CURE®’s publications offer a comprehensive and informative resource covering the entire cancer continuum. From quarterly issues of CURE® magazine to disease-state specific editions, an annual cancer guide, and Educated Patient® Resource Guides, these publications cater to patients, survivors, and caregivers at every stage of the cancer journey.

Did you know that every three minutes someone receives a diagnosis of a blood cancer? According to the National Foundation for Cancer Research, blood cancers account for nearly 10% of new cancer diagnoses in the United States annually. That means that approximately 178,520 people will receive a diagnosis this year — most commonly with leukemia, lymphoma or myeloma. And although survival rates have increased dramatically over the past 20 years, there’s still a long way to go when it comes to this patient population.

In this special issue of CURE®, you’ll read about some of the research going on in blood cancer right now, including new treatment options for acute myeloid leukemia and a novel therapy using BK virus-specific T cells to treat BK virus-associated hemorrhagic cystitis (a painful side effect of stem cell transplants).

Dive into the issue for two patient stories, one about a three-time acute lymphoblastic leukemia survivor who now works as a nurse on the bone marrow transplant floor at Barnes-Jewish Hospital in St. Louis. This year also marks the 20th anniversary of the Food and Drug Administration’s approval of Gleevec (imatinib mesylate), the tyrosine kinase inhibitor that saved Mel Mann. Who is Mel Mann? He is the longest-living survivor who was treated with the drug as a part of a clinical trial for chronic myeloid leukemia.

And because cancer is not a disease one should have to face alone, our cover story looks at the responsibilities and experiences of caregivers to patients with blood cancer. Not only will you read about what they’ve gone through, but you’ll also find extra resources and tips for navigating the patient-caregiver relationship.

For more news on cancer updates, research and education, don’t forget to 

Articles

From the Chairman

New research in blood cancer includes new treatment options for acute myeloid leukemia and a novel therapy using BK virus-specific T cells to treat BK virus-associated hemorrhagic cystitis.

New Treatments and Tips for Dealing With Blood Cancer

Myeloproliferative neoplasms (MPNs) can be difficult to understand, but patients should not feel alone. Many patients with this rare type of cancer are collaborating to not only bring the MPN community together but to also advance treatment options for the disease.

As part of its “Speaking Out” video series, on behalf of the MPN Research Foundation, CURE® spoke with Dr. Gabriela Hobbs, clinical director of leukemia at Massachusetts General Hospital in Boston, about the disease, why patients should be informed, how they can learn more and what they can be hopeful for in the future.

Why is it important for patients to learn more about their treatment options?

That's really important. For a patient with a diagnosis that's rare, I think it's really difficult to feel comfortable with their diagnosis and to feel in control. When (patients receive a diagnosis), there’s a sense of loss of control where something happened that was not something that anybody asks for. I think a part of gaining some of that control is information. I really am a big believer in patients being informed patients, understanding what their disease is ... even being educated in terms of knowing what the name of the disease is. 

Thankfully, in the MPN world, there are lots of great foundations (such as the MPN Research Foundation) that can help patients get reliable information. And I think that’s one of the things that’s really difficult about this, the world we live in, where there’s so much information out there. It’s hard sometimes to get reliable information. I (would recommend) going to the MPN Research Foundation, the National Cancer Care Network guidelines, American Cancer Society guidelines — reputable sources (that) are written by reputable people. It is really important to learn about what the (disease is), what trials or treatments exist, what potential complications are, etc. Once you’re an informed patient, you can go to your physician, nurse or whoever is treating you with a set of questions and things that you’ve learned online, and that makes the visit much more productive — even something as simple as saying, “I found the MPN symptom assessment form online, and I have the symptoms; what do you think about that? Am I a candidate for treatment?”

On the flip side of that, I also think that we need to be very careful with what we find online. Some of my patients definitely spend a lot of time on social media. And though I’m somebody who really likes social media (because it) makes us all connected, it can sometimes also have a lot of information that is shared that is anecdotal, meaning it is the experience of only one patient. And although that can certainly bring community to some degree, sometimes the information that’s shared in these groups is just one person’s experience and doesn’t necessarily reflect what a group of large patients may experience. Sometimes I spend a lot of time talking to my patients (telling them that) just because this person had a bad side effect doesn’t mean that (will happen to you). I think we have to be really careful with the information that we get, both in social media and just online in general. Make sure that it’s from a reputable source.

Why should patients be hopeful looking toward future treatment options?

Now is definitely a time to be hopeful. One of the things that I say is that the reason why I was hired to work where I work is because there’s so much understanding about MPNs now that they can hire a person who just treats MPNs. Whereas before, that would have been funny, right? (Before), how do you hire somebody to treat diseases that don’t have any treatments? That’s just one sign of the changing times.

There are lots of clinical trials (evaluating) medications for advanced stages that will, hopefully, get approved in the next couple of years. I feel optimistic about that because I’ll be able to offer more treatments to my patients. Another thing to remember is that in the past decade, our understanding of how these diseases start and progress or evolve over time has really changed exponentially. The amount of people who are doing research on these diseases has increased significantly. And nothing is more proof of that than the fact that there are dozens of clinical trials across the country testing a variety of medications to treat MPNs.

And so, even though when a patient has an MPN they may feel like they’re the only one that has it, remember that you’re not the only one who has it. A lot of people are really thinking about these diseases and trying to improve treatment and improve quality of life for these patients.

Speaking Out

Dr. Gabriela Hobbs offers insight into a rare cancer, myeloproliferative neoplasms, to help patients learn more during their treatment journey.

Becoming an Informed Patient With Rare Cancer

Using BK virus (BKV)-specific T cells from healthy donors to treat BKV-associated hemorrhagic cystitis, a painful side effect associated with immunosuppression from stem cell transplants, may relieve the complication faster in patients with lymphoma or leukemia, according to trial results.

