What does an 11-year-old boy have in common with some of the country’s exceptional oncology health care professionals? Each one is someone’s hero.

At CURE Media Group’s annual MPN Heroes® event, audience members saw that heroes come in all shapes and sizes, and not all of them are saving lives — some are fighting for their own.

Eight heroes and one Canadian champion were honored for the work that they do for people with a rare group of blood cancers known as myeloproliferative neoplasms, or MPNs: polycythemia vera, essential thrombocythemia and myelofibrosis.

This is one of the memorable events that CURE® hosts throughout the year to put a spotlight on clinicians, researchers, patient advocates and caregivers. Within these pages, you will meet people who turned their passion and, in some cases, pain into purpose. Read how they have helped others through their commitment to either individual patients or the MPN community. 

Also within this special issue, a feature story explores the latest in treatment options for patients with diffuse large B-cell lymphoma, more commonly called DLBCL, the most common type of non-Hodgkin lymphoma. Chemotherapy has been a major player in the treatment of this disease, and combining newer medications, such as Rituxan (ritux- imab), with older drugs has helped patients live longer.

Leading-edge therapies are also working wonders for patients who have relapsed disease or stopped responding to treatment. These include chimeric antigen receptor (CAR)-T cell therapies, which enlist a patient’s own T cells to help fight off their disease. Experimental drugs called bispecific T-cell engagers, or BiTEs, are also making waves. Although the research on BiTEs is still in its early stages, the drugs are generating hope for what’s to come — scientists have seen them lead to responses in patients who didn’t respond to CAR-T cell therapy.

And a hematology expert highlights the most recent Bruton tyrosine kinase inhibitor approved by the Food and Drug Administration to treat patients with chronic lymphocytic leukemia. Dr. Lindsey Roeker compares the drug Calquence (acalabrutinib) with Imbruvica (ibrutinib) and discusses what these medications mean for patients regarding both extending life and affecting its quality.

Articles

From the Chairman

In the 2020 Hematology 1 special edition of CURE magazine, we highlight what it means to be an everyday hero by living with MPN or helping patients with the disease cope with it.

Being an Everyday Hero For Patients With MPN

on the history of acute myeloid leukemia (AML), it is clear that the most crucial step involves getting patients with the disease into complete remission. Clearing the bone marrow of leukemia cells, thus improving remission rates, quickly became the goal of both scientists in research labs and oncologists who are on the front line of treating patients. Induction treatment that yields remission is followed by consolidation to, hopefully, lead to a long-term cure.

Interestingly, the induction medications that decades ago were found to achieve that remission remain relevant and effective. The protocol for the initial treatment for many patients hasn’t changed much. But researchers and other health care professionals recognized that as medicine became more sophisticated — understanding cytogenetics, looking at cells under a microscope and, later, developing molecular techniques &mdash; some patients had a more difficult time achieving remission. Scientists understood that without that remission or relapse after remission it was a bad sign.

At that point, researchers discovered different translocations and mutations involved in this disease state. With next-generation sequencing, scientists can identify a plethora of mutations that are associated with worse remission rates and determine how effective a new treatment might be for a patient. For instance, patients with specific genetic alterations in their leukemia cells may receive the modified induction therapy with standard chemotherapy plus biological agents. Other cases might call for different consolidation approaches.

As knowledge, biology and sequencing techniques expand, new targeted drugs have been developed to achieve this first remission in certain patients with AML. In this special issue

, a feature story breaks down the latest therapies approved for patients with AML over the past two years — eight innovative options in total. Read how this emergence of targeted therapies has helped patients such as Heather Hibbard. At 37, Hibbard noticed some bruising while on vacation; upon her return home, she went to the doctor, who in just over a week confirmed an AML diagnosis.

Genomic testing revealed a FLT3 mutation, which meant she was a candidate for Rydapt (midostaurin), the first targeted therapy for AML approved in 2017. The medication became part of her treatment regimen, in addition to chemotherapy and stem cell transplant. Two years later, she remains cancer free.

Stories like Hibbard’s motivate the men and women working behind the scenes to keep looking for the next cutting-edge medication that will extend the lives of people battling not only blood cancers but all cancers.

The creation of better tools, such as blood and bone marrow tests, allows medical professionals to monitor for recurrence early before patients clinically recur, so they can be treated ahead of the curve.

Editor's Page

Targeted therapies have changed the landscape of cancer care, and now, hope for remission is a possibility for certain patients with acute myeloid leukemia with new approved therapies.
 

Remission Drives Ambition: Experts Look to New Methods in AML Treatment

sent Terry White to his doctor, who discovered a tumor on White’s pelvic bone. After being treated with radiation, White was told that he would likely develop multiple myeloma, a blood cancer that affects the plasma cells.

