Blood Cancer | City of Hope

Groundbreaking new therapies provide hope to blood cancer patients

For two groups of patients — older people diagnosed with acute myeloid leukemia (AML) and patients whose aggressive B cell lymphoma did not respond to treatment or had relapsed — the prognosis has not been rosy. Now, thanks to the success of two recently completed studies, there is new hope for them.
City of Hope physicians played prominent roles in both trials. Vinod Pullarkat, M.D., clinical professor in the Department of Hematology & Hematopoietic Cell Transplantation, was principal investigator on the AML study, published in August in The New England Journal of Medicine and Tanya Siddiqi, M.D., director of the chronic lymphocytic leukemia program, was senior author of the aggressive B cell lymphoma study, published in September in The Lancet.
Let’s take a closer look at each trial and their effective new treatments.

New Hope for Older Patients with AML

Acute myeloid leukemia is a disease that is most common in older individuals. The median age is about 68, and many patients are in their 70s, 80s and even 90s, which made treating the disease difficult.
“High-intensity therapies were so poorly tolerated, with side effects that often made people worse. But the treatments we could use for older patients were not very effective,” said Pullarkat. “The most we could do was prolong their lives for a few months. Now we have an option with a high rate of complete remission while preserving quality of life.”
With previous standard-of-care treatments for older patients, such as azacitidine, the complete remission rate was between 15 and 20%. For this study, azacitidine was combined with a drug called venetoclax. The result was a complete remission rate of almost 70%.
This combination treatment has other advantages, too. It’s very well tolerated, with no major toxicity to other organs like the liver or kidneys. A hospital stay is usually not required, and most patients can be treated in an outpatient setting.
What’s more, in order to have a stem cell transplant, a patient should ideally be in complete remission. This new treatment means that many more older patients will be eligible for a transplant — the only permanent cure for most cases of AML.
The combination of azacitidine and venetoclax has been approved by the Food and Drug Administration (FDA) and is the new standard of care for older people with AML.
The study yielded many success stories, but you can hear the joy in Pullarkat’s voice when he talks about one woman in particular.
“I had a patient who was 89 when she presented with AML. She had no option but to go on supportive care, so she was referred to me for this study,” he said. “She has now been in remission for three years, is very active and has excellent quality of life. In fact, before COVID limited everyone’s activity, she was going out to the theater, to the movies, even boating on the lake.”
Here’s how these two drugs work in tandem.
Azacitidine is a hypomethylating agent, which means it can modulate the abnormal gene expression seen in AML. By itself it is not very effective in causing apoptosis, or cell death, in leukemia cells. That’s because AML cells have a high level of BCL-2, a protein that protects them from apoptosis. Venetoclax is a small molecule drug that can inhibit BCL-2. Given alone, it too doesn’t work very well. But pairing the two drugs produces a highly effective treatment.
Might younger patients also benefit from this treatment? A new study is now being planned to answer exactly that question.
“This is a major change in the way we treat AML,” said Pullarkat, “both in terms of its effectiveness as well as its impact on a patient’s quality of life.”

Promising Treatment for B Cell Lymphoma

In the three years since chimeric antigen receptor (CAR) T cell therapy was first approved for lymphoma, it has been nothing short of a miracle for many patients. But the treatment did have some drawbacks.
The side effects could be severe — among them neurological problems and cytokine release syndrome, which can be life threatening. Hospitalization is required for the course of the treatment, and patients whose lymphoma had spread to the brain were not eligible.
Tanya Siddiqi
Tanya Siddiqi, M.D.
The study published in The Lancet by Siddiqi and her colleagues is about a new type of CAR T cell treatment, lisocabtagene maraleucel (liso-cel), which promises to be a game-changer for patients with aggressive B cell lymphoma. It was tested on 344 patients — far more than in previous CAR T studies — and included patients with brain involvement.
To understand how this new treatment works, Siddiqi first explained the basics of CAR T cell therapy.
“It’s not like giving a pill,” she said. “We actually take the immune system’s T cells from each patient and send them to the lab, where they’re engineered to develop the ability to attack the lymphoma. Then they’re sent back to us to be given to the patient.”
Once the cells are reintroduced into the patient’s body, they continue to reproduce and may provide lifetime immunity.
“The beauty of CAR T cell therapy is that if it works, it works extremely well,” she said. “If you don’t relapse within the first six months, there is a good chance that you probably never will.”
The difference between liso-cel and other CAR T cell treatments has to do with two specific types of T cells in our bodies — CD8 cells, which are cytotoxic and kill cancer cells, and CD4 cells, which signal and strengthen the CD8s.
In other CAR T cell therapies, the ratio of CD4 and CD8 cells is random and can vary widely. In liso-cel the ratio is consistently 1 to 1, and it is believed that this potentially helps limit side effects.
On this trial, about 70% of patients responded to treatment, while only up to 10% of patients had severe CAR T cell related side effects, far fewer than with previous CAR T cell treatments. For example, up to 32% of patients treated with axicabtagene ciloleucel had severe side effects, and up to 22% with tisagenlecleucel.
There was another major benefit as well. This was the first CAR T cell trial in which people were successfully treated in the outpatient setting. This is not only more convenient for the patient, it can also greatly reduce the costs associated with CAR T cell treatment.
Liso-cel is currently being reviewed for approval by the FDA.
Both studies represent significant leaps forward for blood cancer patients who have, until now, been extremely difficult to treat. Future studies are already being planned to make these treatments increasingly more effective.
“We have a very strong hematology department, and we’ve come a long way in improving the quality of care for our patients,” said Siddiqi. “And we are still striving very hard to get even better, to attain the holy grail of achieving and maintaining long-term complete remissions.”