NEW YORK CITY—Novel agents such as brentuximab vendotin may provide sufficient disease control for selected patients with relapsed/refractory Hodgkin lymphoma to act as a bridge to allogeneic stem cell transplant. That was the conclusion of two experts here at the Great Debates and Updates in Hematologic Malignancies meeting here, who were asked to debate the question: How should a young patient with Hodgkin lymphoma that relapses after an autologous stem cell transplant be managed?
About one-third of the audience thought the answer should be an allogeneic stem cell transplant, and about two-thirds said novel systemic agents. Only a small percentage of the attendees changed their minds after the debate, but the experts all agreed that novel agents can keep some patients alive long enough to allow for allogeneic stem cell transplantation (ASCT).
Moskowitz: Treat with Allogeneic SCT
Craig Moskowitz, MD, Clinical Director of the Division of Hematologic Oncology at Memorial Sloan-Kettering Cancer Center, noted that about 8,500 patients are diagnosed each year with Hodgkin lymphoma—about 15 to 20 percent with early-stage disease and 20 to 35 percent with advanced-stage disease who relapse or have primary refractory disease. About 90% of these patients are eligible for an ASCT, he said. “Salvage chemotherapy followed by high-dose therapy with ASCT cures up to 50% of these patients.”
Following ASCT failure, the median survival is only about two years, so approximately 3,000 Hodgkin patients need novel therapies at any given time, based on median survival, he said. He likened the question of using investigational agents as a bridge to non-myeloablative ASCT to the one rock songwriter Neil Young posed about Johnny Rotten, the lead singer of the Sex Pistols: “Is it better to burn out or fade away?”
A few drugs, notably brentuximab, may work as a bridge to transplant. Pivotal data on brentuximab in the treatment of relapsed/refractory Hodgkin lymphoma (HL) show an overall response rate (ORR) of more than 70%, with one-third of patients achieving a complete response (CR). “Almost all patients get clinical benefit in clinical trials of brentuximab. By far, this is the best drug I have seen for this disease,” he said.
Panobinostat has shown good clinical results, with a median duration response of about seven months. Bendamustine also shows response rates similar to those of the other two drugs, but “the response duration is so short it's difficult to bridge to allotransplant,” he said. “The best agent for patients who fail autotransplant is brentuximab.”
However, he pointed out that with brentuximab, “patients have prolonged remission duration, but are they cured? It's unlikely.”
If HL patients are able to get an allogeneic transplant and get past early complications, there is a survival advantage with ablative transplants, Moskowitz noted. The median survival of second transplants is 40 months, and reduced-intensity and non-ablative allogeneic SCTs have shown improved outcomes and lower treatment-related mortality: “One in three patients who have allogeneic SCT is progression-free after two years in the pre-novel treatment era,” he said.
Largest Series in This Patient Group
Moskowitz highlighted recent research at City of Hope to estimate the efficacy of allotransplantation following brentuximab treatments in 31 relapsed/refractory HL patients, which is the largest series available in this patient group. Of the 31 patients, 14 (45%) underwent reduced-intensity allogeneic transplantation. These patients were young (average age of 30), heavily pretreated, and most had received previous radiation. All but one showed a clinical benefit from brentuximab. The CR rate was 39 percent and the one-year progression-free survival (PFS) rate was 92.3 percent.
“Personally, I think the winner [of the debate] is a bridge to transplant. Brentuximab enables successful reduced-intensity allogeneic SCT in relapse/refractory HL,” Moskowitz said. “The addition of brentuximab prior to allogeneic transplantation does not appear to adversely affect engraftment, graft-versus-host disease, or survival. Brentuximab may provide sufficient disease control for selected patients to successfully proceed to allogeneic SCT.
“For me, the best available therapy, off study, is three doses of brentuximab, followed by a repeat PET scan. If the PET scan is negative, I give one or two more doses of the drug and then do an allotransplant.”
Straus: Best Course: Novel Systemic Agents
Taking up the argument that use of novel systemic agents is the best course of therapy, David J. Straus, MD, Attending Physician at Memorial Sloan-Kettering Cancer Center, said, “I don't disagree with Dr. Moskowitz, but I approach this from a different point of view.” He said treatment options for relapsed/refractory Hodgkin lymphoma after ASCT include third-line chemotherapy, novel new agents, or new agents or chemotherapy as a bridge followed by a second ASCT.
A conventional chemotherapy option might be a combination of gemcitabine, vinorelbine, and liposomal doxorubicin. This combination leads to response rates of 58 percent with no prior transplant and 68 percent with prior transplant. Remission duration is longer for those with no prior transplant, he noted.
