Andrew M. Evens, DO, MSc

 Case-Based Roundtable, Andrew M. Evens, DO, MSc, an associate director of Clinical Services and director of the Lymphoma Program at Rutgers Cancer Institute of New Jersey, as well as the medical director of Oncology Service Line at RWJBarnabas Health in New Brunswick, NJ, discussed testing and treatment for a 22-year-old patient with Hodgkin lymphoma.

: Would you order additional testing for this patient at this time?

: We used to do bone marrow [biopsies], but now—at least for younger patients, if not for everyone—a bone marrow [biopsy] is not more sensitive [than a PET scan]. When you look at positive/predictive/negative, even though she had bone uptake, not bone marrow, you could argue you already know she’s stage IV. And so, we usually do not do bone marrow [biopsies], and at least [currently] there is no molecular testing [for Hodgkin lymphoma]. This isn’t like some of the solid tumors or even non-Hodgkin lymphoma. There’s no MYC or other molecular testing to do. We want to have more molecular markers. The only other test you would think about— [and] you don’t have to get it if you’re going to give bleomycin— might be pulmonary function test. We still get echocardiograms, not because we expect there to be any problems in a healthy 22-year-old, but we just want a baseline. We’re not going to repeat it. We just want a baseline for future reference [before we give] anthracycline....[But there is] no other real testing at this point.

Do you calculate prognostic scores for your patients with Hodgkin lymphoma?

I don’t vary treatment based on [a prognostic score]....It’s prognostic, it doesn’t tell me what to do different, per se. I know NCCN [National Comprehensive Cancer Network] guidelines prompt us one way, but...it’s not critically wrong if you don’t.

There are 2 issues with [the International Prognostic Score (IPS)].

 One, [it was] published in 1998. Two, there’s no real diving down score. Yes, there is some...updated literature where a lot of these [survival] curves have come together. If you use ABVD [doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine] and other modern therapy—for what it’s worth, this patient would qualify with higher-risk disease by the IPS score [because of her] anemia, stage IV [disease], [white blood cell] count, and lymphocyte count being low.

What are your thoughts on the results of the poll? What would you have chosen of these options?

OK, so [half of the respondents chose] PET-adapted therapy with ABVD, so-called RATHL [response-adapted therapy for advanced Hodgkin lymphoma]; some would give her escalated BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone], hit her hard out of the gates. Others [chose the] ECHELON-1 [NCT01712490] [regimen], brentuximab vedotin [BV; Adcetris].


I would have chosen BV plus AVD [doxorubicin, vinblastine, dacarbazine] for this. I used to give RATHL all the time. I’ve become dissuaded from using BEACOPP. I had a patient [to whom] I’d probably given it 25 times, and I can tell you it’s 25 hard times. One patient developed leukemia. Another one had osteonecrosis, and she was in her 30s. It was a nightmare, what you can see with BEACOPP; it’s not a wrong therapy, though.

Before the ECHELON-1 trial, [I would have used BEACOPP more] because it was more gestalt. If anything, there’s a PFS [progression-free survival] advantage, but it’s a hard treatment, especially escalated BEACOPP. [To me, it’s] the hardest outpatient treatment to give. You have to give Aloxi [palonosetron hydrochloride]/Emend [aprepitant]. It’s a really tough therapy. By the way, do not give it to anyone over age 50 or 60. Even with baseline BEACOPP, the treatment-related mortality rate is [greater than] 20% for patients over age 60. If you had a patient such as this who presented 6 years ago, and we knew her outcome with ABVD was 60, we would say, “Oh, let’s do something.” Now that we have another alternative that’s better tolerated, frankly, and maybe as effective, [although] it’s never been tested head-to-head, I don’t have a reason to give it nowadays.

How do you decide between PET-adapted ABVD or non– PET-adapted therapy?

PET-adapted [would] let me start with ABVD, and if my PET-2 is positive, meaning if it shrinks but I have a site still as hot as the liver, I’m then going to change to escalated BEACOPP, which ends up being about 20% to 25% of patients. The problem is that you ask [practitioners if they escalate to BEACOPP] and most say, “You know what, no.” So...if you keep giving ABVD in a [patient who is] PET-2 positive, your 4-year PFS [rate] is about 45%. That’s another reason why I’ve morphed to [giving] BV plus AVD; you still get a PET scan, but you’re not changing or escalating.

