Targeted agents trigger ‘paradigm shift’ in treatment of Hodgkin’s lymphoma

The success of targeted drugs and immunotherapies has triggered a seismic shift in cancer treatment.

As the potential increases for these personalized approaches to selectively destroy tumors while preserving healthy tissue, oncologists are increasingly favoring them over other standard-of-care regimens that have proved effective but carry risks for considerable short- and long-term toxicities.

Two studies presented at the ASH Annual Meeting in December suggest this trend may become more prevalent in the treatment of Hodgkin’s lymphoma, which traditionally includes chemotherapy alone or in combination with radiotherapy.

Ligand activation of the programmed cell death 1 (PD-1) receptor is common in patients with Hodgkin’s lymphoma.

In one of the ASH studies, researchers determined nivolumab (Opdivo, Bristol-Myers Squibb), a fully human immunoglobulin G4 monoclonal antibody that blocks ligand activation of PD-1 on activated T cells, induced an 87% response rate in a heavily pretreated cohort of patients with relapsed or refractory classic Hodgkin’s lymphoma.

Results of the second study showed pembrolizumab (Keytruda, Merck), a humanized monoclonal IgG4 antibody that targets the PD-1 receptor, conferred an 86% clinical benefit rate in patients with Hodgkin’s lymphoma. All patients in that study failed previous therapy with brentuximab vedotin (Adcetris, Seattle Genetics), an antibody–drug conjugate that targets the protein CD30, highly expressed in Hodgkin’s lymphoma.

“We’re continually looking for the Holy Grail,” Andrew M. Evens, DO, MSc, chief of the division of hematology and oncology and director of the lymphoma program at the Tufts Cancer Center, told HemOnc Today. “It is difficult to identify one silver bullet that will be effective in all cancers, or even in a certain cancer subtype.

“Unfortunately, cancer cells are often sophisticated, so we have to build treatment regimens through a strategic paradigm,” Evens said. “Instead of one silver bullet, we have the opportunity of combining several bullets, and hopefully these new agents in rational sequences and combinations can be added to our armamentarium.”

HemOnc Today spoke with several clinicians about the questions that must be answered before these novel targeted agents become a standard of care, the effect that cost may have on treatment selection, and the possibility that highly effective targeted agents may one day eliminate the need for chemotherapy in the treatment of Hodgkin’s lymphoma.

‘New territory’

The FDA granted breakthrough therapy designation to nivolumab last year for the treatment of patients with Hodgkin’s lymphoma who failed autologous stem cell transplant and brentuximab vedotin. The decision was based on results of a phase 1b study of patients with relapsed and refractory hematologic malignancies.

Results of a dose escalation and cohort expansion study, in which 23 patients received nivolumab 3 mg/kg every 2 weeks until progression or extreme toxicity, were presented at ASH.

The majority (87%) of patients had undergone at least three prior treatment regimens, 78% had undergone prior autologous stem cell transplant and 78% had received prior brentuximab vedotin.

Armand and colleagues reported an 87% objective response rate — including a 70% partial response rate and 17% complete response rate — and a 24-week PFS rate of 86% (95% CI, 62-95). Every patient demonstrated a reduction in tumor burden at one or more efficacy assessments.

“Even in this resistant group of patients, the response rates were dramatic … and every single patient benefited in some way from the treatment,” Stephen M. Ansell, MD, PhD, professor of medicine at Mayo Clinic in Rochester, Minnesota, a HemOnc Today Editorial Board member and a researcher on the nivolumab trial, said in an interview. “Because it is highly effective and does not have typical chemotherapy side effects, it may well replace some of the chemotherapy components in current treatment combinations and, hopefully, lead to better results for patients.”

Initial follow-up showed many of the responses have been durable, according to Margaret A. Shipp, MD, leader of the lymphoma program at Dana-Farber/Harvard Cancer Center, professor in the department of medicine at Harvard Medical School and a researcher on the nivolumab trial.