Later that year, another tumor appeared, and White received a cancer diagnosis. Since then, the resident of Juneau, Alaska, has climbed Mount Kilimanjaro and trekked to Patagonia with the Moving Mountains for Multiple Myeloma program. He is also active in the search for a cure for the disease that affects more than 32,000 men and women each year in the United States.

White served as the keynote speaker during 

, he discussed living with cancer, offered advice to other patients and shared the song that got him through difficult days.

®: You have lived with multiple myeloma for more than 10 years. How has the disease changed your life?

You learn to appreciate the smaller things that you (might otherwise) take for granted ... like waking up every day and knowing you have another day. So far, I’m 100% at getting through bad days. There were times early on after my diagnosis where I was just like “Wow, I can’t imagine doing this forever.”

There are some low points that you go through, and as the years go by, the further you can get it to the back of your mind, the easier it is, (at least) for me. It’s a new normal living with cancer, but it’s still living.

Do you remain on treatment today? If so, do you experience any side effects?

I’m still doing maintenance chemotherapy and am on Revlimid (lenalidomide). I’ve been fortunate that it has kept me in remission and with tolerable side effects. (I’ve had) fatigue, but

you learn to live with it. It’s OK to take a nap — I quickly learned that. Listen to your body. When I first started (treatment), GI (gastrointestinal) side effects were an issue. I was on no rest period, and I spoke with my oncologist and asked what we could do. And so, we tried a rest period after about five years, and it seemed to help.

®’s patient-focused sessions on multiple myeloma. What do you hope other patients took away from your speech? 

Having multiple myeloma is like climbing a mountain every day. The message that I presented was: Just because you have cancer doesn’t mean you have to stop living. There’s a lot of work to be done. I encourage people to get active, go to support groups and help other people. When I find out that someone I know has been diagnosed with cancer, because I’m in the club, it’s very easy for me to pick up the phone and say “Hey, what’s going on?” That’s the thing that I appreciate ... I’m able to do that. People want help. We just don’t know how to do so because we don’t know what’s going through their minds.

Do you try to live by a particular quote or philosophy?

I remember one of the first myeloma patients that I met on a message board. He passed away many years ago. He was great at giving advice to the newly diagnosed. One of the things I remember from him was: “Don’t borrow tomorrow’s troubles today.” I try to live by

There’s also a song by Bob Marley — it’s called “Three Little Birds.” It goes ‘Cause every little thing gonna be all right.” That was my theme song on the many trips I made back and forth from Juneau to Seattle for this test and that test and coming back for results. It seems like all the tests took about a week. Music is my therapy, and I get a lot of peace from it.

People Report

Terry White, who has lived with multiple myeloma for more than a decade, offers reassurance to other patients.
 

Overcoming Multiple Myeloma Takes One Patient to New Heights

Almost three years to the day since doctors told Cheryl Williams she was in remission from diffuse large B-cell lymphoma (DLBCL), a routine mammogram in 2014 revealed the cancer’s return.

“They called me back to redo the mammogram, then they wanted an ultrasound, and then later a breast biopsy. In a few days, my primary care doctor called to confirm that it was the same type of lymphoma again,” recalls Williams, a 60-year-old retired early childhood educator in Chicago.

After her initial stage 4 diagnosis in 2011, Williams received standard chemotherapy,

a protocol referred to as R-CHOP — Rituxan (rituximab), Cytoxan (cyclophosphamide), Adriamycin (doxorubicin), Oncovin (vincristine sulfate) and prednisone &mdash; and went into remission. During her relapse, she received another round of chemotherapy followed by a stem cell transplant. November 2019 marked five years of remission.

During those five years, Williams underwent numerous scans, blood tests and other follow-ups to confirm her cancer-free status. “I used to worry about every single scan and blood test, but I don’t do that as much anymore,” she says. And, if Williams were to relapse, she would have more options than she did following her first diagnosis.

A large percentage of patients with DLBCL respond to initial treatment, and 71% survive more than five years. For those who don’t respond or later relapse, the condition has been harder to treat. But, in recent years, new therapies have brought hope and promising outlooks.

“This is extremely encouraging,” says Dr. Stephen Ansell, a researcher and consultant in the division of hematology at Mayo Clinic in Rochester, Minnesota. “There are now multiple therapies becoming available for patients who have had the misfortune of having the disease return.”

DLBCL, the most common type of non-Hodgkin lymphoma, affects more than 18,000 people each year in the United States — most often, those over age 60. The aggressive disease involves B lymphocytes, immune cells that produce antibodies to fight germs and infections entering the body. When these cells become cancerous, it wages war on the body’s built-in defense system

But, as with the growing consensus about most cancers, DLCBL is not one disease, according to Dr. Nina Wagner- Johnston, director of lymphoma drug development at Johns Hopkins’ Sidney Kimmel Comprehensive Cancer Center in Baltimore. “It’s multiple diseases, and the better we understand their biology, the better we can target the cancer,” she says.

