The Middle Ages: Controversies in the Treatment of Adolescents and Young Adults With Leukemia

Over the past few decades, survival rates for pediatric patients with acute lymphocytic leukemia (ALL) have improved dramatically, with five-year survival rates now often exceeding 90 percent and 10-year survival rates exceeding 80 percent, according to a review of Children’s Oncology Group ALL trials between 1990 and 2005.1 These improvements were seen regardless of patient sex, age, ethnicity, and immunophenotype.

These statistics pertain to patients diagnosed in infancy through those diagnosed at age 22, however, leaving out a substantial portion of one of the most challenging-to-treat segments of the ALL population: adolescents and young adults (AYAs).

Patients who fall into this age group (typically defined as people aged 15 to 39 years) experience worse outcomes than their pediatric counterparts and have not seen similarly dramatic increases in survival.2 According to a 2009 study published in Blood, five- and 10-year survival rates for patients between the ages of 20 to 29 were just 44.8 percent and 38 percent, respectively.3

The contrast between the two groups’ survival outcomes has sparked new efforts to figure out what makes ALL in AYA patients distinct from ALL in pediatric – and even adult – patients.

Research into the survival outcomes of AYA patients has only highlighted the group’s heterogeneity. Studies have suggested that patients aged 15 to 39 years have better prognosis when treated with a pediatric regimen rather than an adult regimen, but survival rates vary significantly based on where they receive that treatment and a host of other psychosocial factors.

“Depending on the center or the site, the issue of where AYA patients should be treated – and whether they should receive a pediatric or adult regimen – is still up for debate,” said Anjali Advani, MD, director of the inpatient leukemia unit and professor of medicine in the Cleveland Clinic Lerner College of Medicine.

ASH Clinical News spoke with Dr. Advani and clinicians specializing in the treatment of pediatric and AYA patients with leukemia about what defines this distinct patient group, who should be treating them, and why the issue continues to ignite controversy.

Who Are AYAs?

Age is only a number, and there are many qualities that distinguish AYA patients with leukemia from patients at either end of the age spectrum – and that affect their overall survival.

“Everything changes during the adolescent and young adult years, compared with childhood,” said Wendy Stock, MD, the Anjuli Seth Nayak Professor in Leukemia at the University of Chicago. “That has to do with the biology of the disease and, of course, with the biology of the person with the disease.”

These factors all play a role in how ALL affects patients’ lives. “Psychologically, these people are very different from children with leukemia and they face different problems,” she added. Until recently, there had been little research focused on AYA patients, according to Dr. Stock, making it difficult to draw any conclusions about why ALL in this patient population traditionally responded poorly to treatments, compared with ALL in pediatric patients.

“[AYAs] have been under-represented as an entity in clinical trials. They are  the patient group with the lowest accrual for any kind of clinical trial in cancer because there was virtually no focus on this age group in clinical trials,” said Dr. Stock, who directs the leukemia program at the University of Chicago. Enrollment rates in NCI-sponsored trials for people aged 15 to 22 years, for example, averaged about 22 percent, while rates among pediatric and adult patients averaged 38 percent and 27 percent.4

“These patients often were just split in terms of where they would seek care, without little information about why,” Dr. Stock said, but recently, research has given hematologists/oncologists more insight into how ALL manifests in this patient group.

Certain factors of leukemia in the AYA population confer a worse prognosis than is seen within pediatric patients: For example, the presence of the Philadelphia chromosome (Ph) increases with age, and more AYA patients than pediatric patients have Ph-positive disease – a genetic signature that often signals that a patient will not respond as well to treatment.5

According to Dr. Advani, Ph-positive B-cell ALL occurs in approximately 20 to 30 percent of the AYA population and is seen much less frequently in pediatric patients. “Now, there are clinical trials ongoing to specifically treat patients with this type of disease, which is important, because results from those trials could give us insights about a feature that is unique to this population,” she said.

In addition, pediatric patients under the age of 10 are more likely than older AYA patients to display favorable cytogenic features, such as having hyperdiploidy in leukemic blasts, favorable trisomies of chromosomes 4, 10 and 17, or the TEL/AML translocation.6 AYA patients also are more likely than children to present with more high-risk factors, including the T-cell phenotype or the BCR-ABL–like molecular signature.

Compared with patients older than 40 years, on the other hand, AYA patients in general have genetic and molecular differences that confer a more favorable prognosis.

As a patient ages, his or her ability to tolerate certain medications critical to the treatment of leukemia – particularly ALL – also changes. Older patients often are not able to tolerate high-intensity regimens as well as children.

“Older patients have more toxicities and also have a ‘biologically harder’ disease that is more resistant to the standard treatments we have,” Dr. Stock noted, “so treating ALL in AYA patients poses a particular challenge.”

Psychosocial Challenges

As patients transition from adolescence to adulthood, their lives become exceedingly more complex – emotionally, financially, and socially. People at the lower end of the AYA age spectrum may no longer be living at home with their parents and might be immersed in college life or beginning their careers or families; people on the higher end of the age spectrum may be concerned about treatment and side effects taking away time from their family and careers.

