Exploring First-line Therapies in Peripheral T-Cell Lymphomas

Javier Munoz, MD

During the Targeted Oncology Case Based Peer Perspectives event, Javier L. Munoz, MD, Hematologist/Oncologist Director, Lymphoma Program Mayo Clinic, discussed the case of 60-year-old patient with peripheral T-cell lymphoma (PTCL).

Targeted Oncology™: What are the standard regimens in treating T-cell lymphoma?

MUNOZ: Historically, we have been prescribing CHOP [cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone] or CHOP-like regimens. There are retrospective German data showing the addition of etoposides, so CHOEP instead of CHOP, may be beneficial, particularly for patients who were younger than 65 years.¹ That is not a randomized trial, it was a retrospective study, so the strength of the data was relatively weak.¹ The data of brentuximab vedotin [Adcetris] plus CHP [cyclophosphamide, doxorubicin, prednisone] versus CHOP [was from] a randomized trial, so it’s a stronger level of evidence compared with that etoposide data.

What do the National Comprehensive Cancer Network (NCCN) guidelines recommend?

The category 1 recommendation for ALCL [anaplastic large cell lymphoma] is brentuximab vedotin plus CHP, according to the NCCN.² For that particular indication, I think most people are not going to argue that brentuximab plus CHP is the way to go.

For the other subtypes—and numbers for the other subtypes were smaller compared with ALCL—it’s a bit more blurry. You still have brentuximab vedotin plus CHP, but you also have the options of CHOP, CHOEP.

What was the rationale for ECHELON-2 [NCT01777152] in this population? This was a randomized study, brentuximab vedotin plus CHP versus CHOP.³ The bottom line is that this trial was a replacement strategy. Vincristine, or Oncovin, is a vinca alkaloid, and it causes neuropathy. For brentuximab, an antibody-drug conjugate, its payload is also a vinca drug. Vinca alkaloids cause neuropathy, so the trial replaced those agents, resulting in this trial. It was a double-dummy, [double-blind] study, so patients received placebo—brentuximab and CHP or they received CHOP. The CD30 expression needed to be 10% or higher for the patient to be able to enroll. The investigators allowed multiple subtypes of T-cell lymphomas: PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, enteropathy-associated T-cell lymphoma.

The reality is that most of you are going see PTCL, not otherwise specified, because it’s the most common subtype I see; maybe the runner-up is angioimmunoblastic T-cell lymphoma, and then the next one is going to be ALCL. And again, there are a couple of flavors: ALK-positive and ALK-negative. ALK-negative is, prognostically, closer to PTCL. The primary end point was progression-free survival [PFS] but, of course, they looked at other things like overall survival.³

What were the outcomes of this trial for patients? PFS was a primary end point, and this was the most important factor or variable that they looked at, and with CHOP you get 20.8 months of PFS; with brentuximab plus CHP you got 48.2 months. So, more than double the primary end point, and that is why I like to start with PTCL, because ECHELON-2 definitely looked more impressive than the ECHELON-1 trial [NCT01712490]. They’re both important papers; ECHELON-1 was published in New England Journal of Medicine,⁴ ECHELON-2 was only published in Lancet. The difference, the numbers that you see, are more dramatic in ECHELON-2 in PTCL compared with Hodgkin lymphoma, but both are relevant papers. More than double the results, and you could see that that separation is maintained over time.

They looked at overall survival, and there was also a difference. Even though the primary end point was PFS, your patients are also going to live longer if you go with brentuximab plus CHP.

The complete response rate was 68% for [brentuximab vedotin plus CHP] versus 56% for CHOP. Of course, the objective response rate is also higher for brentuximab plus CHP, as well [TABLE5 ].

As I said, both drugs can potentially cause neuropathy. Let’s take a look at the safety profile. Peripheral neuropathy for brentuximab plus CHP, grade 3 or higher, was 4%, for CHOP, it was 3%. Remember, vincristine in the CHOP regimen can also cause neuropathy. Not a big difference there. For any grade of neuropathy, the numbers are 45% for brentuximab plus CHP and 41% for CHOP.

Now, could you die from CHOP, or brentuximab plus CHP? Of course. Luckily for us, it’s single digits. It’s rare—I’m sure that we have all had patients that we have lost during CHOP or R-CHOP [rituximab (Rituxan) plus CHOP] for B-cell lymphomas, but 3% for brentuximab plus CHP and 4% for CHOP.

If this patient achieved a complete response to frontline therapy, would you consider transplant?

Before the ECHELON trials, most of us knew that CHOP was suboptimal; we just did not know what was better than CHOP. That’s why we were playing with etoposide, based on that retrospective German data and doing CHOEP, sometimes even EPOCH [etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride] for these patients. Because CHOP was suboptimal, we wanted to do something additional, and that is why many patients have received consolidation with transplants.

We consider so many factors for transplant-eligible patients—the performance status, comorbidities, age; but in general, I’m prone to offer [transplant] to patients who have these T-cell lymphomas because, again, it’s a bad disease, and it’s not a curative intent. You are not giving the treatment with a curative intent. You want to keep the disease at bay as much as possible.

What is the impact of consolidative stem cell transplant after frontline brentuximab plus CHP for patients?

In a post hoc analysis, for the patients who achieved complete remission [CR], 38 patients in CR, received the transplant, and 76 patients in CR did not; it was certainly not the primary end point.5 It was presented at the American Society of Hematology Annual Meeting in 2019. Again, we are tempted to prescribe the transplant because, historically, these patients have done so poorly. The majority of these patients in CR after brentuximab plus CHP did not receive a transplant, 38 patients did receive a transplant, and it seems that the patients that received the consolidation with the transplant did better than the patients who did not receive the transplant. You have the 3-year progression-free survival numbers: 76% and 53%, though my bias at this point would be young, relatively young, or with few comorbidities, good performance status—I would certainly send the patient to get a second opinion.

What would be your approach toward second-line therapy at progression?

The number 1 option is a clinical trial. I’d also consider pralatrexate [Folotyn]. Belinostat [Beleodaq], pralatrexate, and romidepsin [Istodax] are going to give an overall response somewhere between 20% to 30%, and complete remissions that are approximately 10%, give or take. Duration of response is usually going to be less than a year. Bottom line, we need to do better for PTCL when it’s relapsed/refractory. We need to do good when it comes to our frontline therapies, so, hopefully, we can provide a long period of time of remission for our patients.

_References:

_{1. Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German high-grade non-Hodgkin lymphoma study group. Blood. 2010;116(18):3418- 3425. doi:10.1182/blood-2010-02-270785}

_{2. NCCN. Clinical practice guidelines in oncology. T-cell lymphomas, version 1.2021. Accessed October 14, 2020. https://bit.ly/3kcUHLL}

_{3. 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}

_{4. Connors JM, Jurczak W, Straus DJ; 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}

_{5. Savage KJ, Horwitz SM, Advani RH. An exploratory analysis of brentuximab vedotin plus chp (A+CHP) in the frontline treatment of patients with CD30+ peripheral T-cell lymphomas (ECHELON-2): impact of consolidative stem cell transplant. Blood. 2019; 134(suppl 1):464. doi:10.1182/blood-2019-122781}