DLBCL breaks down into five subtypes based on behavior, appearance and defining protein or gene: T-cell/histiocyte-rich B-cell lymphoma, primary DLBCL, primary cutaneous DLBCL, Epstein- Barr virus-positive DLBCL and DLBCL not otherwise specified.

In earlier stages, when the cancer is limited to one or two lymph nodes on the same side of the diaphragm, patients typically receive three to six cycles of R-CHOP at 21-day intervals. At stage 3 or 4, patients receive six or more cycles. People at high risk of recurrence may receive different chemotherapies.

The international prognostic index score helps doctors predict risk of recurrence. This measurement takes into consideration the patient’s age and normal daily activity function, disease stage, whether the lymphoma has reached organs outside the lymphatic system and blood level of lactate dehydrogenase, a lymphoma marker. The higher the score, the higher the risk.

Williams received eight cycles of R-CHOP and felt hardest hit by the side effects of the regimen’s prednisone, a steroid. “I would have mood swings,” she recalls. “One minute I’d be happy or my normal self, and then just one word would set me off. I’d cry or have bouts of anger, and sometimes I’d be awake for 36 hours.” Other common side effects associated with R-CHOP include nausea, hair loss, fatigue, weight loss, risk of infection and loss of appetite.

The regimen might be tough to take but it is highly effective. “With R-CHOP, we are able to cure 60%-80% of patients, depending on which study you look at,” says Dr. Loretta Nastoupil, director of the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center in Houston.

Yet studies that examine R-CHOP don’t include enough people with a type of DLBCL known as double-hit lymphoma, who typically don’t respond well to the regimen.

B-cell lymphoma cells tend to have one or more of three possible gene mutations — BCL2, BCL6 and MYC &mdash; that occur when parts of genes swap places within the chromo- somes that contain them. Double-hit lymphoma involves two of these rearrangements, one in the MYC gene and the other in either the BCL2 or BCL6 gene.

Rather than using R-CHOP, oncologists will consider a more intensive treatment regimen of dose-adjusted EPOCH-R — etoposide phosphate, prednisone, Oncovin, Cytoxan and Adriamycin plus Rituxan, according to Nastoupil. Doctors might also consider EPOCH-R for people who have a higher international prognostic index score. Unlike other chemotherapy regimens, EPOCH is given slowly over five consecutive days.

This slow approach can reduce the toxic side effects on healthy organs,

such as the heart. The dose gradually increases until the maximum amount the patient’s bone marrow can tolerate is reached. Many patients need to stay in the hospital during the infusion.

“It was a shock to me when they told me I would need to go into the hospital for dose-adjusted EPOCH,” says Mary Chamberlain, 65, a social worker from Herndon, Virginia, who is currently receiving the regimen.

“I thought I would spend one day a week every three weeks getting chemotherapy, not five to seven days living in the hospital.”

Chamberlain gets through the stay with visits from her husband, daughter and friends. “My husband brings me breakfast every day on his way to work, and my friends bring puzzles and games,” she says. She also reads or walks the oncology ward. “Sixteen laps is a mile, so I get up and walk that, and drag the chemo machine with me,” she says. “You have to take it with you everywhere. It’s like having a dance partner.”

EPOCH-R, like R-CHOP, brings high survival rates. A 2018 study found that about 71% of people with double-hit lymphoma who received EPOCH-R remained cancer-free for four years.

If a patient doesn’t respond to therapy or, like Williams, has a relapse, the next step is typically high-dose chemotherapy followed by stem cell transplant. Now there is a new option: chimeric antigen receptor (CAR)-T cell therapy. “In the last two years, the biggest thing that’s happened in diffuse large B-cell lymphoma has been the development and approval of CAR-T cell therapy,” Nastoupil says.

The therapy involves removing a patient’s T cells, re-engineering them in a lab, and then putting them back into the patient’s body to help fight the lymphoma. The treatment forces T cells to recognize a molecule called CD19 on the surface of cancerous cells and attack.

The Food and Drug Administration has approved two CAR-T cell therapies, Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel), for people who continue to progress after at least two types of treatment. “Prior to CAR-T cell therapy, these patients were looking at a median overall survival of six months,” Nastoupil says. “Now survival is dramatically better. For the 40% of patients who are cured, we think they will have a normal life expectancy.”

Since these treatments were approved, researchers have collected data on patients who have received the therapy. That’s important, because often drugs that impress researchers in clinical trials disappoint when used in more widespread groups of patients. Clinical trial participants are often “the healthiest of sick patients,” Nastoupil says, and might do better than others would on an experimental drug. But CAR-T cell therapy continues to perform as well as it did in

It works so well, in fact, that researchers want to know if CAR-T cell therapy might be more effective than high-dose chemo- therapy followed by stem cell transplant. Current clinical trials are making that comparison. If CAR-T cell therapy beats stem cell therapy, it could be used as

a second-line treatment. If the two competitors perform equally, stem cell therapy might keep its second-line spot because it costs less. Both treatments have associated risks and side effects.