“What was very important was that within a week of giving the cells, the majority of patients’ symptoms improved,” Dr. Katy Rezvani, professor of stem cell transplantation and cellular therapy at The University of Texas MD Anderson Cancer Center in Houston and lead study author, said in an interview with 

. “The effect of the cells is relatively rapid.”

BKV-associated hemorrhagic cystitis occurs more frequently in patients with leukemia or lymphoma who received a treatment of allogeneic stem cell transplantation. As a result, it can lead to patients having blood in their urine and passing clots, which can cause urinary retention (difficulty urinating or completely emptying the bladder) and, in more severe cases, kidney disease.

In patients who receive stem cell transplants, those who have a half match (when patients only have some genetic similarities with the donor’s immune system) are at an increased risk for BKV-associated hemorrhagic cystitis because they are more immunosuppressed. Approximately 40% of patients who have a half match develop this complication.

In the phase 2 trial, BKV-specific T cells, which recognize and attack BKV, from healthy donors were given once intravenously, with the option to receive additional doses every two weeks if needed. Of the 59 patients enrolled in the trial, 67.7% had complete (all symptoms resolved) or partial (almost all symptoms resolved) responses within 14 days. This increased to 81.6% after 28 days.

Some intolerance was observed in patients who were previously treated with steroids, which can kill T cells. There were no side effects, and there were no reports of new liver or gastrointestinal graft-versus-host disease (GVHD, occurs when the donor's cells attack the patient's cells) associated with the antiviral T cells, aside from a few cases of skin GVHD that quickly resolved with corticosteroids.

This treatment has the potential to stop the vicious cycle that comes with the current standard of care, which consists of hospitalization with continuous bladder irrigation (using a catheter to wash out the bladder) and morphine infusion to help patients tolerate the pain, according to Rezvani.

“This outpatient treatment is preventing patients from having to be admitted (to the hospital), which is wonderful because patients come into hospital with one thing, they stay in the hospital for a few weeks, then they develop other complications,” Rezvani explained. “They start getting other infections, they get pneumonia, they become malnourished, etc.”

According to Rezvani, one donor can produce up to 50 doses of T cells, which are frozen until needed. “Every time the patient comes (into the hospital), within 24 hours we can treat them,” she said.

Of note, the therapy is only available at MD Anderson, so patients with the complication would need to travel to the health center to receive it — an option that may not be possible because of physical condition or finances. “I’m hoping that we will get to a situation where we’ll be able to start a multicenter study at some point,” Rezvani said, which would make the care more accessible to patients. “In the meantime, I think the greatest limitation really is that patients will have to come to MD Anderson to receive the treatment, and for many patients with the terrible BKV hemorrhagic cystitis, this is not obviously possible.”

Until then, Rezvani is focusing on the next generation of the treatment: genetically modifying BKV-specific T cells that are more resistant to steroids, thus broadening the patient spectrum that the treatment could help.

“It’s important to realize that the use of immunotherapy against viruses and cancers (has) opened up a very exciting new era of treatment for our patients,” she concluded. “We are learning a lot more from the immune system (and are harnessing) the power of the immune system to fight infections and cancers. ... I think the field is going to continue to grow, and many more such treatments to target both viruses and cancers (are) going to become available.”

Research News and Updates

A new T-cell therapy can be highly effective in treating BKV-associated hemorrhagic cystitis while minimizing side effects.

The Power of the Immune System: New Treatment for Painful Blood Cancer Side Effect

As an almost 30-year veteran of the Secret Service, Jim Helminski took pride in maintaining his physical health — both for his own sake and to be better fit to protect others. His demanding career placed the safety of Presidents Bill Clinton and George W. Bush and then-Vice President Joe Biden in his hands.

In late 2015, he retired as deputy assistant director to live a more tranquil life on Orcas Island, Washington, with his wife, Teresa Patrick, a former Department of Justice attorney. Not one to sit still, Helminski started a security consulting business on the side while running, weightlifting and practicing karate. He even earned his private pilot’s license and began flying a vintage Cessna.

During a routine yearly checkup in 2019, his primary care doctor remarked that Helminski was in better shape at 61 than most 30-year-olds who came into the office. But later, that changed.

“I went for a jog one day that week after my exam, and my cell phone rings. It was my doctor, and he said, ‘Jim, there’s something wrong with your blood. Your white blood cell count is dangerously low,’” Helminski, now 63, recalls. “I had no symptoms. I felt nothing.”

The direness of the situation hit him when he arrived at a Seattle-based health facility for a consultation with a hematologist that ended with a bone marrow biopsy. A few days later, he received a diagnosis of myelodysplastic syndrome (MDS), a type of cancer in which immature blood cells in the bone marrow do not mature or become healthy blood cells. MDS can be a precursor to different types of leukemia. His myelodysplastic syndrome progressed rapidly to acute myeloid leukemia (AML).

AML, which starts in the bone marrow, usually moves quickly into the blood. From there it can spread to other parts of the body, including the lymph nodes, liver, spleen, brain and spinal cord. Typically, AML develops from the malignant transformation of cells that would turn into white blood cells, but it also may start in very immature forms of red blood cells or cells that make platelets. Approximately 19,940 new cases of AML were diagnosed last year in the U.S., with most occurring in adults.

“It was a huge shock,” Helminski says. “I scheduled an appointment at the (regional) cancer center to see one of their top leukemia doctors, and it became the lowest point in my life.”

The reviewing oncologist advised him that standard treatment gave him only a 10% to 20% chance of remission and provided little guidance about which therapy to pursue. Instead, he simply recommended that, rather than attempting standard chemotherapy, Helminski and his wife look online to find a list of clinical trials for AML and pick one.

