COMMENTARY

Hodgkin Lymphoma: New Drug Breakthroughs

Bruce D. Cheson, MD; Nancy L. Bartlett, MD

Disclosures

December 15, 2010

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Introduction

Bruce D. Cheson, MD: Hello. I'm Bruce Cheson, Head of Hematology at Georgetown University Hospital and Directory of Hematology Research for the Lombardi Comprehensive Cancer Center in Washington, DC. This is Medscape Oncology Insights on Hodgkin lymphoma coming to you from the American Society of Hematology (ASH) 2010 in Orlando, Florida.

I am pleased to have joining me today Dr. Nancy Bartlett, the Komen Chair in Medical Oncology at Washington University in St. Louis. Welcome, Nancy.

Nancy Bartlett, MD: Thank you.

Regimens: ABVD vs Stanford 5

Dr. Cheson: Today we are going to be talking about Hodgkin lymphoma, which is a real success story of modern oncology. The oncologist in the community thinks that we are curing almost all these patients with ABVD [adriamycin, bleomycin, vinblastine, anddacarbazine] but other regimens are out there. At this meeting, there were some abstracts on the Stanford V program. Could you tell us what that is and what the abstract taught us at this meeting?

Dr. Bartlett: Stanford V is a regimen that was developed at Stanford University about 15 years ago and is a weekly chemotherapy regimen, during which the chemotherapy is given in 12 weeks instead of the 6 months required to administer ABVD. So Stanford V is shorter. The goal initially was to give lower total doses of chemotherapy (anthracyclines) that would hopefully result in less cardiac toxicity; and lower doses of alkylator, which hopefully will decrease problems with infertility.

The studies that are being presented at this meeting are actually phase 3 studies comparing Stanford V with ABVD.[1,2] The objective of the study was to see if Stanford V was better. Unfortunately, the results show that the 2 regimens are equivalent. Both of them resulted in an approximate 70% progression-free survival at 5 years and overall survival of approximately 85% at 5 years. The Stanford V results are very encouraging, but no better than those with ABVD.

One concern that people have had about Stanford V is that most of the patients receive radiation in addition to the short course of chemotherapy and there are concerns about the late effects of radiation. We need longer term follow-up. At least in the short term, the 2 regimens looked about the same in terms of toxicity. Both are associated with fever and neutropenia in the same number of patients, with slightly more neurotoxicity in the Stanford V regimen. My guess is that ABVD will remain the standard of care because the 2 regimens are equivalent.

Dr. Cheson: Now, the Stanford V regimen has been compared with ABVD or other regimens in the past, and one of the criticisms has been that the radiation has to be delivered as it is done at Stanford. Stanford V may even be inferior chemotherapy salvaged by the radiation therapy. Is that a fair assessment?

Dr. Bartlett: I think it is. As you were pointing out, there have been a few other studies before now conducted by an Italian group, and Stanford V did look inferior. I think it was because fewer patients had radiation along with Stanford V. So, the chemotherapy regimen should not be given alone; if the patient has bulky disease, they always need the radiation. In this study, bulk was defined as 5 cm, which is a little unusual. Normally, we only radiate when patients have bulk defined as 10 cm.

Dr. Cheson: In fact, the second presentation of this meeting looked only at the bulky patients.

Dr. Bartlett: Right. I was actually a little surprised about those results because they were also equivalent, but the P value actually trended toward favoring ABVD and radiation in that study. Because of the shorter course of chemotherapy and ability to administer radiation sooner, I thought perhaps that was where we would see the benefit of Stanford V. But it does, even in that setting, look like it is equivalent to the ABVD.

Radiation and Risk-adapted Studies

Dr. Cheson: Returning to the radiation issue, we may have been irradiating a lot of people unnecessarily in the past. Now that we have the ability to distinguish tumor from scar tissue fibrosis with PET scans, perhaps we can improve outcomes by reducing toxicity or reducing the number of patients subjected to radiation. In fact, another abstract from Germany at this meeting addressed this point.

