The Hematologist

January-February 2013, Volume 10, Issue 1

International Clinical Collaboration Produces High Cure Rate of Acute Promyelocytic Leukemia in Developing Countries

Published on: January 01, 2013

Data demonstrating that the work of the International Consortium on Acute Promyelocytic Leukemia (IC-APL) has improved cure rates in patients with APLin developing countries was recently published in Blood. By focusing on implementing a standard-of-care protocol adapted to local conditions and resources, this international collaborative effort has succeeded in achieving outcomes comparable to those reported for patients in the United States and Europe where complete response (CR) rates of 90 percent and long-term disease-free survival (DFS) rates of 85 percent are the norm.

Recognizing the need to improve outcome in developing countries where overall survival (OS) rates for APL are below 60 percent, the ASH International Members Committee founded the IC-APL in 2005. “We chose APL as a model disease for the initiative because of the opportunity to improve patient outcomes in the developing world by collaborating with and learning from colleagues who have already successfully made these strides against this disease,” said Eduardo Rego, MD, PhD, a founding member of the IC-APL and professor of hematology/oncology at the University of São Paulo in Brazil. “This initiative aims to build the capacity of local clinicians in the developing world to conduct clinical trials by introducing and fostering clinical and laboratory procedures that represent the standard of care for the treatment of acute leukemia in many countries around the world.”

The participating countries were Mexico in North America and Brazil, Chile, and Uruguay in South America. From June 2006 to September 2010, 183 patients were enrolled in the study. Eligibility criteria included age 15 years or older and a molecularly confirmed diagnosis of APL (demonstration of expression of PMLRAR by PCR performed by a central laboratory). Although treatment was based on the PETHEMA LPA 2005 protocol, a change to the induction regimen was made, replacing the commonly used, more expensive, and less available anthracycline idarubicin with the less expensive, more readily available anthracycline daunorubicin. Starting on day 1 of the induction cycle, patients received oral ATRA in two daily doses until complete remission with idarubicin given intravenously on days 2, 4, 6, and 8.

Sites registered all cases through the Pediatric Oncology Network Database and collaborated with national coordinators and reference laboratories from each country to confirm the integrity and accuracy of treatment data. Governed by a panel of experts in acute leukemia from Latin America, the United States, and Europe, the group met face-to-face twice a year to discuss each participating country’s progress and to share data. Using the Web-based facility Cure4Kids (kindly provided by the International Outreach Program of the St. Jude Children’s Research Hospital), national coordinators and international APL experts took part in virtual meetings to discuss patient data and clinical and laboratory information including genetic studies that confirmed the presence of t(15:17) and expression of PML-RAR transcripts.

Twenty-seven patients (15%) died within the first 30 days of enrollment (defined as early mortality). Based on historical controls, early mortality was reduced by approximately half, and overall survival improved by 30 percent. Of 180 evaluable patients, 153 (85%) achieved CR. For patients entered into the IC-APL study on an intention-to-treat basis, the two-year OS was 80 percent and DFS among patients who achieved a complete remission was 91 percent, with a cumulative incidence of relapse of 4.5 percent.

After five years of follow-up, 75.4 percent of all patients enrolled and 90.2 percent of those who achieved CR remained alive. The most frequent hematologic toxicity was grade 4 neutropenia, which was observed in 3.3 percent. No significant toxicities were reported during maintenance therapy, and no secondary malignancies were reported.

By refining and standardizing diagnostic procedures, implementing a standard-of-care treatment protocol, and collaborating through virtual and face-to-face meetings, overall survival for patients was improved. “We can now close the gap in treatment outcomes between patients in developed countries and those in developing countries,” added Dr. Rego, who also serves as the IC-APL’s Brazilian National Coordinator. “Building on our initial success, we are now expanding this initiative to additional countries where we hope to further integrate education and networking and refine our treatment design to determine if we can further improve outcomes and possibly translate this model to other diseases.” Based on the success of the IC-APL, the consortium’s governing body has voted to expand the collaborative model to address other subtypes of acute leukemia, beginning with acute myeloid leukemia. To reflect this change in scope, the cooperative group is now called the International Consortium on Acute Leukemia (ICAL).

To read more about the IC-APL and now ICAL, please see the article that ran in the November/December issue of The Hematologist titled, “Using Communication Technology to Improve Global Hematologic Care.”

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