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Molecular and hematologic relapses in adult patients with acute promyelocytic leukemia: a cohort study

Abstract

Objective:

To evaluate factors predictive for relapse in a cohort of adult patients with acute promyelocytic leukemia monitored by molecular methods during consolidation and during at least one month of maintenance therapy.

Methods:

The charts and laboratory data of 65 adult patients with acute promyelocytic leukemia treated according to the International Consortium on Acute Promyelocytic Leukemia 2006 protocol were reviewed. The identification of the promyelocytic leukemia-retinoic acid receptor-alpha gene rearrangement at diagnosis, post-induction, post-consolidation and during maintenance treatment was performed by qualitative and quantitative reverse transcription polymerase chain reaction.

Results:

Eighty-nine patients were diagnosed with acute promyelocytic leukemia over a seven-year period and of these 65 were eligible for treatment with the protocol. Among the 45 patients who received consolidation and maintenance treatment, six (13%) relapsed, three of whom presented hematologic and three presented molecular relapse. The first relapses occurred at a median of 39 months. Relapsed patients were from all risk groups (low, intermediate and high) and both morphological types (M3 and M3variant) were found. Three of these patients are alive and in molecular remission after salvage treatment. There were no statistically significant differences regarding gender, age, risk group, morphology, promyelocytic leukemia breakpoint cluster region, use of all-trans retinoic acid, development of differentiation syndrome and number of days to complete remission between the patients who relapsed and those who did not.

Conclusion:

Our results reinforce the importance of prolonged monitoring of acute promyelocytic leukemia patients using molecular methods to detect relapse early.

Keywords:
Acute promyelocytic leukemia; Relapse; Survival; Monitoring

Introduction

Once considered a leukemia with poor prognosis, currently by means of adequate treatment, acute promyelocytic leukemia (APL) is highly curable, with remission rates of 90% and disease-free survival at six years of over 80%.11 Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004;103(4):1237-43. Despite the increase in overall survival, cases of relapse still occur and need to be promptly identified, thus allowing pre-emptive treatment in the case of molecular relapses or re-induction in cases of hematologic relapse.22 Seftel MD, Barnett MJ, Couban S, Leber B, Storring J, Assaily W, et al. A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults. Curr Oncol. 2014;21(5):234-50.

The International Consortium on Acute Promyelocytic Leukemia (IC-APL 2006) aimed to deploy a network of National and International centers to improve diagnosis, treatment, monitoring of treatment response and support therapy and as a consequence the survival of patients with APL in developing countries. The treatment was based on the APL 2005 protocol of the Programa Espanhola de Hematologia (PETHEMA) group, adapted to the reality of the participating countries (Brazil, Mexico, Chile, Uruguay) with the substitution of the anthracycline idarubicin for daunorubicin which is more affordable and is widely used in the treatment of other leukemias.33 Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte Mdel R, Jacomo RH, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121(11):1935-43. Of the eight Brazilian centers participating in the IC-APL, the center of this study is the only representative of the northeastern region and included almost one third of the patients of the study.

The recently published results of the IC-APL33 Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte Mdel R, Jacomo RH, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121(11):1935-43. demonstrated an improvement in early mortality rates and overall survival compared with historical controls.44 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. In the present study, a cohort of patients diagnosed with APL was evaluated for risk factors associated with relapse.

Methods

Patients

This study retrospectively analyzed 89 adult patients diagnosed with APL between January 2007 and August 2014 at the Hospital of the Fundação de Hematologia e Hemoterapia de Pernambuco (Hemope), Recife, Brazil. Clinical and laboratory data were obtained from the patients' charts. The project was approved by the Research Ethics Committee of the institution (#028/2006) and was conducted after informed consent was obtained from the patients.

Diagnosis and monitoring

The diagnosis was established by clinical, cytomorphological, immunophenotypic and molecular criteria.55 Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-51. The identification of the promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARα) gene rearrangement was performed by reverse transcription polymerase chain reaction (nested RT-PCR and/or RT-qPCR) according to the international BIOMED-1 and BIOMED-2 protocols.66 van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13(12):1901-28.,77 Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of "real-time" quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer program. Leukemia. 2003;17(12):2318-57. Samples for RT-qPCR were sent to the reference laboratory of the IC-APL study in the Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP).

Molecular tests were performed using bone marrow (BM) samples obtained at initial diagnosis, post-induction, post-consolidation (after the third course of consolidation) and during maintenance. Standard monitoring recommended tests every three and six months, respectively, during maintenance and after treatment for up to two years.