Novel new agents include brentuximab: “The pivotal trial of brentuximab showed quite astounding results,” said Strauss. In patients who were heavily pretreated, half refractory to the most recent treatment, there was “an astounding ORR of 75 percent and CR of 34 percent,” Straus said. “Almost any other agent has no better than 30 percent response rate.” The success of brentuximab has led to a number of clinical trials to incorporate the drug into treatment.
Other drugs also show some benefit, he continued. For example, panobinostat leads to an ORR of 27%, and while it is not being further developed for Hodgkin lymphoma, this may be a class effect, since similar drugs also show activity in HL.
Lenalidomide, which leads to an ORR of 17 to 50 percent (mostly partial responses), is a drug of some potential for HL, he said. And off-label use of brentuximab is “very promising” with a high overall response rate around 60 percent and complete response rate of 35 percent in heavily prior treated patients. Everolimus leads to an ORR of 47% in a small number of patients, and a large clinical trial in HL is ongoing.
Straus said that a second autotransplant could be an option for patients with late relapse after a first autotransplant. In published studies of relapsed/refractory HL patients who undergo allogeneic SCT with myeloablation, overall survival rates range from 21 to 30 percent and progression-free survival from 15 to 26 percent. But treatment-related mortality is about 50 percent, and “that has dampened enthusiasm for this approach,” he said. Reduced-intensity conditioning has a “reasonable” overall survival rate of 29 to 66 percent, PFS of 20 to 50 percent, and a “reduced but still substantial” treatment-related mortality rate of about 20 percent.
Straus suggested a strategy to incorporate novel agents for a young patient with refractory disease after ASCT. Third-line treatment could include a clinical trial of a novel new agent, such as the PI3K inhibitor Cal101; commercially available new agents, such as brentuximab or lenalidomide (off-label use); or second-line chemotherapy or bendamustine (off-label use).
“If the patient goes into remission, and has a negative PET scan, this could be a possible bridge to SCT,” Straus said. Consider a second autologous SCT if the duration of remission following first ASCT is at least 12 months. Consider an allotransplant with reduced conditioning if remission following first ASCT is at least six months. For primary refractory disease, or with relapses within six months, the results with a second transplant, either allogeneic or autologous, are not very good. Sequential palliative treatment should be considered in these patients.”
Treatment recommendations versus watchful waiting are driven by an assessment of risk/benefit ratios. Clinicians need to consider the risks of treatment, including doctor visits, hospitalizations, and transfusions; expenses; chemotherapy side effects; and late toxicities, including graft-versus-host disease and myelodysplastic syndromes.
The benefits of treatment, he continued, include prolongation of and a more active life, and cure. For watchful waiting, the risks include clinical deterioration and inefficient subsequent therapy, and the benefits include a better lifestyle and avoidance of acute and chronic toxicity.
“It's a moving target,” said Straus. “Treatments are in evolution, as is our knowledge of disease patterns.”
This thought was reflected in the audience poll after the debate—only 3% switched their vote in favor of allogeneic SCT.
John Leonard: Difficult Question
Panel moderator John P. Leonard, MD, Professor of Medicine at Weill Cornell Medical College in New York City, commented: “What is definitive treatment, allotransplant or a novel systemic agent? This is a difficult question because of evolving new agents for HL. It's probably not so much either/or, or both, but how or when. The nuances of how to treat such a patient outside a clinical trial include where to sequence, what to do first, and when to stop. It's a challenge.”
In the question-and-answer period, he asked why the toxicity with brentuximab was so good in the City of Hope allotransplant experience. Moskowitz answered: “City of Hope researchers have the largest experience in the world with brentuximab, and the country's largest experience with allotransplant in HL. They select only responding patients going into transplant. The single best predictor of good long-term outcome is remission duration of at least one year from autotransplant and being in remission at time of allotransplant. You have to pick your patients wisely.
“In older studies, the patients were beat up by chemotherapy. Certainly, less MOPP prior to transplant is probably a good thing.”
Straus said one problem is the heterogeneous nature of HL patients: “If transplanters could develop a model to clearly define the risks, it would be helpful to know who should not be sent for transplant.”
The last word went to Leonard: “I tend to take the approach of Dr. Moskowitz to keep HL patients going. In all broad series of patients, people don't do that well with novel agents alone. The message is we have to keep looking for new things, whether it's an allogeneic transplant or other novel drugs.”