THERE ARE THREE STAGES of treatment for acute promyelocytic leukemia: induction therapy, consolidation therapy and maintenance therapy.

Induction therapy refers to the start of treatment with all-trans retinoic acid (ATRA) and another agent, usually arsenic, following one of several different regimens. Because of the recent findings about arsenic’s superiority to chemotherapy, most treatment regimens today will be intravenous arsenic trioxide (0.15 mg/kg/ day until bone marrow remission) with ATRA (45 mg/m2/day, taken in two doses).

Regimens for highrisk patients will also include daunorubicin (or possibly idarubicin) plus cytarabine.

, determined based on a patient’s risk of remission, aims to bring a patient into molecular remission. The ATRA/ arsenic regimen typically includes a five-day cycle of arsenic every other month for four cycles along with the same daily ATRA doses during two weeks a month for seven cycles. A reverse transcription polymerase chain reaction test to detect the PML-RARa protein determines whether a patient has achieved molecular remission. If oncologists suspect relapse, they may conduct a bone marrow analysis to look for evidence of disease.

 after molecular remission is beneficial for patients. A review of 10 trials, published in 2013 and involving over 2,000 patients, found that maintenance therapy increased the amount of time people remain free from disease, but it did not increase overall survival. The review also found that any maintenance treatment, particularly treatments involving chemotherapy, are more toxic.

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Side Note

Treatment Stages for a Rare Leukemia

Patients with cancer face many challenges following diagnosis, and one obstacle that can mean the difference in receiving a lifesaving treatment is location of care. Baylor Scott & White Oncology Program is changing this by bringing the best treatment possible closer to home at its facilities in North and Central Texas.

Its clinical trials stand out among the hematology program, in which the latest treatments are being studied to advance the care of patients with blood cancers.

Throughout the system, there is supportive help through social work and, most recently, a revamped survivorship program to guide people on how to put their lives back together after cancer.

®, M. Yair Levy, M.D., who oversees clinical research hematologic malignancies in the North, and Mark Holguin, M.D., in Central Texas, discussed the program and new, promising treatments.

Can you please tell us about the hematology program at Baylor Scott & White Health?

Holguin: Our system has been integrating the oncology services of Baylor Healthcare in North Texas and Scott & White Healthcare in Central Texas since the merger in 2014. Baylor has always had a strong networked oncology program, with Dr. Levy ably leading the hematologic malignancy clinical research efforts at its flagship facility, Baylor University Medical Center in Dallas.

In Central Texas, there is also a network of clinics with our flagship facility in Temple, Texas, and our hematologic malignancy clinical study program led by Dr. Vinit Karur. Since the merger, we have worked to bring these two groups together.

We have a joint membership with the Southwest Oncology Group, which is a National Cancer Institute program that helps to bring clinical trials to large numbers of institutions across our country. We have developed a common (institutional review board) process to permit studies to be shared across the system. We have shared conferences and tumor boards to facilitate sharing of interests and studies across our system Both institutions have had clinical trials programs for years. As researchers, we are interested in trying to develop the new therapies that are coming along and to help bring those new agents out, get them tested and push the field forward to the best therapy for our patients.

You mentioned new agents. Can you discuss these?

There are a wealth of new agents being tested, and there is great optimism for treatment of cancers that up until now have not had good options.

Acute myeloid leukemia (AML) is an area in which we are happy to see new treatments being developed. For over 30 years, we have relied on an aggressive chemotherapy regimen that severely affects blood production, requiring about four weeks in the hospital to deliver that treatment support with blood transfusions and treatment for infections until blood counts recover. Our chances for cure in the adult population were only in the 30 to 50 percent range.

 In the past year, a new agent called Rydapt (midostaurin) has been studied and approved. This is an agent that helps us target a chromosomal change that we have known is common in AML. Changes in the FLT3 gene occur in approximately 30 percent of adult AML cases and confer a worse prognosis. The addition of Rydapt to standard chemotherapy in patients with AML having certain FLT3 mutations has led to improved cure rates. This has spurred further interest in targeted therapies that target other known AML mutations to enhance treatment for more patients with AML.

Even though Rydapt was first to market, it will soon face intense competition from gilteritinib, quizartinib and crenolanib. These are newer FLT3 inhibitors that may provide more complete FLT3 inhibition, with more specificity for the target and perhaps better tolerability.

What advances in blood cancer most excite you?

In AML, there has recently been an approval for Vyxeos (CPX-351). We participated in the study of this drug. It looked at people ages 60 to 75 with either secondary acute leukemia or leukemia with genetic changes suggestive of either chemotherapy as the cause or the emergence from myelodysplastic syndrome. They used the same drugs that we typically use in our induction called 7-plus-3.

They found a synergistic ratio of 5-1 with the cytarabine to the daunorubicin. And the reason it’s interesting is that for the past several decades, people have looked at various combinations of these drugs and various dosing, but they weren’t able to demonstrate a survival benefit. These researchers did demonstrate a survival benefit.

This validates their delivery platform and the importance of drug ratios. That is significant because most of the treatments that we use in oncology are drug combinations. We do that because we know if we use multiple different drugs, we are able to overcome some resistance that can occur in the cancer cells.

This platform shows that how we administer therapies matters. It’s a great platform for optimizing current combinations of therapies.

In addition, Idhifa (enasidenib), an IDH2 inhibitor, was approved. IDH2 is a mutation that occurs in a fraction of patients with AML. This is a drug that inhibits this pathway, providing these cells with a survival advantage. The response rates were impressive enough to earn an approval from the Food and Drug Administration (FDA) on early-phase data.