Before a stem cell transplant, doctors wipe out the patient’s immune system with high-dose chemotherapy, which brings the risk of infections and other illness.

Low blood counts, another result of a depleted immune system, can thin the blood or cause anemia. Patients may experience low platelet levels, nausea, vomiting, fatigue and mouth sores. Long-term side effects, such as early menopause, thyroid problems and lung or bone damage, are also a concern.

Two major, sometimes life-threatening side effects of CAR-T cell therapy include consequences of an exuberant immune reaction, such as cytokine release syndrome and neurological toxicity. Cytokine release syndrome can cause flu-like symptoms, such as headache, fever, chills, severe nausea, vomiting, diarrhea and severe muscle or joint pain, as well as shortness of breath, low blood pressure and fast heart rate. Neurological side effects include confusion, difficulty speaking, altered consciousness and seizures. Most of these side effects can be managed with medication or resolve on their own.

“Until treatment options work for 100% of patients, it’s not enough,” Ansell says.

Experimental drugs called bispecific T-cell engagers, or BiTEs, may help close that gap. Like CAR-T cell therapy, these drugs trigger the body’s T cells to fight lymphoma. But, for CAR-T cell therapy, doctors draw blood to modify T cells outside the body and then reinfuse them into the patient. BiTEs do not require removal and modification of T cells — they do all their work inside the body.

“The advantage is that it’s off the shelf,” Wagner-Johnston says. “It doesn’t require any of this laboratory manipulation of CAR-T cells, so you don’t have that delay.”

The bispecific drugs activate T cells by latching on to CD3, a protein on the surface of T cells, which then attach to the CD19 and CD20 proteins on cancer cells.

A recent phase 2 clinical trial included 47 patients with new diagnoses who either did not respond to R-CHOP or relapsed soon after treatment, a patient group that typically has low survival rates. Eighty-nine percent of those who received blinatumomab, a type of BiTE, responded partially or completely to the medication.

Mosunetuzumab is being examined in a phase 1 clinical trial involving 218 patients who relapsed or became resistant after multiple prior treatments, including some who had received CAR-T cell therapy. The findings showed that many patients went into complete remission after receiving the experimental drug. “One of the most encouraging things about this drug is that it even worked in some of the people who had not responded to CAR-T cell therapy,” Wagner- Johnston says.

With new treatments on the horizon and the potential for more second-line options, doctors and patients may be able to make more personalized choices. “We are already making significant strides with these novel treatments,” Wagner-Johnston says. “Now we need to try to understand which groups to target so we can maximize therapy and minimize toxicity. I think there’s lots of reason to be hopeful.”

Features

Patients with relapsed and resistant diffuse large B-cell lymphoma can look to new treatments beyond tried-and-true chemotherapy.
 

Eyes On New Treatments Beyond Chemotherapy in Diffuse Large B-cell Lymphoma

Mantle Cell Lymphoma, an aggressive type of non-Hodgkin lymphoma, develops when the body makes abnormal B cells. To date, there is no cure for the disease, but in clinical trials, researchers continue to look for therapies that will extend the lives of patients.

, Dr. Lee Greenberger, chief scientific officer of The Leukemia & Lymphoma Society, discussed how the latest advancements may play an important role in mantle cell lymphoma.

: Where do we stand with treatment options for mantle cell lymphoma? 

If you’re a patient and you hear the word “incurable,” that’s a very frightening term. What it means is that, ultimately, we don’t think we can get rid of the disease, but that doesn’t mean that you cannot live with the disease. And if you can get long-term disease control, that can be just as valuable as a cure — basically, keeping (the cancer) at bay. We can do that for mantle cell lymphoma for about 5-10 years with some of the previous therapies.

Mantle cell will typically be treated with cytotoxic therapy along with an antibody — that’s Rituxan (rituximab). Typically, patients will get a response, but it won’t last, and patients come back in two years, five years, with relapsed disease. We can either re-treat or move on to newer therapies.

There have not been a lot of options for patients with mantle cell lymphoma until lately, and one of these is a chimeric antigen receptor (CAR)-T cell therapy. The results of the trial were recently presented, and they are quite exciting. In a CD19 CAR therapy, you basically take the T cells and put it in something called CD19-directed therapy so that an antibody on those engineered cells looks for the CD19 molecule on the tumor cells.

When it recognizes the molecule, it tells the T cells to turn on and multiply and kill that tumor. There are two approved therapies for diffuse large B-cell lymphoma and leukemia, so we understand the safety of CAR-T cell therapy pretty well. When you put those into mantle cell patients who have relapsed or refractory disease, you can get a very high response rate.

The tumors will shrink, and you’ll get about an 80%-90% response rate, but, more importantly, the data is showing us that about 50% of those patients will have long-term disease control about three years out, which means it looks like we have a new therapy. It has yet to be Food and Drug Administration reviewed and approved, but it is highly encouraging.

