Andy Polhamus

Roy Bragadeste received a diagnosis of diffuse large B-cell lymphoma (DLBCL) in April 2019.

He wasn’t expecting a fall during an ice storm to lead to a cancer diagnosis. But that’s what happened to Roy Bragadeste, now 55, an engineer at Microsoft.

Bragadeste, who immigrated from Portugal when he was 8 years old and now lives in Washington, went to an urgent care clinic and learned that he had broken three ribs. As a lifelong athlete, he says he “beat (his) body up pretty good” and was used to aches and pains. But this pain in his side and back was different.

“Three months later, the pain never subsided,” he says. “If anything, it kind of got worse.”

He went back to the clinic, where a doctor recommended that he get a CT scan, though Bragadeste couldn’t imagine why. Doctors told Bragadeste he had a mass on his urethra, which was impeding his kidney function and causing his kidney to swell.

He was diagnosed with diffuse large B-cell lymphoma, or DLBCL, in late April 2019. In May, he started chemotherapy.

Bragadeste experienced some unpleasant reactions to the chemotherapy, including serious fatigue.

“But I got through it,” he continues. “At the end, all of (the lymphoma) was knocked out, except one very small spot in the center of my body. So, we watched it for a bit.

“Unfortunately, it didn’t work,” Bragadeste says.

His cancer came back early in 2020. Bragadeste then received a painful bone marrow transplant in the hope that this second treatment would destroy the lymphoma.

After four or five months, he began to feel as though he’d recovered from the transplant, but scans showed that his cancer hadn’t responded.

On Feb. 2, 2021, his birthday, Bragadeste started CAR-T cell therapy, a technique that engineers the body’s own white blood cells to attack cancer.

Three months after that, his scans looked better, but there were still spots in his body that might indicate the presence of lymphoma.

A lung biopsy confirmed that he still had cancer.

At that point, Bragadeste says, he was ready to try anything. When the opportunity came to participate in a trial of a new drug, Bragadeste saw it as a chance not only to survive, but to help other people living with DLBCL.

He reflected on the many people who had participated in clinical trials that ultimately led to new treatments.

“Those people made sacrifices,” he said. “People sacrificed their lives, maybe because (researchers) put a little too much of this, or not enough of that. At that point, I said, ‘This is the time to give back.’ ”

Bragadeste entered a study of the immunotherapy drug Columvi (glofitamab-gxbm).

Eighteen months after participating in that clinical trial, Bragadeste is cancer-free.

For about two decades, a combination of chemotherapies known as R-CHOP — which consists of the drugs cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisone along with the biological drug Rituxan (rituximab), an antibody that binds to a protein called CD20 expressed on lymphoid cells — was the standard of care for DLBCL.

Researchers spent years trying variations to better suit patients with limited success, but in the past few years, new methods have come to offer better, more effective options for people living with DLBCL.

“I would say the history of trying to improve on R-CHOP has been quite checkered,” says Dr. Jonathan W. Friedberg, director of the Wilmot Cancer Institute in Rochester, New York. “Until very recently, there has not been a positive phase 3 study that has overcome R-CHOP.”

Dr. Manali Kamdar, a clinical researcher in the field of blood cancers at the University of Colorado Anschutz Medical Campus in Aurora, describes the years 2022 and 2023 as “pivotal in terms of having more medications approved for patients with large-cell lymphoma.

“With R-CHOP, about 40% to 60% of patients will be cured,” Kamdar says. “However, the remainder will either initially respond to these treatments and relapse later or will not respond at all. ... At this point in time, just over the last several months, our practice in the clinic has changed. We no longer use R-CHOP for patients with high-risk, advanced-stage DLBCL.”

Minister Edward L. Morgan, associate pastor of Kennerly Temple Church of God in Christ in St. Louis, was undergoing treatment for multiple myeloma when, in early 2021, he received a diagnosis of stage 4 DLBCL. A cancerous lymph node was obstructing his biliary tract, causing jaundice. Other disease characteristics made his case particularly high risk.

“I knew it was a very deadly disease,” he says from his home in Jennings, on the outskirts of the city. “I was concerned as to how my family would survive if I wasn’t around. Being a minister, I just prayed and asked God to give me the strength to go through this.”

Morgan, who has been preaching for more than 50 years, recalled the well- known Bible verse in the 23rd Psalm: “Yea, though I walk through the valley of the shadow of death, I will fear no evil, for thou art with me.”

He placed his trust in his faith and in his oncologist, Dr. Mark Fesler at St. Luke’s Hospital in Chesterfield, Missouri, who had recently read and heard lectures about a new treatment option, an antibody-drug conjugate called Polivy (polatuzumab vedotin-piiq).

