International Partnerships Lead to Strides in Pediatric Leukemia in El Salvador

Although acute lymphocytic leukemia (ALL) is relatively rare, it is the most common cancer diagnosed in children, representing approximately one-quarter of cancers diagnosed in those younger than 15 years.1 Physicians and researchers made incredible strides in treating ALL in children over the past few decades, with the introduction of intrathecal chemotherapy combinations and refinement in dosing and management of adverse events.

These developments transformed what was once considered a uniformly fatal cancer into one with a cure rate approaching 90 percent. However, these advances didn’t translate to many low- and middle-income countries, where the disease remained a death sentence for children.

Until recently, El Salvador was one such country. In 1990, more than 90 percent of children with ALL did not survive into adulthood. That was the grim prognosis facing the mother of a young Salvadoran boy who was diagnosed with ALL in 1990, shortly after his country had emerged from a civil war. The mother, seeing no viable options for treatment in El Salvador, decided to seek treatment in the U.S., recounted Raul C. Ribeiro, MD, a member of the oncology department at St. Jude Children’s Research Hospital in Memphis. She flew with her child to Tennessee for treatment at St. Jude, but unfortunately he died shortly thereafter.

Upon returning to El Salvador, the mother was determined to bring medical expertise found in the U.S. and other high-income countries back to the children in her own country, so that they could consistently receive efficient diagnoses and quality treatment.

She founded the Fundación Ayúdame a Vivir (Help Me to Live Foundation) in 1991 in memory of her son. For two years, the foundation raised money on its own. Then, in 1993, the mother delivered an impassioned plea for help to representatives from St. Jude; the hospital obliged.

Since 1997, Dr. Ribeiro has served as director of the hospital’s International Outreach program – an initiative to share knowledge, technology, and organizational skills worldwide to help increase childhood cancer cure rates. During his tenure, Dr. Ribeiro has helped establish partnerships with 19 medical institutions in 14 countries.

These thriving collaborations have since become models for treating cancer in other low- and middle-income countries throughout the world: In 1993, the five-year survival rate for children with ALL in El Salvador was only 5 percent; in 2000, it climbed to nearly 50 percent.2

“With childhood leukemia, the single biggest predictor of whether you recover or not is where you happen to have been born,” Carlos Rodriguez-Galindo, MD, chairman of St. Jude’s global pediatric medicine department. told The New York Times.3 “We’re talking about many thousands of young children dying every single year of diseases that we have known how to cure for decades.”

ASH Clinical News spoke with Dr. Ribeiro and Roberto Vasquez, MD, a pediatric oncologist at the Benjamin Bloom Hospital in El Salvador, about the challenges of implementing this program, the success it has generated, and where else such a program might flourish.

Lower Income, Higher Prevalence

ALL is the most expensive childhood cancer to treat. Recent estimates place the average cost of inpatient treatment between $191,082 and $216,439, which translated to daily costs ranging between $2,283 and $2,840.4

But it is estimated that 80 percent of children who are diagnosed with cancer live in low- and middle- income countries.5 There, it is rare for a child to have access to high-quality treatment, and those who do are often forced to abandon it due to high costs and long travel distances. Only one in five of these children will be cured.

According to Dr. Vasquez, in 1991, the Benjamin Bloom Hospital in San Salvador, El Salvador’s tertiary care hospital for children, had no pediatric oncologists or nurses on staff who were trained specifically to care for patients with leukemia. At the time, nearly half the country was in poverty – meaning that few of the children who received a timely diagnosis were able to pay for effective treatment. Rates of treatment-related mortality remained high compared with those among children in higher-income countries.

Treating pediatric ALL was not a priority when limited resources might go further in treating patients with simpler, more common diseases, Dr. Vasquez explained.

Beginning With Twinning

After the mother’s appeal, St. Jude agreed to support a program in El Salvador for one year. The group conducted a site visit and developed a plan to deliver high-quality treatment for pediatric ALL at the Benjamin Bloom Hospital.

In 1993, the five-year survival rate for children with ALL in El Salvador was only 5 percent; in 2000, it climbed to nearly 50 percent.

During this 12-month period, researchers and clinicians from St. Jude communicated with doctors in Benjamin Bloom’s new leukemia program, providing guidance for patients’ individual treatment plans through phone calls and emails. Blood and bone marrow samples were sent to the U.S. for immunophenotyping and classification.

