Blood cancer treatment is looking far different than it did years ago, and as a result, patients are surviving longer — and often with fewer side effects.

, we’re honing in on some of the most exciting updates in the treatment of patients with mantle cell lymphoma, including a new chimeric antigen receptor (CAR)-T cell therapy that was approved just a few months ago. The new therapy, which involves programming a patients’ own cells to fight cancer, is helping patients with the dis- ease live longer, better lives. However, CAR-T cell therapy is not without downsides.

For many, the treatment can be extraordinarily expensive. Another feature story in this issue discusses the hefty price tag of CAR-T cell therapy, as well as financial assistance programs that help patients pay for this treatment.

Although the past decade has brought breakthroughs in treatment for adult blood cancers, advances for pediatric blood cancers seemed few and far between. That, however, is changing. Researchers, nonprofit organizations and patients are collaborating to test new therapies for children to bring more options to young patients.

Our third feature story delves into the coming of age for pediatric blood cancer research and highlights a few families who have benefitted from it.

No cancer breakthrough is possible without clinical trials. But many patients are hesitant to participate because they fear they’ll be treated with an ineffective agent or, worse, a placebo. Dr. Susan M. O’Brien, a hematology oncologist at UCI Health in Orange, California, who is actively involved in clinical trials, discusses these misconceptions and the potential benefits of enrolling.

Also in this issue: Mary DeRome of the Multiple Myeloma Research Foundation explains a program that helps patients get the right team, the right tests and the right treatment, including the right clinical trials.

I hope you find this special issue of CURE® both useful and enlightening.

Articles

From the Chairman

In this special hematology focused issue of CURE® we look at all the promising treatments and research for both adults and children with blood cancers. 

New Therapies for Adults and Children With Blood Cancers Hold Promise

Mantle Cell Lymphoma (MCL), as described in this issue of CURE®, has an interesting and inspiring story. It was one of the first cancers known to have a genetic abnormality-chromosomal translocation t(11;14).

This mutation causes an over expression of the protein cyclin D1, which drives cells to grow, ultimately become malignant and then multiply. However, until recent years, t(11;14) and other mutations were only used to diagnose MCL, not as a target in treating the disease. MCL was treated like most other lymphomas, with chemotherapy and steroids and then eventually Rituxan (rituximab).

Like many times with cancer, scientific discoveries broke the stalemate of MCL that had become refractory, meaning it stopped responding to treatment. Additional cancer promoters were discovered, including Bruton tyrosine kinase (BTK) — an enzyme that promotes cancer proliferation. 

That eventually led to drugs that inhibited BTK to be tested — and effective in — refractory MCL. Continued study of the disease also found more targets, leading to other drugs like Venclexta (venetoclax). Most recently, Tecartux (brexucabtagene autoleucel), a genetically engineered T cell therapy was approved for MCL treatment. All the while, researchers are still studying cyclin D1 and the cell cycle pathways it controls, in a continued quest for more treatments for MCL.

Outcomes continue to improve for patients with MCL, as the disease has gone from being highly resistant and difficult to treat to one of the more manageable types of blood cancers, thanks to newer and intelligently designed drugs — many that are the fruits of basic science research. 

This highlights the critical value of clinician expertise in diagnosis and treatment. In this day and age, we hope that telemedicine and simple awareness can bring these treatments to more patients who need them, improving outcomes and quality of life for all with the disease.

Editor’s Note from Dec. 21, 2023: The has been edited to update the comment about improved outcomes for patients with MCL from “one of the more curable types of blood cancers” to a blood cancer type that can go into remission.

Editor's Page

Mantle Cell Lymphoma (MCL), as described in this issue of CURE®, has an interesting and inspiring story. It was one of the first cancers known to have a genetic abnormality-chromosomal translocation t(11;14).


Closer to a Cure for Mantle Cell Lymphoma

It’s important for patients who have been diagnosed with an uncommon cancer to see or consult an experienced medical team with expertise in treating that particular disease. However, many patients — especially those who don’t live near a large cancer center — may not know where to start.

 with Mary DeRome, director of medical communications and education at the Multiple Myeloma Research Foundation (MMRF) in Norwalk, Connecticut, about her organization’s collaboration with other cancer groups to ensure patients get the best possible treatment.

®: How important is it that patients with myeloma see a treatment team who specializes in myeloma?

This is really important. One of the main reasons is because of the relative rarity of multiple myeloma. Some oncologists may only see one or two patients with myeloma every year because it’s not that prevalent of a disease. And because they see so few myeloma patients, (these oncologists) might not be aware of the most modern and recent treatments and testing protocols and may not be aware of the best clinical trials that are available to their patients.

In addition, myeloma is a very complicated and heterogeneous disease, and every patient’s disease is different. So it’s really important for the right care team to be very aware of all the most modern treatments and testing.

Clearly, some patients are just not going to have the resources available to them to travel to major academic medical centers and to see a myeloma specialist as often as necessary for them. But it’s super important for every patient with myeloma to get at least a second opinion from a myeloma specialist who sees a lot of myeloma patients and is really up on the latest ... in myeloma.

Then, if a patient continues to be treated locally, it’s great if their oncologist can be in touch with this myeloma specialist (to) really stay abreast of this patient’s treatment. And then maybe they can see a specialist like once a year just to stay on track.

Speaking of staying on track, the MMRF has The Right Track program. Can you discuss what that is?