Morgan and his doctor connected from the moment they met, and Morgan credits Fesler not only with his survival, but with having a real emotional investment in caring for his patients.


Treatment with Polivy and R-CHP (the same as R-CHOP but without vincristine) began in February. By August, treatment was over, and one year later, Morgan was looking forward to his 81st birthday, his body clear of lymphoma.

In April, the Food and Drug Administration (FDA) approved a regimen combining the antibody-drug conjugate Polivy and R-CHP for patients with newly diagnosed, higher-risk DLBCL.

As an antibody-drug conjugate, Polivy works by attaching to proteins on lymphoma cells called antigens.

When Polivy attaches to antigens, it allows the chemotherapy drug bound to the antibody to enter and to attack cancerous B cells more effectively.

“The antibody is a vehicle that carries chemotherapy drugs on it. The antibody allows the poison (chemotherapy) to be targeted directly to a cancer cell,” says Friedberg, who co-authored the POLARIX study upon which the FDA based its approval of Polivy in this setting. “And at least theoretically, the normal cells aren’t seeing the poison, because the antibody is only recognizing the antigens on the cancer cell.”

In the POLARIX trial, which weighed the effectiveness of the Polivy and R-CHP combination against R-CHOP, Friedberg and colleagues concluded that the Polivy treatment reduced patients’ risk for disease progression or death by 27% compared with the standard of care.

Furthermore, a slightly larger proportion of patients who were treated with Polivy and R-CHP achieved a benchmark called two-year event-free survival, meaning they did not experience disease progression or complications during that time frame.

Researchers reported that patients assigned to Polivy did not experience side effects at greater rates than those assigned to R-CHOP; people in the Polivy-combination group had a side effect rate of 57.7%, compared with 57.5% in the R-CHOP group. Similar proportions of people in both treatment groups experienced complete responses, meaning the number of patients whose disease completely disappeared was similar. Also, the overall survival, or total amount of total time that patients lived, was not significantly different.

However, patients taking Polivy spent more time living disease-free.

Friedberg explains this statistic by pointing out that the Polivy regimen lets people live longer without cancer, and that DLBCL is considered a curable cancer.

“So, when you improve progression- free survival in DLBCL at two years, we believe that’s an extremely strong surrogate for cure,” he says.

However, he points out that there are salvageability options for people who relapse. With these additional, more aggressive treatments, Friedberg says, “there’s still a chance at curing the disease.”

Second-line treatment options for relapsed disease (when the disease responds only partially or not at all to first-line therapies) include stem cell transplantation and CAR-T cell therapy.

Two new immunotherapies have been approved this year for use in situations where the transplantation or CAR-T therapy fails.

New Treatments for Relapsed or Refractory Disease 

Epkinly (epcoritamab-bysp) and Columvi recently became available for patients whose disease has relapsed or not responded to two or more prior treatments.

In May, the FDA approved Epkinly for adults with relapsed or refractory DLBCL. One month later, the FDA approved Columvi for relapsed or refractory DLBCL in the third line and beyond.

Both drugs belong to a type of immunotherapy called bispecific antibodies, meaning they help activate the immune system by bonding to two different targets on the lymphoma cell at once, guiding white blood cells to lymphoma cells and helping them to attack the cancer.

Epkinly works by both bonding to the CD20 antigen, a common marker on lymphoma cells, and engaging CD3 T cells, which are a type of white blood cell that kill the cancerous lymphoma cells.

“The idea behind a bispecific T-cell engager is that it’s an antibody. This antibody has two prongs,” Kamdar says. “One prong sits on the CD20 cell, the B cell. And the other prong sits on the T cell, or the fighter cell, and redirects the fighter cell to kill the lymphoma cell.”

The FDA approved Epkinly, delivered through a subcutaneous injection, based on results from the EPCORE NHL-1 trial, an open-label, single-arm trial of 148 patients with relapsed or refractory DLBCL.

The main purpose of the study was to evaluate how many people experienced a partial or complete response to Epkinly.

Researchers reported an overall response rate (the percentage of patients with a partial or complete response to treatment) of 61%, while 38% of patients had a complete response. Researchers reported that patients responded to Epkinly for a median of 15.8 months.

“It has shown exceptional responses based on the two pivotal studies that led to FDA approval,” says Kamdar.

The June approval of Columvi, which is also a CD20-directed CD3 T-cell engager, was based on the NP30179 trial.

In that study, which was also an open-label, single-arm trial, 132 patients with lymphoma received the medication. Like the EPCORE NHL-1 trial, the participants in this study previously had at least two failed lines of therapy.

