Hodgkin Lymphoma: Considerations for Frontline Therapy

Leo Gordon, MD:This patient had an international prognostic score [IPS] of 2. She had risk factors regarding age and a low serum albumin, but her white cell count was normal, her hemoglobin was normal, and her lymphocyte count was normal. She was female, not male, which is a positive prognostic sign. And so, one wonders, is it the international prognostic score that dictates your therapy? We know that in the higher IPS scores, the differences weren’t as apparent between the 2 regimens. I think the main driving factor for considering the use of brentuximab vedotin over bleomycin is her age and especially her smoking history.

Our experience has been—and the data suggest—that patients over the age of 40, especially smokers, have an incidence of anywhere from 30% to 50% of bleomycin lung injury. And in that cohort of patients, mortality is around 20%. Once one develops bleomycin lung injury, the chance of dying from that is 1 in 5. It’s a significant toxicity. I think we have been looking for a long time for alternatives to the use of bleomycin in patients who are at higher risk for bleomycin lung injury.

Now, what are some of the risks for that? I’ve mentioned age, over 40; smoking history; and also, shown by the Mayo Clinic study published a number of years ago, the use of the growth factor. The use of Neupogen [filgrastim] and Neulasta [pegfilgrastim] stimulates the production of white blood cells. Those white cells release toxic oxygen radicals and other enzymes when they get to the first capillary bed, which is in the lung, and we think that increases the risk of bleomycin lung injury. I think the driving force for the use of this regimen, for a non—bleomycin-containing regimen, was her smoking history and her age.

What are some alternatives? Well, one might have used AVD—just Adriamycin [doxorubicin], Velban [vinblastine], and DTIC [dacarbazine]—leaving out the bleomycin and not adding brentuximab vedotin. In studies from the German Hodgkin Study Group, leaving out bleomycin and not substituting anything for it results in a slightly worse progression-free survival and overall response rate. Although that is an option, I think that based on the data from the ECHELON study, the addition of brentuximab is a very reasonable option for this patient.

Now, are some of the toxicities this patient had expected? Certainly, the febrile neutropenia was expected. We tend to use a preventive, prophylactic antibiotic in our patients getting ABVD chemotherapy [doxorubicin/bleomycin/vinblastine/dacarbazine], and I would say this also applies to ABVVD [doxorubicin/brentuximab vedotin/vinblastine/dacarbazine] chemotherapy. We’ve used Bactrim [sulfamethoxazole/trimethoprim] as prophylaxis, fluconazole, and acyclovir. We don’t routinely use antibacterial prophylaxis with drugs such as Levaquin [levofloxacin] or ciprofloxacin. I think the febrile neutropenia in this patient is not unexpected. The lesson there is probably having to use growth factor in patients getting this regimen.

Subsequent toxicities on later cycles included 2 major problems. One is neuropathy. It appears that the neuropathy developed fairly early, after the first day of cycle 2, and then progressed as she went through her course of treatment. The neuropathy can be limiting. Dose reductions do help. And sometimes one has to stop the drug entirely, which I think was done at the end of the course of chemotherapy in this particular patient. The neuropathy might be mild and not limit normal functions, ADLs [activities of daily living], but for this patient, it really had some significant effects on her quality of life.

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