In addition to CAR-T therapy, is anything else exciting coming down the pipeline?

Yes. Imbruvica (ibrutinib) is an oral medication directed toward an enzyme called BTK (Bruton tyrosine kinase). BTK is a switch inside the mantle cells that, when it’s turned on, will activate a growth pathway and you’ll get abnormal growth of those cells. Ibrutinib is a BTK inhibitor and shuts down that pathway. The problem is that, unlike with chronic lymphocytic leukemia, where it works well, Imbruvica does not work that well in patients with mantle cell lymphoma.

However, Imbruvica plus another oral drug called Venclexta (venetoclax) when used in combination is now giving exciting results of prolonged disease control. So, taking two oral medications together that are both approved in mantle cell lymphoma might improve outcomes.

There is also something called a CDK4 inhibitor — Ibrance (palbociclib) &mdash; and it’s FDA-approved for breast cancer. The drug is being tested in combination with Imbruvica for mantle cell lymphoma with good results.

What is your best piece of advice for a patient with newly diagnosed mantle cell lymphoma?

Unlike breast cancer, which occurs in over 200,000 women per year in the United States, mantle cell lymphoma affects 5,000 patients a year. That means you need a specialized doctor to recognize what it is, and you need a good pathologist who will make the call as to whether it’s mantle cell lymphoma or not.

The best advice if you have swollen lymph nodes and fatigue is to get a blood test — that’s the start of it. But you really need to go to a trained hematologist/oncologist &mdash; someone who has seen mantle cell lymphoma multiple times &mdash; to figure out the best therapy.

Quite often, that involves going to a major medical center that has seen tens or hundreds of patients. And because most of the advances are happening in clinical trials, it’s best to go to a major medical center that is running clinical trials in mantle cell lymphoma, because you may be a candidate for some of these new therapies and avoid some of the toxic therapies.

Patients and caregivers should contact The Leukemia & Lymphoma Society’s free Information Resource Center at 1-800-955-4572, where specially trained master’s degree level nurses and social workers can answer questions about your diagnosis and direct you to resources and support services, or visit 

Speaking Out

An expert sheds light on the latest therapies in clinical trials and promising drug combinations to thwart the aggressive disease.

Speaking Out: Treatment Options May Expand in Mantle Cell Lymphoma

In December 2017, Heather Hibbard had just returned home from a weekend getaway in Las Vegas with her family when she noticed she had several massive bruises. Dark, bluish-purple blotches marked her forearm and thigh, and the rest of her body appeared deathly pale.

“As a mother of three, I don’t focus on myself a lot,” says Hibbard, who lives in Yorba Linda, California, and was then 37. “I was having a lot of bone pain in Vegas, but I have scoliosis, so I always have some pain. Everything just multiplied when I got back home.”

She rushed to schedule a same-day appointment with her doctor. As someone in the medical field — she works as an ultrasound technician &mdash; Hibbard had no hesitation about learning what could be wrong. Her doctor appeared alarmed about how sick she looked and immediately ordered bloodwork.

Her platelet count was astoundingly low. A normal count ranges from 150,000 to 450,000 platelets per microliter of blood; Hibbard’s hovered around 20,000. She initially assumed something had gone wrong with her intrauterine device, because she had recently experienced heavy vaginal bleeding — abnormal uterine bleeding can be a symptom of certain hematologic cancers.

“I thought I was anemic because I had lost a lot of blood. Cancer didn’t even cross my mind until the doctor came in and told me I had leukemia,” she says.

A week and half after returning from her vacation, Hibbard received a diagnosis of acute myeloid leukemia (AML). This cancer of the blood and bone marrow affects more than 20,000 people each year in the United States.

For years, prognosis remained poor for patients with the disease, which has a 24% five-year survival rate for people ages 20 and older and 67% for those younger than 20, with limited treatment options. But the past two years brought an explosion of new medications approved by the Food and Drug Administration (FDA) to treat AML, particularly therapies targeting specific genomic mutations that may confer a worse prognosis.

“For more than 45 years, the treatment for AML only involved intensive chemotherapy, and that was the only chance at a cure,” says Amer Zeidan, an associate professor of internal medicine at Yale Cancer Center in New Haven, Connecticut. “But since 2017, we’ve had a revolution in the treatment of AML after many years of no approved agents. I give an analogy in (terms) of ‘before Christ’ and ‘after Christ’ because the landscape has changed so much.”

Historically, chemotherapy for the treatment of AML involves two phases: induction therapy followed by consolidation therapy. Shortly after diagnosis, a patient will undergo induction therapy to rid the body of any signs of the disease.

Most often, patients receive the combination of cytarabine and an anthracycline drug such as Cerubidine (daunorubicin) or Idamycin (idarubicin). Approximately 75% of younger adults with AML and 50% of patients older than 60 achieve complete remission, or disappearance of overt leukemia in the bone marrow, after induction treatment. Once a patient has recovered, consolidation therapy, chemotherapy or a stem cell transplant kills any remaining leukemia cells.