Also, Mylotarg (gemtuzumab ozogamicin) was recently re-approved. This is an antibody with an attached chemotherapy payload, functioning like a smart bomb that targets the leukemia cells directly. The Oncologic Drug Advisory Committee, which provides recommendations to the FDA, ruled in favor of it following a phase 3 trial that showed a progression-free survival benefit. Mylotarg was a drug previously on the market in the United States, but it was withdrawn because of toxicity.

Immunotherapy has become a huge area of interest. What lies ahead in this treatment?

 For decades, there has been hope that we could somehow modify or support the body’s own immune system to recognize cancer cells as foreign and destroy them using our own body without having to add to toxic agents. This has been steadily developing, and in the past couple of years, there seems to have been an explosion.

 There are different techniques for this. The first techniques were to use antibodies that could be directed against proteins that live on the surface of cancer cells that would help the immune system recognize those cells and get rid of them. Rituxan (rituximab) was one of the first and most successful antibodies that helped us to find a protein on the surface of many lymphoma cells. It has revolutionized treatment for B-cell lymphomas.

More recently, we now have monoclonal antibodies directed against other proteins that are active in Hodgkin lymphoma. An agent known as Adcetris (brentuximab) is an antibody that is coupled with a toxin that will bind to the CD30 protein. This has provided an option for relapsed Hodgkin disease and is effective as maintenance therapy after highdose chemotherapy.

Although AML comprises the majority of acute leukemia in adults, a significant minority can develop acute lymphoid leukemia (ALL). Patients who do not respond or relapse after initial chemotherapy have not had many options outside allogeneic bone marrow transplantation. Recently, a new bispecific antibody has been developed that can bind to CD19 on ALL cells and can also bind to CD3 on normal T cells of the immune system. This double-ended antibody allows the immune system to target ALL cells more effectively and has shown improved survival for relapsed and refractory patients with ALL. Multiple myeloma has also benefited from monoclonal antibody therapy development. The most exciting is Darzalex (daratumumab), which targets the CD38 protein on the surface of myeloma plasma cells.

Finally, chimeric antigen receptor T-cell therapy, or CAR-T cell therapy, has shown remarkable responses in patients with a variety of hematologic malignancies including ALL, chronic lymphocytic leukemia, lymphomas and myeloma.

What are some of the biggest concerns that patients have about clinical trials?

Anytime people enter a clinical trial, they are concerned about being on a placebo — an inactive treatment &mdash; controlled study, but those are quite rare in oncology trials, and all treatment arms should at least contain what would be considered a standard treatment.

I explain to patients that every clinical trial is an experiment, but it is a controlled experiment with known parameters. A physician’s job is educating patients on their disease and treatment options. We explain standard-of-care options as well as clinical trials (when applicable).

My bias, as a researcher, is to enroll patients in studies that seem promising and applicable to their situation. We have participated in many studies that have led to approved therapies (including all the drugs mentioned in this article), which allowed patients to be treated with these new treatments before they were commercially available. The only way to get better treatment is to continue trying novel approaches.

M. YAIR LEVY, M.D., is a physician on the medical staff at Baylor University Medical Center at Dallas, where he serves as the medical director of the Blood Cancer Research and Treatment Center. The center specializes in advanced research and the latest treatments in hematologic malignancies, including acute leukemia, lymphoma and myeloma.

MARK HOLGUIN, M.D., is a medical oncologist on the staff of the Scott & White Medical Center in Temple. He is the director for the Division of Hematology/Oncology at Scott & White and is a clinical associate professor of medicine at the Texas A&M Health Science Center College of Medicine.

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Baylor Scott & White Health merger allows patients to access new treatments with ease.

Bringing Cancer Care Closer to Home

Surviving cancer is no easy feat; raising children during this ordeal is even more difficult. When I was diagnosed with acute myeloid leukemia (AML) six years ago, my children were 9, 12 and 14 years old. It wasn’t always (or ever) smooth sailing, but optimism was my armor as I tried to battle my illness and remain a positive example for my kids.

Ironically, my husband is an oncologist. This helped us receive test results quickly but required us to assemble and integrate information at a rapid speed. We didn’t have time for processing. How would we tell the kids that their mother had an illness that she might not survive? Who would take care of them when their mother could barely get off the couch or out of bed? How would we deal with questions like, what if the cancer comes back? How would the kids integrate these thoughts into their lives?

There are three basic approaches to talking to your kids about a life-threatening disease: Tell them everything, nothing or something in between. Telling them everything will frighten them—creating drama when it’s not necessary. Telling them nothing will create a secretive atmosphere, where conversations are whispered and kids are generally confused about what’s going on. Hence, the in-between approach &mdash; telling enough to keep them knowledgeable but not so much that it scares them. The entire family does a double take, cries, laughs or just plain ignores it, then takes a collective breath and moves along, most likely in a totally new direction. My kids took the news in stride. They were the tell-me-what-I-need-to-know types. We laid out the facts, answered a few very basic questions and were done.

The saying “It takes a village” applies to caring for kids whose caregiver is going through cancer treatment. Other people truly want to help. It makes them feel better about the situation, because it allows them to express how much they care by actually doing something. So, accept their offers, if not for yourself, then for them. Let them drive your kids places, take them on vacation or just bring you food. If you do not have a good support system, don’t be scared to speak up and tell people you need help. Tell someone at your children’s school or religious center. I know of a mother who was embarrassed to tell the moms of her kids’ classmates about her cancer, then wondered why no one was there to help her. People cannot help if they don’t know that there is a problem.

Both cancer survivors and their families have to deal with living with the fear of recurrence. The cancer survivor, especially if she is the main caregiver, sets the tone for the others. If she feels as though a sword always hangs over her head and is therefore “half living,” then she is not truly living at all. If she can focus on the moment and cherish every day to the fullest extent possible, then she is truly living a rich life, and everything will flow from there for the whole family.