Understandably, they left the appointment dissatisfied and began looking elsewhere for guidance. Meanwhile, Helminski broke the bad news to family and friends, including his flight instructor, whose daughter happened to be an oncologist at the University of California, San Diego. She shared his patient profile with a colleague at Johns Hopkins Medicine in Baltimore, who in turn recommended that Helminski consider a clinical trial helmed by her friend, Dr. Courtney DiNardo, an associate professor of leukemia in the division of cancer medicine at The University of Texas MD Anderson Cancer Center in Houston.

Less than two weeks later, Helminski had an appointment and jumped on a plane to Houston to meet DiNardo in person. The study was planning to test a novel three-drug therapy: Tibsovo (ivosidenib tablets), a targeted therapy for patients with the IDH1 gene mutation; Venclexta (venetoclax), an oral medication approved for adults 75 years and older or adults who cannot tolerate chemotherapy; and azacitidine. After an extensive new-patient visit, he was accepted into the clinical trial as one of 48 participants.

Similarly, Irma Smith saw her doctor for isolated pain in her toe and received a diagnosis of AML in 2016. The 75-year-old lived in Fort Wayne, Indiana, with no major health problems and had worked as a real estate agent for the past 29 years.

“I didn’t have a clue. I felt great. I went into shock when I heard the diagnosis because I thought, ‘How can somebody feel so good and then get hit with AML?’” Smith, now 80, says. “The doctor gave me two weeks to two months to live.”

Smith and her daughter decided to seek a second opinion from Dr. Hamid Sayar, a professor of clinical medicine at Indiana University School of Medicine in Indianapolis. Instead of painting a bleak picture, he went straight to work by putting Smith on induction chemo- therapy followed by consolidation chemotherapy. After successfully achieving remission in early 2017, Smith was entered into a clinical trial for oral azacitidine as maintenance therapy to prevent relapse.

In September 2020, oral azacitidine was approved by the Food and Drug Administration (FDA) for patients aged 55 years and older with AML who achieve remission after chemotherapy and are not able to complete intensive curative therapy with a stem cell transplant.

After decades of stagnation, progress in AML treatments has experienced a resurgence in recent years due to rapid advances in genetics, understanding of molecular mechanisms and development of novel therapeutics. Since 2017, nine new drug approvals by the FDA have significantly changed the treatment landscape of the disease. As a next step, clinical trials such as DiNardo’s aim to find which combinations of therapies will offer patients the best outcomes.

“AML is still, unfortunately, a very life-threatening cancer. Cancer is clever — it’s going to figure out a resistance mechanism to evade a single agent,” DiNardo says. “Putting agents together, if you don’t have overlapping toxicity, is just a smarter way of giving cancer therapy. So we’re trying to move these drug combinations into the frontline setting where they have the best chance of eradicating all disease and preventing relapses.”

Other studies focus on improving treatment for elderly individuals with AML, given that the average age at receiving a diagnosis is 68. Researchers are also testing new targeted therapies, immunotherapies and different ways of delivering drugs that are more convenient for patients.

“AML is more a disease of older populations. Historically, one challenge in the treatment of older adults has been exposing them to intense therapies, which we can do for the younger patients,” Sayar explains. “But treatment of AML at any age, at any phase of the disease, is a challenge. There is an unmet need at every aspect
of treatment.”

The approval of more therapies has certainly helped many patients, and researchers such as DiNardo are looking to optimize their administration even more by finding the most effective combinations and timings. The clinical trial that Helminski participated in brought together three approved agents for the first time in the frontline setting for patients who have AML with an IDH1 mutation.

Helminski underwent a 28-day isolation in his hospital room at MD Anderson while receiving the three medications due to his immunocompromised state from the leukemia and the treatment. It kept him as infection-free as possible until his immune system recovered. He remained as active as he could — using an exercise bike daily, strength training with resistance bands and meditating with the help of a smartphone app — but did experience some setbacks, such as pneumonia and minor liver inflammation attributed to an antifungal drug.

On the 28th day, the results of Helminski’s follow-up bone marrow biopsy showed that he went from 40% leukemic myeloblasts — immature blood cells that serve as a marker of AML progression — to just 1%.

“He’s a great example of someone who went into a really deep remission. He’s been leukemia-free and doing great for over a year now,” DiNardo says. “We have all of these new approvals now, and they were approved in the single-agent setting. But that’s probably not the best way to actually use them in the real world.”

Two years after going into remission, Smith’s disease returned in 2019 while she was still participating in the clinical trial for oral azacytidine. When the randomized trial was unblinded, it was revealed that she was administered a placebo as part of the control group instead of the maintenance therapy. She is currently being treated indefinitely with Venclexta (venetoclax) and decitabine, a chemotherapy drug, every six weeks — which temporarily takes a toll on her body.

“I don’t want to go out or see anybody. I’m pretty miserable, but I know it’s not going to last,” Smith says. She still enjoys maintaining her house, going on long walks with her dog and spending quality time with family: “The side effects stop in a week and a half, and the rest of the time, I’m just fine. I have a lot of energy.”

Other studies aim to help patients like Smith who relapse after undergoing therapy. Sometimes another round of chemotherapy can put the leukemia into remission again, but it is not likely to be long-lasting. A stem cell transplant or newer targeted therapy for a specific genetic mutation could be better options, but with much more toxicities, and patients must be eligible for these therapies.

“Unfortunately, AML still is a disease where the leukemia does recur or come back, so a lot of research is focused on treating patients who have relapsed after upfront therapy,” Dr. Sangmin Lee, an assistant professor of medicine at Weill Cornell Medicine in New York City, says.

“Several ongoing clinical trials are geared toward relapsed and refractory settings, such as those investigating cell-based therapies, targeted therapies and drugs that overcome resistance.”

