Issues in the Treatment of Relapsed or Refractory Hodgkin Lymphoma: An Expert Interview With Dr. Craig Moskowitz

 

Hodgkin lymphoma (HL) is a relatively uncommon malignancy involving nodal and extranodal sites that can be very effectively treated. With 5- and 10-year survival rates of 85% and 81%, respectively,^[1] the disease has shown unprecedented improvements in survival rates in the past 3 decades.^[2] Indeed, cure rates for HL have increased so dramatically that treatment is often driven by considerations of long-term toxicity and secondary malignancy, particularly for patients with early- or intermediate-stage disease. Standard of care includes chemotherapy -- most often ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), but also potentially Stanford V (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, prednisone) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) -- with or without radiation therapy.^[3]
The outlook varies for patients with refractory or relapsed disease. High-dose chemotherapy followed by autologous hematopoietic stem cell transplant (HSCT) is the standard of care, and cure can still be achieved. However, there is a subset of patients who are chemo-refractory to standard-dose salvage regimens and who fail or are not eligible for HSCT -- and who therefore require novel approaches to treatment. New agents, such as bendamustine, histone deacetylase (HDAC) inhibitors, and SGN-35, and novel strategies, such as reduced-intensity allogeneic therapy, are under study, with research ongoing into their effectiveness as well as how best they may be incorporated into standard treatment regimens. Preliminary results on some of these new agents were presented at the 2009 annual meeting of the American Society of Hematology (ASH).
On behalf of Medscape, Dina Acciai Basile, RPh, MBA, spoke with Craig Moskowitz, MD, Clinical Director, Division of Hematologic Oncology-Memorial Sloan Kettering Cancer Center, Associate Member Lymphoma Transplant Services at Memorial Sloan-Kettering Cancer Center, and Associate Professor of Medicine at Weill Medical College of Cornell University, to discuss the latest advances in relapsed and refractory HL.
Medscape: Let's start briefly with first-line treatment of HL. What issues do you think need to be addressed?
Craig H. Moskowitz, MD: The main issues that I would identify in first-line treatment are late-treatment effects and the decreased use of radiation therapy (RT). To the first point: once patients have survived about 10 years past initial therapy, their cause of death is almost never from HL. It is from issues related to therapy.^[3] A critical aspect of treatment therefore is patient stratification: Do not overtreat the patients who are expected to do well, and do not undertreat the patients who are expected to do less well with primary therapy. But how do you distinguish?
There are 2 main ways to stratify patients: one used by the German Hodgkin Study Group (GSHG) and the other in US trials.^[3] The GSHG approach divides patients into 3 prognostic groups: early-stage favorable, early-stage unfavorable, and advanced-stage HL. The US approach divides patients into 4 risk groups: early-stage favorable, early-stage unfavorable, bulky-stage II, and advanced-stage disease. In addition, there is a different treatment strategy based on gender. Women with nonbulky disease are almost never administered RT, while men usually do receive RT as part of consolidation after primary chemotherapy. Although the assumptions underlying each of them differ -- the GHSG assumes there is only 1 chance, or at the most 2 chances, to be cured, while the US approach assumes 3 points of intervention for cure -- both approaches are an attempt to individualize treatment to have the best chance of cure without raising the subsequent risk for treatment-related toxicities. As such, the US treatment approach for favorable disease is most often ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine] alone, with RT use based on more risk factors. Patients who experience relapse are autotransplanted. If treatment fails, depending upon remission duration, the disease is still potentially curable with either a nonmyeloablative transplant from a matched related donor or an unrelated donor, or a cord blood transplant.
The second point, the decreased use of RT, relates to the risk for late-treatment effects as well as an increased use of fluorodeoxyglucose- positron emission tomography (FDG-PET) scanning, especially among patients with B symptoms, with bulky stage, or with poor risk, early-stage HL. PET scanning upstages patients to stage III or IV by finding disease in small lymph nodes below the diaphragm or in extranodal sites that we did not see before^[4] -- and these patients receive chemotherapy alone. In terms of late-treatment effects, the risk of developing secondary malignancies is highest in patients who receive RT as first-line therapy.^[3] This is particularly the case for women and breast cancer, and therefore the irradiation of women has been discouraged. Nevertheless, we are seeing more women with relapsed and refractory disease, so I should note that although we try to avoid RT in women because of fertility and breast cancer issues, not all women should be non-irradiated.
