continued):

The patient was treated with doxorubicin, brentuximab vedotin (Adcetris), vinblastine, and dacarbazine (A[BV]VD). Interim PET/CT with a Deauville score of 3. She tolerated therapy well with granulocyte colony-stimulating

factor support.

TARGETED ONCOLOGY:How did you proceed with treatment for this patient?

Pro:The patient was treated with AVD with the addition of brentuximab vedotin. The interim PET/CT scan shows a Deauville [score] of 3, which is considered negative according to most of the studies. I think one of the major discoveries in the treatment of Hodgkin lymphoma together with a checkpoint inhibitor has been the introduction of brentuximab vedotin. The unique feature of Hodgkin lymphoma is the presence of CD30, which is strongly expressed on the surface of the Reed-Sternberg cells. We have an antibody-drug conjugate, brentuximab vedotin. It links the naked antibodies, the anti-CD30 antibodies, with a chemotherapy agent, which in this case is monomethyl auristatin E. The beauty of this compound is that it binds to the surface of the cell and then gets internalized inside the cell, and that’s where the chemotherapy agent gets released. It is targeted and tailored therapy to the CD30-expressing lymphoproliferative disorder. Brentuximab vedotin has shown good activity in patients with relapsed disease after having failed an intolerable stem cell transplantation. The question over the last 5 years has been “Can we include brentuximab vedotin in frontline treatment of Hodgkin lymphoma and achieve better results?”

TARGETED ONCOLOGY:Please discuss clinical trials showing the efficacy for brentuximab vedotin in patients with advanced-stage Hodgkin lymphoma.

Pro:A phase I study showed it was possible, and it was associated with significant activity. Based on those preliminary findings, there was a major randomized study that included patients with advanced-stage Hodgkin lymphoma. Patients were randomized to either ABVD or the experimental arm, which was brentuximab vedotin integration with AVD. The change here is that the bleomycin is not there and instead, you add brentuximab vedotin.²

[ECHELON-1] was a large study with over 600 patients in each arm. The unique feature of this study was that the major endpoint was a modified progression-free survival [PFS]—not the typical PFS, but the modified PFS was defined as time to progression, death from any cause, or the patient having to have subsequent anticancer therapy when complete response was not achieved. That endpoint, which has been criticized, somehow was chosen. I think the idea behind choosing that endpoint was to see how curative this approach is.²

The major endpoint was met. We had patients treated with brentuximab vedotin in combination with AVD having a better PFS compared with the standard ABVD. This was done by an independent group, and when you look at the investigator assessment, you can see an even more striking difference in the 2 [Kaplan-Meier] curves. The 3-year PFS rate was 83.1% in the experimental arm versus 76% with AVBD. The 2-year PFS was 84% versus 78%.³

TARGETED ONCOLOGY:What differences were observed across the subgroups in the study?

Pro:When we look at the different subgroups of patients to see if there were any differences in patient or disease characteristics in terms of efficacy of the experimental arm, [we see that almost] every single group benefited from the experimental arm. However, there are some differences that I think are striking: Patients living in North America did better than patients within Europe and Asia; patients who had extranodal disease, more than 1 extranodal site, did better; and patients who were 65 years of age or older did not do well compared with the ABVD arm.

TARGETED ONCOLOGY:How did the toxicity profile of brentuximab vedotin affect the study?

Pro:One important aspect of this study is in the toxicity profile and the differences in the experimental arm versus the standard arm. Growth factor support was not mandated at the beginning of the study, so it was left to the discretion of the investigator. But we know that brentuximab vedotin causes myelosuppression. Myelosuppression was associated with the experimental arm, more so than in the standard arm. When you look at [events associated with] neutropenia, there was a significantly higher rate of events in the A(BV)VD arm when compared with ABVD even in patients who received growth factor support. It is something to remember if you have a patient who you are treating with A(BV)VD for advanced-stage Hodgkin lymphoma. You need to pay attention to the risk of infection even when you give growth factor, and everybody should receive growth factors.

A major problem [with the toxicity profile of brentuximab vedotin] is peripheral neuropathy. We sometimes forget about it, but patients who are treated with ABVD can have neuropathy. Consider the rate is much higher when you use brentuximab vedotin paired with AVD. However, at 30 months follow-up—close to 3 years—the neuropathy either resolved or improved in most of the patients. I think that’s important to know that the majority of this neuropathy is reversible, but it is something you need to pay attention to, because if you consent to give the drug and the patient has neuropathy, the neuropathy can get significantly worse, and then you can affect them long term. These are young patients, so you cannot afford to have long-term sequelae. I think it is important to pay attention to these 2 adverse effects, which are the rate of neutropenia and risk of infection, and the rate of peripheral neuropathy.

TARGETED ONCOLOGY:What’s your approach toward monitoring toxicity and management for patients receiving first-line A(BV)VD?

Pro:I tell my patients that peripheral neuropathy is the real deal. This does not happen right away…and patients try to play it down. I tell my patients to walk when I see them, because I need to see their gait. I’ve had patients with terrible neuropathy, and they will not mention it to me. I want to caution them about the risk of infection and the neutropenic precautions, just like you do with patients undergoing aggressive chemotherapy.

TARGETED ONCOLOGY:Has the study changed how you decide on treatment for patients?

Pro:I think for advanced-stage Hodgkin lymphoma, I have switched over [to the brentuximab vedotin regimen]. This trial was powered to tell me that there is an improvement in PFS. I think if we are going for a curative intent, we should consider giving it.

References

1. Diehl V, Franklin J, Pfreundschuh M, et al; German Hodgkin’s Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease.N Engl J Med.2003;12;348(24):2386-2395. doi: 10.1056/ NEJMoa022473.
2. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma.N Engl J Med.2018;378(4):331- 344. doi: 10.1056/NEJMoa1708984.
3. Connors JM, Younes A, Gallamini A, et al. Brentuximab vedotin plus chemotherapy in patients with advanced-stage classical Hodgkin lymphoma (cHL): evaluation of modified progression-free survival (mPFS) and traditional PFS in the phase 3 ECHELON-1 study.Blood.2018;132(suppl 1; abstr 2904). doi: 10.1182/blood-2018-99-118828.