The partnership also provided funding for an essential component that was missing from Benjamin Bloom: specialized staff. The hospital could not justify spending more on one department at the expense of its others, so St. Jude supplemented salaries for some physicians. “Overall, our investment totaled $100,000, more or less,” Dr. Ribeiro recalled. He noted that the hospital’s physicians were eager to take on extra work and responsibility.

Along with the constant communication, St. Jude sent members of the Salvadoran hospital staff to Mexico to train in pediatric oncology and gave them opportunities to visit St. Jude in Memphis for additional guidance on specific techniques.

Next, the group set up a training program for staff physicians and nurse specialists at Benjamin Bloom.2

After the collaboration’s initial 12 months, securing sustainable financing remained the biggest challenge. The program was backed by St. Jude, but in the long term, the country would have to find ways to rely on minimal outside support.

“[After hearing about the new leukemia program], people came to our center to be treated,” said Dr. Vasquez. “We actually had not only families, but also churches and communities bringing children in just to ensure that the children would have the chance to be treated.”

Once the program gained the support of the surrounding community, it became easier to show the local government the importance of funding the care. The program’s early success was “a very energizing thing for the locals, and that spread to the government,” said Dr. Ribeiro.

Now, El Salvador’s public health-care system covers ALL treatment for all children. This support is crucial, Dr. Vasquez explained, because, without it, most patients would not be able to complete the multiple rounds of therapy.

In the subsequent years, the Benjamin Bloom Hospital began performing immunophenotyping and flow cytometry on site. The results are still shared with doctors in Tennessee, but the Salvadoran team no longer needs to send the samples to the U.S. via express mail.

The newly established infrastructure also helped patients with cancers outside of ALL. “We could now treat other pediatric cancers that are also curable with chemotherapy,” said Dr. Ribeiro, including Hodgkin and non-Hodgkin lymphoma.” The longstanding stigma around a cancer diagnosis in childhood was reduced, as residents had contact with more and more survivors.

Customizing Treatment Plans

The gains in survival are undeniable, but establishing a team of specialists and increasing funding are only the first steps toward the goal of raising survival rates in El Salvador to those in higher-income countries. Researchers at St. Jude and in El Salvador have been working together to identify other barriers to successful treatment.

One study published in 2015 showed that, even when treatment was provided at no cost to patients, 13 percent of families still neglected appointments.6 To address this issue, researchers from San Salvador and Memphis designed a treatment-adherence tracking system: Families were contacted any time a patient missed an appointment and were interviewed about their reasons for treatment abandonment and nonadherence. If clinicians were unable to contact families of patients who missed appointments but who had a good prognosis, they turned to law enforcement to connect with the family.

The partnership between St. Jude and Benjamin Bloom also provided funding for an essential component that the Salvadoran hospital was missing: specialized staff.

The most common reasons for missing appointments or stopping treatment were “financial needs,” “unforeseen barriers,” and “domestic needs.” After identifying the cause for treatment abandonment, clinicians worked with families to develop plans or allocate aid to help patients and families avoid these issues in the future.

After two years of diligent follow-up, the Benjamin Bloom doctors substantially reduced treatment abandonment, from 13 percent to 3 percent.

However, according to Dr. Ribeiro, the treatment itself proved to be an obstacle, after it proved toxic to certain patients. Even those who received timely and consistent therapy were less likely to be cured than their higher-income counterparts.

At the program’s launch in 1993, the St. Jude team began using a relatively simple outpatient chemotherapy protocol. The regimen had been well tolerated in the U.S., but the outreach team quickly noticed abnormally high rates of adverse events in El Salvador. Seven of the first 25 patients treated in El Salvador died from toxicities.2

“You have to adapt the treatment intensity to the support and care capabilities of the local area,” Dr. Ribeiro commented. “You can’t just go to a lower-income country and say, ‘We’re going to do this very intensive chemotherapy.’ You will end up killing people.”

Through constant telecommunication with a doctor in Memphis, clinicians at Benjamin Bloom altered the protocol, in particular by eliminating the drug daunomycin and its potentially fatal adverse effects.

Treatment-related mortality has been decreasing since the 1990s in certain lower-income countries, Dr. Ribeiro noted, but even in 2011, its prevalence remained greater in lower-income Central American countries (ranging from 11 to 21 percent) than in higher-income countries (ranging from 1 to 3 percent).7 To describe the incidence, timing, and predictors of treatment-related mortality, researchers followed patients in El Salvador, Guatemala, and Honduras who were diagnosed with ALL between 2000 and 2008, when the St. Jude protocol had been implemented in El Salvador.