The 2 key points to remember in the first-line setting are: (1) the relapse rate is higher for patients who failed chemotherapy alone compared with those who failed combined modality therapy, and (2) patients who fail chemotherapy alone are still curable but need to undergo transplantation.
Medscape: When a patient presents with relapsed or refractory disease, what drives your treatment strategy?
Dr. Moskowitz: The approach I take to patients with relapsed and refractory HL is that they are curable. Indeed, at least half of patients with chemosensitive disease who undergo autotransplantation will be cured.^[5] However, as in all aggressive lymphomas, outcomes are very poor if the disease is not chemosensitive.
Although we have made progress reducing the toxicity and cost of HSCT, relapse and progression rates after HSCT have changed little in 10-15 years. CBV (cyclophosphamide, carmustine, etoposide) and BEAM (carmustine, etoposide, cytarabine, melphalan) are standard conditioning regimens, and there is no evidence to date that supports adding additional agents to these regimens to improve outcomes. Treatments continue to avoid RT, despite evidence that relapse occurs at the sites of bulky disease that should have been irradiated.^[6]
Still, there are a number of questions in the treatment of relapsed/refractory disease that arise: Can we develop reliable prognostic models that will predict outcomes for patients in a relapsed or refractory state? How can we incorporate FDG-PET scans into the way we treat patients? And how do we incorporate new agents and strategies into curative therapy for HL? Are there times when we should do an allogeneic transplant in lieu of an autotransplant -- keeping in mind that the disease must be in remission so that the graft vs lymphoma response that occurs in about 3-5 months can take effect?
In the 1990s, our group^[7] explored a new approach toward treatment by first giving 2 cycles of the ICE (ifosfamide, carboplatin, etoposide) chemotherapy regimen to determine chemosensitive disease and then performing a radiation-based transplant. This approach resulted in a 58% event-free survival at 43 months. In the study, we also identified 3 risk factors that predicted outcome: extranodal disease, B symptoms (fever, night sweats, and weight loss), and remission duration of 1 year or less. The more risk factors a patient had, the poorer the outcome -- such that patients with 0 or 1 risk factor had an 83% event-free survival vs 27% for those with 2 risk factors vs 10% for those with 3 risk factors.
More recently, we published a study in the British Journal of Hematology that evaluated patients treated according to risk factors while also examining the predictive value of FDG-PET scans.^[8] Patients with favorable risk factors received standard-dose salvage chemotherapy with 2 cycles of ICE and underwent autotransplantation after high-dose chemoradiotherapy if they responded. Intermediate-risk patients received augmented ICE and underwent autotransplantation if they responded. Patients with 3 risk factors received a tandem transplant -- either 2 autologous transplants or autologous followed by a mini allogeneic transplant. Survival tripled in patients with negative FDG-PET scans pre-transplant, with three fourths of patients who were FDG-PET negative being cured vs only one third of patients who were FDG-PET positive but with improvement on computed tomography (CT) scans, prior to transplant. The importance of the negative FDG-PET scan was also validated by another study.^[9] In 100 patients with 2 or fewer risk factors, we gave risk-adapted salvage chemotherapy and repeated their FDG-PET scan. If they were FDG-PET negative, patients underwent RT and autotransplantation. If they remained FDG-PET positive despite improvement on CT, patients did not receive transplantation but received additional chemotherapy for 2 months with gemcitabine, vinorelbine, and liposomal doxorubicin to try to achieve an FDG-PET-negative state. Those who improved when restaged underwent transplantation.
A key point is that it takes different levels of treatment to normalize the FDG-PET scan based on the number of patient risk factors. The goal of salvage chemotherapy in patients with relapsed and refractory HL should be to normalize the FDG-PET scan pre-transplant.