For example, a number of clinical trials are exploring the use of chimeric antigen receptor (CAR)-T cell therapy, a novel treatment that involves engineering a patient’s own immune cells, for AML. CAR-T cell therapy has shown promise in other blood cancers. Research is still in the early stages for AML, with initial studies looking at the safety and feasibility of the therapy in adults and children.


Overall, experts agree that several avenues are being explored by researchers to help patients with AML, who are recommended to look into clinical trials as soon as they receive their diagnosis. Helminski, for example, emphasized that he would not have been eligible for DiNardo’s study if he had undergone standard therapy first.

“There is a lot of research trying to see if novel therapies provide benefit, so patients should be on the lookout for clinical trials — both in an upfront setting and also in the relapsed or refractory setting — when they (receive a diagnosis of ) leukemia,” Lee says.

Since the trio of medications Helminski received worked well enough to induce a deep remission, he was able to undergo a curative stem cell transplant in February 2020 from an unrelated donor.

After the stem cell transplant, he gradually regained his strength over the course of 100 days. Today, at more than 500 days post-transplant, Helminski shows no signs of measurable residual disease. He is back to having a full life on Orcas Island with his wife, exercising regularly, flying his airplane and building furniture.

“I initially believed that I was terminally ill, and there was no hope for me. And there’s always the monster of a possibility of a recurrence,” Helminski says. “But I take life one day at a time, and I’m very appreciative of every day that I have.”

Features

An abundance of clinical trials is giving patients with acute myeloid leukemia (AML) hope for a better future.

Better Days Ahead for Patients With AML

The 1966 movie "Fantastic Voyage" envisioned a nanotechnologic approach to fighting disease using miniaturized tools. In 2017, the Food and Drug Administration approved the United States’ first chimeric antigen receptor (CAR)-T cell therapy, which employs an immune cell that has been adapted to recognize tumor-specific antigens and destroy the cells that bear them. Since then, the field of engineering cells has matured as researchers begin to dive into the potential use of natural killer (NK) cells through the same technology used for CAR-T cells, but, hopefully, with less of the collateral damage that can result from excessive immune activation and inflammation. Although we are still learning about NK cells, we do know that they function similarly to CAR-T cells as effector lymphocytes of the immune system and work to control several types of tumors and microbial infections.

Currently, there is much sophisticated research behind the new therapy, and it is hoped that it may also have fewer side effects than CAR-T cell therapy. In this special issue of CURE®, read more about the therapy and how it’s being used in different types of blood cancers. One patient tells his story of receiving NK cell therapy through clinical trials after receiving a diagnosis of metastatic lymphoma in the throat, lung and liver. His disease went back into remission in early 2021, and he is thankful for the novel therapy. Another patient, who received a diagnosis of multiple myeloma in 2016, participated in a clinical trial in which she received a dose of allogeneic NK cells. She experienced no side effects except fatigue. Both patient outcomes show promising results of the new therapy for hematologic cancers. Engineered cell technology is an example of ingenuity that brings together cutting-edge laboratory science and clinical trials to address aggressive cancers in a “Star Wars”-style strategy that is already paying off yet continues to evolve as a potential option for more common types of cancers.

Editor's Page

Engineered cell technology is an example of ingenuity that brings together cutting-edge laboratory science and clinical trials to address aggressive cancers.

The Future of Cancer Looks Bright With Engineered Cells

In 2010, Kerry Tracy ran a half-marathon for his daughter’s best friend’s mom. She had just received a diagnosis of multiple myeloma and, knowing he was an avid runner, she asked him to participate.

“You do obviously learn about (the disease) and see what it’s all about,” he said of the time spent leading up to the event.

Two years later, after going to the doctor for back pain, he, too, received a diagnosis of multiple myeloma.

“As my oncologist said, ‘This is not your garden-variety multiple myeloma,’” explained Tracy, who lives in New York City. “I had multiple compression fractures throughout my vertebrae and needed three kyphoplasty surgeries immediately.” Kyphoplasty is a minimally invasive surgery used to treat vertebral compression fractures by inflating a balloon to restore bone height. Bone cement is then injected into the vertebrae.

“It was kind of a shock. I was in pretty good shape and never really had any medical issues,” said Tracy, who was 52 when he received his diagnosis. The then-CEO of Working Media Group was used to working out six days a week, skiing, coaching and playing golf with his children — two were in high school and one was in elementary school — and wife.

One of the first things Tracy did after receiving his diagnosis was reach out to experts at centers well known for treating multiple myeloma, including Memorial Sloan Kettering Cancer Center, NewYork-Presbyterian Hospital, Mount Sinai Health System, The University of Texas MD Anderson Cancer Center and Dana-Farber Cancer Institute. All told him the same thing: If you’re going to do your research, do it on legitimate websites.

“MMRF (Multiple Myeloma Research Foundation) was one of the places that I looked at and kind of relied on,” he explained, noting that foundation staff members helped connect him with doctors. “I’ve been really thankful for what they’ve done.”

Tracy said that the MMRF helped him zero in on the most accurate information. “I subscribe to Google alerts on everything and anything about myeloma, and there’s a lot of information out there that you see that’s credible, and there’s some information out there that’s not,” he said.

This realization, combined with his positive experience with the MMRF, led Tracy to start his company, Digitent, nine years after receiving his diagnosis.

Through his company, he is striving to produce accurate health and wellness multimedia content.

“It goes back to what the doctors told me when I was diagnosed,” he explained. “(They) ... gave me three sites to try to stick to because when you first get diagnosed, you’re looking up everything. You want to be as well-informed as possible, and some- times it’s pretty scary in terms of the stuff that you read. ... There’s no police out there saying what you can (and) can’t post.”

One of his upcoming series includes a podcast with doctors and patients who have orphan diseases (diseases that affect less than 200,000 people worldwide) such as multiple myeloma, providing a space for those patients and experts to learn and connect.