Dr. Bartlett: There are 2 questions in terms of early stage V, the more advanced-stage patients, and we are trying to answer those questions. The abstract you are referring to from Germany specifically looked at the advanced-stage patients to determine whether radiation is needed after a more aggressive chemotherapy regimen, referred to as escalated BEACOPP [bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin, procarbazine, prednisone]. In that study, they performed PET scans on all patients at the completion of their aggressive chemotherapy. Only patients who were still PET-positive at the completion of treatment received radiation. These results were compared with those of a previous study that had been conducted with similar chemotherapy. In that study, approximately three fourths of the patients required radiation, and in this current study, only approximately 11% of patients required radiation at the completion of chemotherapy. Hopefully this will result in better long-term outcomes and fewer second malignancies related to the radiation. The results looked excellent, even in the patients who were PET-positive and received radiation.

Dr. Cheson: PET scans are widely used, not only following therapy, but also during therapy after 1, 2, 3, or 4 cycles. In Hodgkin lymphoma, some interesting studies were presented by Galamini and coworkers, where survival is down here if the patient is PET-positive, and up here if the patient is PET-negative after a couple of cycles. We really need some risk-adapted studies. I know that you are involved in a few that are ongoing right now. Could you tell us about this work?

Dr. Bartlett: Sure. We are, as you pointed out, trying to find better ways to determine how much therapy a patient needs and avoid this whole issue of giving too much therapy. The current trend is to use these PET scans that we describe as "interim PET scans," sometimes after 1 cycle, but more commonly after 2 or 3 cycles of chemotherapy, and then make a decision about what further therapy the patient should have. Three studies are ongoing in the United States as part of a cooperative group, (CLGB) and one of them is an advanced-stage study which is being run by all the cooperative groups. In that study, patients received 2 cycles of ABVD, followed by a PET scan. If the PET scan is negative, which we are hoping correlates with a better prognosis, they just go on to receive additional ABVD. If it is positive, then they go onto receive a more aggressive regimen of escalated BEACOPP.

Two CLBG studies are currently ongoing. If the patient has what we describe as "nonbulky early stage disease," they receive 2 cycles of ABVD, and then have a PET scan. If the PET scan is negative, the patient would receive only 2 additional cycles of ABVD. That is less therapy than we usually give. In circumstances in which we typically give 6 cycles, we are going to try to cut it back to 4 cycles. If the patient is PET-positive, we would escalate to more aggressive BEACOPP chemotherapy and irradiate that subset of patients.

We are doing a very similar study for patients who have bulky stage I or II disease, in which we are making the treatment decision based on whether they are PET-positive or -negative.

Dr. Cheson: Those studies are very important so that we improve outcomes by not overtreating some and undertreating others.

Dr. Bartlett: I agree and hopefully we will get those accrued.

New Drugs for Relapsed Hodgkin Lymphoma

Dr. Cheson: For the small proportion of patients who are not cured by initial therapy (and we seem to get a lot of these patients who have failed initial therapy), we had nothing with which to treat them. You developed the GVD (gemcatibine, navelbine, doxil) regimen and published that study a number of years ago, and the results were superb, but the disease relapsed in all patients. We still need something to use after GVD.

Some new exciting therapies are out there, 2 of which were presented at this meeting -- panobinostat, an HDAC inhibitor, and SGN-35. Could you review these 2 drugs for us?

Dr. Bartlett: Yes. It has been a very exciting time for Hodgkin lymphoma in the past couple of years. We have gone a long time without any new drugs, and now all at once we have 3 or 4 new drugs coming at the same time. The SGN-35 (also known as brentuximab vedotin) is an antibody drug conjugate. The antibody is against target CD30, which is on all Hodgkin cells, and it is connected to a tubulin inhibitor (MMAE). The patients are all receiving outpatient therapy. They get a dose once every 3 weeks, and toxicities are minimal. Neurotoxicity -- peripheral neuropathy -- has been the main toxicity.

At this meeting, investigators are presenting the results of a phase 2 study that included about 100 patients.[3] Objective response rates were 75%, and 95% of patients actually had some reduction in their tumor, which I think is unprecedented in this setting of refractory Hodgkin lymphoma in patients who have relapsed multiple times. The fact that the drug has minimal toxicity is also very encouraging.