As time goes on and, hopefully, treatment ends, everyone begins to move on. Life may be a new kind of normal with the cancer ever present in the background, but a new normal it is. The entire family should embrace this new normal and integrate it into their lives. Kids will likely need time to process the entire situation and discussions about what happened can take place over time, when they are ready.

Let us also acknowledge that grandchildren are affected when grandparents are diagnosed with cancer. Grandparents are often just one step removed from parents in the caretaking of children, but whether or not grandchildren are close to their grandparents, seeing someone they love suffer is difficult. Grandparents can rely on their own children to explain the situation and can make it known when they feel up to interacting with the grandkids. It’s best to talk to the grandchildren in an honest and straightforward way.

Cancer is serious, and dealing with AML or any type of cancer along with family life will have its ups and downs. Laughter and optimism can go a long way toward helping survivors cope with the changes in their lives. Children are generally resilient, and it’s helpful to include them in what is going on in a way that they can handle. When my children reflect on that time period, they remember people bringing dinners and the outpouring of love more than the difficult times. It has become so integrated into their lives that it is part of our family’s story.

JILL WEISKOPF BRUFSKY, Pharm.D., is a 6-year survivor of acute myeloid leukemia. She is an adjunct assistant professor at the University of Pittsburgh School of Medicine and works at the Cancer LiveWell Survivorship Program of UPMC Hillman Cancer Center. She spends her free time relaxing with her husband and three children.

Speaking Out

An acute myeloid leukemia survivor shares her insight on raising 3 kids while fighting for her life. 

Helping Children Cope With Your Cancer

JULIANNA GUEVARA was diagnosed with cancer at 23 weeks pregnant with her daughter. - PHOTO BY ELENA EFREMOVA

After four and a half years of trying to get pregnant, Julianna Guevara had finally made peace with the idea of never bearing a child. So when she took a routine pregnancy test in November 2016, prior to taking Mucinex for a cold, the 32-year-old from Pembroke Pines, Florida, was stunned to see the test come back positive.

Her baby would be a miracle in more ways than one: Guevara partly credits her then-unborn daughter with saving her life from cancer. While nine weeks pregnant, Guevara learned that another pregnant woman, whom she had been following on Instagram, lost her baby because of a pregnancy complication in the mother’s liver called intrahepatic cholestasis of pregnancy (ICP). The major symptom was extreme itching, especially on the palms and feet — a symptom Guevara was experiencing. At 19 weeks, she was diagnosed by her obstetrician (OB) with ICP too. As risky as ICP is, the blood work Guevara now needed to get every two weeks would become crucial just four weeks later.

A high fever and rapid heart rate sent Guevara to her OB, who referred her to a hematologist. The hematologist suspected flu, but when he saw Guevara’s blood work from ICP checkups before her illness, he immediately admitted her to the hospital. She had flu and pneumonia, but a bone marrow biopsy revealed another diagnosis: acute promyelocytic leukemia (APL).

APL is a subtype of acute myeloid leukemia (AML), which is one of the four main types of leukemia. With AML, blood cells produced in the bone marrow do not mature normally and begin to crowd out the normal cells. What distinguishes APL from other leukemia types is the specific genetic mutation that prevents maturation of white blood cells. A translocation occurs between chromosomes 15 and 17 such that the promyelocytic leukemia protein (PML) gene on chromosome 15 fuses to the retinoic acid receptor alpha (RARA) gene on chromosome 17.

The RARA gene is responsible for producing the protein that ensures normal maturation and differentiation of new white blood cells, and the PML gene produces a protein that stops cells from growing out of control. But the fusion gene produces an abnormal protein, PML-retinoic acid receptor, alpha (RARa), that does the opposite of the PML and RARA genes: The white blood cells never mature beyond their promyelocyte stage (giving the leukemia its name), and they grow uncontrollably. Researchers don’t yet know what causes this mutation, but it’s neither inherited nor present at birth.

APL is among the less common leukemias, making up an average of 10 percent of all AML cases in the United States. The rates are higher, however, in Latin America because this cancer occurs more frequently in those of Hispanic origin, explains Elihu Estey, M.D., professor of hematology at the University of Washington School of Medicine and director of AML clinical research at Fred Hutchinson Cancer Research Center, both in Seattle.

He says people who develop APL also have a higher likelihood of obesity. This appears to be related to abnormalities in the leptin — the hormone that controls how full someone feels after eating &mdash; receptors, which also play a role in blood cell differentiation. Patients with APL tend to be younger, often in their 30s to 50s, than those with AML, who are more frequently in their 60s to 80s. Guevara, who is Latina, was stunned, particularly because she practiced a healthy lifestyle involving CrossFit workouts, eating organic food and skipping all meat except fish for five years.

“I was doing everything I could to avoid cancer,” Guevara says. But after all she had been through, her reaction was counterintuitive. “Getting that news, I felt a peace come over me. I just knew we were going to be OK.” And Guevara was right. Much like most patients with APL, she was OK. Outcomes are good if the cancer is diagnosed early and treated appropriately.

Patients typically come in with an infection, fatigue or shortness of breath, generalized symptoms that can occur with many conditions. The only distinctive symptoms are abnormal bleeding or bruising, although not all patients experience those, explains Matthew Mei, M.D., assistant professor of hematology at City of Hope National Medical Center in Duarte, California. Once a blood test reveals very low blood counts, the doctor orders testing — fluorescence in situ hybridization, often referred to as FISH; molecular polymerase chain reaction; or chromosomal karyotyping &mdash; to look for the 15;17 translocation.

But even before those results come back, doctors who suspect APL usually start patients immediately on all-trans retinoic acid (ATRA).

