NEW YORK—The International Congress on Hematological Malignancies here kicked off with a debate on a challenging malignancy, peripheral T-cell lymphoma (PTCL), and the role of high-dose therapy with autologous stem cell rescue (HDT/ASCR) as initial management.
Most PTCL subtypes have a worse prognosis than that for aggressive B-cell non-Hodgkin lymphoma, with a median overall survival time of one to three years, and a five-year overall survival rate of 26 percent. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) is an exception, with a five-year survival rate of 65 to 90 percent.
Lauren Pinter-Brown, MD, Clinical Professor of Medicine and Director of the Lymphoma Program at David Geffen School of Medicine at UCLA, argued in favor of HDT/ASCR for PTCL, but not for all patients; and Pierluigi Porcu, MD, Associate Professor Internal Medicine at Ohio State University, argued against that treatment, but also with exceptions.
Place Emphasis on Consolidation
Pinter-Brown noted that PTCL continues to have a poor prognosis despite being a chemosensitive tumor, mostly because the duration of remission is typically quite short. The focus of treatment, she said, should therefore be placed on consolidation or maintenance in attempt to extend remission.
Phase III data evaluating the role of ASCR upfront as consolidation is unfortunately not available, but prospective Phase II data suggest that ASCR upfront may benefit patients with high-risk PTCL in first response, despite an early failure rate of 27 percent.
Prognostic factors include scores on the International Prognostic Index (IPI) or Prognostic Index for T-cell lymphoma (PIT), and the complete response rate at the time of transplantation. “I personally feel that for patients in partial response, transplantation may not be in their best interest,” she said. “There is a lot of work we need to do for PTCL. Auto transplant probably improves people's outcome a little, but it is not the answer.”
She said that at her center almost any patient who does not have ALK+ ALCL is considered for transplantation, and not just patients with high IPI scores, as noted in the NCCN guidelines.
Because PTCL is chemotherapy-sensitive, high-dose therapy should be of benefit to some patients, and many studies do show a statistically significant difference when patients are transplanted, she said, citing the Nordic Lymphoma Group NLG-T-01 trial with 160 previously untreated PTCL patients, which showed that among the 79 percent of patients who had a response and went on to have a transplant, the five-year survival rate was 51 percent, and the progression-free survival rate was 44 percent (JCO 2012;30:3093-3099).
The dose-dense induction there was CHEOP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone with etoposide omitted for patients over age 60), followed by HDT/ASCT. The study authors concluded that this outcome was encouraging, particularly considering that the patients had a high median age of 57.
Etoposide may not be helping in this regimen, Pinter-Brown said. The 42 “elderly” patients in the trial (median age of 64) who did not receive etoposide had the same overall response rate and progression-free survival as the 50 corresponding patients 55 to 60 years old who did receive etoposide.
Because of data from German trials, she said, hematologists started to think that etoposide is an important agent, “but I'm not sure it that it adds so much, and I don't believe it adds so much that we can abandon transplantation, or sit on our laurels [and think] we're doing very well for these patients.”
The role for auto transplantation today in relapsed and refractory disease is not the same as in the past, when there were not many approaches for salvage treatment. “Auto-transplant may have a more important role in relapsed and refractory disease going forward, as our induction therapies improve or we have more of an ability to salvage patients who fail first induction,” she said, noting that both pralatrexate and romidepsin are FDA-approved for patients with relapsed or refractory PTCL.
“In the pralatrexate data there are patients who went to transplantation and who remain in complete response. Back in the day they would have been included in the group for whom there was nothing more we could do.”
Should Good Candidates for Transplant Receive Transplant at All?
In his talk, Porcu questioned whether patients in the subset who make it to transplant should continue to autologous stem cell rescue, considering that the post-transplant relapse rate is still about 20 percent.
“We know who should not be considered for transplantation—those with progressive disease and those who don't respond well to frontline therapy,” he said, elaborating on his remarks after the session. “But what about patients who are somewhere in between, who don't have complete remission, who have some persistent activity on PET scan? We don't know if they will or will not benefit from stem cell transplant.”
A better question, he continued, is should patients who make it to transplant be transplanted at all?
“If somebody achieves a very good response to frontline chemotherapy, how much does the stem cell transplant add to the odds of those patients who have a prolonged disease-free survival or a cure? We don't know that because a randomized study has not been done, but I think that is the big question.”
Porcu noted that new agents—for example, brentuximab for CD30-positive disease, pralatrexate, and romidepsin—may well obviate the whole transplant question, “And in the pipeline are some signal transduction inhibitors and tyrosine kinase inhibitors that are gradually being applied to PTCL,” he said. “One or more of those may be game changers, and at that point we can do without the high-dose chemotherapy.”
Porcu said HDT/ASCR has some applications but not as broad as currently being used. “We know a lot of patients do not benefit from high-dose chemotherapy and stem cell transplant—in many cases the patients themselves show it to us because they don't make it to transplant or they relapse after transplantation.”
Even though the procedure is safe and has a low toxicity, which may incentivize physicians to use it, patients must be carefully selected—and, the heterogeneity of the different subtypes of PTCL makes selection a challenge.
Another challenge is that even in those patients who reach HCT/ASCT under optimal conditions and with a very good response to front-line therapy, relapses still occur after that, which means there is an undetectable underlying residual disease not controlled by high-dose chemotherapy. “We need to find better ways to deal with that subset of patients,” he said.
New Agents May Take More Patients to Transplant
In an interview after the session, Pinter-Brown had a different take on the promise of new agents in PTCL—that they might take more patients to transplantation even if the patients do not respond to CHOP or CHOEP.
These regimens could benefit patients who now are being transplanted in relapse or refractory situations, she said. “If someone has progressive disease on their initial induction therapy and can't get to transplant as per the studies, that may not be the case any longer [with new agents]. Effective drugs may salvage those patients and allow them to go to transplant after a second attempt at getting into complete remission.”