Definitions

Complete hematologic remission (CR) and relapse were defined using conventional criteria.88 Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised Recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21(24):4642-9. Hematologic relapse was diagnosed based on the presence of >20% blasts or abnormal promyelocytes in the bone marrow any time after hematologic remission. Molecular remission (MR) was defined as a negative RT-PCR result of bone marrow cells after the third and last cycle of consolidation.99 Sanz MA, Lo Coco F, Martín G, Avvisati G, Rayón C, Barbui T, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000;96(4):1247-53. Molecular persistence was defined as PCR positivity in two consecutive BM samples collected within a minimal interval of 15 days after the end of consolidation therapy. Molecular relapse was defined as the reappearance of the PML-RARα-specific band in two consecutive BM samples collected at an interval of 15 days at any time after consolidation therapy.33 Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte Mdel R, Jacomo RH, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121(11):1935-43.,1010 Lo Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM, et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood. 1999;94(7):2225-9. Arbitrarily, early relapse was defined as that occurring within two years after proven CR and late relapse beyond this period.1111 Lou Y, Suo S, Tong Y, Tong H, Qian W, Meng H, et al. Outcomes and prognostic factors of first relapsed acute promyelocytic leukemia patients undergoing salvage therapy with intravenous arsenic trioxide and chemotherapy. Ann Hematol. 2014;93(6):941-8. Differentiation syndrome (DS) was defined according to standard criteria.1212 Montesinos P, Sanz MA. The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the Pethema group and review of the literature. Mediterr J Hematol Infect Dis. 2011;3(1):e2011059.,1313 Rego EM, De Santis GC. Differentiation syndrome in promyelocytic leukemia: clinical presentation, pathogenesis and treatment. Mediterr J Hematol Infect Dis. 2011;3(1):e2011048.

Treatment

The standard treatment protocol used was the IC-APL 2006 with patients being categorized according to the risk of relapse as described elsewhere.33 Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte Mdel R, Jacomo RH, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121(11):1935-43.,99 Sanz MA, Lo Coco F, Martín G, Avvisati G, Rayón C, Barbui T, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000;96(4):1247-53.,1414 Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, et al. 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.,1515 Pagnano KB, Rego EM, Rohr S, Chauffaille Mde L, Jacomo RH, Bittencourt R, et al. Guidelines on the diagnosis and treatment for acute promyelocytic leukemia: Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Guidelines Project: Associação Médica Brasileira – 2013. Rev Bras Hematol Hemoter. 2014;36(1):71-92. The treatment options of the relapsed cases included re-induction with all-trans retinoic acid (ATRA), chemotherapy and arsenic trioxide (ATO) followed by stem cell transplantation (SCT) whenever possible.22 Seftel MD, Barnett MJ, Couban S, Leber B, Storring J, Assaily W, et al. A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults. Curr Oncol. 2014;21(5):234-50.,1616 Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002;100(13):4298-302.

17 Pemmaraju N, Tanaka MF, Ravandi F, Lin H, Baladandayuthapani V, Rondon G, et al. Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2013;13(4):485-92.
-1818 Soignet SL. Clinical experience of arsenic trioxide in relapsed acute promyelocytic leukemia. Oncologist. 2001;6(Suppl. 2):11-6.

Statistical analysis

Statistical analysis was performed using the Stata 12.0 software. The t-test was used to compare the groups regarding age, days to CR, and months of follow up. Fisher's exact test was used for categorical variables (gender, risk of relapse, morphology and type of transcript). Relative risk (RR) was calculated with a 95% confidence interval (95% CI). p-Values <0.05 were considered statistically significant.

Results

Eighty-nine patients were diagnosed with APL during the period and of these, 65 were eligible for treatment using the IC-APL 2006 protocol. The median age at initial diagnosis of the relapsed patients was 37.5 years (range: 24–46 years). Hematologic remission was achieved with a median of 32 days (range: 27–56 days).

As the main purpose of this study was to evaluate factors predictive for relapse, analysis was restricted to the 45 patients who achieved remission and who were monitored during consolidation and maintenance. Therefore, 20 out of 65 patients were excluded because they died during induction or consolidation. Six patients out of 45 (13%) presented molecular (three) or hematologic (three) relapse. The first relapse among the patients occurred at a median of 39 months (range: 21–48 months) following initial treatment. Median follow-up of the six patients from diagnosis was 46.5 months (range: 28–71 months) and mean number of sequential samples analyzed during monitoring was 12 per patient (range: 5–21 months).