“Every time I had a (stem cell or bone marrow) transplant, the thing that ... I always wanted to see was who had it done before me, and what was their experience? I think podcasts are a great way to tell your story and hear other people’s stories,” he concluded.

Feature

After receiving a diagnosis of multiple myeloma, a patient relied on the Multiple Myeloma Research Foundation for information and is becoming part of the conversation.

Paying It Forward for Other Patients With Multiple Myeloma

A fixed-duration treatment regimen of Imbruvica (ibrutinib) and Venclexta (venetoclax) may lead to better progression-free survival, as well as less time spent in the hospital, for patients with chronic lymphocytic leukemia (CLL).

Results from this study were presented at the European Hematology Association 2021 Virtual Congress.

“These are promising times for patients with CLL. Unfortunately, we still (can’t) say that we have cured the disease, but, for sure, we have prolonged progression-free survival,” lead study author Dr. Arnon P. Kater, a professor at Amsterdam University Medical Centers, locatie AMC, in the Netherlands, told CURE®. “These new agents also improved quality of life, not only when (a) patient is in remission, but specifically also when a patient is under treatment.”

Of note, the standard of care is indefinite treatment with anti-CD20 therapy in combination with chemotherapy or Venclexta, or Imbruvica alone.

In the study, the combined treatment of Imbruvica and Venclexta, compared with the standard of care of Leukeran (chlorambucil) and Gazyva (obinutuzumab), reduced the risk of disease progression or death by 78% after a median follow-up of 28 months. The treatment regimen was 12 weeks.

The drug combination works well because the cancer cell behavior of CLL in the lymph nodes creates a microenvironmental protective niche, Kater said. This niche uses protective signals from other cells in the body and allows the cancerous cells to proliferate rapidly. Imbruvica inhibits this, prevents new cells from migrating to the lymph nodes and causes them to exit the lymph nodes. Venclexta, on the other hand, is an inhibitor of the protein BCL-2, which is known to be increased in patients with CLL and is responsible for the survival of cancerous cells in the blood. The cancerous cells die when this protein is inhibited.

“That’s why, theoretically, there might be very much of a synergy between the two drugs because one drug is very good (at) killing cells in the blood (Venclexta), and the other drug is very good in getting the cells out of these protective niches in the lymph nodes and maybe other organs as well,” Kater said.

After reviewing the data, Dr. Akiva Diamond, an assistant professor of medicine in hematology and oncology at Baylor College of Medicine in Houston, wondered what oncologists would be able to do next if the combination did not work for the patient. “These are our two best drugs, and we’re starting with them together. What do we do next?” he said. “That’s going to be a very important question for us as investigators and for patients. Are we able to reuse this again later? If, let’s say, they get a good few years of benefit, can we try it again? ... Or is there going to be a resistance to these two agents and then we need to move to the next line of therapy? So there (are) still a lot of questions to be answered, but certainly (the treatment has) promising efficacy.”

Outside of the projected efficacy of the two drugs, other benefits include that the regimen is fixed duration and that it is administered mainly in an outpatient setting. “I think that a fixed-rate treatment is the preferred option (for three reasons),” Kater said. These reasons include the fact that patients have a shorter time frame for experiencing side effects, the possibility of reducing financial burden by shortening the duration of treatments and the increased possibility of using the same agents for years versus treating a patient until cells become resistant.

Diamond also emphasized the importance of outpatient treatment options such as this combination compared with others like Leukeran and Gazyva, as well as Venclexta and Gazyva. “Currently, (taking Venclexta and Gazyva) ... does require quite a bit of hospitalization. So during the (COVID-19) era, we’ve been using a lot less of it and using that less frequently because patients (are) really looking to avoid hospitalizations,” he explained. “I’m hopeful that with this therapy, we might have the option to first start with (Imbruvica), decrease the disease burden and then be able to do the rest of the treatment maybe as an out- patient. I think that would be a benefit.”


Kater added that there is the possibility of differentiating data due to regional differences for older and frail patients from the study. Of note, there were no new side effects outside of those already common to the drugs when used as single agents. Common side effects of Venclexta and Imbruvica include arrythmia (irregular heart rhythm) and hypertension. “I think it’s a very promising combination,” Kater explained. “But I think this is really something that both the doctor and the patient should be aware of.”

A fixed-duration treatment regimen may result in better outcomes and less time in the hospital for patients with CLL.

‘Promising Times’ for Patients With CLL

Bob Schulz knew something was wrong when he had a hard time walking up the hill while golfing in December 2018. At 73, he still walked the 18 holes at the Albuquerque, New Mexico, golf course every week. After a chest X-ray, his doctor sent him to the hospital immediately. Two liters of fluid were removed from Scholz’s lungs several times during his four-day hospital stay. Extensive testing revealed malignant pleural effusion, or excess fluid and cancer cells between the tissues separating the lungs from the chest cavity.

Scholz sought a second opinion at The University of Texas MD Anderson Cancer Center, in Houston, a 13-hour drive away. There, he received a diagnosis of diffuse large B-cell lymphoma. He and his wife, Cindy, quickly packed up and moved to Houston for six months of R-CHOP chemotherapy, a combination of five drugs infused to kill cancer cells.

After chemotherapy, Scholz thought he was cancer-free, but in late 2020 he lost his voice completely, which sent him back to his oncologist at MD Anderson. A positron emission tomography scan revealed a recurrence of lymphoma in his throat, lung and liver. This time his doctor offered him treatment through a clinical trial for natural killer (NK) cell therapy, a type of infusion therapy that uses the body’s natural killer immune cells or donor NK cells, which are grown into larger quantities and sometimes genetically engineered with additional targeting abilities.