Do you use radiation for patients with advanced-stage disease?

No. The only caveat might be if someone in a weird case came in with advanced stage and a 15-cm mass...and maybe it would consolidate. There are some data that bulky disease in advanced stage is a poor prognostic factor. We’re not sure what to do about it. The Germans use a PET scan. But my problem is if someone’s still PET positive, you do see 1% or 2% who are primary refractory.

What do you consider to be the most important factor when deciding on a treatment recommendation for someone such as this patient?

These are hard questions because it’s rarely 1 factor that drives decision-making. It’s usually a lot of different things. So, even though [I said I don’t use] prognostic score, you’d like to know it. Of course, [knowing] performance status—can I be aggressive? Does she have lung disease? Smoking history really doesn’t affect anything....She’s 22, so you’ll be aggressive; if she were 72, you’d be less aggressive.

Another [factor is] fertility. The problem is BEACOPP causes infertility in a 22-year-old and at least half of women. You usually don’t have time. [A 22-year-old woman may not] have a partner. You [could] bank ovarian tissue, but it’s harder to do. It’s even harder if they don’t have a partner to do in vitro. We try to do it sometimes. At least the data with BV plus AVD would tell us we don’t think it affects fertility. You can’t say 0. For ABVD, I’ll quote1% to 2%. But BEACOPP is a bigger issue with fertility.

What would the guidelines recommend for such a patient?

The NCCN guidelines [are] a little formulaic in Hodgkin lymphoma.

 My friends and colleagues give ECHELON-1 here a category 2A [recommendation]. Where I disagree with my esteemed colleagues is when they talk more about high IPS or bleomycin being contraindicated. Well, to me, bleomycin being contraindicated is subjective. I would say bleomycin is contraindicated in almost everyone if I don’t have to give it on that. I, personally, do not use IPS to select it. They still try to steer patients toward RATHL. The problem is many patients, I can tell you, do not end up going to escalated BEACOPP. But I, frankly, don’t blame them because it is a tough therapy.

What data support the use of this regimen?

This is the alpha [trial that] we’ve already mentioned several times—ECHELON-1, an international phase 3 randomized study.

 A lot of the response-adapted data had not matured yet, so that’s why this was not, in part, response adapted. The standard arm was ABVD. At the time, the experimental arm—well, it’s now approved—was BV plus AVD. BV given 1.2 mg/kg on the same days as AVD, days 1 and 15. Patients received 6 cycles. They did a PET-2 scan but did not recommend changing therapy based on this. All [patients were] advanced stage...and over age 18.

The 2-year [data were] published in the New England Journal of Medicine in 2018.3 David Straus, MD, gave the 3-year data [of 83.1% with BV plus AVD versus 76.0% with ABVD].

 Usually in the Hodgkin lymphoma setting, [almost] 99% of all data is about PFS. It’s going to be hard in Hodgkin to show overall survival [OS]. We know we can salvage patients with transplant and checkpoint [inhibitors], etc. What you’re left with is an absolute improvement of 7 percentage points. To some people, that’s modest. To others, [including] me, that’s pretty good. I think it’s hard to ask 1 drug in lymphoma, or any cancer, to go up that point. This is, to me, also where hazard ratio is helpful.

The hazard ratio [was] 0.7. The way to phrase that is that it was a 30% risk reduction in PFS, which is progression or death. There [are] 5-year data that were presented at [the American Society of Hematology annual meeting] that basically show the same thing [of 84.7% with BV plus AVD versus 78.8% with ABVD in patients who are PET2 negative].

There are relapses. Most relapses happen in the first 2 years, 80%. But 15% to 20% of relapses happen in years 2 to 5, probably closer to 15%. So, it was important to see this persistent threat and advantage at 3 years and 5 years.

