The results of the International Consortium on Acute Promyelocytic Leukemia: a 'proof of concept' of networking as a strategy to improve the outcome of treatment of hematological malignancies in developing countries

EDITORIAL

The results of the International Consortium on Acute Promyelocytic Leukemia: a 'proof of concept' of networking as a strategy to improve the outcome of treatment of hematological malignancies in developing countries

Eduardo Magalhães Rego

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo - USP, Ribeirão Preto, SP, Brazil International Consortium on Acute Promyelocytic Leukemia

^{Corresponding author}

On January 14th 2013, the results of the International Consortium on Acute PromyelocyticLeukemia (IC-APL)⁽¹⁾ were published online in the journal Blood. Eight Brazilian institutions participated in the IC-APL: the Faculdade de Medicina de Ribeirão Preto, Universidade deSão Paulo (USP) as coordinator, the Hematology Divisions of the Universidades Federal do RioGrande do Sul (UFRGS), do Paraná (UFPR) and de Minas Gerais (UFMG), the Hematology and Transfusion Medicine Division of the Universidade Federal de São Paulo (UNIFESP), Hematology and Hemotherapy Center of the Universidade Estadual de Campinas (UNICAMP), the HematologyDivision of Santa Casa de São Paulo (SCSP) and Fundação Hemocentro de Pernambuco (HEMOPE). The IC-APL was developed under the auspices of the American Society of Hematology and gathered specialists from Latin America, the United States and Europe with the aim of improving the cure rates of patients with acute promyelocytic leukemia (APL) in developing countries through the establishment of an international clinical network. Four developing countries were selected to participate in the IC-APL: Brazil, Chile, Mexico and Uruguay; 183 adult patients with suspected diagnosis of APL were enrolled in this registered trial between June 2006 and September 2010.

In order to participate in the IC-APL, countries had to fulfill minimum requirements, which included availability of drugs, pre-existing transfusion medicine services, a hematology lab capable of performing basic fluorescence microscopy and ability to report data and participate in meetings using web tools. APL was selected as a model disease to test the hypothesis that networking is an effective strategy to improve the outcome of patients with hematological malignancies in developing countries. The main reasons that guided this choice were: a) APL has become a highly curable disease since the introduction of combination therapy with alltrans retinoic acid (ATRA) and anthracycline-based chemotherapy, b) ATRA is of relatively low cost and available in the four developing countries, and c) the prompt diagnosis and immediate introduction of therapy can revert the coagulation abnormalities common in the disease and associated with high mortality rates due to bleeding.

In order to perform a prompt diagnosis and the immediate introduction of ATRA, the IC-APL adopted the anti-PML immunofluorescence staining test which was developed by Falini etal.⁽²⁾ and requires minimal infrastructure. This test is based on the molecular pathogenesis of APL, which is characterized by its association with chromosomal translocations involving the loci of the Promyelocytic Leukemia (PML) and Retinoic Acid Receptor Alpha (RARa) genes on chromosomes 15 and 17, respectively. The PML-RARA fusion protein retains most of the functional domains of the parental proteins and interacts with several proteins in the nucleus, in particular with the native PML causing its delocalization from the nuclear body⁽³⁾. As a consequence, in APL cells, the PML protein is dispersed throughout the nucleus and generates a microspeckled pattern identifiable by the immunofluorescence staining test using the anti-PML (PG-M3) antibody (Figure 1).

Yet the introduction of a method for rapid diagnosis was only one of the items in the IC-APL strategy. By fostering collaboration between researchers, clinicians, and laboratory scientists from institutions in developing countries and well established international cooperative groups based in the United States and in Europe, the IC-APL group generated guidelines, trained personnel, developed medical educational material, facilitated lab research and enforced requests to health authorities to guarantee ATRA availability.