So "The Right Track" is something that our founder and chief mission officer Kathy Giusti has been working on up at Harvard Business School ... with a number of other nonprofit cancer organizations, including the Pancreatic Cancer Action Network, Prostate Cancer Foundation, LUNGevity and the Metastatic Breast Cancer Network. So together these five nonprofit organizations came up with steps that every patient can take to make sure that they’re moving toward their best possible outcome.

(The Right Track involves) four steps: See the right team, have the right testing done, be placed on the right treatment and share data at every step. It’s really important for patients with cancer to be seen by a specialist, either at an academic medical center or at a National Cancer Institute-designated cancer center where the doctor sees a lot of patients who have the same type of cancer — so they can be assured that their doctor knows a lot about the disease.

Then, once they’re with the right care team, it’s really important to have the right testing done. That includes genomic testing. That will enable their doctors to learn more about the subtype of the disease, which can be especially important for myeloma and can help potentially inform treatment options. (Patients can then get started on the) right treatment. The right treatment can be based on the subtype, the level of risk associated with the specific disease and the previous outcomes they may have had on other therapies.

The other important part is sharing their data every step (of the way). We always encourage patients to share their data because that will really accelerate new therapies for all patients.

How can patients learn more so that they can Q become their own best advocate from diagnosis through treatment?

Certainly, in the case of patients with myeloma, it’s really important to learn as much as they can about it and what treatments are available out there. The MMRF has a lot of education programs for patients. We have live education programs, patient webinars, materials such as our patient kits and a lot of resources on our website. Those are all great resources for patients to learn about the disease so they can advocate for their own care.

We always encourage patients to have substantive discussions with their doctor whenever possible and to ask as many questions as it takes to get the answers that allow them to understand exactly what’s happening and why they’re being treated with a certain therapeutic. We also encourage patients to reach out to resources such as the MMRF Patient Navigation Center and to ask our experienced myeloma nurses any questions they might have, which can really help them advocate for themselves and for the disease.

Research News and Updates

Finding the best care team can make all the difference for patients with diseases like multiple myeloma.

Program Leads Patients With Cancer on ‘The Right Track’

Clinical trials are essential in the development of new cancer therapies, yet many patients have misconceptions about clinical trials that may make them apprehensive to enroll in one.

, CURE® spoke with Dr. Susan M. O’Brien, a hematology oncologist at UCI Health in Orange, California, who is actively involved in clinical trials as director of the UCI Health Sue and Ralph Stern Center for Cancer Clinical Trials and Research. O’Brien discusses the importance of clinical trials for advancing the field of chronic lymphocytic leukemia (CLL) and offers advice for patients who may be interested in a trial but don’t know where to start.

What are the different kinds of clinical trials, and why are they important?

: Clinical trials come in a lot of different flavors. They can be trials of new agents, completely novel agents that don’t yet have FDA (Food and Drug Administration) approval. And they could be drugs that are next generation. So for example, we have a BTK (Bruton tyrosine kinase) inhibitor, but ... some company might think that they have a better BTK inhibitor. There can be trials looking at treatments for relapse disease; there (can) be trials looking at initial frontline (treatments).

I think a lot of people sometimes have the misconception and anxiety of enrolling in a clinical trial because they might be treated with a placebo. That’s very rare to see in a cancer trial. I don’t think I’ve ever seen (a CLL clinical trial) in patients who need treatment where there’s any kind of assignment to a placebo.

I think it’s important for a patient to consider a clinical trial, particularly with the novel agents if they’re available. ... Think about the fact that Imbruvica (ibrutinib) completely changed the landscape for CLL. It’s really been a total game changer. Consider how long it takes to get a drug FDA approved, and that one, by the way, went really fast. What that means is that people who are on the clinical trials actually have access to the drug years before that drug becomes FDA approved. So it can really get you access to novel, great drugs before they’re even out there for the rest of the community to use.

We also have to keep in mind that clinical trials are very important because (they’re) the only way we get new drugs. Every drug that is approved by the FDA had to be tested in usually more than one clinical trial. (The phase 1 trial determines) the appropriate dose, and the second trial looks at how well people respond. And then when we go to what we call phase 3; those are the randomized trials where a patient is randomly assigned to what’s usually considered the standard of care or to the newer drug. 

There are different places along the way where we have to accumulate that trial data before it goes to the FDA for approval. That’s why people who happen to get on a great drug can have years of early access to it before it even gets approved.

Can you talk a bit more about the misconceptions that people have about clinical trials that may make them apprehensive?

I think some people have anxiety (and think), “You’re experimenting on me.” We don’t like to call it experimenting. But yes, you can think of it as the fact that you are testing out a drug that maybe has not been given to a lot of people.

If you’re (on a phase 1 trial), then yes, you are one of the first people ever to get that drug. If you’re on a phase 2 trial, you’re looking at response (to the drug): We’ve already defined the dose, we know what the dose is, we know what the (side) effects are. People did get (the drug) before you, and (it was deemed promising enough to move) forward to phase 2. By the time it gets to phase 3 — where you’re randomly comparing it to standard of care — there’s plenty of knowledge. (There’s often already publicly) presented data or published data from the prior clinical trials, so you are going into a trial to get ... a drug or combination that you (might not be able to) get outside the trial. But hopefully that’s something that will benefit you and then benefit society as a whole if (it) leads to subsequent approval of that drug.

How can patients learn more about clinical trials?

Of course the Leukemia & Lymphoma Society is a great (resource) that really helps to match up patients with trials in their area. This is one of the issues about clinical trials: It’s probably easier for patients in larger metropolitan areas to participate than it might be for someone who lives in a really rural area where they’re not that close to their medical center. They have to be able to get there.

