Pro Talks Treatment for Peripheral T-Cell Lymphoma

Barbara Pro, MD

During a Targeted Oncology Case Based Peer Perspective event, Barbara Pro, MD, professor of Medicine, Division of Hematology and Oncology, Feinberg School of Medicine Robert H. Lurie Comprehensive Cancer Center, at Northwestern University in Chicago, IL, discussed the case of a 60-year-old male patient with peripheral T-cell lymphoma.

Targeted Oncology™: What is your initial impression of this case?

PRO: It appears that the patient has localized, but bulky, disease. This is important when you think about the treatment strategies.

How do the National Comprehensive Cancer Center (NCCN) guidelines suggest treating a patient in this setting?

For PTCL-NOS, specifically looking at first-line therapy, [the guidelines] still list [enrollment in] a clinical trial because this is an area of unmet need where the prognosis is dismal with standard approaches, so clinical trial is still indicated.¹

For other histologies [besides PTCL-NOS], they say the preferred regimen is BV CHP [brentuximab vedotin (Adcetris), cyclophosphamide, doxorubicin, prednisone] for CD30-positive histology. We can debate what is considered CD30 positivity—is 5% positive enough to be able to have a good response and a durable response with BV CHP? Unfortunately, we don’t know that. Then the other regimens listed are CHOEP [cyclophosphamide, doxorubicin, etoposide, vincristine (Oncovin), prednisone], CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], and dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin].

The use of CHOEP is based on a German study that proved that CHOEP was making an impact in terms of progression-free survival, [but] only for patients who are young and have [ALK-positive] anaplastic large cell lymphoma [ALCL]. But the benefit in other histology was marginal.

If this treatment is used for other histologies, why has this patient received it?

This was based on the [ECHELON-2] clinical trial [NCT01777152].² Brentuximab vedotin is approved for patients with relapsed/ refractory ALCL and has also shown activity in patients with relapsed/refractory PTCL with other subtypes.³

The eligibility criteria, which I think are important when you try to interpret the data in order to help the patients you see in your clinic, indicate that CD30 positivity was defined as 10% or more in neoplastic cells. Remember, patients can have CD30 positivity in the background, in the microenvironment. This was a strict criterion.

Eligible histology is also important to remember. The majority of patients treated [in] this study had systemic ALCL; 70% of patients had that histologic subtype. [Patients also had] good performance status and no significant peripheral neuropathy. So, patients with peripheral neuropathy of grade 2 or higher were excluded from this study.

Nevertheless, this was the largest study conducted in the frontline treatment to randomize patients with PTCL. For 452 patients, the comparator arm was CHOP and the experimental arm was brentuximab and CHP; so, CHOP without vincristine because of the possibility [of] and a concern about overlapping neurotoxicity. The primary end point, as opposed to the one in the ECHELON-1 study [NCT01712490], was standard definition of progression-free survival [PFS].

What was the efficacy of the ECHELON-2 trial?

The study met the primary end point. The median PFS with CHOP was 20.8 months. This doubled in patients receiving brentuximab in combination with CHP [48.2 months; 95% CI, 35.15–not reached]. There was a nice separation of the Kaplan-Meier curves.

The improvement in PFS translated into improvement in overall survival [OS], with a median OS at the time of last follow-up as not reached for both arms. But, again, there was a nice separation of the curves. The hazard ratio was 0.66 [95% CI, 0.46-0.95; P = .0244]. So [it was] significant by a point or 2.

The complete remission [CR] rate in PTCL is not an important end point because even in patients who achieved CR, the risk of relapse is 80% with standard CHOP. CR rates were 68% in the arm with brentuximab and 56% in the CHOP group. This high number of CR rate with the CHOP arm is probably due to the fact that a significant percentage of patients here had ALCL and not the other histology. A higher number of patients in the CHOP arm had progressing disease.

How did CD30 positivity play a role in this study?

The study was done with a strict entry criterion, which [was] the CD30 positivity [in 10% or more in neoplastic cells]. What about patients who had lower positivity? There are a number of studies that have shown, mainly in patients with cutaneous T-cell lymphoma mycosis fungoides where…2 biopsies [were] done, that CD30 positivity does not correlate with the response. But the question is, you probably need some positivity. [But] what is some positivity? Some physicians will say 1% or above is enough to be able to have a response with brentuximab vedotin. We don’t have a larger study that has addressed that.

What do you think of the poll answers?

My experience is that [deacetylase inhibitors] are effective in [ALCL] and a bit less effective in other histologies, but [this is] definitely something that is approved.⁴ Pralatrexate is more effective in PTCL-NOS. For brentuximab, we need to know whether or not the patient has CD30 positivity, to see whether or not it’s going to be effective.

The NCCN Guidelines lists the 4 drugs that are approved and they specifically say brentuximab is for CD30-positive PTCL.1 Then you have [the] combination regimens DHAP [dexamethasone, cisplatin, cytarabine], ESHAP [etoposide, methylprednisone, cytarabine, cisplatin], GDP [gemcitabine dexamethasone, cisplatin], ICE [ifosfamide, carboplatin, etoposide], and then another combination of [gemcitabine]. [Single agents include bendamustine], gemcitabine, and lenalidomide [Revlimid].

Some [oncologists] said “clinical trial” because the outcome of this disease in terms of effective therapy for salvage is dismal, so a clinical trial still should be considered for this patient.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. T-cell lymphomas, version1.2020. Accessed August 28, 2020. http://bit.ly/2G0YfBi}

_{2. Horwitz S, O’Connor OA, Pro B, et al; ECHELON-2 Study Group. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229-240. doi:10.1016/S0140-6736(18)32984-2}

_{3. FDA approves brentuximab vedotin for previously untreated sALCL and CD30- expressing PTCL. FDA. Updated December 14, 2018. Accessed August 27, 2020. http://bit.ly/3gxYjVF}

_{4. Lee HZ, Kwitkowski VE, Del Valle PL, et al. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin Cancer Res. 2015;21(12):2666-2670. doi:10.1158/1078-0432.CCR-14-311}