Not surprisingly, on the forest plot pretty much everything was shifted over, favoring BV plus AVD. [Age] is [another underappreciated part] of all the BEACOPP data. I alluded to this with RATHL; nobody is over age 60. Anyone over age 60 is going to bring down [the Kaplan-Meier] curves. There were almost 200 patients on this ECHELON-1 study that were over age 60. Because if you’re not using BEACOPP, you have no upper age limit. There was a benefit to [patients] over [age] 60. It is shifted a little bit, it’s a much smaller [percentage of patients, only] 186 patients, but certainly, it is not worse. And you avoid the bleomycin on this.

Looking at other factors, pretty much any risk factor is kind of shifted over to the left [favoring BV plus AVD].

Response rates were slightly better with BV plus AVD.

What about the safety data from the ECHELON-1 trial?

Of course, in Hodgkin it’s not all about PFS and other efficacy [points]; we want to know about adverse effects [AEs] Because we want to cure and mitigate, minimize AEs, especially anything post therapy.

 There were a couple of signals [which] were increased [in one arm] versus the other. The pulmonary [effects were] much higher on ABVD, and there were a couple fatalities from bleomycin on ABVD.

What about BV plus AVD? Peripheral neuropathy, diarrhea, and febrile neutropenia were a little higher.

What about neuropathy? This is important and not surprisingly so. BV has antitubulin [antibodies] in it. It’s an antibody-drug conjugate, but the drug is monomethyl auristatin E, or MMAE. [It has] a little antitubulin [antibodies in it]. Thankfully, most [neuropathy seen with BV] was low grade. Most either completely resolved or improved over time.

Should you routinely be giving growth factor prophylaxis with BV plus AVD?

The answer should be yes. This one is a right or wrong. And it’s OK [if you aren’t] because [the investigators] didn’t know it when they started the study or didn’t appreciate it—they knew there was going to be higher neutropenia, but about three-fourths of the way through this study, they noticed the febrile neutropenia rate was a little over 20%. Then they instituted, or highly recommended, growth factor prophylaxis and cut it down to 11%.

So, even for younger patients, you want to use growth factor out of the gates. I give Neulasta [pegfilgrastim]. It’s probably more than we need, but it’s just easier for patients to get on the day of their visit.

Almost every case I’ve seen, in 1 in 10 patients, [febrile neutropenia comes up during] cycle No. 1. Sometimes if I’m worried about someone, I might add on some antibacterial Levaquin [levofloxacin] or something such as that to try to help decrease that. You want to use growth factor throughout. 


What is your approach toward treatment selection for patients with comorbidities?

The No. 1, 2, and 3 [top] risk factors for bleomycin [are] age. And from looking at a lot of data, it’s exponential by decade. Usually, you don’t see it until the 40s, then 50s, then 60s, then 70s. A lot of it is because bleomycin is renally excreted. I guess renal function is an issue, too. The problem is that over age 70, the rate is almost 30% and there is a mortality rate of 20%. So, to me, you cannot predict it. In a random older patient, I’ve looked at everything. I’ve looked at smoking history, pulmonary function tests, echoes; it’s difficult [to judge outcomes based on comorbidities].


And [in] some of the bleomycin events, [the] benefits do not outweigh the risks. For older patients, I don’t use [bleomycin], or [for] anyone with pulmonary comorbidities.

What is your approach toward toxicity monitoring and treatment on BV plus AVD?

It’s [all about] communication. As it starts affecting function—instrumental ADLs [activities of daily living] and CTCAE [Common Terminology Criteria for Adverse Events]—working on a computer, a calculator, or cooking, laundry, etc—or if it’s ever painful, that’s a time to intervene. You hope it doesn’t affect self-care; that’s grade 3. The self-care [is] bathing, dressing, feeding, things such as that. So, [be] proactive, whether [a patient is] on BV or on CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] for that matter.

The only other thing I’ll do, too, is for older patients who tend to get dehydrated. I’ll bring them in weekly for fluids or do home fluids...try to be more proactive. And then also—and you can argue [for this] for any older [patient with] aggressive lymphoma— I’ll sometimes do a little prephase steroids. Because for that older patient who comes in with 18 comorbidities, it’s always the first cycle [where] you run into trouble. You give them a little pulse of 100 or 60 mg a day for 5 days, you’ll see their performance status bump up a point. I think we don’t talk enough about prephase.

Would you dose reduce if you saw a patient had a neuropathy issue?