There are certain trials where the larger centers will partner with smaller practitioners. ... In some of the cooperative groups, that hub-and-spoke model is how they operate. So for example, there are major academic centers, but then there are affiliated, much smaller centers that participate in those trials too. So cooperative group trials are sometimes easier for patients to have access to because of their design. And you don’t have to (go) to one of, say, the four centers that’s doing that trial. So that can be really helpful.

A number of different sites can be really helpful when trying to identify trials, particularly in a certain region, (because you probably don’t want) a patient who lives in Arizona (to have) to fly to New York on a weekly basis. I mean, that’s realistically not going to work. There are other trials at major centers where they have to go to the trial to enroll, but some of the treatment — particularly if it’s an oral agent that the patient takes themselves — can actually be administered at home.

So those kinds of trials, the patients do have some back and forth to the trial center, but much less than if it’s a drug that actually has to be delivered at the trial center. Some do, some don’t. There are a variety of possibilities, even for people who don’t live in highly populated metropolitan areas, to potentially (participate) in a clinical trial.

Speaking Out

Clinical trials lead to new cancer treatments — and can give a patient access to effective drugs years before they’re made available to the public.

Clinical Trials are Fueling Medical Breakthroughs in Cancer

Over Mother’s Day weekend 2011, Kimberly Schuetz took her 2-year-old son on a road trip from their hometown of Fall River, Wisconsin, to visit family in Illinois. Leading up to the journey, Austin had been his normal, energetic self.

“He was eating like a horse and being very active, very playful. No sicknesses, fevers, or anything like that,” Schuetz says.

On Saturday, Schuetz’s father-in-law noticed something alarming while tickling his grandson. One of Austin’s lymph nodes on his neck had swollen to the size of a golf ball. As an oncology nurse, Schuetz immediately had a sick feeling in her stomach. Her mind went straight to thoughts of cancer.

While her gut reaction told her to take Austin to the emergency department, Schuetz decided to wait until Monday to visit his pediatrician back home. After all, her son was acting fine.

A week later, after visits to two pediatricians, the emergency department at their local hospital and pediatric hematologists at a children’s hospital, a bone marrow biopsy confirmed that Austin had acute lymphoblastic leukemia (ALL). A cancer of the blood and bone marrow, ALL is the most common type of cancer that occurs in children.

“I literally felt like I was living somebody else’s life, like I was watching a movie. I remember sitting there and listening to the doctor, but I also felt like I was floating above myself,” Schuetz says. “I was numb and couldn’t cry. Your brain just goes into this state of shock.”

Omar Durani, a family physician in Dallas, Texas, went through similar feelings when his 9-month-old daughter Kenza received an acute myeloid leukemia (AML) diagnosis. In 2016, her swollen lymph nodes signaled to Durani and his wife that something wasn’t right.

“As a physician and dad, it’s kind of difficult to figure out what hat to wear when, and how much to worry about things like that,” he says. “When the swelling worsened, we started advocating for blood work, but all the doctors we visited only kept giving her antibiotics.”

Finally, an emergency department physician who Durani knew personally listened to their concerns and performed blood testing. The results came back with white cell counts through the roof, confirming the family’s worst fears: Kenza had cancer.

Both ALL and AML are treated initially with chemotherapy, and for the vast majority of children, it works. More than 95% of children with ALL and about 85% to 90% of those with AML enter remission after the first phase of chemotherapy. However, remission does not necessarily mean a cure.

Austin relapsed in October 2012 after two phases of chemotherapy, and despite receiving a bone marrow transplant, his ALL came back a third time in May 2013. About 10% to 20% of children with ALL have a disease that relapses or is resistant to treatment. At that point, with no treatment options left, Austin’s parents were told he had three to six months to live.

“We live 45 minutes away from the hospital, and our doctor ended up driving to our house, not to offer any solutions, because we didn’t have a plan, but just to sit and cry with us, because she was so heartbroken and, in such disbelief,” Schuetz says.

Some cancer in children does not respond to chemotherapy. After three rounds of chemotherapy, doctors told Durani that his daughter’s only hope would be a bone marrow transplant. But as a child of Asian descent and mixed ethnic background, Kenza had a less than 2% chance of finding a bone marrow donor match.

While research in adult blood cancers has led to an explosion of new targeted therapies and immunotherapies, such progress has been slower for younger patients. This can leave children such as Austin and Kenza without a path forward. Even for patients who do achieve long-term survival, the lingering toxicity of chemotherapy can lower their quality of life as adults.

“Only four cancer treatments have been approved for first use in children in the last 40 years, compared with hundreds approved for treating adults during this same time frame,” said Dr. Gwen Nichols, chief medical officer of the 

“Out of all the federal funding that goes into cancer research, only 4% goes toward pediatric cancer research,” said Dr. Deepa Bhojwani, director of the Leukemia and Lymphoma Program

at Children’s Hospital Los Angeles in California. “That being said, I would say within the last five to 10 years, there has been a lot more progress in terms of targeted treatment and immunotherapy than there was in the past.”

But the tide may be turning for this young, vulnerable population with new research initiatives dedicated to applying precision medicine to pediatric blood cancers. Much of today’s research in pediatric blood cancers aims to find tailored alternatives to chemotherapy that could prove just as or more effective with fewer harmful side effects.

Cancer is still the leading cause of death from disease among children and adolescents in the United States. From 2012 to 2016, leukemia and lymphoma accounted for 38.7% of all cancer types for patients under age 20. Approximately 40% of children with AML and 20% of those with ALL experience a relapse of their disease. Non-Hodgkin lymphoma, the most common type of lymphoma in children under age 14, that is resistant to first-line therapy has a very poor prognosis.

