CAR Pool: Immunotherapies Improving Outcomes in ALL

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Article
CUREHematology Special Issue
Volume 1
Issue 1

For adults with acute leukemia, CAR T cell immunotherapies, targeted drugs and pediatric chemotherapy regimens are improving outcomes.

When a disease is incurable in 60 percent of the adults who develop it, the idea of a new treatment that can spark complete remissions in the majority of those affected seems tantalizing.

Based on recent testing of a promising immunotherapy technique in patients with relapsed acute lymphoblastic leukemia (ALL), the idea also seems like a real possibility.

Hope was inspired after the treatment — part of a new class known as chimeric antigen receptor (CAR) T cell therapies — was tested in youngsters with ALL. In late 2014, researchers announced that the one-time treatment, called CTL019, produced full remissions in 92 percent of children with relapsed ALL in an early clinical trial. The oncology community was understandably ebullient. The treatment involves removing T cells from each patient’s immune system, inserting a gene sequence into the T cells that prepares them to home in on and destroy cancer cells, and then infusing them back into the patients, where they not only do that work, but multiply. Although it’s too early to say what the long-term survival rate will be, the data suggests that the engineered cells continue to keep cancer at bay for upwards of two years.

Now, two other CAR T treatments — JCAR015 and KTE-C19 — have demonstrated remarkable response rates in relapsed/refractory ALL, and adults are among the patients enjoying those outcomes. The treatments work by targeting the protein CD19, which is commonly found on the surface of ALL cells. Full remission rates range from 70 to 90 percent in childhood and adult ALL patients; larger phase 2 trials with CD19 CAR Ts are under way.

CAR T is one of several experimental treatments for adults with leukemia that centers around using patients’ immune systems to beat cancer — a growing area, known as immunooncology, that has engendered tremendous optimism among patients and their oncologists.

New strategies are sorely needed in ALL and AML, which, especially in adults, can be marked by treatment followed by periods of remission — and then recurrence.

ALL will strike more than 6,200 Americans in 2015, 60 percent of them children, according to the American Cancer Society. But while the condition is highly curable with chemotherapy in kids, four out of five deaths from the disease occur in adults; among adults with the condition, the survival rate is around 40 percent.

There is also a second major type of acute blood cancer that affects adults — in fact, almost exclusively adults: The American Cancer Society estimates that there will be about 21,000 new cases of acute myeloid leukemia (AML) in 2015, with the average patient being diagnosed at age 67. With current chemotherapy strategies, two-thirds of patients achieve remission, but the five-year survival rate is only about 25 percent, with patients over 60 faring less well than younger adults.

Better results in both diseases are hovering on the horizon, studies of new treatments suggest.

Both ALL and AML are typically treated with chemotherapy, and some AML patients who do well go on to receive bone marrow transplants. Many of the drugs coming down the pike promise to enhance the effectiveness of chemotherapy or to help patients who don’t respond to it. In addition to all their work in developing CAR T treatments — which are being tested in AML and even solid tumors based on the encouraging results in ALL — researchers are discovering other immune-based approaches, as well as genetic abnormalities that can be targeted with drugs, leading to a plethora of treatments that are greatly improving the outlook for patients.

Engaging the Immune System

“The most common approach nowadays is referred to as ‘precision medicine’ — using targeted molecules against certain cellular pathways,” says Stefan Faderl, chief of the John Theurer Cancer Center’s leukemia division at Hackensack University Medical Center in New Jersey. “The list of targeted treatments is expanding at quite a rapid pace.”CAR T therapy is just one of the immune-based treatments that’s offering new options for adult patients fighting leukemia. Another option is a drug for ALL called Blincyto (blinatumomab), approved by the FDA in December 2014 specifically for patients who have relapsed or refractory precursor B-cell ALL, an uncommon form of the disease that grows quickly and causes the bone marrow to make too many immature white blood cells; the drug is for ALL that is Philadelphia chromosome-negative.

Blincyto is the first in an emerging class of medicines that engage cancer-killing T cells in a whole new way. It is an antibody, or protein, that has been specially constructed to create a bridge between the patient’s own T cells and CD19- expressing leukemia cells. Once the cancer cells are within reach, the T cells release toxins that prompt the cancer cells to die; thus, this treatment aims to activate the patient’s own immune system to destroy leukemia cells.

In the pivotal trial of Blincyto, nearly 42 percent of patients achieved complete remission with two cycles of treatment. As is the case with CAR T treatments, patients are warned of a risk of a potentially fatal condition involving systemic inflammation called cytokine release syndrome, as well as neurological toxicities, but the more common side effects are headache, fever and swelling.

