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International Collaborations Help Improve Pediatric Leukemia Outcomes in the Caribbean

December 30, 2021

Children around the world can develop leukemia, but a patient's chance of survival varies greatly based simply on where he or she is born. Children in the U.S. and other high-income countries who are diagnosed with acute leukemias, for example, have a five-year survival rate of 84%, with most patients being able to eventually reach "cure."1

"It's a long treatment," said Leslie S. Kean, MD, PhD, professor of pediatrics at Harvard Medical School and the director of the pediatric stem cell transplant program at Boston Children's Hospital and Dana-Farber Cancer Institute. "It's not easy, but it is associated with a high cure rate." For children living in resource-poor settings, however, the outlook is less optimistic.

In English-speaking Caribbean countries, on the other hand, the estimated two-year event-free survival (EFS) for pediatric patients diagnosed with leukemia ranged from just 22.7% for acute myeloid leukemia (AML) to 62.1% for acute lymphocytic leukemia (ALL).2

Hematologists attribute this discrepancy to a variety of factors related to treatment, including limited access to care, inconsistently available medications, discrepancies in supportive care protocols, and a lack of local hematologists and oncologists trained to treat these disorders.

New initiatives, such as collaborations between medical centers, professional societies, and nonprofit organizations, have sprung up to close the outcome gap for children living with leukemia in limited-resource areas. In the Caribbean region, that includes projects such as the SickKids-Caribbean Initiative and the Children's International Consortium on Acute Leukemia (C-ICAL). These programs have a goal of helping strengthen Caribbean countries' ability to care for patients and improve patient access to services. Each innovative partnership brings together hematologists and oncologists from around the world for one common goal: improving the management of pediatric acute leukemias for children in resource-poor settings.

Prevalence of Pediatric Acute Leukemias

Although AML and ALL are relatively rare, they are the most common cancers diagnosed in children and adolescents worldwide, representing approximately 33% of cases.3

Management, treatment, and prognosis can differ tremendously based on location. "When a child has standard risk leukemia in the U.S. and in many developed countries, he or she has a great chance of survival," Dr. Kean noted, calling the high survival rates of acute leukemias "one of the success stories of continuous clinical trials."

Those successes, owing to the development of new chemotherapy agents and better management of treatment-related adverse events, have not equally benefited all patient populations. Children living in the Caribbean region or other resource-limited areas still face poor outcomes.

In 2013, The Hospital for Sick Children (also known as SickKids) in Toronto partnered with seven Caribbean institutions across six countries (the Bahamas, Barbados, Jamaica, St. Lucia, St. Vincent and the Grenadines, and Trinidad and Tobago) to address these discrepancies. The partnership became known as the SickKids-Caribbean Initiative, a not-for-profit collaboration with a stated objective of "building sustainable, local capacity to diagnose, treat, and manage" pediatric cancers and blood disorders in the Caribbean.4

As of 2019, SickKids staff have assisted in-stitutions in partner countries with building up local resources, training medical personnel, establishing standard treatment protocols, and tracking patient outcomes.

The key to the program is that it empowers the Caribbean countries to improve their own capacities, rather than bringing the children to Canada to receive treatment, according to Victor Blanchette, MB BChir, FRCP, the McCaig Magee Family Medical Director of the SickKids-Caribbean Initiative. "We are building a solid foundation," said Dr. Blanchette, who also is medical director of the Pediatric Thrombosis and Hemostasis Program in the Division of Haematology/Oncology at SickKids.

One of the SickKids-Caribbean Initiative's first projects was determining the prevalence of acute leukemias in the Caribbean region.

In 2013, researchers established a multicenter childhood cancer database, including retrospective data, to track patient demographics, disease subtype, treatment, and outcomes. A report published in 2015 found that 130 children were diagnosed with leukemias since 2011, representing 35.4% of cases.2 Death within 60 days of diagnosis was "relatively common" in acute leukemia (13.3% of patients with ALL and 30.8% of patients with AML).

Data collection and analysis is still underway, the results of which researchers hope will point them to interventions for improving supportive care and modifying treatment protocols to meet the challenges of treating patients in these resource-limited areas.

Underserved Areas, Oversized Challenges

Experts cite varying reasons for the vast discrepancies in survival rates between patients in the Caribbean and those in the U.S., Canada, and other developed countries.