NK cells are a type of white blood cell in the immune system that can kill cancer and virally infected cells. “They have the innate ability to recognize and attack cells infected with viruses or cancer cells,” says Dr. Sarah Holstein, a multiple myeloma researcher and an associate professor of internal medicine at the University of Nebraska Medical Center in Omaha. However, cancer cells can sometimes evade NK cells’ ability to interact with and kill cancer cells. “The idea behind NK cell therapy is to augment the body’s natural NK cell response and increase it and, hopefully, lead to a more direct cell-killing effect against the cancer cell,” she explains.

Over the past two decades, researchers have studied various ways to do this; for example, by collecting the patient’s NK cells, growing them and then reinfusing them. When using the patient’s cells, it’s called an autologous adoptive transfer. Doctors also are growing cells from donors, called allogeneic adoptive transfer. These cells come from sources such as cell lines, peripheral blood or pluripotent stem cells, which can be found in neonatal foreskin or the umbilical cord, for example. Pluripotent stem cells have the ability to differentiate into many types of mature cells and can develop into NK cells or other needed cell types. “One cell in the lab can produce millions of NK cells,” says Dr. Paolo Strati, an assistant professor in the department of lymphoma and myeloma and the department of translational molecular pathology at MD Anderson Cancer Center. More recently the field has evolved to study genetically engineered NK cells, such as chimeric antigen receptor (CAR)-NK cells, that have the ability to recognize a specific target on the cancer cell.

Following three days of chemotherapy to prepare his immune system, the doctors gave Scholz three infusions of modified NK cells. He finished his treatment in early 2021 and is in remission. “I’m thankful every day about how fortunate I was to go there. I’m thankful to have that kind of a place with treatments with that chance of success,” he says.

Dr. Jeffrey Miller, a professor of medicine in the division of hematology, oncology and transplantation at the University of Minnesota in Minneapolis, has been researching NK cell treatments for more than 25 years. He published a paper in 2005 about administering haploidentical allogeneic NK cells, which were taken from a related donor, to patients. The research showed that the cells can persist and expand in the body and may have a treatment role. His 2014 update, which was published in 

, included 57 patients with relapsed/refractory acute myeloid leukemia (AML). Researchers used the immunotoxin interleukin (IL)-2 diphtheria toxin fusion to deplete T regulatory cells and thereby help improve NK cell growth rates. In the study, successful NK cell expansion correlated with remission. Patients were given NK cells, cytokines and lymphodepleting therapy.

“There was excitement in the field when we started to see (complete) response rates between 25% and 40% with those updates,” Miller says. “These were patients who progressed after standard therapy and had no other options.” The response allowed some patients to become eligible for allogeneic bone marrow transplants, even when they were not previously eligible.

Today, researchers are trying different trial designs, including an NK multidose strategy from allogeneic cells. “We couldn’t do it when we had to collect cells from individual donors. That only gave us one cell dose,” Miller explains. Allogeneic cells can be expanded much faster, allowing for multiple doses and freezer storage until needed. Some trials are now giving up to six weekly doses of these off-the- shelf cell products, and doctors can infuse the cells in an cell expansion correlated with remission. Patients were given NK cells, cytokines and lymphodepleting therapy.

Today, researchers are trying different trial designs, including an NK multidose strategy from allogeneic cells. “We couldn’t do it when we had to collect cells from individual donors. That only gave us one cell dose,” Miller explains. Allogeneic cells can be expanded much faster, allowing for multiple doses and freezer storage until needed. Some trials are now giving up to six weekly doses of these off-the- shelf cell products, and doctors can infuse the cells in an outpatient clinic instead of during a hospital stay. “The cells are thawed at the bedside and given, and the patients are watched for a few hours for allergic reactions,” Miller says.

The idea behind multidosing is that NK cells don’t persist in the body for as long as T cells, which are used in CAR-T cell therapy. “Think of it as a living drug,” Holstein says. “Once you put them in, those engineered cells persist and continue to fight against the tumor, should there be any remaining tumor cells that flare up again.” Researchers don’t think the NK cells can live as long as T cells, “but we don’t know if they need to live that long. Perhaps they’re super effective early on and we don’t need them to persist,” Holstein says.

In her multiple myeloma research, Holstein led a study that explored the use of off-the-shelf NK cell therapy given shortly after the time of a stem cell transplant. “There are data showing that early recovery of the patient’s own NK cells after a stem cell transplant is associated with improved outcomes. It is hypothesized that this early recovery of NK cells is contributing to the killing off of residual myeloma cells,” she says. By giving multiple doses of off-the-shelf NK cells — or allogeneic cells — researchers are hoping to boost the effect, ensuring that there’s enough time for NK cells to attack any errant myeloma cells during the critical bone marrow recovery time. “At this time, we’re not sure yet if this approach is effective,” Holstein explains.

Although more recent trials are studying multiple dosing, earlier trials such as Holstein’s used one dose. That’s partly because it was difficult to grow enough cells for multiple doses per patient, even using donor cells. Nancy Gessmann was 59 years old when she enrolled in Holstein’s earlier trial in 2017.

She hadn’t heard of multiple myeloma before back problems and a fever sent her to her primary care doctor in Harlan, Iowa, in 2016. After receiving her diagnosis, Gessmann sought treatment an hour away at the University of Nebraska Medical Center, where she received chemotherapy followed by a stem cell transplant in May 2017.

During her 18 days in the hospital for the transplant, she received a single dose of allogeneic NK cells as part of Holstein’s phase 1 study, along with a series of seven cytokine shots (they help stimulate the NK cells) to help the cells expand. “It gave me hope that if there was anything out there that could help me, it was worth trying,” she explains. Aside from feeling tired after the transplant and growth factor shots — which are given to aid the therapy — Gessmann does not think she experienced any side effects from the NK cell infusion.

With the clinical trial, “I had the opportunity to possibly help myself, my family and others. I benefited from clinical research done by others before me with stem cell transplants and chemotherapies. Others helped my treatment plan and made it easier for me. I’m paying it forward,” Gessmann says.