It’s an absolute balance beam. You don’t want to start dose reducing and then compromise their treatability and cure. It is a fine line, for sure. But neuropathy, [according to] the clinical trial, if it hits a certain grade, especially grade 3, there was a dose reduction. One dose level down to 0.9 mg of BV. What I do is bring down the vinblastine. We might try Neurontin [gabapentin] or Lyrica [pregabalin]....It doesn’t always work. I had a patient who had acupuncture, even though I don’t recommend that during treatment, but it helped.

If I have to bring down [the dose], if I had to choose between BV and vinblastine, I think BV is the more effective between the 2 tubulins. I’ll maybe bring down the vinblastine a little bit, and I’ve rarely had troubles after doing that. Maybe I can think of 1 case where I also had to bring down the BV. For most younger patients, you stay ahead of this. You’re able to do that and whichever one you bring down, I probably wouldn’t bring down both at once, just bring down 1 at a time.

Looking ahead, what other regimens are in development for the treatment of patients such as this one?

I am the ECOG [primary investigator] for [the S1826 study (NCT03907488)], so I’m a little biased. But that’s why I have to have equipoise to give an IPS of 1 BV because we’re looking at IPS and they’re stratified on it, but the patient can be IPS 0, and if they still have stage III advanced-stage Hodgkin, they’re eligible for this study....It took about 18 months to design it before [coronavirus disease 2019].

It’s open in North America—United States and Canada. It’s open to ages 12 and above. There is no upper age limit because we don’t have BEACOPP. We had a heated debate about our standard arm. We went to the National Cancer Institute at the end of 2018. The BV data came out that January, so [the data were] about a year old. We knew RATHL. The reason we did not use PET [is that] as a group we said we’re not sure PET response adapted is the future in Hodgkin. Why? When we looked at our study, and if you looked at RATHL, the majority of relapses happened in patients who are PET-2 negative. In other words, the 5-year PFS rate was right around 75% in PET-2 negative. So, even in PET-2 negative, a quarter of patients relapsed.

Now, for the small percentage who are PET-2 positive, it’s even worse. It was 65% lower. But when you look at the total numbers, we [asked ourselves], “If most of the patients who are relapsing are PET-2 negative, how helpful is PET-2 negative?” And we couldn’t do a 3-arm study, so we had to choose our standard arm for this advanced-stage study in North America. And long story short, we chose ECHELON-1 as our “standard therapy” for this.

[The experimental arm is] nivolumab [Opdivo] plus AVD. We’ve accrued about 250 of 1000 patients; there is still plenty of time. There are a bunch of correlatives [such as quality of life] that we’re going to be looking at, [including] metabolic tumor burden.

1. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on advanced Hodgkin’s disease. N Engl J Med. 1998;339(21):1506-1514. doi:10.1056/NEJM199811193392104

2.NCCN. Clinical Practice Guidelines in Oncology. Hodgkin lymphoma, version 1.2021. Accessed December 21, 2020. https://bit.ly/3oDAEZ4

3. Connors JM, Jurczak W, Straus DJ, et al; 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


4. Straus DJ, Dlugosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemo- therapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study.

 2020;135(10):735-742. doi:10.1182/blood.2019003127

5. Straus DJ, Dlugosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for patients with previously untreated, stage III/IV classical Hodgkin lymphoma: 5-year update of the ECHELON-1 study.

. 2020;136(suppl 1):26-28. doi:10.1182/blood-2020-137089

Articles

During a Targeted Oncology Case-Based Roundtable, Andrew M. Evens, DO, MSc,  discussed testing and treatment for a 22-year-old patient with Hodgkin lymphoma.

Expert Explains Why He Uses BV Plus AVD Instead of BEACOPP in Hodgkin Lymphoma

Hodgkin lymphoma (HL) represents approximately 10% of all cases of malignant lymphoma. This group of diseases most commonly affects adolescent and young adults, although approximately 20% to 25% of patients are aged &ge;60 years at diagnosis. Advanced-stage disease is generally classified as Ann Arbor stage III to IV, but clinical trials often incorporate patients with high-risk stage II disease, such as those with B symptoms, multiple sites, or bulky disease. Approximately 65% to 75% of patients with advanced-stage HL will remain disease free at 5 years with conventional chemotherapy. This is in contrast with early-stage classical HL (cHL), in which the long-term cure exceeds 90%. Different prognostic indices are used for early-and advanced-stage disease. Prognosis in advanced stage is defined by the International Prognostic Index (IPS), which includes measurements of albumin and hemoglobin, sex, age >45 years, stage IV, and the presence of leukocytosis or lymphocytosis. Patients with an IPS &ge;3 have inferior treatment outcomes.