The objective response rate (the portion of patients who had a partial or complete response to treatment) in NP30179 was 56%, researchers reported, whereas 43% of patients experienced complete responses.

Researchers reported that patients responded to the drug for a median of 18.4 months, and 68.5% responded to Columvi for 9 months.

While Epkinly can be adminis- tered for indefinite periods of time, Columvi is currently given to patients for a fixed duration of 8.5 months. And whereas Epkinly is administered by injection, Columvi is delivered by IV drip.

All three new treatments come with side effects, many of which are mild, but some of which are serious.

Although side effects occurred at similar rates in both groups of the POLARIX trial, the Polivy treatment commonly comes with fatigue, peripheral neuropathy (nerve damage that occurs away from the spine or brain), constipation, diarrhea, nausea, mouth sores and hair loss.

Its more serious side effects are neutropenia and lymphopenia (low counts of two types of white blood cells).

Nearly 10% of people who took Polivy in the POLARIX trial had to reduce their dosage because of side effects, compared with 13% of those who received R-CHOP. Similar proportions of people in both groups of the study died from side effects: 3% of the Polivy group and 2.3% of the R-CHOP group.

Morgan experienced some mild gastrointestinal side effects, and neuropathy in his feet and hands as well as fatigue, while taking Polivy.

“I would be kind of weak, and I would just go home and go to bed,” he says.

He opted to receive the chemotherapy portion of his therapy through his arm, rather than through a port in the neck or chest, and developed a necrotic ulcer that required treatment.

Still, Morgan was able to complete treatment without needing to be hospitalized. He continued to preach and teach Sunday school throughout his therapy.

Columvi and Epkinly have side effects similar to those of other immunotherapies.

The most notable of these is cytokine release syndrome, a potentially deadly but manageable condition that can occur when the body’s immune system responds aggressively to infection, or, in this case, cancer cells.

Other common side effects for both drugs include musculoskeletal pain, fatigue and reactions at the injection site.

Epkinly is also associated with fever, abdominal pain, diarrhea and nausea.

The drug comes with a special warning for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, a condition that can cause seizures, aphasia (the inability to speak or process language) and, in severe cases, coma or death.

Experts say, however, that these side effects are usually manageable. It’s also worth remembering that side effects vary from person to person.

Bragadeste says he suffered significantly from CAR-T cell therapy, his second line of treatment, mostly from losing his hair, which he describes as both physically painful and disheartening. He was also warned about the side effects that might come from Columvi.

“I went (into the Columvi study) fully eyes wide open, knowing that one of the things I might prove is, ‘Oh, there’s this other side effect,’ ” he recalls.

However, he says he experienced no side effects from taking Columvi.

“It was a very painless, uneventful process,” he says.

Bragadeste also continued to work throughout treatment — not as a show of strength, but as a way of coping. He fully supports people who decide to take time off from work to focus on treatment.

“For me, it was what gave me my only sense of normalcy,” Bragadeste explains. “It wasn’t for Microsoft. It was for me.”

Unanswered Questions and the Future of Care 

Researchers are learning more about DLBCL all the time. Lymphomas comprise a variety of cancers, and Friedberg notes that as research progresses, the category of DLBCL is being broken down into more subtypes.

Currently, although the Polivy regimen is the new standard for newly diagnosed disease or after relapse following initial therapy, experts do not know which patients with relapsed or refractory disease are better suited to Epkinly or Columvi.

Dr. Yasmin H. Karimi, a co-author of the EPCORE NHL-1 trial that led to the approval of Epkinly, says that while a variety of factors can play into a patient’s initial prognosis, there is not enough data available right now to tell whether Epkinly or Columvi is preferable based on a single person’s disease characteristics.

“We do not know yet how to select therapies based on risk factors at the time of progression,” she explains. “That’s why we talk about other factors, like side effect profile, patient preferences and administration.

“The biggest limitation is not being able to predict who’s going to respond to which treatment.”

Karimi and her colleagues are still monitoring people who took part in the EPCORE NHL-1 trial.

In addition, future research of both Epkinly and Columvi will likely focus on new ways to use the drugs.

“On the horizon, it’s about getting these excellent agents either with better combinations, or to test them in an earlier-line setting,” Kamdar says. “For example, we do have a study with a CD20 (bispecific antibody) and (Polivy). And impressively, they have had great responses.”

He expressed great optimism for the future.

“I do believe that things are looking really good for patients with DLBCL,” says Kamdar. “But clearly, we need to continue to strive to do even better.”