“APL can come on very explosively. It can be so aggressive that you start bleeding that day,” Mei says. Roughly 10 to 15 percent of patients with APL die very early, right around or even before diagnosis, from internal hemorrhaging, he added.

“The major cause of treatment failure is early death from this propensity to hemorrhage, since it can be very sudden,” Estey says.

Patients will also receive multiple blood transfusions early on to replace platelets and fibrinogen, a protein that helps blood to clot, explains Martin Tallman, M.D., hematologic oncologist, chief of Leukemia Service at Memorial Sloan Kettering Cancer Center in New York City.

“Although uncommon, APL is highly, highly curable,” Tallman says. “It’s a remarkable story that we’re able to not only cure this disease but cure it without chemotherapy.”

But when Guevara was diagnosed, she didn’t know any of this.

“I didn’t want to know the survival rate for my daughter or myself because it wasn’t going to help me,” she says. “I chose to keep my head in the sand for my family. I had my daughter’s life to fight for, and that gave me the extra bravery I needed.”

Thanks to three major advances since APL was first identified in 1957, the once highly fatal disease now sees complete remission rates of 90 percent and cure rates of 80 percent and even higher rates among low-risk patients.

The earliest treatments put only 5 to 14 percent of patients into remission, but the arrival of the chemotherapy agent daunorubicin in 1973 increased those rates to the 50 to 60 percent range and nearly halved the death rate. Then came a big breakthrough in the ’80s with the discovery of ATRA, a derivative of vitamin A that “opened a new era in the treatment of APL,” according to a 2015 article in Blood Cancer Journal.

“It was really the introduction of retinoid acid that dramatically changed outcomes,” Tallman says. “Before that, APL had a high mortality rate because of catastrophic bleeding in the central nervous system most commonly but also on the gastrointestinal tract.”

ATRA works by inducing the malignant white blood cells to mature normally, the first time a treatment countered cancer by encouraging normal development of the cells instead of outright killing them, Tallman says. Although ATRA could lead to complete remission in about 85 percent of patients, it wasn’t enough to completely cure people. Relapses from ATRA therapy alone were frequent, so the standard therapy became ATRA with daunorubicin or a similar chemotherapy agent, idarubicin.

The final breakthrough came in the 1990s with the discovery of arsenic trioxide’s therapeutic success. Although initially approved by the Food and Drug Administration as a second-line therapy in 2000, arsenic has now become standard first-line therapy because it’s so incredibly effective. Like ATRA, it induces differentiation and maturation of the malignant cells, but it also induces programmed cell death in those cells, allowing healthy cells to grow. ATRA and arsenic are now the backbone of all APL treatment protocols, Mei says, raising the cure rate into the 90 percent rate or higher range where it is today.

The use of these treatments also represents “one of the first and best examples of the future, which is precision medicine, the concept of providing specific targeted therapy for a patient with a specific molecular genetic abnormality,” Tallman says. “ATRA and arsenic specifically target the PML-RARa fusion protein.”

The next question was whether chemotherapy was needed at all. Estey was at MD Anderson Cancer Center in Houston when it became the first cancer treatment center in the United States to try a treatment protocol without a chemotherapy agent after seeing results from a Chinese study that suggested ATRA and arsenic were enough. “We said, ‘Well, maybe we only need to give ATRA and arsenic and not do chemotherapy,’” Estey says. Despite receiving some criticism for altering a treatment plan for a disease that already had a 90 percent cure rate, MD Anderson showed that using ATRA and arsenic alone led to complete remission in 96 percent of low-risk patients. Lowrisk patients are those with a white blood cell count of 10,000 or less and represent about 75 percent of all patients with APL. The remaining quarter are high-risk, with a white blood cell count above 10,000 and a higher risk of early hemorrhaging.

The ATRA-arsenic protocol cured only 79 to 81 percent of highrisk patients, so they continued to receive chemotherapy.

Then, in 2013, Italian researcher Francesco Lo-Coco published a critical study in the New England Journal of Medicine showing that treatment with ATRA and arsenic without chemotherapy led to better remission rates than with chemotherapy in low-risk patients. Highrisk patients are still recommended to receive chemotherapy on top of the ATRA and arsenic therapy.

“It turns out the treatment is probably less toxic,” Tallman says. “With that approach, we really cure 98 percent of low-risk patients.” The other 2 percent are patients who relapse but may still be cured by adding chemotherapy. High-risk patients remain at high risk for early hemorrhaging but have a similarly high cure rate when treated with ATRA, arsenic and chemotherapy — as long as they are treated quickly enough. The biggest obstacle that researchers haven’t been able to beat is the early death rate from hemorrhaging.

The early death rate is about 10 to 15 percent, higher than the relapse rate, Mei says, and researchers haven’t gotten below that number.

Thus, it’s one of the biggest areas of research. Another area of study is looking for ways to reduce chemotherapy in high-risk patients to reduce its toxicity. Patients typically receive four doses of idarubicin, daunorubicin or sometimes a similar agent, but some trials are looking at using just two doses, Tallman says.

Arsenic, like ATRA, can cause problems in the fetus during the first trimester of pregnancy. Initially, Guevara received only ATRA. But just over a week after starting the ATRA, she developed stomach cramps and shortness of breath.

“I kept trying to sleep, but I kept waking up gasping for air,” she says. Guevara went to the hospital and was soon coughing up blood. “They rushed me to the intensive care unit, and everybody was rushing around. It was a 24-hour blur. I was crashing, and they were prepared to take my daughter if I continued to crash. I couldn’t get any oxygen. Thankfully, she remained safe in my womb."

Guevara was experiencing differentiation syndrome, a serious side effect of ATRA. “Your body goes into overdrive and creates a whole army of blood cells at once,” Guevara says. As hordes of white blood cells mature at once, they release cytokines that leak out of the blood vessels and into the lungs and other parts of the body. Fortunately, the treatment is straightforward: a dose of steroids. And if the patient is at risk for it, this can prevent it.

