International Initiative Improves Outcomes for Acute Promyelocytic Leukemia in Developing Countries

Roxanne Nelson

December 08, 2009

December 8, 2009 (New Orleans, Louisiana) — The morbidity and mortality rates for acute promyelocytic leukemia (APL) are significantly higher in developing nations than in industrialized ones. However, the establishment of an international network of clinicians and researchers is helping to improve these rates and to bring them on par with the industrialized world, according to data presented here at the American Society of Hematology (ASH) 51st Annual Meeting.

Dr. Eduardo M. Rego

Eduardo M. Rego, MD, PhD, professor of the Medical School of Ribeirão Preto at the University of São Paulo, Brazil, told a plenary session how introducing such an initiative in 3 Latin American countries has resulted in an approximately 40% decrease in early mortality and a marked improvement in the long-term outcome of patients with APL, similar to levels reported in developed countries.

Progress and understanding of the pathogenesis and treatment of APL has been rapid, explained Martin S. Tallman, MD, who introduced the study. Dr. Tallman is professor in the Division of Hematology/Oncology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois. "In a relatively short period of 50 years, with the routine administration of ATRA [all-trans retinoic acid] with anthracyclines, the outcome for patients with acute promyelocytic leukemia has changed from one characterized by high early mortality to one distinguished by a high cure [rate] even among patients with high-risk disease," said Dr. Tallman.

"However, current standards for diagnosis and treatment are not available in many developing countries, including some in Latin America, where the disease may be particularly common," he noted. In the current study, contemporary methods of diagnosis and strategies for effective therapy "are brought to 3 developing countries in the spirit of international collaboration, to exchange scientific information and to improve outcome."

APL serves as an excellent paradigm for such an endeavor.

APL serves as an excellent paradigm for such an endeavor, since there can be intriguing geographic variation in incidence and manifestation, Dr. Tallman explained. It is common in young patients and the early death rate has a high impact. "There is an excellent molecular marker and the disease is highly curable," he said.

However, the accomplishments of this endeavor have broader implications. "Similar efforts are likely to be successful in many other diseases and in many other countries throughout the world," he said.

The International Consortium on Acute Promyelocytic Leukemia (IC-APL) is an initiative of the International Members Committee of the ASH, and was launched to improve treatment outcomes of APL in developing countries.

Dr. Rego reported on the impact this initiative has had in Brazil, Mexico, and Uruguay.

APL Selected as Model

APL was selected as a model disease because "it is rapidly fatal if left untreated, yet highly curable if patients have access to rapid diagnosis and appropriate treatment," he said. "Treatment is relatively inexpensive, but there are still relevant scientific challenges to be addressed."

Current treatment regimens are based on the combination of ATRA and anthracyclines, which results in median overall 5-year survival rates of approximately 90%.

The complete remission rate with contemporary treatment is in the range of 73% to 97%, disease-free survival is in the range 69% to 89%, and overall survival is between 69% and 86%. "Unfortunately," said Dr. Rego, "these rates were not observed in developing countries."

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Dr. Eduardo M. Rego

As an example, he pointed to a Brazilian study in which the 2-year survival rate was only 52%. "The poor results were due mainly to a high early mortality caused by bleeding," he said. "Approximately 20% of patients died within 1 week of treatment."

Since the initiative was launched, a total of 114 patients have been enrolled in the study; median age was 35 years and one third were classified as high risk. It was agreed upon from the outset that there was a need for a diagnostic and treatment protocol suitable for patients of low socioeconomic status, and a key issue was to have a diagnostic tool that would lead to early treatment, according to Dr. Rego.

The "pillar" of the project was to begin ATRA before genetic confirmation of the disease. ATRA therapy was begun in patients with a suspicion of APL after collection of bone marrow samples. After genetic confirmation, usually within 24 hours, daunorubicin was started.

All patients were begun on a regimen identical to the 2005 protocol established by the PETHEMA working group of the Spanish Association of Hematology and Hemotherapy, which consisted of ATRA, idarubicin, mitoxantrone, and cytosine arabinoside combination therapy.

The only difference is that, in this study, daunorubicin was administered instead of idarubicin. This change was made because daunorubicin is considerably less costly than idarubicin and is more accessible in these nations, Dr. Rego explained during his presentation.

Outcomes Similar to Those in Developed Nations

There was a complete response rate of 81%. Early mortality, defined as death within 7 days, was 7.6%, and mortality within 30 days was 16%, said Dr. Rego. "Approximately one quarter of patients presented with symptoms of differentiation syndrome, yet there were only 2 deaths due to this syndrome."

When the results of this trial are compared with historical data, the mortality rate was halved. "This was due to a substantial reduction in deaths from bleeding — from 31.3% to only 8.8%," he said. "The probability of overall survival in the IC-APL study at 2 years was 77%."

The 2-year disease-free survival was 95% and the cumulative incidence of relapse was 3.6%.

The results of the IC-APL are within the same range as the ones obtained in developed countries. "An educational program aimed at the dissemination of essential clinical management guidelines has increased the awareness of APL and has demonstrated the feasibility of improving the outcome of APL in selected Brazilian, Mexican, and Uruguayan institutions," he concluded.

Twinning Approach

In a related presentation, Scott Howard, MD, discussed how relatively inexpensive strategies can be used to improve outcomes for children with acute lymphoblastic leukemia in developing countries. Dr. Howard, who is director of clinical trials for the St. Jude International Outreach Program in Memphis, Tennessee, explained that St. Jude has successfully used an approach called "twinning" to foster collaboration among medical centers in developed and developing nations, as well as a long-term commitment to improving childhood cancer treatment across the globe.

The twinning approach is defined as a close, long-term relationship between a center in a low- or middle-income nation and one in a developed country; this relationship has been successful in improving cure rates of many childhood cancers and improving access to care. In this case, Dr. Howard explained that, during the 20-year collaboration with St. Jude, childhood acute lymphoblastic leukemia cure rates at a center in Recife, Brazil rose from 32% to 70%.

Dr. Rego's coauthor, Miguel A. Sanz, MD, PhD, from Hospital Universitario La Fe in Valencia, Spain, is a member of the Board of Directors, advisory committee, or speakers bureau of Amgen. None of the other researchers have disclosed relevant financial relationships.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 6. Presented December 6, 2009.

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