Editor’s note: In the print publication, the percentage of patients who died from Polivy and R-CHOP, respectively, were incorrect. The statistics were corrected online on Sept. 13, 2023.

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Articles

Recent advancements in treatment options for patients with diffuse large B-cell lymphoma have been practice-changing.

New Horizons for Diffuse Large B-Cell Lymphoma

David Alexander was a passionate runner. He belonged to a running club, and regularly ran marathons. So when he found himself having trouble keeping up with his running buddies, he was concerned.

“I was marathon trained,” recalls Alexander, a lawyer for the Environmental Protection Agency in Washington, D.C., and a native of Queens, New York. “I was in good shape. I knew what I could do, but then I couldn’t do it.”

In addition to having trouble running, Alexander found himself experiencing “horrible brain fog.” He once caught himself looking for his keys as he got ready for work in the morning, searching all over the house before he realized they were in his hand. Other times he’d come home and find that he’d put the shredded wheat cereal in the refrigerator and the milk in the cupboard. Once, in trying to find his way through an unfamiliar area of New York, he realized he couldn’t read a map.

“In retrospect, I knew something was wrong with me,” says Alexander. So he went to see his doctor, who seemed unconcerned. Alexander recalls his physician asking: “What do you want me to diagnose you with? Not being able to run a marathon anymore?”

“He later apologized,” Alexander adds.

Within two days of taking a JAK inhibitor, David Alexander felt 20 years younger.

The answer came in 2005, when Alexander was participating in a medical trial run by the National Institutes of Health as a healthy volunteer. He was part of the study’s control group. Investigators left him a message asking him to call for the results of a blood test, but he put it off. When he got in touch, he learned that his hematocrit levels were “sky-high,” meaning that red blood cells constituted too large a proportion of his blood. He was told to get to a doctor soon. On his way out the door, a receptionist wished him good luck.

“I knew it was not the kind of ‘good luck’ I wanted to hear,” says Alexander. “But I was damn lucky.” 

Alexander followed up on the advice and was diagnosed with polycythemia vera (PV), a rare blood cancer characterized by an excess of red blood cells that belongs to a group of diseases called myeloproliferative neoplasms, or MPNs.

In patients with MPNs, the bone marrow produces inappropriate amounts of different types of blood cells. Other examples of MPNs include essential thrombocythemia (ET), in which the blood contains too many platelets, and primary myelofibrosis (MF), in which a person’s bone marrow develops scar tissue, causing low red blood cell and platelet counts. 

Symptoms of MPNs are varied and can include anemia, splenomegaly (an enlargement of the spleen that may cause abdominal pain, weight loss and loss of appetite), fever, night sweats, fatigue, cognitive difficulties and itchy skin. Patients with MPNs often experience a decline in their quality of life, and as many as half of myelofibrosis patients can become dependent on blood transfusions within a year of diagnosis. Worse than that is the possibility that an MPN can progress to life-threatening acute leukemia.

Twenty years ago, few registered treatment options existed for patients with MPNs. There were medications to help with symptoms, but nothing to address the diseases themselves. In recent years, however, a fairly new class of drugs called Janus kinase (JAK) inhibitors has offered relief, though not a cure, to the hundreds of thousands of people estimated to be living with MPNs, according to the MPN Research Foundation.

Although the famous hematologist William Dameshek posited the idea that MF, ET and PV were all related in 1951, it wasn’t until 2005 that several groups of researchers independently identified a mutation in the JAK2 gene as one genetic driver of these diseases. In the several years that followed, researchers also identified the roles of the MPL and CALR genes.

The first JAK inhibitor, Jakafi (ruxolitinib), was approved by the Food and Drug Administration (FDA) for treating MF in 2011.

“It really has not been around that long, when you consider other drugs that we’ve had forever,” adds Dr. Aaron Gerds, an assistant professor of medicine and deputy director for clinical research at Cleveland Clinic Taussig Cancer Institute in Ohio, who has worked as a principal investigator on several JAK inhibitor clinical trials. For example, compared with certain chemotherapy options, JAK inhibitors are practically brand new.

“The unmet need that JAK inhibitors fill is the ability to have an agent that significantly improves quality of life for the majority of patients, particularly in regard to constitutional symptoms and bothersome spleen-related symptoms,”
says Dr. Olatoyosi Odenike, a professor of medicine and the director of the leukemia program at University of Chicago Medicine who has also worked on studies of JAK inhibitors. “There is also a modest survival benefit,” she adds.

Like all cancers, MPNs are rooted in a problem with the mechanisms that control cell growth.