Before joining LLS, Nichols worked for a pharmaceutical company. She says that getting pediatric drugs tested and approved may be difficult because they typically do not bring in as much revenue as adult therapies.

As a result, upon arriving at LLS she was determined to figure out a faster, more efficient way to bring new agents and therapies to children with blood cancers.

In 2016, LLS launched the Beat AML Master Trial for adults with AML. It represented a paradigm shift in the format of clinical trials by testing several different targeted therapies in individual study arms instead of only one drug or combination of drugs at a time. Patients had a genomic screening to determine whether they had one of the genetic mutations that would make them eligible for one of the study arms to test a particular targeted therapy.

“It’s about 50% less expensive to do a master trial than it is to do one drug at a time. So, we needed to do something similar in pediatrics to make it more cost-efficient. But even more than that, if you want to get targeted therapies to kids, you have to have the right kids to test the drug,” Nichols said. “If you’re doing one drug at a time, you have to screen thousands of kids to find the five that fit your drug, which costs time and money.”

In 2019, LLS announced a collaboration with the National Cancer Institute and the Children’s Oncology Group called LLS PedAL (Pediatric Acute Leukemia), a global precision medicine master clinical trial in the same vein as the Beat AML trial. Children with relapsed acute leukemia will undergo genomic screening to match the specific abnormalities driving their cancer with one of several targeted therapies.

As part of The LLS Children’s Initiative: Cures and Care for Children, a $100 million, multiyear effort to take on pediatric blood cancers, LLS PedAL will test multiple agents simultaneously at up to 200 sites worldwide. Trials will follow the same format so that data from multiple institutions can be shared and consolidated.

Nichols and her colleagues hoped to begin the trial this year, but with the coronavirus disease 2019 pandemic, LLS PedAL’s start date has been pushed back to early 2021.

Another inspiring research project is the Pediatric Cancer Genome Project (PCGP), a joint initiative from St. Jude Children’s Research Hospital and Washington University School of Medicine. Since 2010, the two insti- tutions have pioneered efforts to define the genomic landscape of pediatric cancer by sequencing the genomes of normal and cancer cells from 800 patients.

“That work really filled in much of the landscape of mutations that drive ALL, AML and many of the other kinds of pediatric cancer,” says Dr. James R. Downing, president and CEO of St. Jude, who was instrumental in launching the PCGP. “In particular, important fundamental discoveries came out for ALL in terms of new understandings related to the identification of new genetic subtypes, amplifications, fusions and chromosomal translocations of the disease.”

For instance, the PCGP pinpointed genes linked to an ALL subtype with a poor prognosis known as Philadelphia chromosome-like ALL (Ph-like ALL). In 2009, St. Jude scientists were among the first to describe Ph-like ALL in children. Five years later, next-generation sequencing revealed the genetic alterations that give rise to Ph-like ALL, which could be targeted with drugs widely used to treat other types of leukemia more common in adults.

A 2017 study from the PCGP identified potential targets for immunotherapies in pediatric cancers, finding that 88% of leukemias have at least one that could be exploited. A 2018 pan-cancer analysis that examined commonalities and differences among various cancer types, including ALL and AML, suggest that half of the cancers studied may have a targeted treatment available or under development.

“The second phase of the genome project is moving all that technology into frontline diagnostics,” Downing says. “So now we’re getting the whole genome, whole exome and RNA sequencing of every patient, and we gain insight that can be funneled into a protocol that allows them to be treated.”

St. Jude’s frontline ALL protocol includes an unparalleled level of genomic sequencing on the patient, on both cancer and normal cells, which allows physicians to make personalized therapeutic decisions. Downing hopes that collecting such a wealth of data will help usher in new therapies and lead to a further improvement in outcomes.

“So the momentum is there, the studies are ongoing, and hopefully five years from now, we will have a huge variety of therapies to offer our kids instead of just one,” Bhojwani says.

Bhojwani participates in the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) consortium, which has its headquarters at Children’s Hospital Los Angeles. TACL brings together children’s hospitals and universities to accelerate the progress of new therapies for pediatric leukemia and lymphoma. The consortium includes 31 institutions in the United States and Australia that collaborate on clinical trials of new drugs and novel therapy combinations in the hopes of expanding the number of treatments available.

Both Kenza and Austin were saved by an experimental treatment called chimeric antigen receptor (CAR)-T cell therapy administered in a clinical trial. It involves engineering the body’s T cells, a type of white blood cell, to produce receptors on their surface called chimeric antigen receptors (CARs). The engineered cells are infused back into the patient, where they can recognize and kill cancer cells.

The Duranis couldn’t find a bone marrow donor match for Kenza, despite having more than 60 donor drives inspired by her diagnosis that registered more than 5,000 new potential bone marrow donors around the country. At that point, they decided to move forward with CAR-T cell therapy coupled with a haploidentical, or partially matched, stem cell transplant in August 2016.

“It was a no-brainer for us since there were no other therapies available besides a standard bone marrow transplant,” Durani says. “Now Kenza’s been in remission for four years, and she’s doing fantastic. She’s a thriving, spunky 5-year-old.”

After his third relapse, Austin’s parents enrolled him in a clinical trial to receive CAR-T cell therapy as a last- ditch effort to save their son. He received the treatment at the beginning of October, and on Halloween – which also happens to be his mother’s birthday – they received the good news that his biopsy showed no traces of cancer.