Michelle Reece-Mills, MBBS, DM, pediatrician and pediatric hematologist and oncologist at the University Hospital of the West Indies in Jamaica, notes that timely recognition of cancer is one of the major obstacles to improving children's prognosis. Clinicians are limited by the lack of resources available to make a diagnosis, as well as late presentation of the disease. Curt Bodkyn, MBBS, MR­CPI, MH­PE, a pediatric oncologist at The University of the West Indies in Trinidad and Tobago, noted that several islands do not have access to flow cytometry services, a main method for diagnosing acute leukemias.

After a diagnosis is made, other factors, including a parent's refusal of care or the eventual abandonment of care due to cost or availability, can also impede treatment success, Dr. Reece-Mills added.

"The University Hospital of the West Indies is a semi-private institution, so we are only partially funded by the government," explained Dr. Reece-Mills, who also serves as an associate lecturer at the university. "Therefore, our patients often bear the brunt of the full cost of therapy. That increases the risk of abandonment and makes it challenging for patients to receive treatment per protocol, without delays."

"When you are trying to create something like [the C-ICAL], the best partners are obviously countries where survival gaps exist, but where the physicians are outstanding."

—Leslie S. Kean, MD, PhD

Dr. Reece-Mills said Jamaica is faced with occasional drug shortages and an importation time of at least two weeks, further contributing to delays. Limited blood availability also is a challenge for patients who require transfusions.

Cheryl Alexis, MBBS, FRCP, a consultant pediatric hematologist and oncologist at the Queen Elizabeth Hospital in Barbados, added that, because of the relatively small number of patients diagnosed with and treated for acute leukemias each year, some of the medications may expire before they can be used. Hospital staff can ask drug manufacturers to send supplies in smaller quantities, but the requests aren't always granted.

Improving Local Resources

Dr. Blanchette, who grew up in Barbados himself, said another critical issue identified by SickKids-Caribbean Initiative staff was a lack of hematologists and oncologists in the area. Some islands may only have one specialist in the area, while others have none, he said.

"The essential human resources to deal with diagnosing, treating, and managing children with cancer in these countries is very sparse," he noted. Education and training of hematologists, nurses, and other medical professionals has been a central component of the program.

To advance pediatric nursing practice and build clinical competence, the SickKids-Caribbean Initiative established the Paediatric Haematology/Oncology Nursing Education Program (PHONEP) at the University of the West Indies School of Nursing in Trinidad. During the one-year training program, nurses from partner countries attend sessions and lectures delivered jointly by educators from SickKids and the University of the West Indies. In the three years since its launch, 27 nurses from five of the partner countries have graduated from PHONEP.5

In addition, four Caribbean pediatricians have completed multi-year, pediatric hematology/oncology fellowships at SickKids, then returned to their home countries to provide much-needed expertise for patients and their families. Dr. Blanchette noted that, when the next fellow finishes the program, she will return to Barbados as only the second pediatric cancer and blood disorder specialist in that country.

Dr. Reece-Mills was one of the first pediatricians to complete the SickKids fellowship, before returning to Jamaica. "The initiative has breathed fresh life into pediatric oncology and sickle cell disease [treatment] in the region," she said, noting a "marked improvement" in her medical team's expertise.

Data collection on outcomes improvement is ongoing, but, as the SickKids-Caribbean Initiative enters phase two, stakeholders have celebrated the milestones achieved in the program's first six years, including 418 case consultations between physicians in the Caribbean and SickKids. Participants also have sent 259 blood samples for specialized diagnostic testing to SickKids pathologists.

Through these consults, physicians can send challenging cases out for review without ever having to leave their home country. For Dr. Bodkyn in Trinidad and Tobago, where the initiative has provided consultations for 69 cases, this aspect of the program has been enormously helpful.

"We have case consultation rounds at least once a month [at the Queen Elizabeth Hospital]," as well as educational sessions for staff clinicians, said Dr. Alexis, who serves as a physician lead for I-CAL in Barbados.

Assistance from SickKids also has allowed Caribbean partners to establish seven local oncology databases – and hire seven database managers to maintain them – at the participating hospitals. These databases, which now include information from 616 patients, will enable SickKids-Caribbean Initiative partners to evaluate the effects of their efforts and design future interventions tailored to the local resources.