“The JAK2 protein is central to a number of processes in the body, but particularly blood cell production,” says Odenike. She adds that not all diseases that can be described as MPNs are suitable for treatment with JAK inhibitors. This class of drugs works specifically on what are called the “classical” MPNs: PV, MF and ET.

JAK inhibitors are oral drugs that block the JAK-STAT pathway, a signaling system in the body’s cells that regulates how the bone marrow produces blood cells.

“Patients with myeloproliferative neoplasms all have one unified theme of hyperactivity of the JAK-STAT signaling pathway that seems to be occurring in their bone marrow cells, and this is irrespective of the driver mutation present in these cells,” explains Dr. John Mascarenhas, a professor of medicine at Icahn School of Medicine at Mount Sinai in New York who has also worked on multiple JAK inhibitor trials. “We realized that this common theme of hyperactivity of the JAK-STAT signaling pathway could be interrupted by these small-molecule inhibitors, whereas previously, the treatments we gave were really nonspecific chemotherapies like hydroxyurea. This was a targeted therapy that depresses the activity of the signaling pathway, and in doing so, it quiets down the proliferation of cells that leads to problems in the disease.”

These corrections in cellular activity reduce many of the signs and symptoms associated with MPNs, such as an enlarged spleen and its related problems, making JAK inhibitors an ideal example of targeted cancer therapy, notes Mascarenhas. JAK inhibitors are also used in other hematological, rheumatologic and dermatological diseases, as well as in graft-versus-host disease, which occurs as a complication following transplants.

One of the most striking effects of JAK inhibitors is how quickly they can reduce a patient’s symptom burden.

“Folks who practiced before 2011 will often talk about patients with huge spleens, (who were) emaciated with loss of weight, fevers and night sweats, and incredibly short lifespans,” says Gerds. “And you would put them on these JAK inhibitors, and overnight, almost, it seemed like these people would have miraculous turnarounds.”

Not only were patients living better lives with major reductions in symptoms, but they were also living longer.

Alexander, who is president of the MPN Education Foundation, managed his PV without medication for 12 years. To lower his hematocrit counts, he underwent regular phlebotomy, or blood drawing. He began taking Jakafi after he developed pruritus, a severe, painful itching of the skin and a common symptom in MPNs.

“They call it itching,” he says. “I’m here to tell you, when it gets bad, it ain’t itching. It was life-stopping.”

The pain, he continues, was comparable to the worst sunburn imaginable topped off with being bitten by horseflies.

After Alexander began Jakafi treatment, his symptoms reduced in a matter of days. It particularly helped with the pruritus, but he says it did not help with episodes of transient global amnesia, a sudden, passing memory loss.

“Within a day or two, and I am not exaggerating, of taking the first pills, I just felt 20 years younger,“ he says. “My legs didn’t ache when I bounded up the steps at work. Within two days, according to my stopwatch, I could get up the steps faster.”

In 2014, three years after approving Jakafi for the treatment of patients with MF, the FDA approved the drug for the treatment of PV, making it the first drug specifically approved for that disease. The agency based its initial approval of Jakafi on two phase 3 clinical trials in which Jakafi outperformed both placebo and the best previously available therapy in reducing patients’ spleen sizes and overall symptom burdens. The 2014 expansion to use the drug for PV came on the heels of a study demonstrating that Jakafi reduced the need for phlebotomy among patients with PV and significantly reduced splenomegaly.

In 2019, a second JAK inhibitor, Inrebic (fedratinib), received FDA approval, also for MF related to MPNs, after study results showed that it significantly reduced spleen volume. Further, the clinical trial that served as the basis for Inrebic’s approval found that the drug reduced symptom burdens by more than half in about 40% of patients. Inrebic, Mascarenhas notes, can even be useful for patients whose treatment with Jakafi fails.

Joseph Cusati benefited from the approved JAK inhibitor Vonjo while participating in a clinical trial.

More recently, the FDA has approved Vonjo (pacritinib) for treating patients with myelofibrosis. And another JAK inhibitor, momelotinib, also shows promise for patients with MPNs and is the subject of a phase 3 trial.

One of Mascarenhas’ patients, Joseph Cusati, of Long Island, New York, received a diagnosis of MF in October 2019 and opted to participate in a trial of Vonjo rather than undergo a bone marrow transplant.

When he first began treatment, Cusati was told his red blood cell count was less than half of what it should be.

“I’d had nothing — absolutely nothing,” Cusati says when asked about his symptoms at the time of diagnosis. “I got a call from my primary physician who told me I had an issue with my blood. I went, and then they told me to go to the hospital. And I’ve been on this program ever since.”