If there’s anything that has tempered the excitement about immuno-oncology, it’s cost concerns. Blincyto’s maker, Amgen, charges $178,000 for two four-week courses of treatment, placing it among the most expensive cancer drugs ever marketed. CAR T costs have yet to be determined, but some analysts predict they could be priced at $500,000 per patient.

Targeting Errant Genes

Despite those concerns, the pace of immuno-oncology research shows no signs of slowing. “In the last 10 years, we’ve come to understand the immune system much better, and also the technical skills needed to manipulate the immune system have markedly increased,” says Lee Greenberger, chief scientific officer of The Leukemia & Lymphoma Society, which has been funding CAR T and other immunotherapy research intensively since the 1990s. “So immunotherapy will be one of the key pieces of new treatment options for ALL.One of the most important discoveries in ALL was the fusion of the BCR and ABL genes found on the Philadelphia chromosome. This genetic abnormality activates the ABL protein, contributing to cancer cell growth, and is present in about 20 percent of adult patients with the disease. Gleevec (imatinib), Sprycel (dasatinib) and Iclusig (ponatinib) inhibit the activity of the ABL protein and are approved for the treatment of Philadelphia chromosome-positive ALL. Tasigna (nilotinib) and Bosulif (bosutinib) also inhibit ABL, and while they are not approved for the treatment of ALL, they are being tested in the disease. Integrating one of these drugs with chemotherapy boosts remission rates into the 90 percent range, and studies are ongoing to determine long-term survival rates. The most common side effects are swelling, stomach discomfort, water retention and low blood-cell counts. Oncologists should routinely test patients who have ALL for this mutation, experts say, to determine whether they can be helped by these treatments in addition to standard ALL therapy.

Immunotherapy is also being examined in the other type of acute leukemia, AML. However, this has been more challenging than in ALL, since there is no single target that clearly distinguishes AML cells from normal blood-forming cells. Still, many oncologists are optimistic about just how much has been learned about AML that’s improving the outlook for patients.

Rather than immunotherapies, drugs that target newly discovered genetic mutations within the AML cancer cells — for instance, by blocking the activity of abnormal proteins that drive cancer — have comprised the major course of research. One patient who has benefited from that growing knowledge base is Erin Fox, a 31-year-old patient at the Mayo Clinic in Phoenix, Ariz., who was diagnosed with AML two years ago. After a first round of chemotherapy didn’t work for Fox, she underwent a stem cell transplant that put her into remission. But one year later, she experienced a relapse.

Fox’s oncologist had tested her genes and discovered that her disease harbored a genetic mutation called FLT3, found in about 30 percent of patients with AML. Patients who test positive for FLT3 face tough prognoses, because the mutation is associated with a poor response to chemotherapy.

So Fox enrolled in a trial of ASP2215, a drug that inhibits FLT3 and is now in mid-stage testing. In a preliminary study, more than 57 percent of patients with FLT3 mutations responded favorably to the drug.

The experimental regimen, which Fox started in April 2015, consisted of two pills a day for 28 days — a routine that was easy, she says, compared to what she had already been through. Aside from an upset stomach the first day and some chills, “the side effects were pretty minimal. Within a week I felt totally normal,” Fox says. “After the first 28-day cycle I achieved total remission and the FLT3 mutation disappeared.”

Raoul Tibes, who manages a trial of ASP2215 at Mayo Clinic, believes the experimental drug represents an important advance because it inhibits not just FLT3-ITD, the most common FLT3 mutation, but also FLT3-TKD, the second most common mutation. Further, the drug inhibits a mutation called AXL, which promotes the growth of cancer cells. “It’s a very promising drug,” says Tibes. “Compared to chemo, it’s very well tolerated. Now we test all AML patients for the FLT3 gene, and if they have it, we try to get them into this clinical trial, or use a FLT3 inhibitor plus chemotherapy for newly diagnosed patients.”

Once she went into remission for a second time, Fox was able to undergo a second stem cell transplant in August 2015, after which her doctors planned to put her back on ASP2215. All in all, Fox says, she feels fortunate to have the opportunity to gain from the rapidly expanding understanding of her disease. “The FLT3 mutation is scary — I knew it would make my disease harder to treat,” Fox says. “When I heard there was a drug that could inhibit it, I felt like it was meant to be. It’s exciting.”