“This treatment approach, which is based on the biology of the disease, suggests that waking up the immune system has real efficacy in Hodgkin’s lymphoma,” Shipp said in an interview.

Based on recent results, the prospects for nivolumab — either as a single agent or in combinations — have become “extremely interesting” and may help it “move from the back of the line in treatment choices to somewhere up front,” Ansell said.

The possibilities — particularly with regard to a potential combination with brentuximab vedotin, associated with an approximately 75% response rate — are compelling, according to Anas Younes, MD, chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center.

“We have never combined two agents that are combinable at full doses and each one has a response rate near 80%,” Younes said. “This is a new territory for us, and I don’t think anyone knows how to combine these things in a front-line setting. Would two drugs be sufficient? Do we need more? Even though the excitement is so high, it has to be done in a multi-step process, even though the single-agent activity is remarkable for each drug.”

Results of the KEYNOTE-013 trial also generated interest at ASH.

Craig H. Moskowitz, MD, clinical director of the division of hematologic oncology at Memorial Sloan Kettering Cancer Center and HemOnc Today’s lymphoma section editor, and colleagues evaluated pembrolizumab in 29 patients with relapsed or refractory classical Hodgkin’s lymphoma.

Patients received 10 mg/kg IV pembrolizumab every 2 weeks until progression, excessive toxicity or completion of 2 years of therapy.

Researchers reported a 66% overall response rate, a 21% complete response rate and an 86% clinical benefit rate.

The nature of the cohort makes the outcomes even more impressive, researchers said.

“These results are particularly compelling since they are demonstrating complete responses to a drug in a patient population who had failed all other therapies,” Moskowitz told HemOnc Today at ASH. “This was their last chance. It will be important to further evaluate this drug in combination with others, or perhaps even as a maintenance treatment, to enhance the posttransplant immune response.”

A cautious approach

The Internet and social networking are among the reasons patients arrive to their oncologists’ offices armed with more information than ever before. A growing percentage of those with Hodgkin’s lymphoma have embraced the concept of newer treatments.

“They surprisingly are on board,” Evens said. “Sometimes we put the cart ahead of the horse. We have to be careful and respect the fact that, even though this disease is highly curable, we’re talking about a disease where the cure rates are high with conventional chemotherapy. But more often than not, patients want to be progressive and desire targeted and tailored therapy.”

Although preliminary research into targeted agents suggest they offer tremendous promise for patients with Hodgkin’s lymphoma and may one day transform how the disease is treated, experts said it would be irresponsible to alter therapeutic standards based solely on results of early-phase, single-agent studies.

Chemotherapy became a backbone of Hodgkin’s lymphoma treatment in the 1960s, yet the severity of treatment-related adverse effects — such as severe organ failure or secondary cancers — were not fully understood until decades later.

Similarly, many questions remain about the potential toxicities associated with targeted agents, and these questions should be answered before these agents are thrust into front-line treatment, according to Andreas Engert, MD, professor of internal medicine, hematology and oncology at University Hospital of Cologne in Germany.

“Researchers should be cautious,” Engert told HemOnc Today. “If these drugs were to be given, it could lead to severe autoimmune diseases like colitis or pneumonitis, because these T cells are usually active in autoimmune diseases. That’s something that has not been fully accounted for because the time has been too short. … We don’t know what the long-term effects might be, and that has to be balanced against potential benefits.”

Ansell also urged caution with regard to potential toxicities.

“There was a lesson learned with brentuximab vedotin,” Ansell said. “When that agent was combined with bleomycin, there was significantly more lung toxicity.”

Lung toxicity also has been observed in approximately 1 in 10 patients treated with nivolumab, Ansell said.

“These are the things that require one to meticulously do trials to prove that you can safely combine certain agents,” Ansell said. “The hope is that by modifying the regimen or picking exactly how the doses are administered, you can work around that.”

The level of success already achieved in the field clouds the picture.