The majority of clinical trials over the past 10 years in advanced-stage HL have used response-adapted designs leveraging early PET imaging to guide subsequent therapy (eg, intensification vs de-escalation for patients with cHL with positive vs negative PET2 scans, respectively).

The randomized phase III RATHL (Response-adapted therapy for advanced Hodgkin lymphoma) trial from Johnson et al

assessed a PET-adapted therapy in patients with advanced-stage disease who were treated initially with doxorubicin (Adriamycin)/bleomycin/vinblastine/ dacarbazine (ABVD). Patients had stage IIB to IV disease or stage IIA disease with adverse features such as bulky disease or at least 3 involved sites. Interim PET was performed after 2 cycles, and the investigators defined a Deauville score of 1 to 3 as negative. Patients with a negative interim scan were randomized to either continuation of ABVD (ABVD group) or omission of bleomycin (AVD group) in cycles 3 through 6. The group with PET positivity received escalated bleomycin/ etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/ prednisone (eBEACOPP). Radiotherapy was not recommended for patients with negative findings on interim scans. Results demonstrated that the ABVD and AVD groups with PET negativity on interim scan (87%) had similar progression-free survival (PFS; 3-year PFS, 86% and 84%) and overall survival (OS; 97% and 98%) rates, respectively. The group with PET positivity had a 74% rate of negative repeat PET after BEACOPP; the 3-year PFS rate was 68.0%, and the OS rate was 87.8%. Respiratory adverse events were more severe in the bleomycin-containing group.

In addition, the S0816 US Intergroup study of response-adapted therapy in patients with stage III/IV disease by Press et al

assessed patients initially treated with ABVD. Of 60 eligible patients with PET2 positivity, 49 switched to eBEACOPP as planned, and 11 declined. With a median follow-up of 39.7 months, the Kaplan-Meier estimate for 2-year OS rate was 98%, with a 2-year PFS of 64% for patients with PET2 positivity. With extended follow-up (ie, median 5.9 years) for S0816, the estimated 5-year PFS rate was 74% for all patients. The 5-year PFS rate was 76% for patients with PET2 negativity versus 66% for those with PET2 positivity. The estimated 5-year OS rate was 94%. Furthermore, 14% of patients treated with eBEACOPP had a reported second cancer versus 2% of patients treated with ABVD (

Brentuximab Vedotin and Chemotherapy Combinations

Investigators and clinicians have made efforts to incorporate promising new therapies into traditional chemotherapy backbones to further improve outcomes in advanced-stage cHL. Brentuximab vedotin (Adcetris) is an FDA-approved anti-CD30 antibodydrug conjugate for the treatment of relapsed/refractory HL.

ECHELON-1 was a multicenter, randomized, phase III trial of patients with stage III or IV cHL.5 Patients were randomized to brentuximab vedotin/ doxorubicin/vinblastine/dacarbazine (A+AVD; n = 664) versus standard ABVD (n = 670). Two-year modified PFS rates in the A+AVD and ABVD groups were 82.1% and 77.2%, respectively, resulting in a difference of 4.9 percentage points (HR for an event of progression, death, or modified progression, 0.77;

= .03). The A+AVD group had more neutropenia, but the rate of febrile neutropenia was lower among patients who received primary prophylaxis with granulocyte colony-stimulating factor versus those who did not (11% vs 21%, respectively). Peripheral neuropathy was more common in the A+AVD group but was reversible in 67%. Grade &ge;3 pulmonary toxicity was rare, reported in <1% of patients receiving A+AVD and 3% of those treated with ABVD.