The main features of the six relapsed cases are shown in Table 1. Four patients achieved MR after salvage treatment and were subjected to autologous (auto)-SCT (Cases 1, 3, 4 and 5); two of these are alive and in MR. One patient (Case 6) was in consolidation phase of the treatment until the closing of this article.

Table 1
Main features of relapsed patients from a total of 65 cases of acute promyelocytic leukemia of the Fundação Hemope.

Two patients had a second relapse, one patient (Case 2) twelve months after the first hematologic relapse while in salvage treatment waiting for auto-SCT. This patient had no human leukocyte antigen (HLA)-compatible donor and was treated with ATO without achieving a third remission. The other patient (Case 1) presented a second hematologic relapse fourteen months after the first molecular relapse. He was submitted to ATO treatment followed by auto-SCT, but relapsed 3 months later and died.

Table 2 shows the main clinical and laboratorial features of patients with or without relapse. No significant difference was observed between the two groups of patients regarding gender, age, risk of relapse, morphology, PML breakpoint, duration of ATRA treatment during induction, frequency of evolution of DS and number of days to CR.

Table 2
Analysis of 45 patients with acute promyelocytic leukemia treated at Fundação Hemope considering the cumulative incidence of relapse.

Discussion

The 13% incidence of relapse in this study with 45 patients from a single center is consistent with other works. Cassinat et al.1919 Cassinat B, de Botton S, Kelaidi C, Ades L, Zassadowski F, Guillemot I, et al. When can real-time quantitative RT-PCR effectively define molecular relapse in acute promyelocytic leukemia patients? (Results of the French Belgian Swiss APL Group). Leuk Res. 2009;33(9):1178-82. reported a relapse rate of 14.6% among 260 patients with APL in a multicenter study in France. Moreover, Karim et al.2020 Karim F, Shaikh U, Adil SN, Khurshid M. Clinical characteristics, outcome and early induction deaths in patients with acute promyelocytic leukaemia: a five-year experience at a tertiary care centre. Singapore Med J. 2014;55(8):443-47. in a study with 26 patients, found a 11.5% relapse rate of both molecular and of the central nervous system (CNS). In the matched-pair analyses of the PETHEMA LPA-2005 and IC-APL-2006 studies,2121 Sanz MA, Montesinos P, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte MR, et al. All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia: a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies. Ann Hematol. 2015;94(8):1347-56. relapse rates were 7.4% and 5%, respectively. No CNS relapse was detected in this series. All PETHEMA/Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) risk groups were represented among relapsed patients with proportions similar to other studies.2222 Lu J, Huang X, Bao L, Jiang H, Zhu H, Jiang B. Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all-trans retinoic acid and arsenic compound-based combined therapies. Oncol Lett. 2014;7(1):177-82.,2323 Yoshii M, Ishida M, Yoshida T, Okuno H, Nakanishi R, Horinouchi A, et al. Clinicopathological features of acute promyelocytic leukemia: an experience in one institute emphasizing the morphological and immunophenotypic changes at the time of relapse. Int J Clin Exp Pathol. 2013;6(10):2192-8. The only patient with low risk for relapse had a bcr3 PML variation which is considered of adverse prognostic factor.2424 Castro-Mujica Mdel C, Sullcahuamán-Allende Y. Subtipos moleculares de PML/RARα en pacientes con leucemia promielocítica aguda. Rev Peru Med Exp Salud Publica. 2013;30(1):37-40.

The results of this study are consistent with published data regarding age and gender of the relapsed APL patients.1111 Lou Y, Suo S, Tong Y, Tong H, Qian W, Meng H, et al. Outcomes and prognostic factors of first relapsed acute promyelocytic leukemia patients undergoing salvage therapy with intravenous arsenic trioxide and chemotherapy. Ann Hematol. 2014;93(6):941-8.,2222 Lu J, Huang X, Bao L, Jiang H, Zhu H, Jiang B. Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all-trans retinoic acid and arsenic compound-based combined therapies. Oncol Lett. 2014;7(1):177-82. Both morphological types (M3 and M3v) were found among relapsed patients. In one of the three cases of hematologic relapse, there was a change in morphology from variant (M3v) to classical type (M3). Morphological changes at relapse in APL may not be a rare event, and the leukemic cells can show variable morphological features at the time of relapse, which could result in misdiagnosis as a different type of acute myeloid leukemia as pointed out by Yoshii et al.2323 Yoshii M, Ishida M, Yoshida T, Okuno H, Nakanishi R, Horinouchi A, et al. Clinicopathological features of acute promyelocytic leukemia: an experience in one institute emphasizing the morphological and immunophenotypic changes at the time of relapse. Int J Clin Exp Pathol. 2013;6(10):2192-8. This author recommends a comprehensive approach to the diagnosis and appropriate treatment of relapsed APL.