Dr. Cheson: How many of those patients had failed a previous transplant?

Dr. Bartlett: I do not know the exact numbers. But the majority of them, probably 90% of them, had failed previous transplant.

Dr. Cheson: These are heavily pretreated patients.

Dr. Bartlett: Absolutely. The second trial, of the HDAC inhibitor panobinostat, has also been very exciting. A number of these HDAC inhibitors are being looked at right now. Panobinostat is the drug that is furthest along for Hodgkin. It is an oral drug, which is very easy for the patients, and is taken 3 times a week. The investigators are presenting their follow-up phase 2 study for that drug as well, along with response rates.[4]The objective response rate was approximately 27% but they are also presenting data showing that nearly three fourths of the patients have stabilization of their disease. That is a clinical benefit for the patient with Hodgkin disease, because many of them are asymptomatic and they feel well. So, if you can contain their disease, even if remission is incomplete, you probably still have provided a benefit for that patient. What we may be seeing with more of these new biologic therapies is that they maintain stable disease for extended periods of time and the patients may need to stay on these therapies. This is in contrast to chemotherapy, where we are used to giving 6 cycles and then stopping and waiting for the disease to come back. Panobinostat may be more of a maintenance type of treatment.

Dr. Cheson: So, where do you think we will be going? Are we going to save these drugs for the refractory patients or are we going to move them up?

Dr. Bartlett: I am all in favor of moving them up. Our frontline treatments, as you pointed out at the beginning, are effective for Hodgkin disease, but there are some downsides. Some of the drugs that we currently use, such as bleomycin, have a high risk for toxicity. If we could replace it with a drug such as SGN-35 that has a single-agent 75% response rate in resistant disease, I think our up-front cure rates will be even higher with less toxicity. There is no reason that these drugs should not come forward (hopefully quickly) because the single-agent response rates are as good, if not better, than some of the agents that are already incorporated into the first-line treatments.

Dr. Cheson: Are any other drugs out there that we should be keeping an eye on?

Dr. Bartlett: One drug that I would mention is the mTOR inhibitor everolimus, which is also in phase 2 testing right now with some preliminary but very encouraging results.

Dr. Cheson: At 40%.

Dr. Bartlett: Yes, at least -- and in patients who have been quite refractory. So hopefully in the next year or 2 we will see the follow-up on that study. Lenalidomide is another agent that we have been testing at our institution and a few other institutions. The German investigators are presenting an abstract at this meeting about a compassionate use protocol that they used in Germany. Patients were given single-agent lenalidomide for refractory Hodgkin disease, and responses were reported in 12 of 24 patients (50%). At our institution, the responses have been 20%, but again, these are primarily patients with stable disease, so we may be seeing clinical benefit without getting an objective tumor reduction.

Both of those agents are probably also going to be incorporated in the treatment of Hodgkin disease.

Dr. Cheson: Combined with each other?

Dr. Bartlett: Absolutely.

Summary and Closing Remarks

Dr. Cheson: Well, I think that what we tried to get across today is all the excitement in Hodgkin lymphoma that has occurred all of a sudden. For years, we could study only 1 chemotherapy regimen vs another. Now we are learning better how to tailor therapy. We are learning better how to use PET scans, when to use radiation, when not to use radiation, but the biggest news is the excitement over drugs like SGN-35.

One last note of caution with SGN-35. As you well know, the backbone of SGN-35 is SGN-30, an anti-CD30 antibody. You have had some experience in trying to combine that with other drugs and ran into a little snag.

Dr. Bartlett: Yes. We tested SGN-35 with the GVD regimen as you mentioned, and had an unexpected pulmonary toxicity in that subset of patients. So when we are using these new drugs all of the initial studies are single-agent studies, and so we just need to be very cautious and do phase 1 studies of the combination therapies, and keep a close eye on potential complications. Hopefully we will not see that with the 35 drug, but I think it needs to be monitored.

Dr. Cheson: Great. Thank you, Nancy, for joining me today. This has been an exciting program. Thanks to all our viewers for tuning into Medscape Oncology ASH 2010, a focus on Hodgkin lymphoma.

Thank you and have a good day.

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