Early signs of AML, which is typically associated with older age (more than 65 years), history of tobacco smoking and certain inherited genetic disorders, include weight loss, fatigue, fever, night sweats, bruising and excessive bleeding. Because AML is generally widespread throughout the bone marrow and possibly other organs, it is not staged like other cancers. About half of patients who achieve remission after initial treatment will relapse.

Genomic testing revealed that Hibbard had a FLT3 mutation. The most common mutation in AML, FLT3 is found in 30% of all cases and associated with a particularly aggressive form of the disease and a higher risk of relapse. “My oncologist told me, ‘Bad news — you have the FLT3 mutation. But the good news is that they just developed an inhibitor you can take,’” recalls Hibbard. “He said it with a big smile on his face.”

In April 2017, the FDA approved Rydapt (midostaurin), the first targeted therapy for AML, combined with chemotherapy to treat adults with a new diagnosis and a FLT3 mutation. The oral medication belongs to a group of drugs called FLT3 inhibitors, which block several enzymes that promote cell growth.

During Hibbard’s month in the hospital to receive induction chemotherapy, she experienced several life-threatening complications, including a blood clotting disorder, two strokes and a bout of sepsis. Believing she was on her deathbed; she made a video saying goodbye to her children.

Hibbard recovered, returned home and began treatment with Rydapt, which made her nauseated. The drug’s other common side effects include low levels of white blood cells with fever (febrile neutropenia), inflammation of the mucous membranes and vomiting.

Hibbard achieved remission following more chemotherapy and a stem cell transplant and remains free of cancer. “I was extremely excited about taking Rydapt because I felt truly blessed that there was an inhibitor for my mutation, since it was so aggressive,” says Hibbard, who is now 39.

“It smells horrible, and it’s a large pill, but I took it willingly because I knew it would improve my chances of survival.”

Rydapt is one of eight drugs for AML that have gained FDA approval since 2017. Xospata (gilteritinib), another type of targeted therapy that inhibits FLT3, was approved in May

2019 for adults who stopped responding to treatment or whose disease had relapsed.

The IDH inhibitors Idhifa (enasidenib) and Tibsovo (ivosidenib) target mutations in the IDH1 and IDH2 genes. Daurismo (glasdegib), Venclexta (venetoclax) and Vyxeos (CPX-351) expand the options for older patients who can’t be treated with intensive chemotherapy because of its toxicities. Mylotarg (gemtuzumab ozogamicin) can be given to patients who express the CD33 antigen.

“We now have a better understanding of the biology behind AML, especially the molecular mutations that drive this disease, and we have developed treatment that targets these mutations,” says Dr. Kevin Kelly, an associate professor of clinical medicine at the University of Southern California in Los Angeles. “One of the most important mutations is FLT3, targeted by midostaurin and gilteritinib. These drugs specifically target the leukemia cells while being less toxic on the normal tissue of the body.”

In a large clinical trial, patients with new diagnoses who took Rydapt along with chemotherapy lived longer than those who received chemotherapy alone. After four years, 51.4% in the Rydapt group were still alive compared with 44.3% in the chemotherapy group.

Findings from the ADMIRAL trial showed that Xospata similarly extended survival. Patients who took the FLT3 inhibitor alone had a median overall survival of 9.3 months compared with 5.6 months for those given chemotherapy alone. Though encouraging, these are early findings from new files, and long-term follow-up could bring significantly different results, cautioned experts.

Side effects of Xospata include nausea, vomiting, diarrhea, constipation, pain or sores in the mouth or throat, shortness of breath, muscle or joint pain and dizziness. The drug can also cause differentiation syndrome, a potentially fatal complication believed

to be caused by release of cytokines from leukemia cells. It can be treated with steroids, but prompt recognition is key. Symptoms include fever, cough, trouble breathing, bone pain, rapid weight gain and swelling in the arms, legs, underarm, groin or neck.

Differentiation syndrome is also a concern for patients treated with Idhifa and Tibsovo. Based on clinical trial results showing that 19% of patients had complete remission for a median of 8.2 months, Idhifa was approved in August 2017 for patients who relapsed or became resistant to treatment for AML. The targeted therapy homes in on mutations in the IDH2 gene, which are found in 8%-19% of patients with AML.

In July 2018, Tibsovo, which targets IDH1 mutations found in 7%-14% of patients with AML, was approved. Roughly two years later, the FDA allowed the drug’s use as a first-line treatment for patients who aren’t eligible for intensive chemotherapy.

Another type of targeted therapy, Mylotarg aims at AML cells expressing the CD33 antigen, found in more than 80% of patients. Reapproved by the FDA in September 2017 to treat patients with new diagnoses and those who relapsed or became resistant to therapy, the agent combines the unique targeting of a monoclonal antibody with the cancer-killing ability of a chemotherapy drug.