The overall incidence of DS reported in the LPA series varies from 7.8% to 48%.2525 Su YC, Dunn P, Shih LY, Kuo MC, Chang H, Wu JH, et al. Retinoic acid syndrome in patients following the treatment of acute promyelocytic leukemia with all-trans retinoic acid. Chang Gung Med J. 2009;32(5):535-42.,2626 Elemam O, Abdelmoety D. Acute promyelocytic leukemia, study of predictive factors for Differentiation Syndrome, single center experience. J Egypt Natl Canc Inst. 2013;25(1):13-9. In the current series, one case, that presented with DS during the initial treatment, suffered hematologic relapse but is alive. The European APL Group reported an increased risk of relapse independent of white blood cell count in patients developing DS.2727 de Botton S, Chevret S, Coiteux V, Dombret H, Sanz M, San Miguel J, et al. Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial. Leukemia. 2003;17(2):339-42. Thépot et al.2828 Thepot S, Gardin C, Chevret S, de Botton S, Raffoux E, Guerci A, et al. Impact of ATRA duration during the induction treatment of newly diagnosed APL. ASH Annu Meet Abstr. 2008;112(11):39. suggested that the total duration of treatment with ATRA of less than 21 days during the induction phase was associated with greater rates of relapse of leukemia. In this series, all patients who relapsed were treated with ATRA for more than 21 days with an average of 30 days.2727 de Botton S, Chevret S, Coiteux V, Dombret H, Sanz M, San Miguel J, et al. Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial. Leukemia. 2003;17(2):339-42.

28 Thepot S, Gardin C, Chevret S, de Botton S, Raffoux E, Guerci A, et al. Impact of ATRA duration during the induction treatment of newly diagnosed APL. ASH Annu Meet Abstr. 2008;112(11):39.
-2929 Dimov ND, Medeiros LJ, Ravandi F, Bueso-Ramos CE. Acute promyelocytic leukemia at time of relapse commonly demonstrates cytogenetic evidence of clonal evolution and variability in blast immunophenotypic features. Am J Clin Pathol. 2010;133(3):484-90. No case of resistance to ATRA was identified as all treated patients achieved remission.

Current studies have shown high rates of hematologic relapse compared to molecular relapse.33 Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte Mdel R, Jacomo RH, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121(11):1935-43.,1111 Lou Y, Suo S, Tong Y, Tong H, Qian W, Meng H, et al. Outcomes and prognostic factors of first relapsed acute promyelocytic leukemia patients undergoing salvage therapy with intravenous arsenic trioxide and chemotherapy. Ann Hematol. 2014;93(6):941-8.,2222 Lu J, Huang X, Bao L, Jiang H, Zhu H, Jiang B. Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all-trans retinoic acid and arsenic compound-based combined therapies. Oncol Lett. 2014;7(1):177-82. In the current series, three relapses were molecular and three hematologic. Molecular monitoring of the PML-RARα transcript is useful to anticipate overt hematologic relapse1010 Lo Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM, et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood. 1999;94(7):2225-9. with the IC-APL 2006 protocol recommending tests every three months for at least two years after completing treatment.33 Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte Mdel R, Jacomo RH, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121(11):1935-43. This approach is important because the majority of the relapses in this study occurred during this period with a median of 44.5 months. In this regard, two cases of hematologic relapse in this series did not strictly follow the monitoring protocol. Although the mean number of samples analyzed per patient was higher than that reported by Cassinat et al.,1919 Cassinat B, de Botton S, Kelaidi C, Ades L, Zassadowski F, Guillemot I, et al. When can real-time quantitative RT-PCR effectively define molecular relapse in acute promyelocytic leukemia patients? (Results of the French Belgian Swiss APL Group). Leuk Res. 2009;33(9):1178-82. who analyzed an average of six samples per patient (range: 1–28), there is a need for more strict monitoring.

Proposed modalities of therapy in the salvage setting for APL patients includes treatment or retreatment with ATRA, ATO, or both, cytotoxic chemotherapy, auto or allogeneic SCT and enrollment in a clinical trial.22 Seftel MD, Barnett MJ, Couban S, Leber B, Storring J, Assaily W, et al. A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults. Curr Oncol. 2014;21(5):234-50.,1616 Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002;100(13):4298-302.