“This is a disease where the expectation is to get it under control and make it stay that way permanently,” Ansell said. “A defined period of treatment is typically given, and there is general acceptance of a more aggressive chemotherapy-based approach to achieve that. That said, there’s enthusiasm from patients and physicians to achieve the best result with the least toxicity.”

Current standards of care tend to be curative for 80% of patients, so — with relatively limited room for improvement — clinicians must be certain there is a strong rationale for changing their approach.

“As you consider moving these novel agents into front-line approaches, and substituting or removing or changing front-line therapy, you want to be certain that you don’t compromise the outcomes of these patients,” Ansell said. “Instead of having curative therapy, you may wind up having patients relapsing. That’s a significant risk.”

Evens agreed.

“This can’t be glacial — we don’t want to take decades to make these changes happen,” Evens said. “But at the same time, we have to proceed somewhat incrementally and scientifically, as we do not want to compromise the already high cure rates that Hodgkin’s lymphoma patients have.”

Cost control

As with most new drugs, the costs of targeted therapies for Hodgkin’s lymphoma — and the ensuing effects those prices have on patient access — must be taken into account.

Bristol-Myers Squibb officials have indicated the company intends to charge about $12,500 per month — or $150,000 per year — for nivolumab, the same amount Merck charges for pembrolizumab.

Incidence of Hodgkin’s lymphoma increases sharply during childhood. An estimated 15% of cases are diagnosed in children, and incidence peaks in early adulthood (age 15-40 years), according to American Cancer Society statistics.

The age of patients who can benefit from the agents is one component of the equation, Shipp said.

“The pricing structure for new agents is an important consideration,” Shipp said. “One of the first things you think about is efficacy, especially if you can change the natural history of the disease — particularly in patients who otherwise would have long, productive lives ahead of them. But you do realistically have to think about what agents cost and how that factors into a total budget.”

The nature of Hodgkin’s lymphoma also must be considered.

“These are not agents you would anticipate using forever,” Shipp said. “The goal with Hodgkin’s lymphoma is to actually eradicate this disease. The idea would be to treat for a finite period of time and, in a best-case scenario, eliminate the disease.”

Younes elaborated on this point.

“Drugs will sell themselves if they are something substantial, like a cure,” Younes said. “In Hodgkin’s lymphoma, if you want to replace chemotherapy — not because it’s ineffective but because everyone worries about long-term toxicity — the new agents have to meet endpoints in efficacy and long-term safety. Right now, we’re treating 100 patients and we can cure 75% to 80%. If novel agents make that 100%, the cost to society could be justified because there’s no need for second-line therapy or transplant, and no death from long-term toxicity.”

Younes cited ledipasvir/sofosbuvir (Harvoni, Gilead), a treatment for hepatitis C, as an example.

“It is expensive, but it cures patients in 6 months, which is remarkable,” Younes said. “It’s priceless. That’s more justifiable than a drug that gives you a 5% improvement in 3-month PFS.

“You have to put it in context,” he added. “I’m not pro high prices, but if an agent is effective and makes a huge impact, the price can be justified.”

Chemotherapy’s role

Once the clinical community has a solid understanding of targeted agents’ long-term efficacy and toxicities, the answer to another question — Can Hodgkin’s lymphoma be treated without chemotherapy? — should become clearer.

Right now, leaders in the field seem to agree this approach will become a reality, but they offer different projections on the timeline.

Some experts said the results of early-stage trials of agents such as nivolumab and pembrolizumab will expedite the next phase of clinical trials — many of which are underway — and that chemotherapy will vanish from Hodgkin’s lymphoma treatment for the next generation of patients.

Others suggest it will take longer, simply due to the series of studies that must be done to compare various uses and combinations of newer agents.

“I don’t think we’ll be completely chemotherapy free in the next 10 to 20 years, but it’s highly likely we will be at a point where more than one novel targeted agent is part of the armamentarium for front-line therapy,” Evens said. “When we say, ‘Will treatment be chemotherapy free in our lifetime?’ I guess it depends on what we mean by ‘lifetime.’ Will it happen in the next 50 years? I would say yes.”