“I immediately started screaming and crying. I was just elated. It was the best birthday present that I could ever, ever have. Nothing will ever top that,” Schuetz says.

Today, Austin is a typical 12-year-old boy who enjoys video games, swimming with his friends and complaining about household chores. He and Kenza are living proof that innovations such as CAR-T cell therapy give children who have run out of options another chance at life.

Feature

For years, childhood blood cancers were understudied forcing patients’ treatments into a one size-fits-all approach. But new efforts are changing that.

Coming of Age: New Research Efforts are Improving Treatment of Childhood Blood Cancers

It’s been nearly a decade since Robyn Stacy-Humphries, a 58-year-old radiologist from Charlotte, North Carolina, first learned she had diffuse large B-cell lymphoma (DLBCL). Today, she’s in remission — a fact she attributes to her treatment with chimeric antigen receptor (CAR)-T cell therapy.

Through the years, Stacy-Humphries’ treatment has included everything from six cycles of R-CHOP chemo/biotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and Rituxan [rituximab]) — the standard of care for DLBCL — to R-ICE (Rituxan, ifosfamide, carboplatin and etoposide), intrathecal chemotherapy (chemotherapy injected into the spinal fluid), myeloablative chemotherapy, high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine and melphalan), rescued with an autologous stem cell transplant (a transplant using her own stem cells), and head and neck radiation. Although she’d gone into remission prior to her stem cell transplant, the cancer returned.

In April 2016, nine months after her stem cell transplant, Stacy-Humphries’ DLBCL returned again. With no matched donor on the horizon for an allogeneic transplant (a transplant using donor stem cells) — the next standard treatment for her cancer — she knew she was running out of time.

That’s when she and her husband got to work, researching clinical trials for an emerging treatment known as CAR-T cell therapy. She landed a spot in the phase 2 JULIET trial of Kymriah (tisagenlecleucel), a CAR therapy made by Novartis, at The Ohio State University’s Comprehensive Cancer Center.

“My early-phase clinical trial was like jumping out of a plane and hoping the parachute opens,” Stacy-Humphries says.

“I was one of the first 200 people in the world to receive this treatment. And the trial I was in was the basis for the FDA approval of the CAR-T cell product.”

Four years after receiving CAR-T cell therapy, she remains in remission and optimistic. “I’m likely to stay in complete remission,” she says. “But no one will actually give you a guarantee.”

CAR-T cell therapy is an immunotherapy, a type of therapy that helps a patient’s own immune system fight their cancer. Doctors draw blood from the person with cancer. The person’s T cells, white blood cells that develop from stem cells and help fight infection, are then separated from the blood in a laboratory that makes the CAR-T cell product. There, scientists change the genetic make-up of the T cells, making them produce customized receptors called chimeric antigen receptors that recognize specific proteins on tumor cells. These engineered T cells are then grown, or expanded, in the lab.

Once the CAR-T cell product has expanded, the person with cancer receives chemotherapy known as lymphodepleting treatment. This treatment clears the way in the body for an infusion of the re-engineered T cells, which multiply further in the patient’s body. The CARs then help the person’s T cells find a certain protein, known as an antigen, on the surface of cancer cells and destroy the cancer.

In 2017, the Food and Drug Administration (FDA) approved two types of CAR-T cell therapies. Kymriah was approved for patients up to age 25 with B-cell precursor acute lymphoblastic leukemia (ALL) who relapsed after two or more treatments, while Yescarta (axicabtagene ciloleucel) was approved for adult patients with large B-cell lymphoma who have relapsed after, or not responded to, two types of treatment.

In 2018, the FDA also approved Kymriah for adults with large B-cell lymphoma, including DLBCL, who have relapsed after or not responded to two or more standard therapies. In July 2020, the FDA approved Tecartus (brexucabtagene autoleucel) for adults with mantle cell lymphoma who have not responded to other treatments or relapsed after those treatments.

According to Dr. Frederick Locke, a medical oncologist and translational researcher in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida, which was part of the clinical trial that supported the approval of Tecartus, having CAR-T cell therapy as an option for patients with mantle cell lymphoma is critically important.

“We have therapies for relapsed refractory mantle cell lymphoma that can work, but when patients relapse after getting those treatments, the disease can progress very rapidly,” he says.

CAR-T cell therapy offers hope for some patients with certain blood cancers who have not responded to conventional therapies, Locke adds.

“When we look at outcomes in patients with refractory diffuse large B-cell lymphoma, we know from robust historical data that patients who didn’t respond to their last line of chemotherapy or relapsed after an autologous stem cell transplant have a very low chance of responding to more therapy — conventional therapy, that is,” he says, adding that about 1 in 4 patients can expect to respond to another line of chemotherapy and less than 1 in 10 can expect their lymphoma to disappear after additional conventional therapy.

“These are the same patients who are now eligible for CAR-T cell therapy and the results are remarkable,” he says.

Locke adds that 30% to 40% of patients with DLBCL who have CAR-T cell therapy achieve durable remission that stretches beyond three years and counting. “These are results we would not expect and would not have seen with existing therapies for refractory diffuse large B-cell lymphoma,” he says, noting that data from randomized controlled clinical trials on the long-term impact of CAR-T cell therapy are still needed.

CAR-T cell therapy is complicated; it’s also potentially expensive for those who qualify for treatment. In a July 2020 comment on the Centers for Medicare & Medicaid Services (CMS) Hospital Inpatient Prospective Payment System proposed rule, the American Society of Clinical Oncology noted the average cost of a CAR-T cell product at $373,000, with the estimated cost of CAR-T cell therapy and related services at $419,238.