He had heard of JAK inhibitors in passing as part of his job at HealthCare Partners. And when he looked up his diagnosis on the internet, he learned there was no cure.

“That was in the back of my mind, that I needed to make a decision one way or the other,” he says.

Although Cusati briefly considered a bone marrow transplant, he turned it down, in part because he wanted to avoid graft-versus-host disease.

“When you get a transplant, it’s not you that’s the problem,” he says. “It’s the bone marrow. Does it accept your body?”

Cusati received regular transfusions, usually about every week or two, early on in his treatment. But as the months on the study drug went by, he found he no longer needed transfusions.

“Whatever started to work is working,” he says. “It’s like a miracle. My energy level is astronomical. So, something is working.”

Although Cusati needed a wheelchair to move around the hospital during his early visits to see Mascarenhas at Mount Sinai, at his most recent visit, Cusati was able to walk everywhere he went. He can now spend two hours on an exercise bike at the gym.

Gerds notes that whereas many cancer drugs are approved based upon their effects on tumor size, the approval of JAK inhibitors for MPNs is based on reductions in symptoms and improvements in patients’ quality of life. He expects further innovations in the field of MPN treatment to include combining the drugs with other medicines.

JAK inhibitors also have their downsides. One major drawback is that because the drugs lower counts of certain blood cells, they can cause these counts to drop too low.

“If we are blocking JAK1 and JAK2 too much, we can cause worsening of anemia and thrombocytopenia: low red blood cells and low platelets,” says Gerds. “In someone with PV, that’s a wanted side effect. We’d want to control the red blood cell count. Same with ET: We’d want to control that platelet count. But for someone who’s already starting out with anemia and thrombocytopenia, it can certainly make that worse.”

For this reason, experts and patient advocates say that among the current options available, no JAK inhibitor is necessarily superior to another. Jakafi or Inrebic may not be safe for use in patients who have low platelet counts because they could reduce those low counts even further, so pacritinib will offer another option for those with thrombocytopenia. Momelotinib, says Mascarenhas, may be particularly useful for patients with transfusion-dependent anemia.

“It all depends,” says Alexander. “What is an undesired effect in one context (lowering counts) can be treatment in another context (PV)."

In Alexander’s case, Jakafi’s effect on his immune system meant he had to stop using the drug after two years and four months. He developed a dry cough and found himself struggling to bicycle up a small hill that was part of his usual morning commute. Eventually, doctors identified spots on his lungs and determined that he had an infection from Cryptococcus neoformans, a common fungus that occurs virtually everywhere in the world, which can be fatal in people who are immunocompromised.

To beat the infection and avoid similar ones in the future, Alexander had to stop taking Jakafi, which he describes as “very sad.” Treatment with the drug had been a positive experience, largely controlling his symptoms and shrinking his spleen.

“Would I take (Jakafi) again if I could? Sure enough,” says Alexander. “Would I suggest a fellow patient take it, based on my experience? Of course I would, with qualifications.”

Those qualifications, he adds, include being on the lookout for the risk of severe infections.

Beyond side effects, doctors say, one of the biggest caveats is that JAK inhibitors do not cause remission from MPNs.

“For all the good they do, they don’t, unfortunately, cure patients,” says Mascarenhas. “So the disease can continue and progress, despite (the patient) even enjoying some benefits of the drug.”

Odenike points out that the classical MPNs tend to progress to acute myeloid leukemia, which is much more aggressive. “(Researchers) shared the enthusiasm that (JAK inhibitors) would be tantamount to attacking these diseases at their root cause, which would lead to transformational effects,” she adds.

She and other researchers hoped that the medications could stop fibrosis, or scarring of the bone marrow, and perhaps even make the JAK2 mutation undetectable, possibly halting the progression to leukemia. None of this, she continues, has turned out to be true so far.

“It seems now, after 10 years of experience with JAK inhibi- tors, that this is not a realistic goal with this class of drugs in their current form,” Odenike explains.

In addition, although JAK inhibitors demonstrate some improvement in survival for patients who take them, Odenike has been somewhat disappointed by the results.

Alexander encourages anyone with PV or another MPN to consult with an expert because “your hometown internist isn’t likely” to have much experience with these diseases.

“For most people, you’re going to be managing a chronic disease and its symptoms, which can be annoying or more than annoying for a long time,” he says.

Alexander also emphasizes that although receiving a diagnosis of PV is an initiation into a club nobody wants to join, it is possible to live a long and fulfilling life with the disease.