Engert expressed more optimism.

“I’m confident we will see patients cured of Hodgkin’s lymphoma without chemotherapy much sooner than that,” Engert said. “We will see cures in front-line Hodgkin’s lymphoma with these antibodies, or similar antibodies … in the next decade.” – by Anthony SanFilippo

References:

Buske C. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70488-7.

Canellos GP, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.53.1194.

The following were presented at ASH Annual Meeting; Dec. 6-9, 2014; San Francisco:

Armand P, et al. Abstract #289.

Moskowitz CH, et al. Abstract #290.

Moskowitz CH, et al. Abstract #673.

For more information:

Stephen M. Ansell, MD, PhD, can be reached at Mayo Clinic, 200 Center St. SW, Rochester, MN 55905; email: ansell.stephen@mayo.edu.

Andreas Engert, MD, can be reached at University Hospital of Cologne, Kerpener Straße 62, Building 16, 50937, Cologne, Germany; email: andreas.engert@uk-koeln.de.

Andrew M. Evens, DO, MSc, can be reached at Tufts Medical Center, South Building, 800 Washington St., Box 245, Boston, MA 02111; email: aevens@tuftsmedicalcenter.org.

Margaret A. Shipp, MD, can be reached at Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115; email: margaret_shipp@dfci.harvard.edu.

Anas Younes, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: younesa@mskcc.org.

Disclosure: Ansell reports research funding from Bristol-Myers Squibb. Shipp reports research funding from Gilead and Sanofi, as well as consultancy/advisory roles with Bayer, Bristol-Myers Squibb, Gilead, Janssen, Merck and Pharmacyclics. Engert, Evens and Younes report no relevant financial disclosures.

 

Does radiation still have a role in the treatment of Hodgkin’s lymphoma?

Yes, radiation treatment still has a role in Hodgkin’s lymphoma management.

Two trials — one by the EORTC, and also the RAPID trial — support this.

The EORTC H10 trial, a noninferiority trial, closed early because there were a lower number of early relapses in patients treated with combined-modality treatment than with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy alone. This was true, even though the patients who did not receive radiation treatment had negative interim PET scans.

The RAPID trial also showed a trend toward improvement in PFS among early-stage patients who received radiation treatment plus ABVD.

What becomes debatable is the fact that OS was a little bit better among patients who did not receive radiation treatment, but the difference was not statistically significant.

There was a well-written commentary about both of these articles in Journal of Clinical Oncology last year by Ralph M. Meyer, MD, that estimated the benefit of radiation treatment for patients with early-stage disease and negative interim PET scans was positive but small (about 5%). The editorial also suggested that, given the late toxicities that can occur from radiation treatment, patients would need to be followed for longer times in order to answer the question about OS differences.

At our institution, we still recommend that patients continue to receive combined-modality treatment for early-stage disease.

If a patient with Hodgkin’s lymphoma received ABVD as front-line treatment and experienced disease relapse, second-line treatment would still be standard-of-care ICE — which consists of ifosfamide, carboplatin and etoposide — or something similar, followed by an autologous stem cell transplant plus high-dose chemotherapy. Thus, the question becomes, do you want to take the risk of potential higher relapse rate with chemotherapy alone realizing that if your disease relapsed, an autologous stem cell transplant would be recommended? Given that toxicities associated with radiation have been reduced with the use of more limited fields, I’m not sure that is a worthy risk to take.

With time, will that change? Potentially.

Jeremy S. Abramson, MD, of Massachusetts General Hospital Cancer Center is doing the early study with brentuximab vedotin (Adcetris, Seattle Genetics) in combination with AVD in the front-line setting for patients with non-bulky early-stage Hodgkin’s lymphoma. If there was positive data that would emerge from that trial, then we would need a randomized trial that would compare, say, brentuximab vedotin plus AVD vs. ABVD plus radiation for those patients to move away from radiation.

