Balancing Quality of Life and Efficacy in cHL

Leo Gordon, MD:Treatment was continued, and the plan was to give 6 cycles, which I think is standard for patients with stage III or IV, or advanced, Hodgkin lymphoma. That treatment was continued, and as it went along, she began to have worsening toxicities. Among them was worsening peripheral neuropathy, which limited her ADLs [activities of daily living]. She also developed what appeared to be cardiac toxicity with a drop in her ejection fraction. Now, in this case, Adriamycin [doxorubicin] was held somewhere around the fifth cycle because the ejection fraction dropped below 50%. I think there’s some concern about holding Adriamycin, although there’s also concern about cardiac toxicity. It’s been very rare that we’ve had to hold or stop Adriamycin in patients getting AVD [doxorubicin/vinblastine/dacarbazine], ABVD [AVD + bleomycin], or ABVVD [AVD + brentuximab velcade] chemotherapy—any Adriamycin-containing chemotherapy for Hodgkin lymphoma. I think it’s an important part of the regimen. I think one has to be certain that there’s real cardiac toxicity. [Afterward], the ejection fraction improved, and it was restarted. It’s not clear what the course of those events were or why she dropped in ejection fraction.

One alternative to that might have been to add Zinecard [dexrazoxane], which is a cardioprotective agent that chelates iron and diminishes the number of free radicals that are produced and are injurious to the heart. That’s probably the mechanism of cardiac toxicity in patients getting Adriamycin, so that would be an option that one would have.

We usually see these patients if they have any cardiac history or drop in injection fraction. We see them together with cardiologists who are especially well versed in oncology and so-called onco-cardiologists, who we get to work with quite a bit. That has really helped our ability to manage these patients. There’s also the use of echocardiograms and strain echoes and strain patterns that will help determine cardiotoxicity. It sounds like Adriamycin was resumed in this patient, and she finished the course of treatment minus brentuximab for the last cycle or so of her treatment. An end-of-treatment PET [positron emission tomography] scan showed continued complete remission.

What are some lessons from this case? I think the history of smoking and her age made her a noncandidate for bleomycin, so one is already looking for alternatives. I think this regimen is a reasonable alternative, and I think this regimen is a reasonable alternative for that population of patients. I’m not yet ready to make this my standard of care for all patients with [Hodgkin] lymphoma. I think there are trade-offs between the brentuximab and the bleomycin, and one has to weigh the risks and benefit. In this particular patient, I think the benefit would clearly outweigh the risk of using bleomycin because of her smoking history and her age.

The other things to weigh in making these decisions are neuropathies. For example, if she has a history of diabetes or a familial history of peripheral neuropathy, I think one would need to be careful with the use of brentuximab and Velban [vinblastine] together. One might then consider using them separately, where maybe the risk of neurotoxicity would be less. I think one also has to think about what the goal of treatment is in this patient who is age 52 and has stage III disease. The goal is cure it. I think we have to look for the best regimens that will give us the best complete remission rate and the best long-term remission rate, and now we’re hoping for cures in any new patient who is seen with Hodgkin lymphoma.

I think the other thing to look at is potential cardiac toxicity. Is there a preexisting history of cardiac disease? Is there a strong family history of cardiac disease? Do we have to consider frequent echocardiograms after every cycle? We’ve sometimes done that in patients with significant cardiac disease so that we can make adjustments as we go along.

Transcript edited for clarity.

A 52-Year-Old Woman With Stage IIIa Hodgkin's Lymphoma

• History and physical exam
  • A 52-year-old female presented with abdominal pain
  • Labs: B12 deficiency, albumin 3.5 mg/dL, Hgb 11.5 g/dL, white cell and lymphocyte counts WNL
  • No B symptoms
• Right cervical excisional biopsy: classical Hodgkin’s disease, nodular sclerosis, stage IIIa
• Cardiac and lung function were normal
• IPS 2
• AVD + brentuximab (1.2 mg/kg) q2w x 6 cycles was initiated 2.5 months later

Treatment Course

Cycle 1, d 1

Leg cramping; hospitalized for neutropenic fever (d 7-14)

Cycle 1, d 15

Bone pain; constipation

Cycle 2, d 1

AVD + brentuximab delayed 1 wk due to neutropenia hospitalization; elongated QT interval (drug related); PPI initiated for reflux; constipation causing abdominal pain; numbness in hands

Cycle 2, d 5

GERD, constipation, and neuropathy unchanged

Cycle 2, d 16

Hospitalized 8 days for neutropenic fever; discharged on amoxicillin (infection source unknown)

Interim PET-CT

Complete response (Deauville score 2)

Cycle 3, d 1

Filgrastim 5 mgc/kg qd, d 5-10; treatment well tolerated; ED for bronchitis (azithromycin), good response

Cycle 3, d 15

Treatment well tolerated; ANC > 3 throughout treatment; grade 1 neuropathy (numbness in fingertips, palms, and toes)

Cycle 4, d 1

Treatment tolerated well; no fever; grade 1 neuropathy

Cycle 4, d 15

Brentuximab dose reduced to 0.8 mg/kg, due to grade 2 peripheral sensory neuropathy; transient grade 1 skin and mucosal abnormalities around day 8

Cycle 5, d 1

Grade 2 neuropathy; pregabalin for muscle pain and weakness initiated

Cycle 5, d 15

EF < 50%; slightly worsened neuropathy (impacting work and daily life); doxorubicin held (in consult with cardiologist)

Cycle 6, d 1

Doxorubicin restarted (per cardiologist/> 50% EF); grade 3 neuropathy; leg weakness increased; brentuximab held

Cycle 6, d 15

Neuropathy continues; brentuximab held

PET/final restaging

Negative

• Neuropathy resolved; no limitations by 6 months post-treatment