NK cell therapy may have advantages over T cells. Infused CAR-T cells will recognize a cancer cell and attack it. One attack method involves releasing toxins called cytokines, which can lead to a hyperinflammatory state known as cytokine release syndrome (CRS). CRS is caused when a large number of cytokines, proteins made by some immune cells, are quickly released into the blood from immune cells. They can lead to CRS symptoms such as fever, but patients can also experience low blood pressure, low blood oxygen and neuro- toxicities such as difficulty finding words, and severe issues such as a seizure or coma. About 10% of patients receiving CAR-T cell therapy for lymphoma experience severe CRS, and 40% experience severe neurotoxity. “It’s a real problem; hence, we need to look into different treatments,” Strati says.

NK cells potentially can be less toxic than, and as effective as, T-cell therapy. “Treatment for me was extremely easy, and the results were great,” Scholz says. “It wasn’t like serious chemotherapies. I didn’t feel real good for a couple of days, but it was minor. There were no repercussions from treatment.”

The good thing about NK cells compared with T cells, Miller says, is that NK cells don’t induce graft-versus-host disease, which is when infused allogeneic T cells attack the patient’s healthy cells. NK cells are missing the mechanism in T cells that cause it. For NK therapy, “as far as we know, no known neurotoxicity or CRS has been reported in any consistent way today,” Miller says.

The CAR technology also is being used for some NK cell treatments. With CAR, “we engineer NK cells in the lab,” Strati says. “We make them able to recognize specific proteins on top of lymphoma.” Using donor cells, both CAR-T and CAR NK cells can be available to patients more quickly than the patient’s cells.

The first in-human trial in the United States with CAR NK cells was for relapsed/refractory CD19-positive B lymphoid malignancies. The trial encoded NK cells to recognize CD19 and express cytokine IL-15 to improve persistence. Results were published in a 2020 New England Journal of Medicine study, and it continues to receive a lot of attention, Holstein says. The phase 1 and 2 study showed proof of concept that CAR-NK therapy is possible and effective. Of the 11 patients, 8 had a response and 7 had a complete remission.

Researchers developed data for NK cells having a similar cancer-killing strategy but different recognition pattern as T cells, leading to “a crazy interest in NK cells,” Miller says. “Until the past decade, people mostly ignored NK cells.”

It’s not just academic labs pursuing them but also cell companies with their own constructs and expansion strategies. The field opened up considerably with the ability to grow billions of cells for off-the-shelf usage in the past 10 years.

Given the multibillion dollar market for anticancer anti- body therapy and the ability of cell therapy companies to genetically manipulate cells with CARs, “I would expect we’re going to see somebody close to clinical approval in the next three to five years,” Miller says.

Natural killer cell therapy is making strides in blood cancer research, but there’s still much more to learn.

A New Line of Defense in Blood Cancer: Natural Killer Cell Therapy

For Danna Wessels of Austin, Texas, it all began with two itchy patches of skin on her abdomen. In 2007, Wessels, now 63, received a diagnosis of stage 1a mycosis fungoides, a form of cutaneous T-cell lymphoma.

At the time, her then-partner and now wife of nine years, Nancy Noble, made one request: “I asked her not to look at the (internet) when she got the diagnosis,” Noble says. “Because I did.”

Their lives changed quickly as Wessels faced constant itchiness that made normalcy a challenge. “Danna couldn’t really go out,” Noble says. “I felt pretty helpless.” Still, Wessels, who also has

type 1 diabetes and Addison’s disease (an autoimmune disease in which the body attacks the adrenal glands and destroys them), was no stranger to managing chronic medical conditions. But Noble knew from her research that things could get worse — and they did.

The disease moved from Wessels’ skin to her blood, and in June 2011, she required a stem cell transplant. To prepare, Wessels had 40 treatments of total skin electron beam therapy, a type of radiation that treats the skin on the entire body, over 10 weeks. After her stem cell transplant, she remained in the hospital for 28 days.

Noble worked from her wife’s hospital room and then took three weeks off from her high-pressure job at a medical device company to care for her. “She was amazing,” Wessels says. “She was my rock. She did it all.”

“All” included learning how to flush the port in her wife’s chest with sterile fluid to keep it clean. It also included nonstop housecleaning to help prevent infection and preparing food to help Wessels build her strength. When she had to return to work, Noble hired outside help to care for her wife during the day and drive her to appointments.

A blood cancer diagnosis a loved one is frightening, Noble says. “I knew there was only so much I could personally do,” she notes. Instead, she focused on the practical details and relied on her faith that things would work out. “It’s one of those experiences where I say, ‘How did we do that?’” Noble says. “I just remember doing what we had to do.”

Noble knew taking care of herself was critical. “I lost about 30 pounds in preparation for Danna’s transplant because the last thing you need is to get sick yourself,” she says, adding that as the provider of the family’s insurance, she worried about job security. “I told management, ‘This is what’s going on, and it’s a big deal.’ Fortunately, they were sympathetic.”

Wessels says Noble took on another important caregiving role: keeper of information. She spoke with doctors and managed details so Wessels didn’t have to. But for some caregivers, managing those details and participating in the decision-making process can feel overwhelming.

Having a good understanding of disease prognosis can prove critical. Yet sometimes caregivers may not be clear on what they’re being told or may have trouble accepting it. A study presented at the 2021 annual meeting of the American Society of Clinical Oncology found that some caregivers don’t acknowledge that their loved one is terminally ill.

Study author Dr. Elizabeth O’Donnell, director of lifestyle medicine and a medical oncologist in the Multiple Myeloma Disease Center at Massachusetts General Cancer Center in Boston, and her colleagues studied 127 caregivers of patients with multiple myeloma in various treatment stages. They found that although more than 80% of caregivers understood the oncologist’s message that multiple myeloma is an incurable cancer, only 53% said their loved one was incurable.