Aside from differentiation syndrome, ATRA and arsenic are mostly well tolerated, Tallman says. Oncologists watch the liver because too much vitamin A can cause abnormal liver function results. They also keep close watch on the heart rhythm because ATRA can affect the QT interval, potentially leading to an irregular heartbeat or, rarely, cardiac arrest. Other side effects may include nausea, dry skin and cracking of the lips and mouth. For Guevara, she also experienced migraines at the start of each cycle of ATRA. In addition, she had hearing issues, ridges in her nails and mucus in her stools. She found solidarity in Facebook support groups and from the Leukemia and Lymphoma Society (LLS).

Then, in July 2016, at 38 weeks, Guevara gave birth to her daughter, Alianna Love, weighing in at 4 pounds, 10 ounces. “She was perfect in every way,” she says. Guevara was able to breast-feed for one month before she began the next round of ATRA and, now that she was no longer pregnant, arsenic. On February 24, 2017, she received her final treatment and was declared cancerfree in the middle of March.

Today, Guevara is actively involved with the LLS young survivors’ group. She encourages people not to wait if they are experiencing unexplained fatigue or bruising. “Unfortunately, we hear too many stories of people who waited too long for diagnosis and then they die soon after,” Guevara says of stories she has read in the Facebook support group.

These days, cancer isn’t a death sentence, she adds. In her case, a new chapter of life has just begun with the daughter she thought she would never have. “Had she come earlier when we were trying, I would have gone undiagnosed,” Guevara says. “She came at just the right time to save my life.”

Treatment advances mean high cure rate for patients with APL.

Advances Lead to Higher Cure Rate for Rare Leukemia Type

LARRY SALTZMAN, patient - PHOTO BY MARITA MADELONI

Larry Saltzman, 63, a family physician and marathon runner in Sacramento, California, was diagnosed with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in 2010.

Physicians predicted that he’d probably live about eight more years. After three years on a wait and watch protocol, in 2013, his doctors gave him the standard treatment at that time, a course of chemotherapy. He relapsed in 2015, and by June of that year he was losing weight and feeling terrible. He tried one targeted drug, Imbruvica (ibrutinib) but had severe side effects that resulted in abdominal surgery which revealed many cancer nodules and masses. At that point, Saltzman says, he and his medical team knew he was in serious trouble.

While waiting to be accepted into a clinical trial, his doctor advised that he try simultaneously taking two oral drugs that had not yet been tested in combination. This worked in a different way from all the treatments he’d had up to that point. He responded. 

Now Saltzman feels well enough to lead a big data initiative to design and build a national patient registry sponsored by the Leukemia & Lymphoma Society (LLS). The first phase of this project has been launched as the LLS Community.

“As a patient, I’m encouraged. I’m almost jubilant,” Saltzman says. “I’m going to beat that eight-year prognosis, and I’m going to beat it because of new treatments that didn’t exist when I was diagnosed. Each therapy, I view as a bridge to the next. I hope that each bridge I’m on gets longer and longer, because that’s what’s been happening.”

Brian Koffman, M.D., a family doctor and medical director of the CLL Society, a patient-education nonprofit organization, has had CLL for 12 years. “There’s never a good time to have CLL,” Koffman says, “but if you do have it, there’s never been a better time. They have cracked the biology of the disease, and there is now a flood of breakthrough therapies. However, not all patients are consulting doctors who are aware of this change. Patients may need to advocate for themselves. At the CLL Society, our motto is: Smart Patients Get Smart Care.”

CLL is a type of blood cancer, most commonly diagnosed in adults, that affects a type of white blood cell, a B lymphocyte, which grows in bone marrow. The disease often progresses slowly, although a faster-growing variation — SLL &mdash; tends to keep these lymphocytes from maturing properly. With SLL, these cancerous, immature B cells congregate in the lymph nodes rather than the bloodstream.

A decade ago, treatment options for CLL were depressingly limited. Since many cases progress slowly, patients might simply “watch and wait,” often for years, until their disease progressed enough to merit action. Patients could then opt for a type of chemotherapy such as fludarabine, cyclophosphamide and rituximab (FCR). If FCR didn’t work, further chemotherapy could be given. If the patient was healthy enough, the only other option was a harrowing bone marrow transplant.

BRIAN KOFFMAN, M.D., a family doctor and patient, says there is now a flood of breakthrough therapies in CLL. - LEAH LEE PHOTOGRAPHY

All that has changed. Research in the past 10 years has identified many targets that can kill the deranged CLL cells. Some of these are markers on the surface of cells. Some affect proteins that govern normal cell death. Still other treatments enlist the power of the body’s immune system to find and kill cancerous B cells.

Meanwhile, clinical trials are exploring the safety and efficacy of combining these various new treatments in myriad ways, as well as finding out if new immunotherapy approaches that have worked in other cancers might work for CLL. Specialists say we are entering an era in which CLL treatment is not one-size-fits-all but, instead, tailored to the biology of each person’s disease, depending on markers and genetic mutations. Chromosomal abnormalities are detected in up to 80 percent of patients with CLL.

“Two things have really changed: first, our ability to predict risk, and second, the number of choices in terms of therapy,” says Gwen Nichols, M.D., chief medical officer at the LLS. “All of a sudden, you’re a kid in a candy shop with a whole bunch of approved drugs.”

Traditional CLL staging systems — Rai, preferred in the United States, and Binet, used in Europe &mdash; relied on broad indications of disease burden: the amount of cancerous lymphocytes; whether the lymph nodes, liver or spleen was enlarged; and whether red blood cell or platelet counts were affected.