All these factors complicate treatment decisions and concerns about treatment compliance, according to Sumit Gupta, MD, PhD, a clinical investigator at the Hospital for Sick Children in Toronto.

“The psychosocial challenges are significant,” he said. AYA patients often are dealing with a blend of factors unique to their age group, like an increased focus on romantic relationships, body image concerns, or grueling school demands. “I have many patients who don’t want to take steroids because it can lead to weight gain, or perhaps they don’t want to fall behind their peers in their classes because they have to take time away to undergo treatment.”

Dr. Advani said that the same is true for patients in their 30s. “Even though they are young, these patients may be married and trying to support their own families, so this can be a very difficult time to be going through a diagnosis and treatment of ALL.”

Navigating these psychosocial challenges requires time and expertise that not all physicians, nurses, or other health-care providers who typically treat pediatric or older adult patients can provide.

Pediatric patients are more likely than older patients to be adherent with their treatment regimens; living with their parents means having someone available to ensure patients are taking their medications or getting to appointments.7 “However, AYA patients are often independent and have fewer support systems in place,” Dr. Stock said. “These are long, arduous therapies that can take years to complete and [require] frequent visits to the physician’s office, so getting people through treatment is a challenge.”

AYA patients also are more likely than any other age group to lack health insurance. For example, in 2008, 28.6 percent of people aged 18 to 24 years and 26.5 percent of those between 25 and 34 years lacked coverage; by comparison, less than one-fifth of people aged 35 to 64 years, and less than one-tenth of children under age 18 were uninsured.8 Experts say this may be changing though, since the Affordable Care Act allowed children to stay on their parents’ insurance until age 26.

Although the implications haven’t been fully studied yet, Dr. Stock said she hopes this change makes it easier for older young adults to obtain insurance coverage for their treatment medications.

Pediatric vs. Adult Protocols

Economic and psychosocial factors may contribute to the poor outcomes observed in the AYA leukemia population compared with the pediatric population, but the most critical – and most easily modifiable – factor is the type of protocol used in each age group. Within the past decade, research has consistently shown that, despite the biologic and social differences between pediatric and AYA patients, both groups derive a greater benefit from pediatric-directed protocols.

Many of the most commonly used pediatric-based regimens are modeled off the Berlin-Frankfurt-Munster regimen, with a heavy reliance on non-myelosuppressive agents, including vincristine, steroids, and asparaginase, delivered in low single doses, but in high cumulative doses of each individual agent.

Adult protocols, however, are characterized by greater use of myelosuppressive agents, including cyclophosphamide and anthracyclines, with little or no use of asparaginase, which is perceived to be prohibitively toxic in adults, Dr. Advani explained.

She also noted that pediatric regimens typically include more steroids, longer intrathecal chemotherapy, and, typically, longer maintenance phases than adult treatment protocols. “Paradoxically, pediatric-directed regimens are more aggressive than adult protocols,” Dr. Stock said. “It’s all the same medications that most adult groups have studied, but in different proportions and on different schedules.”

Location, Location, Location

With so much evidence favoring pediatric protocols for patients younger than age 40, “most people – myself included – would say that that problem is pretty much solved,” Dr. Gupta said. “If you are an AYA patient with ALL, then you should be receiving a pediatric protocol.”

The next problem to tackle is where patients should be undergoing this type of treatment. Most AYA patients undergo treatment at adult centers, where providers may not be well-versed in pediatric-based protocols. Dr. Gupta pointed out that his research group, along with several others in the U.S. and across Europe, has compared survival outcomes in AYA patients treated at either pediatric or adult centers and “found pretty consistently that the survival outcomes were about 15 to 20 percent better in pediatric institutions,” Dr. Gupta reported. In a review of 15- to 21-year-old patients diagnosed with ALL between 1992 and 2011, he and coauthors found that five-year event-free survival and overall survival was 72 percent and 82 percent for patients treated at pediatric centers, but 56 percent and 64 percent for those treated at adult centers (p=0.03 and p<0.001 for comparisons).9

This finding was replicated once again in a 2018 study led by Lori Muffly, MD, MS, from the Stanford University Department of Medicine. The study examined the patterns of care and outcomes in AYA patients newly diagnosed with ALL between 2004 and 2014 identified from the California Cancer Registry.10 Even after controlling for age and examining the data in multiple analyses, researchers found that those patients who were treated at pediatric centers had significantly better outcomes: Compared with those treated in adult settings, patients treated in pediatric settings had significantly higher overall survival (hazard ratio [HR] = 0.53; 95% CI 0.37-0.76; p=0.001), as well as higher leukemia-specific survival (HR=0.51; 95% CI 0.35-0.74; p<0.001).

“This finding was so significant that it suggests that perhaps the age limit for treating this particular disease at pediatric centers should be increased to at least 25,” commented Dr. Muffly.