Right now, though, radiation is still here. Some private practice doctors have shifted away from radiation treatment because they look at it from a different standpoint. I still look at it from the side that relapse of a disease is definitely not desirable, particularly for patients who have a high cure rate.

 

References:

Meyer RM. J Clin Oncol. 2014;doi:10.1200/JCO.2013.54.6259.

Radford J, et al. Abstract 547. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.

Raemaekers JMM, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.51.9298.

Michelle Fanale, MD, is associate professor in the department of lymphoma/myeloma at The University of Texas MD Anderson Cancer Center. She can be reached at Department of Lymphoma/Myeloma, 1515 Holcombe Blvd., Unit 429, Houston, TX 77030-4009. Disclosure: Fanale reports no relevant financial disclosures.

Use of radiation therapy should be limited in the initial treatment of Hodgkin’s lymphoma.

Radiation therapy is a cause of significant late morbidity and mortality in the treatment of Hodgkin’s lymphoma.

The long-term follow-up of initial treatment of Hodgkin’s lymphoma with radiation therapy-based programs (alone or combined with chemotherapy) between 1960 and 2006 from Stanford demonstrated a 40-year DFS of 82% and freedom from relapse of 70%, but an OS of only 25%. These excess deaths are largely attributable to late complications of radiation therapy, led by second primary cancers and followed by cardiovascular causes. This was also found in our own long-term results with chemotherapy and radiation therapy. In my opinion, this shows that the radiation therapy-based approach was suboptimal; it succeeded in controlling the Hodgkin’s lymphoma but significantly contributed to mortality and morbidity from other causes.

Fortunately, radiation therapy can be safely omitted from the initial treatment of most patients with Hodgkin’s lymphoma. In stage I and II non-bulky early-stage Hodgkin’s lymphoma, three to six cycles of chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) result in identical 3-year OS and 12-year OS as combined-modality therapy with ABVD plus radiation therapy, and a similar PFS that may be 5% to 6% lower than combined-modality therapy. This latter finding is of questionable clinical importance because cures can be obtained with second-line treatment in the minority of patients with relapsed or refractory disease, thereby saving the majority from the toxicity of radiation therapy. In stage III and IV Hodgkin’s lymphoma, limited low-dose radiation therapy does not improve PFS or OS for patients who achieve a complete response following adequate chemotherapy.

The one remaining indication for radiation therapy in addition to chemotherapy is stage I and II patients with bulky disease. A negative PET at the end of treatment and also during treatment is a powerful predictor for a low recurrence rate and has become the gold standard for determining complete response for all patients with Hodgkin’s lymphoma. There is limited data suggesting that a negative PET in patients with a residual mass following BEACOPP or with initial bulky disease and a residual mass after ABVD have a low likelihood of relapse and may not require radiation therapy. The current guidelines for involved site radiation therapy still treat large fields with continued off-target organ exposure. Careful observation rather than radiation therapy can be discussed as an option with such patients, although it is not yet standard. Another possible approach may be to employ even more limited radiation therapy to minimize off-target exposure.

It is likely that limiting radiation therapy will significantly improve long-term survival and lower late morbidity for patients with Hodgkin’s lymphoma in the future.

 

References:

Aleman BM, et al. N Engl J Med. 2003;348:2396-2406.

Canelos GP, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.53.1194.

Engert A, et al. Lancet. 2012;doi:10.1016/S0140-6736(11)61940-5.

Illidge T, et al. Int J Radiat Oncol Biol Phys. 2014;doi:10.1016/j.ijrobp.2014.01.006.

Matasar M, et al. Abstract 8547. Presented at: ASCO Annual Meeting; May 29-June 2, 2009; Orlando, Fla.

Meyer RM, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1111961.

Radford J, et al. Abstract 547. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.

Savage K, et al. Abstract 213. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2007; Atlanta.

Straus DJ, et al. Blood. 2004;104:3483-3489.

David J. Straus, MD, is an attending physician with the Lymphoma Service at Memorial Sloan Kettering Cancer Center. He can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065. Disclosure: Straus reports no relevant financial disclosures.