Advances in lymphoma treatment: new therapies and clinical trials

Lymphoma is a complicated and heterogeneous disease with the Lymphoma Research Foundation recognizing more than 100 different subtypes. “Each subtype is different from the others, spanning from completely asymptomatic and incidentally found lymphoma, to extremely sick patients that may be hospitalized for diagnosis and treatment,” says Michael R. Cook, MD, who specializes in B-cell lymphomas at Penn Medicine. Dr. Cook is an Assistant Professor of Clinical Medicine (Hematology-Oncology) at the Perelman School of Medicine.

Adding a PD-1 inhibitor to traditional chemotherapy regimens led to a 9 percent absolute increase in remission, Dr. Cook says. “With this new approach, 93 percent of patients with advanced-stage Hodgkin lymphoma were alive and in remission after the first three years of treatment. It’s a huge advance that has completely reset the standard for how we treat patients with newly diagnosed advanced-stage disease.”

Despite the complexity of lymphoma, researchers are making important strides in understanding these cancers and improving treatment outcomes. With two dozen active lymphoma clinical trials, Penn Medicine’s lymphoma team is helping to drive the field forward.

Hodgkin lymphoma treatment trends

Hodgkin lymphoma, a cancer most common in individuals under the age of 40, is considered one of the most curable cancers, in part because it is extremely sensitive to chemotherapy. Despite this, a recent clinical trial utilizing the PD-1 inhibitor Nivolumab has changed practice for patients diagnosed with advanced stage Hodgkin lymphoma.

With improvements in outcomes, some of the focus shifts to “survivorship” or minimizing treatment side effects that can affect patients for decades after the end of therapy.

“Historically, we’ve seen risk of cardiovascular toxicities, breast cancer, thyroid cancer and hematologic toxicity with both chemotherapy and radiation treatment,” Dr. Cook says. Advances in radiation therapy techniques and identifying which patients are most likely to benefit from combined modality treatment are helping to reduce those toxicities. “At Penn Medicine, our lymphoma specialists work really closely with radiation oncologists to look at each case in detail and personalize treatment,” he says.

Non-Hodgkin lymphomas treatment trends

B-cell lymphoma

The most common form of non-Hodgkin lymphoma, B-cell lymphoma encompasses a diverse range of cancers, requiring an equally complex array of modern treatment strategies. The treatment of B-cell lymphoma has changed with the advent of newer therapies, according to Dr. Cook.

“Long gone are the days when everyone with B-cell lymphoma is treated just with chemotherapy, or chemotherapy plus rituximab, which were the standards for a long time,” Dr. Cook says. “We now recognize that there are many different B-cell lymphomas that respond just as well, if not better, to non-chemotherapy-based approaches.”

One of the best examples of that progress is mantle cell lymphoma, which for decades was treated with high doses of chemotherapy followed by a bone marrow transplant. “Within the last five years, research has shown that BTK inhibitors can produce similar outcomes to intensive chemotherapy-based approaches,” Dr. Cook says.

Immunotherapy has also shifted the treatment landscape for B-cell lymphomas, particularly for patients with relapsed and refractory disease. In patients with early relapsed or refractory diffuse large B-cell lymphoma, for example, the advent of CAR T-cell therapy has brought long-term remission rates to around 40 percent, versus approximately five to 10 percent with chemotherapy and bone marrow transplant, the prior standard of care. Ongoing CAR T cell therapy research aims to drive those numbers even higher.

In one current clinical trial, researchers are exploring whether bridging therapy with a bispecific antibody given before CAR T cell therapy can improve disease control and make CAR T therapy more effective.

Another trial is exploring the use of a ketogenic supplement, which early data suggests may enhance the effectiveness of CAR T therapy. Meanwhile, Penn Medicine researchers are developing next-generation CAR T treatments, such as “armored CAR T cells” that secrete an immune-modulating cytokine to improve outcomes.

T-cell lymphoma

T-cell lymphomas are less common than the B-cell variant, representing about 10 percent of all non-Hodgkin lymphomas. Like B-cell lymphomas, they are quite heterogeneous. In addition to classic lymphoma symptoms such as swollen lymph nodes, night sweats, and weight loss, T-cell lymphomas sometimes present with unusual skin lesions. Primary cutaneous T-cell lymphomas affect only the skin; in some patients, however, T-cell lymphoma can affect both the skin and other organs.

“One of the things that is special about lymphoma treatment at Penn Medicine is our close collaboration with our dermatology colleagues, who really helped to establish the field of how we manage cutaneous T-cell lymphomas,” says T-cell lymphoma specialist Colin Thomas, MD, Assistant Professor of Clinical Medicine (Hematology-Oncology) at Penn Medicine.

While classic nodal peripheral T cell lymphomas are typically treated with standardized drug regimens, other varieties benefit from targeted therapies or immunotherapy agents. The array of options is even broader for patients with advanced disease, which can be a mixed blessing. “In the relapsed and refractory setting, there are so many different treatment options, and mapping out a treatment can become quite complicated,” Dr. Thomas says.

Unfortunately, outcomes in T-cell lymphomas remain relatively poor compared to other lymphomas. CAR T cell therapy has been ineffective for T-cell lymphoma, since CAR T cells designed to target T-cells can end up destroying one another. But research is underway to sidestep that limitation.

In a trial underway at Penn Medicine, researchers are using CRISPR technology to alter both healthy T-cells and CAR T cells, creating a CAR T product that only targets cancer cells. “CAR T therapy has made such a profound difference in B-cell lymphomas. With studies such as this, we hope to eventually extend that same hope to T-cell lymphomas,” Dr. Thomas says.

Lymphoma diagnosis and treatment at Penn Medicine

New treatment paradigms have been a welcome development in lymphoma, but they add a new layer of intricacy to managing an already complex group of cancers. “B-cell lymphoma treatment doesn’t easily lend itself to algorithms,” Dr. Cook says. “Our experienced lymphoma subspecialists take an individualized approach, considering molecular and genetic factors, disease-related factors, and patient-related factors to determine the best treatment approach.”

The value of that expertise often starts early in a patient’s cancer journey. “Lymphomas are a complicated set of diseases, and getting an accurate diagnosis is of utmost importance,” Dr. Thomas says. Penn Medicine’s surgical team sees patients quickly for PET image-guided biopsies to confirm a lymphoma diagnosis and subtype. Diagnosis also includes a full pathology review with pathologists who specialize in lymphoid cancers.

Whether patients are seeking a new diagnosis or pursuing treatment for relapsed disease, Penn’s large and experienced lymphoma team has a lot to offer. Those specialists often co-manage care with referring providers, enabling patients to receive as many treatments as possible in their home communities.

Referral and consultations

To refer a patient to the Penn Medicine Division of Hematology and Oncology, call 877-937-7366 or refer a patient online.