Overall, A+AVD had superior efficacy, with a 5% lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years (ie, modified PFS). The benefit seemed to be primarily for patients <60 years. Furthermore, several subgroups with higher-risk disease appeared to garner more benefit with A+AVD therapy, including those of male gender and those with stage IV disease, high IPS, and multiple extranodal sites. In addition, the absolute PFS benefit with A+AVD was 12% for patients treated in North America versus those not treated there (ie, 2-year PFS rate of 88% vs 76%, respectively).

also recently analyzed outcomes in older patients with previously untreated advanced-stage cHL. Overall, 186 of 1334 patients in the intention-to-treat population were &ge;60 years and included in a subset analysis. With a median follow-up of ~25 months, modified PFS rates were similar between the 2 treatment arms for older patients (70% vs 71%). The treatment-related mortality rate for older patients was 4% in the A+AVD arm and 5% with ABVD (all pulmonary related). Evens et al

also reported results from a multicenter phase II clinical study (NCT01476410) examining brentuximab vedotin given sequentially as a single agent before and after standard AVD for patients with untreated older HL. The objective and complete response rates after the initial 2 lead-in doses of brentuximab vedotin were 82% and 36%, respectively, and 95% and 90%, respectively, after 6 cycles of AVD. By intention to treat, the 2-year PFS and overall OS rates were 84% and 93%, respectively. Furthermore, geriatric assessments (eg, activities of daily living and comorbidities) were strongly prognostic for patient survival.

In addition, a new substantially modified BEACOPP variant incorporating brentuximab has been evaluated by Borchmann et al

for the German Hodgkin Study Group (GHSG). The eBEACOPP variants met their co-primary efficacy endpoints in a phase II trial of advanced-stage cHL. In particular, the BrECADD regimen (brentuximab vedotin 1.8 mg/kg on day 1, etoposide 150 mg/m2 on days 2-4, doxorubicin 40 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, dacarbazine 250 mg/m2 on days 3-4, and dexamethasone 40 mg on days 2-5) was associated with a more favorable toxicity profile and was therefore selected to challenge standard eBEACOPP for the treatment of advanced-stage cHL in the phase III HD21 study by the GHSG (NCT02661503). Long-term follow-up will be needed from these randomized studies before clinicians can incorporate these regimens into standard practice. However, these approaches may offer an alternative strategy for improving therapy in high-risk patients with advanced-stage disease.

Based on the results of the ECHELON-1 study, the FDA approved brentuximab vedotin in combination with chemotherapy (ie, A+AVD) in March 2018 for the treatment of adult patients with previously untreated stage III or IV cHL. In my practice, I strongly consider A+AVD for patients <60 years with advanced-stage cHL and any of the aforementioned clinical risk factors (eg, high IPS, male gender, stage IV disease). For patients with lower-risk cHL and/or without access to brentuximab vedotin, therapy vis-&agrave;-vis the RATHL design is a valid option for patients <60 years. For older patients with cHL who are fit (eg, with preserved activities of daily living and low comorbidity score), I advocate giving brentuximab vedotin sequentially as a single agent before and after AVD chemotherapy. For unfit, older patients with cHL, therapy with single-agent brentuximab vedotin with or without dacarbazine may be considered.

The recently opened North American Intergroup phase III S1826 study randomizes patients with advanced-stage cHL to receive AVD plus brentuximab vedotin via ECHELON-1 versus AVD plus nivolumab (Opdivo; NCT03907488). Notably, this study will not alter therapy based on PET2 response, in part given the aforementioned findings from the S0816 study. Furthermore, this study was planned as a collaboration of SWOG, the Eastern Cooperative Oncology Group, Alliance for Clinical Trials in Oncology, and the Children&rsquo;s Oncology Group and will enroll patients &ge;12 years. Investigators are continuing to explore integration of novel targeted therapeutic agents and examination of potential predictive biologic biomarkers.

Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin&rsquo;s lymphoma. N Engl J Med. 2016;374(25):2419-2429. doi: 10.1056/NEJMoa1510093.

Press OW, Li H, Sch&ouml;der H, et al. US Intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fluorodeoxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027. doi: 10.1200/JCO.2015.63.1119.

Stephens DM, Li H, Sch&ouml;der H, et al. Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach for stage III/IV Hodgkin lymphoma [published online July 22, 2019]. Blood. doi: 10.1182/blood.2019000719.

Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin&rsquo;s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14(13):1348-1356. doi: 10.1016/S1470-2045(13)70501-1.

Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin&rsquo;s lymphoma. N Engl J Med. 2018;378(4):331-344. doi: 10.1056/NEJMoa1708984.

Evens AM, Connors JM, Younes A, et al. Older patients (pts) with previously untreated classical Hodgkin lymphoma (cHL): a detailed analysis from the phase 3 ECHELON-1 study. Blood. 2018;132(suppl 1;abstr 1618). doi: 10.1182/blood-2018-99-112178.

Evens AM, Advani RH, Helenowski IB, et al. Multicenter phase II study of sequential brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine chemotherapy for older patients with untreated classical Hodgkin lymphoma. J Clin Oncol. 2018;36(30):3015-3022. doi: 10.1200/JCO.2018.79.0139.

Borchmann P, Goergen H, Kobe C, et al. PET-guided treatment in patients with advanced-stage Hodgkin&rsquo;s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet. 2018;390(10114):2790-2802. doi: 10.1016/S0140-6736(17)32134-7.

Hodgkin lymphoma represents approximately 10% of all cases of malignant lymphoma. This group of diseases most commonly affects adolescent and young adults, although approximately 20% to 25% of patients are aged &ge;60 years at diagnosis.

Contemporary Therapy for Advanced- Stage Hodgkin Lymphoma

Hodgkin lymphoma represents approximately 10% of all cases of malignant lymphoma. This group of diseases most commonly affects adolescent and young adults, although approximately 20% to 25% of patients are aged &ge;60 years at diagnosis. Advanced-stage disease is generally classified as Ann Arbor stage III to IV, but clinical trials often incorporate patients with high-risk stage II disease, such as those with B symptoms, multiple sites, or bulky disease. Approximately 65% to 75% of patients with advanced-stage HL will remain disease free at 5 years with conventional chemotherapy. This is in contrast with early-stage classical HL (cHL), in which the long-term cure exceeds 90%. Different prognostic indices are used for early- and advanced-stage disease. Prognosis in advanced stage is defined by the International Prognostic Index (IPS), which includes measurements of albumin and hemoglobin, sex, age >45 years, stage IV, and the presence of leukocytosis or lymphocytosis. Patients with an IPS &ge;3 have inferior treatment outcomes.

assessed a PET-adapted therapy in patients with advanced-stage disease who were treated initially with doxorubicin (Adriamycin)/bleomycin/vinblastine/ dacarbazine (ABVD). Patients had stage IIB to IV disease or stage IIA disease with adverse features such as bulky disease or at least 3 involved sites. Interim PET was performed after 2 cycles, and the investigators defined a Deauville score of 1 to 3 as negative. Patients with a negative interim scan were randomized to either continuation of ABVD (ABVD group) or omission of bleomycin (AVD group) in cycles 3 through 6. The group with PET positivity received escalated bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone (eBEACOPP). Radiotherapy was not recommended for patients with negative findings on interim scans. Results demonstrated that the ABVD and AVD groups with PET negativity on interim scan (87%) had similar progression-free survival (PFS; 3-year PFS, 86% and 84%) and overall survival (OS; 97% and 98%) rates, respectively. The group with PET positivity had a 74% rate of negative repeat PET after BEACOPP; the 3-year PFS rate was 68.0%, and the OS rate was 87.8%. Respiratory adverse events were more severe in the bleomycin-containing group.

In addition, the S0816 US Intergroup study of response- adapted therapy in patients with stage III/IV disease by Press et al

ECHELON-1 was a multicenter, randomized, phase III trial of patients with stage III or IV cHL.