Another new investigational class of drugs for AML targets IDH1 and IDH2 gene mutations, which are found in between 10 and 20 percent of patients with the disease. In an early study presented in late 2014, half of 14 AML patients receiving an IDH1 inhibitor called AG-120 responded well to the drug, including four who experienced complete remissions. Another drug called AG-221 inhibits IDH2 and also performed well in an early trial, with six out of seven patients responding, including three who had complete remissions and two who experienced complete remissions with incomplete platelet recovery.

Improving Chemotherapy

“We’ve seen very remarkable results,” says Harry Erba, professor of medicine and director of the hematologic malignancy program at the University of Alabama in Birmingham. In the patients who do respond, he says, there’s a suggestion that the myeloblasts — the immature white blood cells that proliferate beyond control in the disease — actually develop into normal blood-forming cells. Although it’s still early days for these targeted treatments, he adds, “I believe they will find a place in the treatment of AML.”Another major research priority in acute leukemia is trying to find new methods for improving chemotherapy outcomes. One of the most promising candidates in AML is the investigational drug volasertib, which inhibits one form of an enzyme known as Polo-like kinase (Plk). Volasertib, which has been awarded “breakthrough” status by the FDA, meaning its development and review will be expedited, is being tested along with low doses of the chemotherapy drug cytarabine (LDAC), and the results have been impressive so far.

Photo by Gus Cantavero

Photo by Gus Cantavero

Fabiana Da Silva-Boyce, diagnosed with ALL at age 30, experienced a remission after being treated with a pediatric chemotherapy regimen. [Photo by Gus Cantavero]

In a mid-stage trial whose results were released in July 2014, 31 percent of patients taking the combination treatment responded to it, versus just 13 percent of patients taking LDAC alone. Four patients achieved sustained remissions of two years or longer. The drug’s side effects included fever, infections and gastrointestinal problems, all of which were much more frequent in the trial’s combination arm.

In ALL, oncologists are encouraged by new evidence suggesting that chemotherapy combinations traditionally used only in children might help adults, too. Fabiana Da Silva- Boyce, a high school teacher in Thornwood, N.Y., who was diagnosed with ALL in 2013 at just 30 years old, is helping to test that theory.

After being referred to Memorial Sloan Kettering Cancer Center in New York City, Da Silva-Boyce quickly learned that her ALL presented with a large tumor around her heart but had not spread to her bone marrow. That, plus her young age, made her a prime candidate for an emerging chemotherapy regimen that revolves around the inclusion of multiple doses of pegylated asparaginase — a drug that is a key component in the treatment of pediatric patients with ALL, but had long been thought to be too toxic for adults.

Like most ALL patients, Da Silva-Boyce has undergone three phases of treatment: The first 12 months included the “induction” and “consolidation” phases and involved frequent chemotherapy treatments that caused her to lose her hair. She had to skip a year of work because her immune system was too suppressed for her to spend time with her students. But the mass around her heart quickly disappeared and the intense chemotherapy kicked her disease into remission.

Similar to the regimen given to children, the treatment included six doses of pegylated asparaginase that she tolerated well. Now she’s graduated to the “maintenance” phase, which involves just one chemotherapy infusion a month and daily mild chemotherapy pills. Most of the side effects have disappeared, she says, and she returned to work — and to teaching Zumba in her spare time — in January 2015.

When Da Silva-Boyce’s oncologist at Memorial Sloan Kettering Cancer Center in New York City, Dan Douer, explained the rationale for giving her a child’s dose of chemotherapy, she immediately knew it was her best shot. “The survival rate for kids is 90 percent,” she says, “but for adults it’s much lower. I was only 30, so I thought, ‘Why not try?’ Maybe I would react the same as a kid would.”

Douer, who has led studies of pediatric-inspired chemotherapy regimens in adults, says the cure rate has proven to be as high as 66 percent, and the side effects can be managed with proper monitoring. “Turns out young adults can tolerate the chemotherapy almost like children, with excellent results,” Douer says.

Da Silva-Boyce will stay on the maintenance chemotherapy until the end of 2017, but she doesn’t mind. “I feel the same as I did before I got sick,” she says. “I have the same amount of energy. I’m not tired. This offered me hope.”

Now that she’s feeling well, she wants to share that hope with others. During the year she had to stay home from work, Da Silva-Boyce wrote a book about her treatment experience. Titled “Beating Leukemia with Optimism, Faith and a Good Sense of Humor,” she hopes the book will help others with ALL to stay positive as they navigate their treatment paths.

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