Although physicians do a good job of telling patients and caregivers about prognoses, caregivers often leave “space for hope,” O’Donnell says. Still, understanding prognosis plays an important role in how caregivers cope. In O’Donnell’s study, more than 88% said it was extremely helpful for coping.

“Within our blood cancer population, particularly with multiple myeloma, where you have an incurable but long-term illness, levels of stress and distress can be quite high for most patient caregivers,” she says, adding that that’s why having support is critical for caregivers.

Sarah Miretti Cassidy, director of external affairs for the Chester, New Jersey-based Cancer Hope Network, knows exactly how important support is. The organization trains cancer survivors and caregivers as support volunteers and matches them with clients currently undergoing treatment or caring for a loved one with the disease. Cassidy, herself, was matched with a caregiver volunteer when she was caring for her mother-in-law.

“Connecting with a volunteer helps you know that you’re not alone,” she says. “That’s probably the biggest benefit that Cancer Hope Network offers to caregivers. It may be the first time you’re caring for a loved one, but you’re not the first person who is caring for a loved one.”

Her volunteer helped with practical information such as what to expect when chemotherapy started and a helpful method for moving her mother-in-law without hurting her, Cassidy says.

“Volunteers don’t tell you what you should do,” she says. “They share their experience and offer suggestions. They say, ‘Here’s what worked.’”

Patricia Hlafter of Princeton, New Jersey, volunteers with the organization to help support other caregivers. She cared for her husband, who has been treated for what she calls a “very treatable” hairy cell leukemia. “He did pretty well,” Hlafter says, noting that he had a busy job at the time, so in her role as a caregiver, she had to make sure he ate and took care of himself.

But Hlafter also cared for her mother, who had stage 4 non-Hodgkin lymphoma and died in 2000.

That experience was very different from caring for her husband, she says, adding that she shared caregiving responsibilities with her two sisters.

Hlafter scaled back her work so she could drive her mother to chemotherapy appointments, and the two would chat during her treatments. “One of the benefits was the opportunity to have all that time with her,” she says.

When cancer ultimately returned, Hlafter’s mother decided to forgo a third round of chemotherapy. “That made me sad,” she says. “But I knew there was no choice except to respect her decision.”

Now, Hlafter helps caregivers strategize about how to care for their loved one and themselves. “I think that when someone is a caregiver for the first time, you don’t know what the rules are,” she says. “You have to know that you will make mistakes, and you have to follow your instincts.”

Listening is critical, Hlafter says. She encourages caregivers to talk with their loved one about how they’re feeling. When caregivers pay attention to those everyday conversations, they can learn a lot, she says. “Be alert for the clues your patient gives you,” Hlafter adds. “It helps you to help them.”

It’s also important for caregivers to know as much as possible about the patient’s illness. “The more you know, the more you’ll understand some of the things that might happen during the course of treatment,” she emphasizes. “It helps you know what’s normal for someone who is undergoing cancer treatment and what is alarming and needs to be brought to the attention of the doctor immediately.”

Getting needed information can be challenging for some caregivers, according to Carma Bylund, a professor in the department of health outcomes and biomedical informatics in the College of Medicine at the University of Florida in Gainesville. Bylund and her colleague Carla Fisher, have partnered with the Leukemia & Lymphoma Society to study caregivers of people with blood cancer. Their most recent study, which was published in the May 2021 issue of Translational Behavioral Medicine, examined the effects of COVID-19 on adult caregivers of parents with blood cancer. But some of the themes that emerged are applicable to all caregivers — particularly those around communication, Bylund says.

“We’re seeing more attention being paid to what’s called the triad in the clinical encounter and some of the challenges that come with that,” she says. “You have a caregiver, a patient and a clinician.”

Older patients may have grown up with a paternalistic model, where whatever the doctor says is what must be done, Bylund adds.

Bylund and her colleagues developed models to help caregivers communicate more effectively with doctors. One, called PACES, encourages caregivers and patients to present information, ask questions, check understanding, express concerns and state preferences. Caregivers may need to use some additional communication skills — for example, introducing themselves to the doctor, asking permission from the patient to share information and checking with their patient to make sure what they’re saying is accurate. These conversations help build trust between caregivers and their loved ones and between doctors and caregivers.

Managing clinical conversations and constantly sharing information about a loved one’s condition with friends and family can take a toll on caregivers. Also exhausting: feeling as though they never get a break. Yet many caregivers struggle with the balance of finding the resources they need to make sure their loved one is cared for and feeling guilty when they need a pause.

“Taking care of yourself is one of the most important things that should be on every caregiver’s list, as hard and impossible as it may seem,” Hlafter says, “even if it’s just arranging for someone to have a cup of tea with your loved one while you run out to do something for yourself.”

Cassidy agrees, adding that in addition to offering peer support and mentorship, organizations such as Cancer Hope Network can connect caregivers with other resources to ward off burnout. Some of these resources can help with finding respite care or financial assistance. “Financial toxicity is a massive challenge people face,” she says. “All of a sudden you’ve got these additional burdens at home while you’re trying to keep the job that may be providing the insurance that’s getting your loved one treatment.”

Cassidy encourages caregivers to talk with their treatment center’s navigator or social worker. “They know a lot of resources available in your community,” she says. “It’s a great place to start.”

Talking with others who’ve been in the caregiving role can provide reassurance that feeling overwhelmed, exhausted and afraid is normal. Another critical task in avoiding burnout? Try to find personal meaning in the caregiver role.

“Caregiving is one of life’s great honors,” Cassidy says. “You’re fighting alongside somebody you love. It’s also frustrating. Those two feelings aren’t mutually exclusive.”

Caregivers of patients with cancer may face financial toxicity and stress — with little time to take care of themselves.

Hematology Special Issue (October) 2021 | CURE