Skip to Content

Resource • Article

Second Line Therapy: The Past, Present, and Future of Treating Hematological Cancers

February 24th, 2024 | Cell Therapy | Article

Source: Robert S. Negrin, MD, Professor of Medicine and former Chief of the Division of Blood and Marrow Transplantation at Stanford University, Biorasi Scientific Advisory Board member.

Hematological cancers represent close to ten percent of new cancer cases in the United States. These blood cancers present across three primary types – as lymphoma, leukemia, and myeloma – with 13 different subtypes.1 There are currently over 600K deaths attributed to blood cancer each year.

For the most common form of lymphoma, diffuse large B cell lymphoma, a chemotherapy and antibody regimen, known as CHOP, remains the frontline treatment for this disease. Innovations in cell therapy have led to successful alternatives for patients should the first line of therapy not prove effective.

In our 2021 article, Identifying And Understanding Differentiators In CAR T-Cell Therapy, Dr. Robert S. Negrin remarked that just 20 years ago, “Chimeric antigen receptor (CAR) T-cell therapy was more akin to science fiction.” Today, it is not only an FDA-approved option for the second line treatment of hematological malignancies, but is also being considered as therapy for more common forms of cancer in the brain, lungs, and colon.

“The advantage of CAR T-cell therapy is that it works much differently than other cancer treatments,” said Dr. Negrin. “So, patients who have not responded to chemotherapy could have a significantly better reaction.”

Looking Into Treatment Origins

While each of the primary hematological cancers were first discovered in the 1800s, the first steps to their treatment began to evolve in the 1900s:

  • Radiation treatment had its origins in the discovery and use of X-rays and radium for “radiotherapy” beginning in 1896.
  • Chemotherapy treatment had its roots in the deployment of mustard gas as a weapon during World War I, extracting small amounts of nitrogen mustard to treat lymphoma.
  • Bone marrow transplants began in the 1960s, and were initially developed from the treatment of survivors of the atomic bomb in World War II.

CAR T-cell therapy itself made its first appearance in 1987, and was first used in the 1990s to target HIV-infected cells. Once it was determined that antiretroviral therapies were more effective against the HIV virus, the core of CAR T-cell research transitioned into cancer treatments. 2 In its second generation, CAR T-cell therapy trials initially successfully targeted CD19 – a protein specific to B cell leukemia and lymphoma. And, as of 2017, this therapy is FDA approved for acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL).

“It’s only been within the last five or ten years that CAR T-cell therapy has been developed and deployed,” said Dr. Negrin. “It is still a very novel approach, taking a patient’s own cells and reengineering them to be directed against their cancer. It took some time to develop a CAR that would signal properly, but the results were phenomenal in these refractory, end-stage patients who had failed other lines of therapy. So, of course, the next logical step was to move it up to an earlier line for a patient population that could see better results.”

Present-Day Treatment for Blood Cancers

As previously mentioned, the standard, front line treatment for diffuse large B cell lymphoma remains a chemotherapy and antibody regimen referred to as CHOP, which includes cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (oncovin), and prednisone.

“Unfortunately, about 40 percent of patients relapse after frontline treatment and the cancer returns,” noted Dr. Negrin. “The standard response in this situation had been to recommend a bone marrow transplant. Today, when compared to transplant options, for some patients, CAR T-cell therapy has been shown to be a superior treatment and it has been moved up to the second line of treatment after chemotherapy and CHOP for those patients who relapse within 12 months of initial therapy.”

Moving this therapy to second line gives greater access to patients and allows for a greater impact. However, the use of CAR T-cell therapy as a second line treatment does come with restrictions. Based on the FDA-approved label, CAR therapy can only be used on patients who:

  • Received chemotherapy and antibody CHOP therapy and did not achieve remission, also known as a primary refractory disease.
  • Received chemotherapy and antibody CHOP therapy and relapsed within 12 months.

“FDA approvals are largely based upon how the clinical trials are done,” said Dr. Negrin. “The clinical trials have to specify a certain patient population and also what prior treatments they may or may not have received. You have to specify what patient population you’re studying, what disease, what characteristics of those diseases, often some genetic characteristics, or what other characteristics that define risk. And then eventually you have to apply it to the current standard in that particular patient population.

“So you might ask, ‘what happens if a patient relapses within the 13+month timeframe?’ Unfortunately, they are not eligible for CAR T-cell second line therapy based on the approved FDA label. The treatment can still be performed, but as it is not approved, insurance companies do not need to cover the expense. This treatment is very expensive in off-label usage and there is only a small fraction of individuals that have these financial resources. So, in order to expand the label for a new or different subset of patients, and have it covered by insurance, additional clinical trials would need to be conducted.”

Future CAR T-Cell Therapy

The progression of CAR T-cell therapy from “science fiction” to successful second line therapy for hematological malignancies is an important achievement for clinical research and patients. Proponents are now looking at further applications for other types of cancers.

“CAR T-cell therapy is now being considered for other types of more common cancer,” said Dr. Negrin. “The field is moving very fast, but we are still in the early stage of applying this therapy as a consideration for front line therapy and other diseases.

“One area of exploration is the solid tumor space. Because this is a very different environment and pathology compared to blood diseases, we still have far to go before applying CAR T-cell therapy to tumors.”

CAR T-cell therapy is also examining its current footprint in the hematological disease space and refining its treatment and application. Some areas under review are:

  • Cytokine Variability – Identifying the toxicity experienced during T-cell treatment and developing endpoints to measure cytokine levels, from safe to severe.
  • Inpatient and Outpatient Treatment – Recognizing which patients would require hospitalization from side effects during treatment and which patients might be able to recover at home.
  • Third-Party Therapy – Moving beyond the cultivation of individual patient cells for CAR T-cell therapy and evolving toward the use of third-party cells, as if the treatment were a normal pharmaceutical.

“We’re hopeful and confident, but still learning,” said Dr. Negrin. “We have established CAR T-cell therapy’s viability and usefulness. The next step is to make it simpler, better, and cost effective.”


1 “Facts and Statistics Overview.” accessed May 24, 2023

2 Notman, Nina. “A decade of CAR-T cell therapy.” April 2022, Chemistry World.