The formulated treatment guidelines, based on the experience of the Spanish group, PETHEMA⁽⁴⁾, were adapted to local conditions and resources. An important change in the induction therapy protocol in the IC-APL study was the replacement of the commonly used anthracycline idarubicin with the less expensive and more readily available daunorubicin. The guidelines also covered standardized approaches for supportive care and disease follow-up measures. Throughout the trial, participating sites registered all cases using common clinical record forms in the Pediatric Oncology Network Database (POND) and collaborated with national clinical trial coordinators and reference laboratories to confirm the integrity and accuracy of treatment data.

The results of the study were remarkable, of 180 evaluable patients, 153 (85%) achieved complete hematological remission. Twenty-seven patients (15%) died during induction (early death). About 90% of all patients who achieved complete remission were alive at the time of analysis, five (2.6%) were lost to follow-up and ten (5.2%) died in complete remission. There was one case of molecular persistence of the PML/RARA rearrangement after consolidation and there were nine relapses, of which four were molecular relapses. The 2-year overall survival and disease free survival were 80% (95% confidence interval: 73% - 85%) and 91% (95% confidence interval: 86% -95%), respectively. The 2-year cumulative incidence of relapse was 4.5% (95% confidence interval: 1.8%-9.2%). The results are comparable to those reported in the US⁽⁵⁾ and Europe^(4,6) and represent a nearly50% decrease in early mortality and a nearly 30% improvement in overall survival compared to historical controls⁽⁷⁾.

It is important to stress that there is a disparity between reported outcomes, particularly in hemorrhagic-related death rates, in clinical trials as compared to population based studies. In the study by Park et al.⁽⁸⁾ the death rate within one month of APL diagnosis was 17.3%. Likewise, Lehmann et al.⁽⁹⁾ reported the outcomes of APL patients registered in the population-based Swedish Adult Acute Leukemia Registry between 1997 and 2006 with calculated death rates of 26% and 29% within 14 and 30 days of diagnosis, respectively.

Taken together, the results reported by the IC-APL demonstrate that international networking is an effective strategy to change the reality of treatment of patients with hematological malignancies in developing countries. In addition, it was an xxx opportunity for Brazilian hematologists to strengthen ties, exchange experiences and consolidate the position of the country in the international scientific scenario.

References

1. Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte MD, Jacomo RH, Gutiérrez-Aguirre H, Melo RA, Bittencourt R, Pasquini R, Pagnano K, Fagundes EM, Chauffaille MD, Chiattone CS, Martinez L, Meillón LA, Gómez-Almaguer D, Kwaan HC, Garcés-Eisele J, Gallagher R, Niemeyer CM, Schrier SL, Tallman M, Grimwade D, Ganser A, Berliner N, Ribeiro RC, Lo-Coco F, Löwenberg B, Sanz MA. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013 Jan 14. [Epub ahead of print]

2. Falini B, Flenghi L, Fagioli M, Lo Coco F, Cordone I, Diverio D, et al. Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML). Blood. 1997;90(10):4046-53.

3. Rego EM, Pandolfi PP. Analysis of the molecular genetics of acute promyelocytic leukemia in mouse models. Semin Hematol. 2001;38(1):54-70.

4. Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA and HOVON Groups. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010;115(25):5137-46. Comment in: Nat Rev Clin Oncol. 2010;7(9):484.

5. Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116(19):3751-7.

6. Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA, AIEOP, and EORTC Cooperative Groups. AIDA0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011;117(18):4716-25.

7. Jácomo RH, Melo RA, Souto FR, de Mattos ER, de Oliveira CT, Fagundes EM, et al. Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines. Haematologica. 2007;92(10):1431-2.

8. Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011;118(5):1248:54. Comment in: Blood. 2011;118(5):1188-9.

9. Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Möllgård L, et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 2011;25(7):1128-34.

Submitted: 2/18/2013

Accepted: 2/19/2013

Conflict-of-interest disclosure: The author declares no competing financial interest

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Publication Dates

• Publication in this collection
  05 Apr 2013
• Date of issue
  2013