Medicare covers a portion of CAR-T cell therapy provided in health care facilities that are enrolled in FDA risk evaluation and mitigation strategies (REMS), a federal program that oversees the safe use of drugs, for FDA-approved uses. Medicare may also cover a portion

of some off-label uses of CAR-T cell therapy that meet certain recommendations. While private health insurance plans may cover some or all of the cost of the product for patients who qualify for FDA-approved treatment, there are additional costs related to CAR-T cell therapy for which patients might bear a heavy financial burden.

These additional costs include a pre-therapy consult, chemotherapy to deplete the lymphocytes, and collection procedures, as well as expenses during recovery and ongoing monitoring according to Dr. Stuart Goldberg, chief of the Division of Outcomes and Value Research at the John Theurer Cancer Center at Hackensack University Medical Center in Hackensack, New Jersey.

“It also involves doctor visits, two weeks in the hospital, post-procedure care, all of the X-rays, CT scans, etc.,” he says. “None of that is the $400,000 cost of the CAR T. And CAR-T cells aren’t available in your backyard. So, you’re talking about hotel rooms, transportation, time off work for loved ones and caregivers. There are other costs that sneak in that no one talks about.”

“Everybody thinks that cancer patients are most worried about pain,” he says. “It turns out that more cancer patients are worried about the cost of care. When patients come in to see us, we ask about side effects like fever, pain and nausea. But most times when we see a patient, we rarely talk to them about whether they can pay the bills.”

According to Goldberg, patients who go through expensive treatments such as bone marrow transplant or CAR-T cell therapy talk to a financial counselor as part of the consult. “They map out what the out-of-pocket costs might be, and what costs their insurance might cover,” he says. “If we identify someone who we think may have some difficulty, we start to plug them in to various support programs that might be available. But even then, we cannot anticipate all the costs of travel, hotels, lost wages and other non-medical expenses that could burden the patient and their family.”

Stacy-Humphries says it’s important to keep costs — and outcomes — in perspective when evaluating treatment options. While much of her CAR-T cell cost was covered as part of her clinical trial, she had to pay out-of-pocket costs for all of the tests required to get into the trial before she met her insurance’s high deductible, she says. “But those were the same tests that would be required to have an allogeneic transplant,” she says, noting that her own research puts the cost of an allogeneic transplant, over time, at about $800,000. “And it’s not like chemotherapy is free. It’s very expensive.”

Dr. David Siegel, chief of the Myeloma Division at the John Theurer Cancer Center at Hackensack University Medical Center, says the standard of care for multiple myeloma, a four-drug combination given to newly diagnosed patients with the intention of administering it indefinitely in the absence of progression, is incredibly expensive.

“The cost of these drugs is tens of thousands of dollars a month,” he says. “If you’re a lucky patient and you stay in remission for three or four years, which is certainly not out of the realm of what’s expected, it’s $300,000 a year to give these drugs.” The cost of CAR-T cell therapy, which is not yet FDA approved for myeloma treatment, seems relatively inexpensive by comparison if a patient then doesn’t need to be treated for two years, he adds.

Treating potential side effects of CAR-T cell therapy may add additional costs. Some patients develop cytokine release syndrome, an immune system response that causes high fever and low blood pressure, or neurotoxicity, brain impacts such as seizures or confusion. Although these medical toxicities can usually be controlled, the additional treatments may add to the “financial toxicity.”

Some nonprofit organizations offer assistance for eligible patients — or can help connect patients to programs that help with paying for care, travel and lodging. The Leukemia & Lymphoma Society (lls.org) offers a co-pay assistance program for eligible patients, while CancerCare (cancercare.org) offers travel and other assistance for eligible patients.

Pharmaceutical companies may also offer patient assistance programs; for example, Novartis offers Kymriah Cares. According to Julie Masow, global head of Novartis Oncology External Communications in Cambridge, Massachusetts, assistance and support for eligible patients may include benefit and network investigation, co-pay assistance and travel support. Patients seeking help with private insurance to help cover their portion of financial responsibility for Kymriah should speak to their doctor or treatment center about eligibility and submitting a request for co-pay assistance.

Patients participating in clinical trials find that many CAR-T cell therapy expenses are covered. Chrissy Degennaro, 50, of Ocean City, New Jersey, was 36 when she received a multiple myeloma diagnosis. She has participated in two CAR-T cell clinical trials — one in 2017 and one in 2018 — with Celgene, now a Bristol Myers Squibb company.

During the first trial, when her engineered T cells were infused, Degennaro spent two weeks in the hospital, followed by two weeks in a hotel nearby. A bone marrow biopsy two weeks after completing treatment showed no signs of myeloma, she says.

Her treatment and hotel costs were covered during the trial, she says.

“Participating in the study made it affordable,” Degennaro says. “It wasn’t the financial burden on me that it could have been.”

A year later, her myeloma returned, so she had a second CAR-T cell treatment and was in remission for a few months. Her myeloma has since returned.

“To have even six months off treatment is a treat,” Degennaro says, adding that today, she takes a combination of selinexor, Velcade (bortezomib) and dexamethasone. “Some people say CAR T is not worth it. It was totally worth it for me. It gave me all that time off treatment.”

Weighing the cost of CAR-T cell therapy in treating blood cancers is a finical burden for many patients with blood cancer. 