“What is happening now in AML is similar to what already happened with multiple myeloma. Today, proteasome inhibitors and other biological drugs have almost completely replaced chemotherapy for almost all ages and subsets of myeloma,” says Dr. Naval Daver, an associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center in Houston. “With these new targeted therapies, we can improve outcome and survival in AML while reducing the need for chemotherapy and even stem cell transplants.”

The lack of treatment options for older patients with AML — only about half of patients older than 60 receive intensive induction chemotherapy; the rest get either gentler chemotherapy that doesn’t aim to cure or supportive care without any chemotherapy &mdash; has meant that many are undertreated, with poorer clinical outcomes.

Fortunately, the approvals of Venclexta and Daurismo for patients aged 75 and older bring new options. Venclexta, which blocks BCL-2 proteins, was granted accelerated approved by the FDA based on promising results from early-phase clinical trials, but two larger, ongoing studies are examining its effectiveness and safety. The rate of complete remission was up to 54% for Venclexta plus decitabine but varied depending on which chemotherapy drug was given.

“There has been dramatic progress in the treatment of AML in recent years, with one of the most important drugs being venetoclax for older AML populations, who have been one of the most difficult populations to treat,” Daver says. “It works synergistically with low-dose chemotherapy drugs already being used, which is a major breakthrough in the treatment of older patients with AML.”

Daurismo targets the smoothened, or SMO, protein that fuels the growth and spread of AML. In a clinical trial, the median overall survival in older patients who received Daurismo along with chemotherapy was 8.3 months compared with 4.3 months for those who got chemotherapy alone.

Vyxeos (CPX-351) can also be used in older patients. It's August 2017 approval was for patients with two types of prognoses: newly diagnosed therapy-related AML, which occurs as a complication of cancer treatment in 8%-10% of patients within five years after chemotherapy or radiation, and AML with myelodysplasia-related changes, characterized by a history of certain blood disorders and other significant mutations within cancer cells. Patients with these types of AML tend to be older and have additional medical issues.

A study that compared Vyxeos with traditional chemotherapy showed that patients with new diagnoses who took Vyxeos lived longer, with a median overall survival of 9.56 months compared with 5.95 months, respectively.

In addition, an investigational oral therapy, CC-486, has shown a survival benefit in patients with newly diagnosed AML in the maintenance setting. In a phase 3 trial, researchers saw that the drug extended overall survival by 9.9 months compared with placebo.

“We have new drugs available for subsets of the disease, which is why the management of AML is becoming more like personalized medicine,” Zeidan says. “I think we are going in the direction of more targeted therapy, lower toxicity agents, combinations of different oral agents and, hopefully, incremental improvement in outcomes. I’m very optimistic about where the field is going.”

The wealth of drug approvals certainly gives more hope to patients with AML, especially those with a previously poor prognosis and lack of treatment options. Rapid genetic testing is leading to the early classification of disease subtypes, pushing AML treatment into the realm of precision medicine. Several clinical trials in progress aim to test combinations of the newer agents, such as Venclexta with an IDH inhibitor.

Hibbard remains thankful for the targeted therapy she received. She believes that the trust she had in the newly approved Rydapt and the entire treatment process helped save her life.

“I remember being terrified, with people praying over my bedside. But I’m very pragmatic, so I was very much like, ‘OK, now what do we do? What’s the next step?’” Hibbard says. “That was my entire battle. Today I am more than a year post-transplant and grateful to kiss my kids goodnight every night.”

A wave of new targeted therapies expands the options in acute myeloid leukemia.
 

Extending the Options for Patients with AML by Making It Personal

Patients with Chronic Lymphocytic Leukemia (CLL) may no longer have to head to the hospital for a chemotherapy infusion. Oral targeted therapies such as Imbruvica (ibrutinib), Calquence (acalabrutinib) and Venclexta (venetoclax) have radically changed the field, extending life and reducing side effects.

, Dr. Lindsey Roeker, a third-year clinical fellow at Memorial Sloan Kettering Cancer Center in New York City, discussed these medications and their side effects and explained how oncologists match each with patients.

: Please explain how a Bruton tyrosine kinase (BTK) inhibitor works and why these agents are used to treat CLL. 

To understand why BTK inhibitors are effective in CLL, it’s important to first understand how a normal B cell works and how it uses a B cell receptor. A normal B cell is a type of white blood cell that is born in the bone marrow, travels through the peripheral blood, and then takes up residence in a lymph node or the spleen.

B cells throughout our body use the B cell receptor to help the body identify infections. When a B cell receptor encounters an infection, it activates or “turns on” the B cell through a series of signaling proteins. BTK is one of those signaling proteins that amplifies the “on” signal. This “on” signal prompts the B cell to survive and proliferate, or make copies of itself, in order to fight off infection.