17 Pemmaraju N, Tanaka MF, Ravandi F, Lin H, Baladandayuthapani V, Rondon G, et al. Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2013;13(4):485-92.
-1818 Soignet SL. Clinical experience of arsenic trioxide in relapsed acute promyelocytic leukemia. Oncologist. 2001;6(Suppl. 2):11-6.,2929 Dimov ND, Medeiros LJ, Ravandi F, Bueso-Ramos CE. Acute promyelocytic leukemia at time of relapse commonly demonstrates cytogenetic evidence of clonal evolution and variability in blast immunophenotypic features. Am J Clin Pathol. 2010;133(3):484-90. Patients treated with salvage chemotherapy alone have lower survival compared to those submitted to SCT.1717 Pemmaraju N, Tanaka MF, Ravandi F, Lin H, Baladandayuthapani V, Rondon G, et al. Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2013;13(4):485-92. Auto-SCT should be performed when the patient achieves MR, but may increase the risk of a new relapse. Patients submitted to auto-SCT have higher rates of overall and disease-free survival than those who undergo allogeneic SCT.1717 Pemmaraju N, Tanaka MF, Ravandi F, Lin H, Baladandayuthapani V, Rondon G, et al. Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2013;13(4):485-92. Allogeneic SCT is indicated when the patient does not achieve molecular response after consolidation. These patients seem to have more prolonged remissions and less incidence of new relapse, but a higher death rate due to graft-versus-host disease (GVHD).

The protocol for relapsed patients included ATRA and Idarubicin plus ATO followed by auto-SCT, after confirmation of the MR. Four patients did not receive anthracycline due to clinical conditions, including one patient who had a heart attack at the time the relapse was diagnosed.

The IC-APL 2006 protocol used in the present study significantly reduced early mortality and improved the overall survival of APL patients33 Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte Mdel R, Jacomo RH, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121(11):1935-43. when compared to historical controls.44 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. Increased knowledge of the outcome in the subpopulation of treated patients that exhibit relapse is crucial to understanding the pathophysiology of APL and to improve survival.2222 Lu J, Huang X, Bao L, Jiang H, Zhu H, Jiang B. Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all-trans retinoic acid and arsenic compound-based combined therapies. Oncol Lett. 2014;7(1):177-82. In the real-world circumstances of the healthcare delivery system, costs and availability become issues for patients and clinicians, and show the importance of single center results. This study is the first to report on molecular and hematologic relapse in a cohort of Brazilian APL patients submitted to the IC-APL 2006 protocol.

Conclusion

There were no differences in clinical-biological variables between patients with or without relapse. The data of this study also show the efficacy of the treatment protocol used for APL and the importance of prolonged monitoring using molecular methods to detect relapse earlier in order to improve survival of this subgroup of patients.

Acknowledgments

This study was supported by the American Society of Hematology and Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco–FACEPE. The authors thank Ulisses Ramos Montarroyos for statistical support.

References

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    Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004;103(4):1237-43.
  • 2
    Seftel MD, Barnett MJ, Couban S, Leber B, Storring J, Assaily W, et al. A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults. Curr Oncol. 2014;21(5):234-50.
  • 3
    Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte Mdel R, Jacomo RH, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121(11):1935-43.
  • 4
    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.
  • 5
    Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-51.
  • 6
    van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13(12):1901-28.
  • 7
    Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of "real-time" quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer program. Leukemia. 2003;17(12):2318-57.
  • 8
    Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised Recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21(24):4642-9.
  • 9
    Sanz MA, Lo Coco F, Martín G, Avvisati G, Rayón C, Barbui T, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000;96(4):1247-53.
  • 10
    Lo Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM, et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood. 1999;94(7):2225-9.
  • 11
    Lou Y, Suo S, Tong Y, Tong H, Qian W, Meng H, et al. Outcomes and prognostic factors of first relapsed acute promyelocytic leukemia patients undergoing salvage therapy with intravenous arsenic trioxide and chemotherapy. Ann Hematol. 2014;93(6):941-8.
  • 12
    Montesinos P, Sanz MA. The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the Pethema group and review of the literature. Mediterr J Hematol Infect Dis. 2011;3(1):e2011059.
  • 13
    Rego EM, De Santis GC. Differentiation syndrome in promyelocytic leukemia: clinical presentation, pathogenesis and treatment. Mediterr J Hematol Infect Dis. 2011;3(1):e2011048.
  • 14
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Publication Dates

  • Publication in this collection
    Jan-Mar 2017

History

  • Received
    31 Aug 2015
  • Accepted
    9 Sept 2016
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