Combining Efforts

The SickKids-Caribbean Initiative continues a long tradition of international outreach efforts to improve health care outcomes for underserved populations with blood disorders. In 2004, clinical investigators from Europe, North America, and South America joined forces to create the International Consortium on Acute Promyelocytic Leukemia (IC-APL), with the goals of improving clinical outcomes and infrastructure in developing countries.6 In the project's first 28 months, participating institutions saw a decrease of almost 50% in early mortality for APL, a subtype of AML, with overall survival and disease-free survival rates rivalling those reported in high-income countries.7

Following the success of the initiative, leadership wanted to expand the effort to other leukemias and changed the name to the International Consortium on Acute Leukemia (ICAL). Next, inspired by the accomplishments of ICAL, Dr. Kean and consortium members set out to create a similar program for pediatric patients: the Children's International Consortium on Acute Leukemia, or C-ICAL. The consortium's leadership spoke with hematologists around the world to try to find partner countries with which to align resources, eventually selecting the Caribbean region.

"When you are trying to create something like this, the best partners are obviously countries where survival gaps exist, but where the physicians are outstanding," said Dr. Kean, who serves as the ASH Co-Chair of C-ICAL, along with Dr. Blanchette. Hospitals participating in the SickKids-Caribbean Initiative had clearly demonstrated a strong desire to improve outcomes for children living with blood diseases in their countries, so, in 2017, a new partnership was formed.

At the time of ASH's involvement, Dr. Kean noted that the SickKids-Caribbean Initiative hadn't yet launched standardized management and treatment protocols to be used across all sites. "Our vison was to create a standard protocol specialized to the Caribbean region, adapted to the local resources and specific needs of this region, with the goal of improving survival in pediatric ALL," she said.

The effort – which is focused on Jamaica, Barbados, the Bahamas, and Trinidad and Tobago – will not include conducting clinical research. Instead, it establishes standardized treatment protocols that incorporate best practices and perspective from hematologists in the region.

"While intensive treatment regimens can lead to high rates of survival in resource-rich countries, that same intensive regimen actually could be less successful in a resource-poor country," Dr. Kean explained, "because often those intensive regimens have many attendant toxicities that can be managed in a resource-rich country but can be deadly in a resource-poor setting." The challenge, she noted, comes when clinicians must balance "state-of-the-art diagnostics, prognostics, and follow-up with the realities of the site, to minimize both disease-related mortality and also regimen-related mortality or toxicity."

After more than a year of development, the group delivered the C-ICAL Protocol for pediatric patients with ALL. The regimen consists of a three or four-drug induction phase that includes daunorubicin, methotrexate, and pegaspargase, with daunorubicin being added for patients with high-risk disease features. Based on discussions with partner hospitals, the protocol was adapted to local availability of treatment agents; for example, countries without access to pegaspargase can substitute with native E. coli, implementing pegaspargase if the drug becomes available.

The next steps are to track the safety and efficacy of this protocol through a prospective, multicenter, nonrandomized study in the partnering countries. This is key to understanding whether this consortium is helping improve outcomes, Dr. Kean noted.

As work in the Caribbean continues, Dr. Blanchette hopes that, by focusing on building capacity in the region, hematologists and oncologists will be able to improve patient outcomes for years to come.

"We believe this will have a legacy beyond individuals and will be self-sustaining, … led by a cadre of health care professionals committed to getting better outcomes for children with cancer and blood disorders," he said. —By Jill Sederstrom

References

  1. Surveillance, Epidemiology, and End Results. "Cancer Stat Facts: Childhood Leukemia (Ages 0-19)." Accessed October 28, 2019, from https://seer.cancer.gov/statfacts/html/childleuk.html.
  2. Gibson TN, Beeput S, Gaspard J, et al. Baseline characteristics and outcomes of children with cancer in the English-speaking Caribbean: a multinational retrospective cohort. Pediatr Blood Cancer. 2018:65;e27298.
  3. American Cancer Society. Key Statistics for Childhood Leukemia. Accessed October 28, 2019, from www.cancer.org/cancer/leukemia-in-children/about/key-statistics.html.
  4. SickKids. Capacity Building in the Caribbean. Accessed October 28, 2019, from www.sickkids.ca/globalchildhealth/capacity-building/Capacity%20Building%20in%20the%20Caribbean/CapBuildCaribbean.html.
  5. SickKids. SickKids-Caribbean Initiative Annual Progress Report 2018-2019. Accessed October 28, 2019, from https://issuu.com/globalchildhealth/docs/sci_annual_progress_report_2018-19.
  6. American Society of Hematology. International Consortium on Acute Leukemia. Accessed October 27, 2019, from www.hematology.org/ICAL/.
  7. Rego E, Haesook T, Ruiz-Arguelles G, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on AP. Blood. 2013:121:1935-43.

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