Research has begun to characterize each CLL case with a more biological view, helping doctors predict which cases will be slow growing and acute and which are most likely to respond to various treatments. For instance, if tests show changes in chromosomes — the bundles of proteins that contain our genetic code &mdash; especially in chromosome 17 or 11, that calls for more aggressive treatment. But patients with a 17p deletion are unlikely to respond to chemotherapy, and the current standard is to use novel, approved therapies, experts say. Another worrying change is Richter’s transformation, also called Richter’s syndrome, which occurs when CLL morphs into a more virulent malignancy &mdash; a form of non-Hodgkin’s lymphoma &mdash; and affects 2 to 10 percent of all patients with CLL/SLL during the course of their disease.

However, if a case of CLL shows a mutated gene for the immunoglobulin heavy-chain variable region, or IGHV, which essentially tells how mature the cancer cell is, that improves odds and makes it more likely that the patient will respond to FCR chemotherapy. A deletion in part of chromosome 13 also improves the outlook.

Clinicians now recommend that all patients with CLL get some sort of genetic screening, such as fluorescence in situ hybridization, or FISH, testing, which can map the genetic material in CLL cells to determine which treatment is most likely to work.

“The reason we [the CLL Society] exist is that many patients don’t get tested, or they may be tested, and the doctors still choose the wrong therapy,” Koffman says. “The developments are coming fast, and the news hasn’t got down to community hematologists. That’s why one of our mottoes is, ‘Test before treat.’”

The first class of drugs to create excitement among CLL specialists works by interfering with B-cell receptors. These receptors are crucial if B cells are to do their job, or proliferate; they also play a key role when B cells go rogue and turn cancerous. Various new drugs take advantage of this by jamming this signaling system, creating agents that bind to receptors and block those that allow cancerous cells to multiply, or by interfering with kinases, enzymes that play a role in amplifying or tamping down B-cell signals.

Imbruvica, an oral drug that is approved by the Food and Drug Administration (FDA) for all stages of CLL, blocks Bruton’s tyrosine kinase, or BTK, and inhibits several other kinases. In initial studies, 70 to 80 percent of patients (even those with bad markers) responded to the drug, 5 to 10 percent achieved complete remission, and 60 to 70 percent achieved partial remission. Most patients survived 2.5 years without progression. The median number of therapies tried before starting Imbruvica was four, making this a game changer for those with more advanced, such as relapsed or refractory, CLL. For patients with 17p genetic mutation, this is a first-line treatment.

Zydelig (idelalisib), another FDA-approved oral drug, blocks phosphoinositide 3-kinase (PI3K). PI3K mediates the pathway that is critical for the survival of B cells and often is overactivated in CLL. A phase 3 trial showed that Zydelig was most effective when administered along with Rituxan (rituximab), an approved monoclonal antibody. “In all phases of CLL treatment, chemo is fading away,” says Nitin Jain, M.D., of the department of leukemia at MD Anderson Cancer Center in Houston. “Some younger patients with the IGHV mutation might do well on chemo, but for all other patients, including those with relapsed refractory disease, the standard would be to use one of the new targeted therapies, one that is FDA approved or in clinical trials.”

Rituxan has become a standard part of treatment for CLL and a component of FCR chemotherapy, and is used in combination with various new, targeted therapies. The monoclonal antibody binds to a certain marker, CD20, on the surface of CLL cells. It is thought that through this action, the drug flags those cells for destruction by the body’s immune system.

 Koffman initially responded to the combination of Rituxan and a chemotherapy drug before doing a bone marrow transplant, and then one of the BTK inhibitors. Another anti-CD20 monoclonal antibody, Gazyva (obinutuzumab), has been approved as a first-line treatment for CLL in combination with the chemotherapy drug chlorambucil, and Arzerra (ofatumumab) has been approved in later lines of therapy.

Venclexta, another drug recently approved by the FDA, targets the B-cell lymphoma 2 (BCL-2)protein that blocks a process called apoptosis, or programmed cell death. Cells throughout the body regenerate, making it necessary for older cells to die off so that they can be replaced with new cells. Unfortunately, patients with CLL have more of the BCL-2 protein, so their CLL cells resist normal cell death. Venclexta blocks the protein, clearing the way for the rogue CLL cells to die.

MARK HOFFMAN, patient - PHOTO BY ROB ANDREW

With so many new markers and possible treatments and literally hundreds of clinical trials under way, patients with CLL can expect even more options to be approved in the next few years.

Some teams are investigating second- and third-generation BTK inhibitors with more exact targeting. There have been phase 2 trials of another inhibitor, selective spleen tyrosine kinase, but two trials were halted due to serious side effects such as pneumonitis, or inflammation of the lung tissue.

Although the data from Imbruvica and Zydelig are heartening, it’s rare that a patient has a complete response when taking these drugs alone, experts say. Accordingly, many trials, some as far along as phase 3, are comparing different dosing schemes and using these agents in combination with other treatments, such as chemotherapy or various monoclonal antibodies. Mark Hoffman, 53, a tech salesman in San Diego, has a 17p deletion in addition to other high-risk genetic markers. His white blood cell count peaked at 90,000 (the normal range is 4,500 to 11,000 per microliter). In January, Hoffman began a clinical trial combining Imbruvica with Venclexta. “My blood cell counts are down to normal now,” says the married father of three. “I can work, and I can continue to enjoy backpacking, cycling and other activities.”

Researchers are also exploring different targets for monoclonal antibodies, including different forms of CD20, the target for the FDA-approved Rituxan. They are also looking at completely new targets for monoclonal antibodies including different cell surface proteins: CD37, CD23, CD19 and CD79-B. In the long term, Nichols says, experts are searching for more biomarkers: “We’re now moving from initial risk biomarkers to those that predict the risk of relapse.”