“You’re going to have years and years in front of you,” says Alexander, who remains an active runner and cyclist. “We’ve all gone through the adjustment of having a disease (that) is indeed likely to be life-shortening. The way I think of it, I don’t think (about) my prognosis. According to what I read in the literature, at 17 years, I think I’m at my median prognostic lifespan. Which is ridiculous. I’m not done. I’m not close to done.“

Alexander adds, “Be glad you’re diagnosed in this modern era. Better things are here, and better things are coming for you.”

Gerds agrees. “The combinations that are forthcoming are really exciting,” he says.

A nonprofit group, the MPN Research Foundation, is dedicated to ongoing efforts to treat, and perhaps someday cure, these diseases.

In the MANIFEST trial, pairing Jakafi with another drug appears to significantly improve response rates and the durability of benefit. Another combination is showing responses even with relapsed or refractory disease, and still more combinations attack disease from multiple pathways at once.

“We’re expecting readouts from at least four or five randomized trials in the next year and a half,” Gerds says. “It’s an exciting time.”

Treatments with JAK inhibitors are continuing to make their way into the MPN space, providing symptom relief, but not yet a cure.

One Step Closer to an MPN Cure

Immunotherapy is improving the outcomes of patients with early-state non-small cell lung cacer.

For years, options for people living with non-small cell lung cancer (NSCLC) were limited, says Dr. Jamie Chaft, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.

But as cancer therapies advance, treatments that were once out of reach for many patients with NSCLC have become available. A therapy that began its history as a last resort has slowly made its way into frontline settings, and researchers continue to discover novel treatments.

And each new discovery saves lives. One example of progress in lung cancer is the Food and Drug Administration’s (FDA’s) January approval of 

Keytruda (pembrolizumab) for patients with stage 1B, 2 or 3A NSCLC

 following resection and platinum-based chemotherapy. Keytruda is an immunotherapy drug that has been approved for a variety of cancers, including advanced (metastatic) lung cancer, but was only recently approved as a post-surgery, or adjuvant, therapy for patients with early-stage NSCLC who have also been treated with chemotherapy.

“This is clearly a very busy space,” Chaft says of NSCLC research. “Postoperative and preoperative spaces were stagnant for decades. And then, in the last 3 years, we’ve now seen some advances, (and) we can bring therapies proven to be beneficial for patients with metastatic cancer into the earlier stage.”

Mechanism of Action and Indications for Keytruda

Like all immunotherapies, Keytruda harnesses the power of the body’s natural immunity to kill cancer. Keytruda is a PD-1 inhibitor, meaning it blocks the production of a cell protein called PD-L1, which is involved in the proliferation of tumor cells and evasion of natural tumor immunity. By blocking PD-1, Keytruda allows the body’s immune system to attack tumors.

“(Keytruda) goes back about eight years at this point in terms of lung cancer,” explains Dr. Dwight H. Owen, a medical oncologist at The Ohio State University Comprehensive Cancer Center-The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus. “At least for (NSCLC), the first approvals were only for stage 4 or metastatic disease — and only after previous treatment with chemotherapy.”

Although initial studies earned the drug approvals for use in patients with tumors expressing high levels of PD-L1, further research found that the drug could benefit patients with NSCLC regardless of their PD-L1 status.
This makes Keytruda the second immunotherapy to be approved as a post-surgical treatment in patients with earlier-stage NSCLC. The first, 

Tecentriq (atezolizumab), was approved in 2021

, but that indication only applied to patients with PD-1 expression. One striking thing about Keytruda is that although it is a PD-L1 inhibitor, patients can receive — and benefit — from Keytruda regardless of their PD-L1 expression levels.

“The way that immunotherapy works is, it tries to reorient our own immune system to attack the cancer cells,” Owen explains. “In theory, our immune system should recognize cancer cells as bad actors. They’re not behaving the way that they’re supposed to; they’re growing when they’re not supposed to. So they should be recognized by the immune system, which should attack and
kill them. Some cancers develop a camouflage to protect cancer cells from the immune system. And what these immune drugs do is essentially remove the camouflage, allowing the immune system to recognize, engage, destroy and then remember what those cancer cells look like to go on and destroy other cancer cells.”

What makes the use of immunotherapy important in patients with early-stage NSCLC is that early treatment offers the best chance of a cure.

“Over the last few decades, we’ve realized that surgery alone is curative for some patients with early-stage lung cancer but not nearly as many as we hope,” Owen says. “The reason for that is almost certainly because there is still ‘microscopic’ or ‘micrometastatic’ disease left behind.”

This is when the use of adjuvant therapies that get rid of any remaining tumor cells becomes crucial.

“Taking what we know from metastatic disease from patients who get treated with immunotherapy, we know that when immunotherapy works, it works even better than chemotherapy,” Owen says. “And that’s why we’ve been very excited to see immunotherapy come in earlier into the disease to be able to cure more patients.”