The Price of Hope: Weighing the Cost of CAR-T Cell Therapy in Treating Blood Cancers

When James Landon received a mantle cell lymphoma (MCL) diagnosis in 2017, he was told his disease was “indolent,” meaning it was slow growing and didn’t need to be treated right away, especially since he was feeling fine.

But that changed in 2019. Landon, 50, an attorney in Tucson, Arizona, started to feel tired all the time. His physicians discovered that his white blood cell count was sky-high and his spleen was enlarged.

The first-line treatment for MCL has long been high doses of chemotherapy, often followed by a stem cell transplant. But when Landon traveled to The University of Texas MD Anderson Cancer
Center in Houston to explore his options, he was offered an alternative: an experimental regimen combining the drugs Imbruvica (ibrutinib) and Rituxan (rituximab). Imbruvica blocks a protein called Bruton tyrosine kinase (BTK), which is a driver of MCL, and Rituxan is an antibody that targets overactive B cells of the immune system that have been implicated in the disease.

Five months after starting the combination — four Imbruvica pills every morning and once-weekly infusions of Rituxan — Landon’s positron emission tomography (PET) scan showed no evidence of disease. If he stays clear, he’ll undergo a short course of chemotherapy and then move to a maintenance therapy of one year of Ibrutinib and two of Rituxan.

“Having this option has been fantastic, in my opinion, because the drugs so far have worked well for me, with no toxicity,” says Landon, who adds that he has plenty of energy to work full time and play with his 10-year-old son.

BTK inhibitors and immunotherapy are among the newer therapeutic options for patients with MCL that are greatly improving the outlook for long-term survival. In addition to these targeted drugs, Tecartus (brexucabtagene autoleucel) — the first cell-based gene therapy for MCL in patients who haven’t responded to or who have relapsed following other kinds of treatment — was approved by the Food and Drug Administration (FDA) in July and is a one-time personalized treatment made from patients’ own immune cells.

“We now have several good nonchemotherapy options for treating MCL,” says Dr. Anthony Nguyen, a professor at the University of Nevada, Las Vegas School of Medicine and a medical oncologist at Comprehensive Cancer Centers of Nevada. “We may be able to tell patients we can treat them without toxic chemotherapy, which can be reassuring, particularly for older patients.”

MCL is a subtype of non-Hodgkin lymphoma (NHL) that’s characterized by the overproduction of a protein called cyclin D1. In about 85% of patients, that overproduction is caused by a genetic abnormality called reciprocal chromosomal translocation, which can be detected with diagnostic testing of tumor samples. MCL accounts for about 6% of all NHL diagnoses and is more common in men than in women, according to the Leukemia & Lymphoma Society.

The standard first-line treatment for MCL is high-dose chemotherapy, often with a four-medicine regimen called hyper-CVAD, followed by a stem cell transplant with a patient’s own cells or with those from a donor. The regimen often puts patients into long-term remissions, but the side effects — including nausea, mouth ulcers and kidney damage — can be difficult or even dangerous, particularly for patients with other illnesses.

The newer medicines and cell therapy were approved by the FDA to treat patients with MCL who don’t respond to chemotherapy and transplants or who relapse. But as physicians gain more experience with these therapies, there’s a growing interest in using them earlier in the treatment process to not only improve the chances of long-term remissions, but also to improve the quality of life for patients by sparing them from harsh side effects.

The FDA approved the first BTK inhibitor to treat MCL, Imbruvica, in 2013, based on a study showing an overall response rate (meaning the disease responded to treatment) of 68% and a complete response rate (the disappearance of all signs of cancer) of 21%. The average period that patients lived without their disease progressing was more than a year, and side effects were mild stomach upset and fatigue.

The more recently approved BTK inhibitors Calquence (acalabrutinib) and Brukinsa (zanubrutinib) have improved on those response rates. Patients receiving Brukinsa in a late-stage trial, for example, had an overall response rate of 89% and a complete response rate of 59%.

Another targeted treatment, Venclexta (venetoclax) is also being studied in MCL. Venclexta targets the protein BCL2, which promotes cell survival and is abnormally elevated in MCL — helping to drive progression of the disease. In a small trial of Venclexta, 75% of patients with relapsed MCL responded to the drug, 21% of whom had complete responses. There’s even more interest in studying BCL2 inhibition in combination with BTK blockers. In a recent study of Venclexta combined with Imbruvica, the median progression-free survival time was 29 months.

“This is an extremely promising combination,” says Dr. Abhijeet Kumar, assistant professor in the division of hematology and oncology at the University of Arizona College of Medicine. Kumar is an investigator in an ongoing trial of Venclexta and Imbruvica in MCL.

There is, however, a risk of increased side effects when targeted treatments are combined. Imbruvica can cause bleeding, for example, and both drugs can lower neutrophil (a type of white blood cell) counts. Venclexta is also known to cause tumor lysis syndrome, a rapid release of tumor cells into the bloodstream that can endanger the kidneys and other organs. Still, so far, “the combination seems to be well-tolerated,” Kumar says.

Another two-drug treatment for MCL that has generated enthusiasm among oncologists treating the disease is dubbed “R-squared” because it combines Rituxan with Revlimid (lenalidomide), a drug that works by boosting the immune system’s T cells and natural killer cells, which work together to attack cancer.

In a study of R-squared in 38 patients with newly diagnosed MCL, the progression-free survival rate after three years was 80% and overall survival reached 90%. “The response is durable,” says Dr. Bijal Shah, an associate member in the department of malignant hematology at Moffitt Cancer Center and one of the study investigators. During the R-squared trial, patients typically stayed on the combination for three years and then took Revlimid alone as long as the disease remained stable.