Treatment at a National Cancer Institute (NCI)-designated center or Children’s Oncology Group (COG) center also was associated with higher overall survival, compared with treatment at community hospitals (HR=0.80; 95% CI 0.66-0.96; p=0.019). However, both studies were retrospective and may not have accounted for all factors that influenced outcome.

“Physicians and treatment teams in pediatric and NCI-designated cancer settings may be more experienced in caring for AYA patients with ALL,” Dr. Muffly said, “and this in part may explain why we are seeing better outcomes in these centers.”

This idea was supported by the fact that, when adult centers used the pediatric ALL regimen, there was no significant difference in survival outcomes, compared with adult centers that used the adult regimen. However, she noted that these data were collected only from 2009 through 2014; due to the complex nature of the pediatric regimen, adult centers who used the pediatric protocol included in the study may have still been adjusting to the protocol.

The U.S. adult intergroup trial, C10403, also examined survival outcomes among AYA patients who received a pediatric-inspired regimen in an adult setting.11 Early results from the trial presented at the 2014 ASH Annual Meeting, which included 296 patients, revealed that two-year event-free and overall survival rates were 66 percent and 78 percent, which compared favorably with historic controls.

According to Dr. Advani, one of the study’s coauthors, these numbers also were comparable to AYA survival rates when patients were treated at pediatric centers. “At least on the C10403 trial, outcomes looked equally good if AYA patients were treated at either adult or pediatric centers,” she said.

Dr. Stock agreed that the key to improved outcomes among AYA patients treated at pediatric centers is practitioners’ experience level. “A number of studies have now demonstrated better outcomes with pediatric protocols delivered at pediatric centers,” she said. “That’s partly because pediatricians are treating pediatric patients in one specific way, while adult patients at adult centers are treated with a wider variety of protocols.”

With Age Comes Wisdom

While Dr. Muffly’s study relied on population-level data to give researchers a glimpse of real-world practice outside of the realm of clinical trials, she noted that the inclusion of registry data meant that the authors were unable to account for a number of variables that may have affected patients during their treatment. It is difficult to determine whether the ideas supported by clinical trials and retrospective analyses have translated to the clinic.

For instance, two-thirds of the AYA population in their study received treatment at adult settings, “despite this being the most common pediatric cancer and a very, very rare cancer in adults,” Dr. Muffly said.

Also, just one-quarter of these patients were receiving pediatric-directed regimens at adult centers, though the treatment landscape may have changed since 2014, when data collection ended. “Our data don’t necessarily mean that this will hold true for 2019 and beyond, but it shows us where we may need more answers and guidance.”

Does that mean adult centers should embrace pediatric protocols? Perhaps, according to Dr. Muffly, but adult centers may be reticent to head in that direction. It may make more sense for pediatric centers to take on older patients.

“There’s a big learning curve to understanding how to use pediatric regimens in young patients with ALL,” she said. “For pediatric ALL specialists, this is their bread and butter – they can manage ALL in their sleep. But, for adult specialists, it’s a rare disease unless all you see is ALL.”

However, Dr. Advani said, “patients have to be treated where they are. If a clinician calls me from an outlying facility without good access to pediatric resources, he or she has to weigh the risks and benefits.”

Due to the complex and intense nature of the pediatric regimen and its follow-up, centers often need to have resources in place to aid in scheduling, executing a treatment plan, and overcoming the unique obstacles faced by this patient group. “At a pediatric oncology clinic, our volumes are significantly smaller on average than that of your average adult hematologist,” Dr. Gupta said, offering the following example. “If I have a 17-year-old who is not compliant with oral chemotherapy, I have time to really ask those questions and, hopefully, to figure out whether he or she is compliant or not.”

Crossing the Age Gap

While there is still controversy surrounding the issue, experts who spoke with ASH Clinical News agreed that the evidence points in one direction: AYA patients with ALL should receive a pediatric inspired regimen. This may require shifts of treatment center policy and the mindset of treating oncologists, given the unique considerations of the AYA patient and the complexities of the pediatric chemotherapy regimen, which often require intense patient support. Whenever possible, specialists with experience in treating this patient subgroup should be involved in treatment discussions.

According to Dr. Muffly, if a patient is “on the bubble” and can go to either a pediatric or adult center, but the adult center lacks clinical trial options or clinical expertise in treating ALL, it may make more sense to send the AYA patient to the pediatric center.

Over time, the barriers that exist now between pediatric, adult, and AYA patients may break down, shifting the question from who “owns” ALL to how pediatric and adult specialists can work together to achieve the best outcomes in patients with ALL under the age of 40 – regardless of the setting.

“There’s little reason – outside of regulatory decisions – to separate this disease into pediatric or adult spheres,” Dr. Muffly said. “Pediatric and adult hematologists and oncologists should be working together, learning from each other, and conducting studies across the age spectrum.” —By Jill Sederstrom


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