Patients were randomized to brentuximab vedotin/ doxorubicin/vinblastine/dacarbazine (A+AVD; n = 664) versus standard ABVD (n = 670). Two-year modified PFS rates in the A+AVD and ABVD groups were 82.1% and 77.2%, respectively, resulting in a difference of 4.9 percentage points (HR for an event of progression, death, or modified progression, 0.77;

also reported results from a multicenter phase II clinical study (NCT01476410) examining brentuximab vedotin given

as a single agent before and after standard AVD for patients with untreated older HL. The objective and complete response rates after the initial 2 lead-in doses of brentuximab vedotin were 82% and 36%, respectively, and 95% and 90%, respectively, after 6 cycles of AVD. By intention to treat, the 2-year PFS and overall OS rates were 84% and 93%, respectively. Furthermore, geriatric assessments (eg, activities of daily living and comorbidities) were strongly prognostic for patient survival.

for the German Hodgkin Study Group (GHSG). The eBEACOPP variants met their co-primary efficacy endpoints in a phase II trial of advanced-stage cHL. In particular, the BrECADD regimen (brentuximab vedotin 1.8 mg/kg on day 1, etoposide 150 mg/m2 on days 2-4, doxorubicin 40 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, dacarbazine 250 mg/m2 on days 3-4, and dexamethasone 40 mg on days 2-5) was associated with a more favorable toxicity profile and was therefore selected to challenge standard eBEACOPP for the treatment of advanced- stage cHL in the phase III HD21 study by the GHSG (NCT02661503). Long-term follow-up will be needed from these randomized studies before clinicians can incorporate these regimens into standard practice. However, these approaches may offer an alternative strategy for improving therapy in high-risk patients with advanced-stage disease.

Based on the results of the ECHELON-1 study, the FDA approved brentuximab vedotin in combination with chemotherapy (ie, A+AVD) in March 2018 for the treatment of adult patients with previously untreated stage III or IV cHL. In my practice, I strongly consider A+AVD for patients <60 years with advanced- stage cHL and any of the aforementioned clinical risk factors (eg, high IPS, male gender, stage IV disease). For patients with lower-risk cHL and/or without access to brentuximab vedotin, therapy vis-à-vis the RATHL design is a valid option for patients <60 years. For older patients with cHL who are fit (eg, with preserved activities of daily living and low comorbidity score), I advocate giving brentuximab vedotin

as a single agent before and after AVD chemotherapy. For unfit, older patients with cHL, therapy with single- agent brentuximab vedotin with or without dacarbazine may be considered.

TJohnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin&rsquo;s lymphoma.

. 2016;374(25):2419-2429. doi: 10.1056/NEJMoa1510093

Press OW, Li H, Schöder H, et al. US Intergroup trial of response- adapted therapy for stage III to IV Hodgkin lymphoma using early interim fluorodeoxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816.

. 2016;34(17):2020-2027. doi: 10.1200/JCO.2015.63.1119.

Stephens DM, Li H, Schöder H, et al. Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach for stage III/IV Hodgkin lymphoma [published online July 22, 2019].

Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin&rsquo;s lymphoma: a phase 1, open-label, dose-escalation study.

. 2013;14(13):1348-1356. doi: 10.1016/ S1470-2045(13)70501-1.

Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin&rsquo;s lymphoma.

. 2018;378(4):331-344. doi: 10.1056/NEJMoa1708984.

Evens AM, Connors JM, Younes A, et al. Older patients (pts) with previously untreated classical Hodgkin lymphoma (cHL): a detailed analysis from the phase 3 ECHELON-1 study.

. 2018;132(suppl 1;abstr 1618). doi: 10.1182/blood-2018-99-112178.

Evens AM, Advani RH, Helenowski IB, et al. Multicenter phase II study of sequential brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine chemotherapy for older patients with untreated classical Hodgkin lymphoma.

. 2018;36(30):3015-3022. doi: 10.1200/JCO.2018.79.0139.

Borchmann P, Goergen H, Kobe C, et al. PET-guided treatment in patients with advanced-stage Hodgkin&rsquo;s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.

. 2018;390(10114):2790- 2802. doi: 10.1016/S0140-6736(17)32134-7.

Hodgkin lymphoma represents approximately 10% of all cases of malignant lymphoma. This group of diseases most commonly affects adolescent and young adults, although approximately 20% to 25% of patients are aged &ge;60 years at diagnosis. Advanced-stage disease is generally classified as Ann Arbor stage III to IV, but clinical trials often incorporate patients with high-risk stage II disease, such as those with B symptoms, multiple sites, or bulky disease

Andrew M. Evens, DO, MSc | Authors

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