Similar benefits have been seen with a combination of Velcade (bortezomib), Revlimid and chemotherapy, a regimen called VR-CAP. Velcade is a targeted drug that works by disrupting the growth of MCL cells and prompting them to die.

In a trial of patients with untreated MCL, adding Velcade to Revlimid and chemotherapy extended progression-free survival by 37%. The addition of Velcade more than doubled the median duration of response to 41 months.

Both R-squared and VR-CAP have moved into the frontline treatment setting, Shah says. “With that, we’re able to see really pronounced clinical benefits. We’ve seen very long remissions,” he says.

Several other combination strategies also are being investigated for MCL, including some that incorporate the drug Treanda (bendamustine), which works by causing DNA damage to cancer cells. In one study, combining Treanda with Rituxan improved progression-free survival rates over chemotherapy in patients with MCL or indolent NHL. More than 15 studies are now underway combining Treanda with Rituxan and other MCL treatments.

Even though targeted and combination treatments have extended survival times in MCL, most patients eventually relapse. Now there’s a new option for those patients: Tecartus, a personalized therapy made from a patient’s own immune cells. The one-time treatment was approved by the FDA to treat patients who have not responded or have relapsed following other kinds of treatment.

Tecartus is a chimeric antigen receptor (CAR)-T cell therapy similar to Yescarta (axicabtagene ciloleucel), a CAR-T cell therapy approved by the FDA in 2017 to treat some types of large B-cell lymphomas. Like Yescarta, Tecartus targets CD19, a protein that’s prevalent in cancerous B cells. Tecartus is made by extracting T cells from the blood of the patient with MCL and genetically modifying those cells to recognize and attack the cancer. In addition, the cells are put through an enrichment process designed to prevent them from wearing down before they are infused back into the patient.

In the clinical trial that led up to the approval, 87% of patients responded to Tecartus and 62% went into remission. Side effects, which included the immune overreaction known as cytokine release syndrome and neurological events, were manageable during the clinical trial, says Dr. Michael Wang, a professor in the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center and one of the clinical trial investigators.

Experience with previously approved CAR-T cell treatments led to the widespread use of anti-inflammatory medications such as interleuken-6 inhibitors and steroids to treat cytokine release syndrome, Wang says. “We have a variety of supportive measures to manage the side effects,” he says.

With the approval of Tecartus, Wang says oncologists can envision a “flattening of the survival curve” in MCL. “It’s an option for people who become resistant to targeted therapies and chemotherapy,” he says. “It’s very possible we will be able to put some people into long- term remissions.”

Bob Brixner, a 20-year survivor of MCL, has been watching all the new developments with interest. When he received an MCL diagnosis in 2000, he had no choice but to endure chemotherapy followed by a stem cell transplant with his own cells. When he relapsed in 2004, he was prescribed a more intense chemotherapy regimen, followed by a stem cell transplant from an unrelated donor.

He’s grateful the second treatment put him in a long-term remission, but he still remembers the brutal side effects, which included extreme fatigue and a bout with pneumonia. “And with the transplants, my immune system didn’t come back 100%,” says Brixner, 70, a retired Chicago public schoolteacher. “Nowadays if I catch a cold, instead of lasting a week, it will last three.”

Brixner advises all newly diagnosed patients to ask a lot of questions about their treatment choices — and to get a second opinion. “I think it’s really important to be an informed patient,” he says, especially since there are so many new choices. “Some patients may not have to go through what I did,” he says. “I’m delighted.”

Exciting advances in treatment options for patients with mantle cell lymphoma are greatly improving the outlook for long-term remissions.

Advances in the Treatment of Mantle Cell Lymphoma are Greatly Improving the Long-Term Outlook for Patients

Chimeric Antigen Receptor(CAR)-T cell therapy is an exciting advancement for the treatment of multiple types of blood cancers, but it is not without risk.

CAR-T cell therapy works by removing a patient’s T cells, reengineering them to destroy cancer cells and then infusing them back into the patient’s body, thus improving outcomes for many patients. This process can result in an increased number of cytokines — molecules that mediate and regulate immunity and inflammation — into the blood stream. As a result, patients can experience side effects like fever, increased heart rate, difficulty breathing and low blood pressure.

Researchers at Moffitt Cancer Center recently conducted a study to identify possible risk fac- tors that could help a physician know if patients are more likely to have side effects before they receive CAR-T cell therapy. They analyzed 75 patients with large B-cell lymphoma who were treated with Yescarta (axicabtagene ciloleucel). Patients with an increased level of interleukin

6 (an inflammatory molecule) had higher rates of nervous system damage called neurotoxicity; cytokine release syndrome (a dangerous, inflammatory result of overactive T cells); and death. Also noted was a potential relationship between myeloid cells and regulatory T cells with cytokine release syndrome and neurotoxicity.

“Identifying which CAR-T patients may be more susceptible to those severe toxicities before therapy could allow us to better tailor their care to mediate or reduce those adverse reactions,” said Dr. Marco Davila, study corresponding author, associate member of the Blood and Marrow Transplant and Cellular Immunotherapy Department and medical director of Cell Therapies at Moffitt.

Ultimately, study researchers determined that further research on the side effects of CAR-T cell therapy is needed.

CAR-T Cell therapy is expanding in the field of blood cancers, but it comes with a host of side effects patients need to look out for. One study is looking to get ahead of the side effect curve for patients about to undergo CAR-T cell therapy. 

Hematology 2nd Special Issue 2020 | CURE