What important changes in recent years do those treating patients with lymphoma need to keep in focus? Those treating newly diagnosed T-cell lymphomas, according to Owen A. O’Connor, MD, PhD, professor of medicine and pharmacology and chief of the division of hematologic malignancies and medical oncology at the New York University Langone Medical Center Cancer Institute in New York City, need to enroll their patients in clinical trials of combinations of newer agents, and those treating mantle cell lymphomas can consider upfront autologous stem cell transplant (SCT).
The emphasis on clinical trials comes as a result of an “explosion” in the number of new drugs with independent activity in T-cell lymphoma that are being evaluated in chemotherapy regimens not based exclusively on conventional cyclophosphamide/doxorubicin/vincristine/ prednisone (CHOP) combinations. Why not wait until phase 3 trials are complete and conclusions on the new agents’ efficacy are well grounded? Exploration of new agent combinations is important, O’Connor told The Oncology Pharmacist, given that T-cell lymphomas represent the most challenging subtype of non-Hodgkin lymphoma, with an unfavorable prognosis and few patients surviving beyond 1 or 2 years. “Many of the therapies that we have developed for B-cell lymphomas have been applied to patients with T-cell lymphomas, but it’s clear that strategy hasn’t been very successful—simply because Tcell lymphomas, in general, don’t respond to the same types of therapies that B-cell lymphomas respond to.”
New drugs for T-cell lymphomas
Among candidates for T-cell lymphoma treatment, O’Connor listed the histone deacetylase inhibitors vorinostat, romidepsin, and belinostat as having single- agent activity. The new antifolate, pralatrexate, the first drug approved by the US Food and Drug Administration for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma, has significant single-agent activity in patients with drug-resistant disease. Furthermore, among the proteasome inhibitors, bortezomib has singleagent activity in T-cell lymphomas. “So, you can begin to envision how we might begin to look at combinations of these drugs to concoct a new platform that will be truly T-cell dedicated in its focus, and hopefully in its effects,” O’Connor said.
Patients with newly diagnosed T-cell lymphomas who do not enroll in clinical trials of newer regimens will get conventional therapies unlikely to generate the response rates possible with newer regimens being tested in clinical trials, O’Connor said. National Comprehensive Cancer Network guidelines for treatment of peripheral T-cell lymphoma, both at diagnosis and in the relapsed/ refractory setting, recommend enrollment in a clinical trial as the best treatment option. “That’s a testament to the fact that there is no consensus regarding the optimal therapy. And it supports the fact that we do need to identify new treatment paradigms for the treatment of the disease.”
Unfortunately, only 3% to 5% of patients in the United States are being enrolled in clinical trials. The pattern of insurance company refusal to reimburse expenses of patients enrolled in clinical trials in the United States is a well-recognized barrier. Although drug manufacturers do routinely underwrite drug costs, expenses for other therapies, blood tests, routine visits, and imaging can be substantial and are not covered. That refusal, O’Connor suggested, is shortsighted in that patients not enrolling in clinical trials will be undergoing reimbursable treatment elsewhere. Costs above the standard of care in clinical trials are generally covered by the sponsoring pharmaceutical company, and in 2014, a provision of the Affordable Care Act providing coverage for patients in clinical trials will go into effect. In Europe, where barriers to enrollment are few, large numbers of patients are being enrolled in phase 3 trials.
“I have always argued that if you look at the response rates with newer regimens in our clinical trials in lymphoma, you see they are in the range of 20% to 30%, which rivals any conventional therapy for the average multiplerelapsed or refractory lymphoma. But our experience is that many of the newer regimens in clinical trials are without the hematologic toxicities of conventional therapy, and probably have better overall response rates,” O’Connor said.