“People are living longer,” Koffman says. “Research is ongoing to find combinations to eliminate the disease with no chemo and to be able to stop therapy without fear of relapse. Then, and only then, we might say that CLL is cured.”

Researchers are identifying targets to treat chronic lymphocytic leukemia.

A Personalized Era in Chronic Lymphocytic Leukemia Treatment

When Rose Zumbiel was diagnosed with myelodysplastic syndrome at age 48, she was far from the average patient. Myelodysplastic syndrome, or MDS, tends to affect older individuals — average age at diagnosis: 71 &mdash; and occurs more often in men than women.

The condition can occur when stem cells in the bone marrow are damaged and may not properly mature into red blood cells that carry oxygen, white blood cells that fight infection or platelets that help blood to clot. In fact, until recently, MDS was sometimes called “preleukemia” because the disease can progress into acute leukemia.

Approximately 13,000 people in the United States are diagnosed with the disease each year.

“When I was diagnosed, they told me they did not even really have a name for what I had,” Zumbiel, now 69, recalls. “It was known as a rare blood disease.”

After beginning a regimen of low-dose aspirin to stave off heart disease, Zumbiel began to notice large bruises on her legs and thought the aspirin might be thinning her blood too much. Her family doctor ordered blood work, which came back normal. However, a second blood test several months later revealed a platelet count of 150,000 per microliter of blood, at the bottom of the accepted normal range of 150,000 to 400,000 per microliter. Eventually diagnosed with MDS by a hematologist, Zumbiel was left wondering how this happened to her.

“MDS is a result of damage to the DNA of the cells in the bone marrow. Those injuries accumulate during life,” says David P. Steensma, M.D., an associate professor of medicine at Harvard Medical School in Boston. “A 70-year-old person has more DNA changes than a 40-year-old, and a 40-year-old has more than a teenager. They occur randomly whenever a cell divides and DNA is copied, just as randomly as when medieval scribes used to transcribe manuscripts and accidently put the wrong letter in the wrong place. Most of the time, those mistakes have no major consquence, but, if by random chance the DNA is written in the wrong place on the wrong day, it can cause quite a dramatic change in bone marrow behavior — just like certain letter changes may change the meaning of a word.”

There are few clear risk factors for developing MDS, Steensma said. In addition to older age and male gender, prior treatment with chemotherapy or combination chemotherapy and radiation therapy may increase the likelihood of developing MDS, known as treatment-related MDS. Some evidence also indicates that genetic syndromes, smoking or environmental exposures, such as to the chemical benzene, can also increase risk.

Patients with low platelet counts (thrombocytopenia) might experience bruising, like Zumbiel did, or bleeding in the nose, gums or stool. According to Steensma, a low platelet count occurs in about one of every three cases of MDS and is the only dominant feature of the disease in 5 percent or fewer cases. “Low platelet counts are not a big problem until they get much lower, around 30,000 per microliter or below,” Steensma says.

The most common symptom of MDS is a reduced level of red blood cells, or anemia, seen in 70 to 75 percent of cases, says Thomas Prebet, M.D., Ph.D., an associate professor of hematology at Yale Cancer Center in New Haven, Connecticut. Symptoms of anemia include shortness of breath, unusual paleness and fatigue.

“Low red blood cell counts with larger-than-average red cells, called macrocytic anemia, is one of the hallmarks of MDS,” Prebet says. “More than two-thirds of patients with MDS will at one point of their disease require some transfusion of red blood cells.”

JOAN POWELL, 64, is involved with the Aplastic Anemia and MDS International Foundation to help raise awareness.- PHOTO BY LAURA SCHMIDT

Joan Powell, 64, has become familiar with fatigue and transfusions since her diagnosis of MDS in 2014. Always a go-getter, Powell started consistently experiencing extreme fatigue and weakness. Her sister urged her to visit a doctor and get blood work done. The results revealed anemia, and the physician told her to go to the emergency department right away because she required a transfusion.

Normal hemoglobin levels are above 12 grams per deciliter for women and 13.5 grams for men. “My count was five,” Powell recalls. “I was in crisis mode. I was given three packs of blood, connected to a heart monitor and oxygen, and given a variety of tests. I was in the hospital for three days.”

“In these cases, having anemia is like living with a backpack of 50 pounds on your shoulders each minute of life,” Prebet says.

Powell’s physicians ran a battery of tests in search of an explanation for her symptoms until they finally diagnosed her with MDS. “It was a shock to my world,” Powell says. “They told me it was not curable — treatable but not curable.”

Often, people with MDS have no symptoms and are diagnosed only after undergoing routine lab work. Sometimes diagnosis follows an infection in people found to have a low number of white blood cells called neutrophils, a condition called neutropenia, which increases risk of infection.

People with MDS may have issues with any one — or all three &mdash; of these types of blood counts.

The only potential cure for MDS is stem cell transplantation. However, this often requires a high-intensity preparative conditioning regimen, which limits the number of people healthy enough to undergo the procedure. Transplantation can be done for patients who are under age 75, are otherwise healthy and have a matched donor.

Usually, people with MDS undergo treatments to reduce or manage symptoms, known as palliative or supportive treatments. The use of specific therapies often depends on whether the disease is classified as lower or higher risk. This is based on several characteristics found in the blood and bone marrow, including the number of immature cells (called blasts) and blood counts, as well as the results of studies looking for chromosomal and genetic abnormalities.

“If a patient has lower-risk MDS with a low risk to progression of leukemia, we think the disease will potentially have a long duration and evolution, and we try to focus on the management of the cytopenias (a reduction in the number of blood cells) and delay more aggressive treatments,” Prebet says. “In higher-risk cases with a higher risk to progression of leukemia, we have to use active treatment more systematically and more quickly.”