The FDA based its approval of Keytruda for use in early-stage NSCLC on findings from the KEYNOTE-091 trial, which included 1,177 patients with completely resected lung cancer with disease stages ranging from stage 1B to 3A. Investigators in the phase 3 study randomly assigned patients to receive either 200 milligrams of Keytruda or placebo by IV once every 3 weeks for as many as 18 cycles. Most patients (86%) also received platinum-based chemotherapy after their surgeries.

Investigators reported that patients assigned to Keytruda had a median disease-free survival that was nearly a year longer than that of patients assigned to placebo: 53.6 months in the Keytruda group compared with 42 months in the placebo group. This means that patients assigned to take Keytruda after surgery and platinum-based chemotherapy were disease free for 11.2 months longer than those who received placebo following surgery and chemotherapy.

Dr. Michael Rotkowitz, a medical oncologist with Jefferson Health in Sewell and Cherry Hill, New Jersey, notes that the drug’s improvement in disease-free survival is particularly important.

“What we know historically is that for stage 2, 3A and even stage 1, the recurrence risks after surgery are over 50%,” Rotkowitz says. “The KEYNOTE-091 trial shows a reduction in recurrence risk — a marked disease-free survival benefit. I think this will be practice changing.”

Although a small minority of patients included in the study did not undergo platinum-based chemotherapy, those who did receive chemotherapy appeared to fare significantly better than those who did not.

Using both chemotherapy and immunotherapy appeared especially effective. In KEYNOTE-091, the median length of disease-free survival for patients who underwent platinum-based chemotherapy and were assigned to Keytruda was reported at 58.7 months compared with 34.9 months among patients who underwent chemotherapy but were assigned to placebo.

There were some limitations in the KEYNOTE-091 study. For one, experts were quick to point out that because it was designed several years ago, it makes use of a cancer staging system that is now out of date. By the current staging system, patients in the KEYNOTE trials would all be considered to have disease in stages 2 to 3.

Additionally, one subgroup of patients expected to benefit most from the therapy did not. “The (Keytruda) data showed improvement of disease-free survival irrespective of PD-L1 expression,” says Chaft. “Though oddly, it showed that patients with tumors that did not highly express PD-L1 did not benefit as much.”

Chaft added that she suspects this data point was a statistical anomaly rather than an indication of the drug’s true therapeutic benefit in this subset of patients.

Patients should be aware that Keytruda does come with side effects, although oncologists consider the drug to generally be well tolerated. Most commonly, patients taking Keytruda by itself have experienced nausea, fatigue, muscle and joint pain, rash, constipation, diarrhea, itching, decreases in appetite, fever, coughing and hypothyroidism, a condition in which the thyroid gland produces lower quantities of thyroid hormone than it should.

“The caveat is that anytime you escalate treatment, you are increasing the risk of side effects,” Owen says.

In the KEYNOTE-091 trial, hypothyroidism reportedly occurred in 22% of patients, whereas hyperthyroidism, or an overactive thyroid gland, occurred in 11%. Furthermore, 7% of patients reportedly experienced more severe organ inflammation including pneumonitis, or inflammation of lung tissue. Two patients in the study died of myocarditis (inflammation of the heart).

n general, Chaft says immunotherapies are very well tolerated but says that doctors considering Keytruda for patients with early-stage NSCLC should do so on a case-by-case basis.

“We certainly don’t want to harm patients by trying to increase their chances of a cure,” she explains. “Many of these patients are cured already, either by the surgery or the chemotherapy. Looking at the patient as a whole, what is their likelihood to benefit from the immunotherapy versus harm?”

Chaft and Owen also point out that people with certain genetic alterations, such as those with EGFR and ALK tumor aberrations, are more likely to benefit from treatments targeting those mutations rather than Keytruda.

“If their tumors are driven by one of these genetic alterations, they’re not likely to gain benefit (from Keytruda) and would be more appropriately directed toward a targeted therapy,” says Chaft.

Another important factor for doctors considering Keytruda in this setting is whether the patients have any autoimmune diseases, Chaft notes. In this situation, she says, Keytruda should be avoided.

Unmet Needs and the Future of NSCLC Treatment

Cancer treatments continue to evolve, particularly in the area of immunotherapy. Rotkowitz pointed out that more and more often, patients receive chemoimmunotherapy before surgical resection, even as adjuvant therapies advance.

Treatment for patients with non-small cell lung cancer has evolved to include immunotherapy after surgery and chemotherapy.

Andy Polhamus

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