They found that, while treatment-related mortality decreased overall during the eight-year study period (from 11.2% to 7.9%; p=0.02), it remained high during certain therapeutic timepoints. Of all instances of treatment-related mortality, the majority (59%) occurred during induction and one-quarter during maintenance. According to the authors, this “contrasts sharply with the patterns observed in [high-income countries], where treatment-related mortality in maintenance is considered a rare event.”

Expanding Borders

As Dr. Ribeiro calls it, the “true test” of the international collaboration came when the doctors presented the results of the program’s first few years to the members of St. Jude board of directors: With an investment of $100,000 – the same amount of money that it cost to treat one child in the U.S. – the group treated more than 100 children in El Salvador.

“That is consistent with the hospital mission that no child should die in the dawn of life – and it doesn’t say ‘in Memphis,’ or ‘in El Salvador,’ or in any place else,” he said. Thus, the International Outreach Program expanded beyond El Salvador. St Jude is now working with hospitals in 17 low- and middle-income countries to improve cancer treatment for children using a similar model.

A cost analysis in 2018 showed that the price of running the pediatric oncology unit at Benjamin Bloom in 2016 was $5.2 million, which included seeing an average of 90 outpatients per day and covering 1,385 inpatient stays per year.8 The El Salvador government covered 52.5 percent of that cost and charitable donations made up another 44.2 percent. The last 3.4 percent came from social security contributions. The estimated cost to add one year of healthy life was $1,624, which the authors considered “under the threshold considered to be very cost effective.”

The success of the El Salvador model has spawned other global programs. In September 2018, St. Jude announced a collaboration with the World Health Organization (WHO), with a goal of curing at least 60 percent of children with six of the most common kinds of cancer worldwide by 2030.9

“I knew firsthand the situation in lower-income countries, and I just said, ‘Well, this is may be my contribution to the field. It may not be discovering a new molecule or a new treatment, but I can help translate that progress to other countries,’” said Dr. Ribeiro, recounting his involvement with the global outreach program.

But St. Jude and the WHO will have to be selective about where they focus their life-saving efforts. Countries must meet certain criteria for these kinds of programs to be successful; treating childhood cancers can’t be a priority everywhere.

Lower-income countries recovering from war or natural disasters will not be able to use their limited resources for long, complicated cancer treatments, Dr. Ribeiro noted. Establishing “twinning programs” requires investment “not only in international agencies’ efforts, but also in the infrastructural development of the countries,” he added. “At this point, there are things we can do, and some things that we can’t.” —By Emma Yasinski

References

  1. National Cancer Institute. Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version. Accessed March 29, 2019, from https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq.
  2. Ribeiro RC, Bonilla M. A leukemia treatment programme in El Salvador. Lancet. 2000;356 Suppl;s7.
  3. The New York Times. A promising step in tackling childhood cancer. Accessed March 29, 2019, from https://www.nytimes.com/2018/09/29/opinion/sunday/childhood-cancer.html.
  4. Keegan THM, Alvarez E, Li Q, et al. Inpatients costs of cancer treatment among children and young adults with acute lymphoblastic leukemia (ALL) treated at specialized cancer centers in California. Abstract #324. Presented at the 2018 ASH Annual Meeting, December 4, 2018; San Diego, CA.
  5. Gupta S, Rivera-Luna R, Ribeiro RC, Howard SC. Pediatric oncology as the next global child health priority: the need for national childhood cancer strategies in low- and middle-income countries. PLOS Medicine. 2014;11:e1001656.
  6. Salaverria C, Rossell N, Hernandez A., et al. Interventions targeting absences increase adherence and reduce abandonment of childhood cancer treatment in El Salvador. Pediatr Blood Cancer. 2015;62,1609-15.
  7. Gupta S, Antillon FA, Bonilla M, et al. Treatment‐related mortality in children with acute lymphoblastic leukemia in Central America. Cancer. 2011;117:4788-95.
  8. Fuentes-Alabi S, Bhakta N, Vasquez RF, et al. The cost and cost-effectiveness of childhood cancer treatment in El Salvador, Central America: a report from the Childhood Cancer 2030 Network. Cancer. 2018;124:391-7.
  9. St. Jude Children’s Research Hospital. Collaborating to cure. Accessed March 29, 2019, from https://www.stjude.org/global/collaborating-to-cure.html.

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