Although Zumbiel’s platelet counts remained manageable for many years after her diagnosis, they eventually dropped below 30,000 per microliter, and her hematologist recommended a platelet transfusion.

“Unfortunately, the half-life of platelets is very short,” explains Kebede H. Begna, M.D., an assistant professor of medicine at Mayo Clinic in Rochester, Minnesota. “Even newly synthesized platelets only usually survive about 14 days, meaning that individuals may require multiple transfusions.”

Transfusions are often required in patients with low red blood cell counts, too. Powell calls the red blood cell transfusions she undergoes every 4 to 6 weeks her new normal. “My life has begun centering around MDS,” she says.

For each transfusion, she travels to the hospital for an 8- to 9-hour outpatient procedure. The frequent visits have made her close with the staff and nurses and opened her eyes to the generosity of people who donated the blood that flows into her veins with each transfusion, she says.

Frequent transfusion carries several risks, however. “Platelet transfusions can cause allergic reactions, fever or hives,” Steensma said. “Over time, recurrent platelet transfusion exposes the body again and again to foreign platelets and the body may start to form antibodies — that is called being platelet refractory or alloimmunized.” Alloimmunization can also occur in patients undergoing transfusions for red blood cells.

Patients who undergo multiple red blood cell transfusions per month also run the risk of developing iron overload, Prebet said. Excess iron can be stored in important organs such as the heart and liver and, down the road, impair function. Treatment for iron overload may depend on a person’s life expectancy. In people with lower-risk disease, iron overload can be treated with removal of the blood, or phlebotomy.

This cannot be done in patients who are anemic. In addition, two FDA-approved iron chelators are commonly used for anemia related to MDS. Intravenous Desferal (deferoxamine) is given via a pump, often during nighttime rest. The second iron chelator Deferasirox comes in two tablet forms: Exjade, dissolved in juice or water once daily, or Jadenu, taken once daily on an empty stomach or with a light meal.

White blood cells cannot be transfused, though. “White blood cells’ job is to recognize what is you and what is foreign, so if we put your white cells into me, they would be very confused and vice versa,” Steensma says.

For low white blood cell counts, recombinant human granulocyte colony-stimulating factor or recombinant human granulocyte—macrophage colony-stimulating factor can be used to stimulate production of a patient’s own white blood cells.

Low-intensity chemotherapy may also be given to patients with MDS in an attempt to change bone marrow cells so they produce normal red blood cells, white blood cells and platelets.

After undergoing a platelet transfusion, Zumbiel began receiving Vidaza (azacitidine), a low-intensity chemotherapy shown to increase survival and improve quality of life in patients with MDS. Six months of treatment brought her platelet count back up to about 57,000 per microliter. The two other FDA-approved chemotherapies used for MDS are Dacogen (decitabine) and Revlimid (lenalidomide).

In between transfusions, Powell takes a hematopoietic growth factor called Procrit. Hematopoietic growth factors promote growth and development of blood cells but are not always effective in people with MDS.

Despite the promising treatments being explored in oncology, it is difficult to know what the future holds for patients with MDS. “There have been some exciting new drugs in solid tumors, like immune checkpoint inhibitors, but those tend not to be as effective in MDS or leukemia, especially as single agents,” Steensma says.

More work also needs to be done toward understanding the disease and identifying genetic mutations that might provide a target for treatment. “In MDS, there are more than 40 different genes that have been found to be mutated in the bone marrow, and no single gene is mutated in more than 20 percent of patients,” Steensma says. “That is a real problem for designing targeted therapies, since no single drug is likely to work for a large proportion of patients.”

Begna hopes to begin to more effectively harness next-generation sequencing — now used to classify patients and provide prognosis &mdash; to understand the characteristics of the different forms of leukemia cells associated with MDS.

Two drugs under study, sotatercept and luspatercept, trigger a hematologic response, improving red cell counts in about 60 percent of patients with mutations in the transforming growth factor—beta signaling pathway, according to Prebet. “It will not be used for all patients, but in patients with MDS harboring ring sideroblasts and/or an SF3B1 mutation, there is some real hope that this medication will have some efficacy,” he says.

Like MDS treatments, Powell and Zumbiel both face uncertain futures.

Powell’s disease is currently considered lower risk, and her experience has inspired her to become more active in the MDS community. She is involved with the Aplastic Anemia and MDS International Foundation’s Patient Advisory Committee on Clinical Trials (PAACT+), which was designed to bring a patient voice to the industry and academic researchers focusing on rare bone marrow disorders.

“In this group, we are able to have well-rounded conversations with patients, caregivers, doctors, nurses and researchers to let people know that this disease exists [and] what it is like and to find out more about what they are doing to help us,” Powell says.

After living for two decades with MDS, Zumbiel has begun to consider herself cured. Shortly after receiving definitive confirmation of her MDS diagnosis with chromosomal tests, her platelet counts began to recover, with her most recent counts upward of 180,000 per microliter.

She credits her physician and her prayers to Saint Padre Pio for her recovery. “I am always a mess when I go for my blood counts, but you have to just trust your doctors and pray that you are strong enough to get through it,” Zumbiel said. “Whatever happens, you can take it!”

Injured DNA can hide damaged blood cells in myelodysplastic syndrome (MDS).

Hematology Special Issue (September) | CURE

Treatment Stages for a Rare Leukemia

Bringing Cancer Care Closer to Home

Helping Children Cope With Your Cancer

Advances Lead to Higher Cure Rate for Rare Leukemia Type

A Personalized Era in Chronic Lymphocytic Leukemia Treatment

Why Blood Counts Matter in Myelodysplastic Syndrome

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