Medscape: Where do you see new agents or allogeneic transplant fitting in to that paradigm?
Dr. Moskowitz: There are 3 new classes of compounds that have activity in HL: bendamustine, antibody/drug conjugates, and HDAC inhibitors. When thinking broadly about new agents, I am less interested in using single-agent therapy. However, I am very interested in looking at maintenance therapy post-HSCT. Also, new agents such as HDAC inhibitors or antibodies can be incorporated into salvage chemotherapy to increase the number of patients in remission eligible for transplant. There are also phase 1 and 2 studies beginning to look at AVBD and the antibody SGN-35 in primary chemotherapy.
For patients who fail HSCT for HL, median survival is 2 years.^[10] Most patients are relatively young and in general good health, making them excellent candidates for investigational therapy. Our data suggest that if we can get patients into remission again and perform a second transplant, usually allogeneic, survival doubles. Although this approach is far from standard, my goal for patients who have failed autotransplant is to give investigational agents to potentially achieve an FDG-PET-negative state and prepare them for a nonablative allogeneic transplant. It was in this context that we studied bendamustine.
In my opinion, we also should consider allogeneic transplantation in lieu of autotransplantation for patients expected to have less than a 25% chance of being cured with an autotransplant following relapse from upfront therapy. Just reserving allogeneic transplantation for those who have failed autotransplantation is short-sighted. We have identified 2 subpopulations where allogeneic transplantation can be considered: patients with all 3 risk factors and patients who are still FDG-PET avid after salvage chemotherapy.
Medscape: Let's discuss each class of new agent. Shall we start with the new data on bendamustine presented at ASH in December?
Dr. Moskowitz: Bendamustine is an alkylating agent approved for chronic lymphocytic leukemia and indolent B cell rituximab-resistant non-Hodgkin lymphoma. It causes cell death via several pathways and is active against both quiescent and dividing cells. We presented data^[11] on the first 18 patients in an ongoing clinical trial who had failed autotransplant and, in some cases, allogeneic transplant. Of note, all responding patients had cytoreduction by the first planned restaging evaluation. Three fourths of patients responded -- meaning they could actually receive the allogeneic transplant. The key is to be ready to do the transplant when the patient is in a minimal disease state. The drug is well tolerated posttransplant -- no hair loss, minimal extramedullary toxicity, and very little nausea. There was some hematologic toxicity that was easily managed. In the future, we may also study bendamustine with other combinations.
Medscape: What about drug antibody conjugates?
Dr. Moskowitz: SGN-35 is an antiCD30 antibody conjugated to the antitubulin agent monomethyl auristatin E that causes cell cycle arrest and apoptosis by binding to CD30 and releasing the antimitotic into the cell. Remember that CD30 is a transmembrane glycoprotein receptor that is highly expressed on Reed-Sternberg cells with very limited expression on normal cells. The pivotal study is closed, and the data are not available yet. A recent poster at ASH^[12] discussed weekly dosing with SGN-35 in a heavily pretreated population of patients with relapsed and refractory HL. It was well tolerated and induced a 46% overall response rate, with 29% of patients attaining complete response. We are also enrolling a 400-patient international study in which relapsed, intermediate-risk patients follow their center's HSCT protocol and are randomly assigned SGN-35 or placebo for a year post-HSCT with the goal of doubling progression-free survival.
Medscape: Will you comment on HDAC inhibitors?
Dr. Moskowitz: HDAC inhibitors are small molecules that inhibit histone deacetylase. HDAC decreases oncogene expression, decreases angiogenesis, and induces cell cycle arrest and apoptosis. Vorinostat is approved for use in cutaneous T-cell lymphoma. Panabinostat is being studied in HL. Its single-agent activity is similar to that of SGN-35. There is an ongoing study looking at panabinostat maintenance post-HSCT.
Medscape: Do you have any final comments on the treatment of patients with relapsed/refractory HL?
Dr. Moskowitz: I believe we will see HL become a curable disease. The message for patients is one of hope. New agents will make continued improvements in outcomes possible.
Supported by an independent educational grant from Cephalon Oncology.