In a CLL cell, the B cell receptor is excessively “on” and tells the CLL cell to survive and proliferate. By blocking the B cell receptor “on” signal with BTK inhibitors, the cell no longer receives the message to live or make copies of itself. The CLL cell with blocked BTK either dies or can’t move around normally, thus stopping CLL growth.

Since Imbruvica’s approval by the Food and Drug Administration (FDA) in 2016, what has been shown regarding the agent’s overall survival and toxicity? 

Imbruvica has been studied in patients who have never been treated and patients who have had prior treatments for CLL, also called relapsed/refractory (disease). Many studies examining Imbruvica have been performed. Some of the first studies are those with the longest follow up periods, so they give a window into how well these drugs work over longer time periods.

In the study that examined Imbruvica in patients with relapsed/refractory CLL, we have five and a half years of follow-up, and we know that patients do well with this treatment. Ninety-one percent of patients in this study benefited from the drug with some reduction in their disease, and we see that Imbruvica works for a long time for many patients, even when prior medications used to treat CLL had stopped working. For patients who had never been treated for CLL and were given Imbruvica, a similarly high proportion of patients benefited from the drug and patients who received Imbruvica lived longer on average than patients who received oral chemotherapy.

A few more recent studies have compared Imbruvica to stronger IV chemotherapy regimens and have shown that patients go longer without having CLL progression when they are treated with Imbruvica. The trials really reinforce that Imbruvica works very well.

The most common side effects of Imbruvica are diarrhea, nausea and fatigue. Some other side effects, which are less common but can be more dangerous, are high blood pressure, atrial fibrillation (an abnormal heart rhythm) and bleeding.

When looking at patients who are prescribed Imbruvica by their doctors, as opposed to receiving the medication on a clinical trial, we know that a fair number of patients experience these side effects and stop Imbruvica because of side effects.

Some of these side effects seen with Imbruvica are due to Imbruvica’s ability to block proteins that look like BTK but are different, which we call off-target effects.

In November 2019, Calquence was FDA approved. How is this BTK inhibitor different from Imbruvica?

Calquence is a second-generation BTK inhibitor, and it was designed to be more selective in blocking BTK. By blocking fewer proteins that look like BTK but have other functions, there should be fewer off target effects.

Calquence has been studied in patients who had never been treated for CLL and patients with relapsed/refractory CLL. Like Imbruvica, the proportion of patients who benefit from this drug is really high, and patients are able to take the drug for a long time before the drug stops working.

For instance, in a recent study, 90% of patients who got Calquence in combination with Gazyva (obinutuzumab), an antibody against CD20 that is expressed in B cells, had not had any progression in their CLL after two and a half years.

The most common side effects of Calquence are anemia (low hemoglobin), neutropenia (low neutrophil count, or decreased number of infection-fighting cells), low platelets, headache, upper respiratory tract infections and diarrhea.

One of the goals in designing second-generation BTK inhibitors like Calquence was to minimize side effects by reducing off target effects. It is difficult to compare side effect profiles of drugs studied in the results of different clinical trials since the patients included in one trial might be very different than the patients included in another clinical trial. We are awaiting the results of a trial that compares Imbruvica and Calquence head-to-head. When that trial is done, we will have answers about how well these drugs work compared to one another and whether the side effects are really different.

What factors help a health care professional decide on the best course of treatment for a patient?

When deciding on treatment for a patient, we look at the whole picture. This includes the genetic characteristics of the disease and a patient’s other medical problems. Both Imbruvica and Calquence, as well as Venclexta in combination with Gazyva (obinutuzumab), and chemoimmunotherapy treatments are approved as first therapy for CLL. Imbruvica and Calquence are pills that are taken daily for as long as they’re working. Venclexta and Gazyva is a combination of treatments that are given for one year and then stopped, based on how these drugs were used in the clinical trial that led to their approval by the FDA.

The decision about which to pursue depends on a patient’s preference. Some patients really want to avoid IV medications, in which case Imbruvica or Calquence may be good choices.

Some want to be on therapy for a limited period, in which case Venclexta and Gazyva may be a better fit.

We also look at a patient’s other medical problems to make sure that their treatment won’t make an existing medical problem worse. In general, being open with your doctor about your preferences and, once you start a drug, any side effects that you experience is important. Some patients do really well with one drug while others experience side effects, and patients who have side effects some- times do better with another medicine.

Communicating your experience is an important step in helping your doctor find the right therapy for you.

How have BTK inhibitors changed the treatment landscape in CLL?

BTK inhibitors have really revolutionized the treatment of CLL. CLL used to be a disease that was treated primarily with chemotherapy, and now it is much more commonly treated with targeted medicines. These targeted medicines, including BTK inhibitors, have helped patients experience fewer side effects and control their CLL better.

Newer medications that displace chemotherapy aim directly at mutations in the Bruton tyrosine kinase gene and help patients with CLL live longer.

Hematology 1 | CURE