Meeting the Challenges in Treating Lymphoma: A Conversation With Andrew D. Zelenetz, MD, PhD

Andrew D. Zelenetz, MD, PhD

The 16th Annual International Congress on Hematologic Malignancies was held in Snowbird, Utah, February 23 to 26, 2012. The four-day symposium was chaired by Andrew D. Zelenetz, MD, PhD, chief of Lymphoma Service and vice chairman of Medical Informatics at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City.

Zelenetz, who works as part of a multidisciplinary team, has helped develop agents to treat lymphoma, and through clinical trials is evaluating combinations of new lymphoma drugs.

Oncology & Biotech News had the chance to sit down with Zelenetz to discuss a number of new therapies and interesting challenges regarding the treatment of patients with both Hodgkin and non- Hodgkin lymphoma, as well as promising studies that have helped oncologists to better understand these hematologic malignancies.

OBTN: How effective are today’s available treatments for non-Hodgkin lymphoma, specifically diffuse large B-cell lymphoma? Dr Zelenetz: The standard of care for diffuse large B-cell lymphoma (DLBCL) in the United States remains rituximab (R) in combination with cyclophosphamide, doxorubicin, vincristine, and predisone (CHOP) given every 21 days. There are a number of regimens that have reported better results than would be expected with R-CHOP, such as dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) (developed at the NCI) and sequential R-CHOP-14 followed by ifosfamide, carboplatin, etoposide (ICE) (developed at MSKCC). However, we’ve been in the situation before where phase II trials have suggested improved outcomes that have not been validated in phase III trials. We await the results of CALGB 50303 (R-CHOP-21 vs DA-EPOCH-R) and further evaluation of R-CHOP-ICE to see if we can confirm improved outcomes.

The major issue in DLBCL is that, over the past decade, we have recognized that this is not a single disease. Expression-profiling data suggest that DLBCL is at least three diseases, and certainly more than that. But even within the subtypes (ie, primary mediastinal B-cell, germinal center, and activated B-cell), the genomic studies have demonstrated that there is variability. I believe that the real advances are not going to involve simply juggling cytotoxic chemotherapies. We’re going to have to start selecting patients based on the presence or absence of certain features of the disease.

For instance, the Bruton’s tyrosine kinase (BTK) inhibitor targets lymphomas with tonic B-cell receptor (BCR) signaling that is seen in active B-cell lymphomas (and possibly some germinal center lymphomas). However, additional mutations downstream of BTK, such as CARD 11 or MYD88 mutations, will likely block the activity of this inhibitor. This suggests that, even within a subtype of DLBCL, treatments will be selected based on what we know about the genetic abnormalities.

The R-CHOP regimen appears to be effective in two-thirds of the patients, but that remaining one-third of patients presents a challenge. Where do you go from there in terms of treatment?

The International Prognostic Index (IPI) is a simple clinical tool that can predict clinical outcome in the rituximab era. Patients with low- or low-intermediate-risk disease have a substantially better outcome than patients with high-intermediate or high-risk disease. This can help us select therapy. For patients with low- or low-intermediate-risk disease, R-CHOP-21 may be appropriate. However, for high- or high-intermediate-risk patients, the sequential R-CHOP-ICE regimen we published a few years ago had an excellent outcome where long-term overall survival and progressionfree survival were between 75% and 80%. Furthermore, the French R-ACVBP (rituximab plus doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) regimen has shown a superior outcome for poor-risk patients.

These data suggest that we can improve outcomes with conventional chemotherapy, but at the same time we don’t want to overtreat patients and expose them to excessive toxicity if they won’t benefit from chemotherapy. The IPI can be used to select more favorable patients who are expected to do very well with R-CHOP. One strategy to determine if a new therapy is better than R-CHOP-21 is to enroll patients with unfavorable IPI; in doing so, the difference (if any) with R-CHOP-21 may be magnified. We are looking forward to the results of the CLGB 50303 comparing R-CHOP-21 to DA-EPOCH-R. That is a very important study because it has two features: embedded gene-expression profiling and some limited genomics. This will allow us to determine if there is any correlation between the chemotherapy and specific genomic and gene-expression profile signatures. Ultimately, this may help us select patients who can get R-CHOP with excellent results and patients who might benefit from the more aggressive DA-EPOCH-R.

Are there any clinical trials in progress for proposed non-Hodgkin lymphoma treatments that you consider particularly promising?

The problem is that non-Hodgkin lymphoma is a complex disease with nearly 80 subtypes that have unique natural histories. In follicular lymphoma, a trial of rituximab and lenalidomide conducted at MD Anderson showed extremely high response rates to the novel combination. Although chemotherapy is not included, there are potential concerns about the long-term consequences of lenalidomide use. A GELA (French for Groupe d’Etude des Lymphomes de l’Adulte) and US trial is being launched that will compare rituximab and chemotherapy to lenalidomide plus rituximab. This will address a key issue: Can we get away from conventional cytotoxic chemotherapy with good long-term outcomes? This study is designed to look at outcomes over a 10-year follow-up period.

Clearly, B-cell receptor signaling turns out to be an important target, particularly in small lymphocytic lymphoma, CLL, and mantle cell lymphoma, where response rates are extremely high for both the Bruton’s tyrosine kinase inhibitor PCI 32765 and the PI3-kinase inhibitor CAL 101 (GS 1101).

It’s very interesting that the PI3 kinase inhibitor, which is essentially on the same pathway as the mTOR inhibitors, is substantially more active than mTOR inhibition. So it depends on where you hit a pathway. The mTOR inhibitors have a substantial risk of feedback upregulation resulting in resistance. These drugs might have activity in other lymphomas, namely follicular lymphoma.

With regard to Hodgkin lymphoma, what are some of the challenges associated with treating relapsed or refractory patients?

Until very recently, we didn’t have strategies other than conventional chemotherapy in Hodgkin lymphoma. Fortunately, in most cases, conventional chemotherapy is going to be curative. However, in relapsed Hodgkin lymphoma, even though patients can be cured, there is more resistance to conventional chemotherapy.

We know from randomized trials that high-dose therapy and autologous stem cell rescue is superior to conventional chemotherapy in relapsed/refractory Hodgkin lymphoma. Early on, we thought that as long as you had some response, even a minor response, to the second-line conventional chemotherapy, you would have a good outcome with high-dose therapy and autologous stem cell rescue. We have found that the quality of response is, in fact, important. Recently, we demonstrated that pushing the chemotherapy until you have a PET-negative response prior to the highdose therapy is associated with a superior outcome. Unfortunately, there are still a number of patients with disease refractory to conventional chemotherapy.

This has changed with the development of brentuximab vedotin. This is a drug that targets CD30 in Hodgkin lymphoma (and anaplastic large cell lymphoma). After binding to the CD30, the antibody is internalized and the auristatin is released, which effectively kills the tumor cell. The response to brentuximab vedotin in relapsed Hodgkin lymphoma is very high.

The availability of brentuximab vedotin raises the question: How do we integrate that agent not only into the frontline setting (which is under active investigation), but also into the relapsed refractory setting? What we have right now is a drug that works, but won’t cure anybody. Brentuximab vedotin is a very active antibody drug conjugate, but response and prolongation of progressionfree survival are not adequate endpoints in Hodgkin lymphoma. The endpoint in Hodgkin lymphoma is cure.

We want to see how we can integrate this agent up front, and there are some real challenges. The initial attempt to just integrate brentuximab vedotin with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) resulted in unexpected excessive pulmonary toxicity with some life-threatening complications. So, one has to proceed cautiously.