New approaches to mantle cell lymphoma
Perhaps the most striking recent change in lymphoma treatment strategy is in the treatment of mantle cell lymphoma. The change emerges from recognition that autologous SCTs probably have much less efficacy and should have a much smaller role for patients with relapsed disease than they do for patients with a first remission that is near-complete or complete. Substantial evidence is beginning to emerge supporting com bination chemotherapy regimens that integrate high-dose Ara-C with other induction regimens, such as the Nordic Lymphoma Group’s maxi- CHOP regimen or the hyper-CVAD (cyclo phosphamide/vincristine/doxorubicin/ dex a methasone) regimen, which is modeled on The M. D. Anderson regimen, followed by consolidation with an autologous SCT. The addition of rituximab remains a debatable issue, O’Connor told The Oncology Pharmacist.
He noted, “When I started out in the field, we used to often quote a median overall survival in the order of 3 months, with a median duration of benefit of about 18 months. Nowadays, we recognize that the median progression free survival following hyper- CVAD and autologous SCT may be in the order of 6 to 7 years—and some of the Nordic data suggest even longer.” The possible median survival or progression- free survival rates with many of the new regimens remain undetermined. “I believe that integrating autologous SCT into the upfront treatment of patients with mantle cell lymphoma is going to have a very, very favorable impact on long-term survival,” O’Connor said.
Differentiating subtypes of lymphoma
In mantle cell lymphoma and other lymphomas, another evolutionary advance in the past several years is evident in the ability to divide what was historically thought to be one disease into a multiplicity of diseases through the use of gene expression array and other sophisticated technologies. For example, with diffuse large B-cell lymphoma (DLBCL), based on gene expression profiling, oncologists can identify subtypes based on cell of origin: germinal center or postgerminal center. Patients with postgerminal center DLBCL tend to have an inferior prognosis compared with patients with the germinal center DLBCL.
With DLBCL, as with mantle cell lymphoma, it has become evident that the most important prognostic factor may be the proliferation rate. Mantle cell lymphoma that is growing very rapidly and very aggressively, with a Ki-67 index of more than 30% or 40%, represents highly aggressive disease that needs to be treated in a very aggressive fashion, O’Connor said. Furthermore, subtypes of mantle cell lymphoma have been identified where the proliferation rate is very, very low. These are more like the indolent lymphomas, follicular and small lymphocytic lymphoma, and patients with these lymphomas actually have a very favorable long-term prognosis.
Personalized treatment a possibility
This ability to fractionate disease subtypes based on underlying molecular pathogenesis opens the door for personalizing treatment opportunities. “So the idea that we can now begin to tailor therapies, that we can personalize the treatment for some of the underlying biologies, is becoming a reality,” O’Connor said. He continued, “You might imagine that in the future, we will treat patients who have aggressive mantle cell lymphoma with very aggressive induction chemotherapy regimens followed by transplant, versus those patients with more favorable prognostic disease that can be ‘watched and waited’ or given single- agent rituximab.”
Shift in treatment goals
At the same time that progress in treatment efficacy has been occurring, a change with respect to general attitudes about side effects has led to a shift in treatment goals. The operant question, O’Connor said, has become, “Are we treating that patient with curative intent or as someone with a chronic disease? I think we’re getting much more sophisticated and less addicted to the idea that everybody needs to be cured.” Follicular lymphoma, he continued, is a great example, because it is a disease of people who are older than 60 years. With simple, well-tolerated therapies like rituximab, patients can be kept alive for 15 to 20 years or more, and will likely die of something other than the cancer. If the treatment goal is to cure the patient, for example, someone with Hodgkin lymphoma or with DLBCL, then asking them to tolerate a little bit more toxicity and risk for the bigger gain is justified. But with indolent disease, excessive treatment or overuse of chemotherapy will, with time, only make the lymphoma more drug resistant and the natural host cells more sensitive to future therapy. “There, I believe, we are getting a lot wiser and smarter about titrating therapies for the aggressiveness of the disease. We’re really trying to manage the patients as if they have a chronic disease, much the way cardiologists manage heart disease or an endocrinologist manages diabetes. The idea is that we don’t need to cure everybody, and, in many cases, we now have the pharmacologic tools to manage them.”