Adding, Reducing, or Discontinuing Agents in cHL Therapy

Leo Gordon, MD:When making determinations or decisions about chemotherapy in any patient—chemotherapy for any disease—one has to look at the possibility of dose adjustments or dose reductions or dose modifications. Our sense in Hodgkin lymphoma, in a curable malignancy, is that we don’t like to make dose adjustments, we don’t like to reduce doses, and we don’t like to delay treatment. That was the basis in describing our experience of patients with [Hodgkin] lymphoma treated with ABVD [doxorubicin/bleomycin/vinblastine/dacarbazine]—that we had 0 dose reductions and 0 delays without the use of the growth factor in those patients.

Now, when you’re adding drugs such as brentuximab vedotin, one of the issues with it is that you may have to make dose adjustments. We don’t have a big database to look at and say that dose adjustments have a negative impact on treatment, but I think if we extrapolate from other cancer chemotherapy, dose intensity is probably still important in this regimen, and I have some concerns about making adjustments in doses for toxicity. At the same time, we have to be cognizant of dose toxicities. That’s one of the concerns I have with this particular regimen. By combining brentuximab and Velban [vinblastine], we’re going to see more neuropathy, and I do wonder if giving them separately would allow us to give doses of each without having to make adjustments to the dose of the other.

The Adriamycin [doxorubicin] reduction in this patient is a little bit unusual. Stopping it is unusual. I don’t think that a dose reduction is warranted. If you see a drop in the injection fraction, you have to make a decision that it’s a real reduction, a significant reduction, and consider the use of cognitive protective agents such as Zinecard [dexrazoxane] rather than stopping the drug or adjusting the dosage. Those are the things I would consider if we were in the realm of dose adjustments.

We do have to sometimes deal with neuropathic pain in patients getting brentuximab vedotin and Velban. Our approach has been to treat those symptomatically. Sometimes, we use either gabapentin, pregabalin, or Lyrica [pregabalin], and that is helpful. I will say that I found neuropathic pain a difficult symptom to treat, and I don’t find those drugs to be of major benefit, but we certainly do try them. In those patients, sometimes we use muscle relaxants if there’s a lot of cramping that you can see with Velban. I think the use of Lyrica in this particular patient is reasonable.

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