Pediatric Hematology and Oncology, 31:143–148, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2013.876470
ORIGINAL ARTICLE Myeloid Leukemias and Myeloproliferative Disease
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Treatment of an Acute Promyelocytic Leukemia Relapse Using Arsenic Trioxide and All-Trans-Retinoic in a 6-Year-Old Child Nathalie Rock,1 V. Mattiello,1 C. Judas,1 P. Huezo-Diaz,1,2 J.P. Bourquin,3 F. Gumy-Pause,1,2 and M. Ansari1,2 1
Hemato-Oncology Unit, Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland; 2 CANSEARCH Research Laboratory, Geneva University Medical School, Geneva, Switzerland; 3 Hemato-Oncology Unit, Department of Pediatrics, University Hospital of Zurich, Zurich, Switzerland
In adult therapy, arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) are recognized as active treatment of relapsed acute promyelocytic leukemia (APL). The efficacy of this combination in pediatric APL has not yet been well established. We report the case of a 6-year-old girl with relapsed APL, with a PML-RARα mutation, treated with a combination of ATO and ATRA. Over a period of 5 months, she received in total, 75 doses of intravenous ATO and 40 doses of oral ATRA. Currently, 22 months after relapse, she is still in complete remission. Here, we describe treatment of a relapsed APL in a child with limited treatment of ATO and ATRA and review the literature. Keywords relapse
acute promyelocytic leukemia, all-trans-retinoic acid, arsenic trioxide, children,
INTRODUCTION Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) and arises in less than 5–10% of childhood AML. Blasts have a morphology of French–American–British (FAB) M3 subtype and generally are characterized by a balanced translocation between the promyelocytic leukemia (PML) gene on chromosome 15q and the retinoic acid receptor alpha (RARα) gene on chromosome 17q [1, 2]. The underlying t(15;17) translocation leads to the production of the PML-RAR α fusion gene. The prognosis of APL was further improved after the discovery in the 1980s that all-trans-retinoic acid (ATRA) acts against PML-RARα. Newly childhood APL treatment is currently based on ATRA and conventional chemotherapy with a 90% remission rate [2]. Furthermore, APL relapse in children remains a challenge because of the lack of consensus over treatment and the risk of cardiotoxicity due to cumulative doses of anthracyclines. Arsenic trioxide (ATO) is known as a poison and also as a treatment agent for more than 1000 years in Chinese medicine. More recently, it was reported that ATO binds PML to PML-RARα protein and leads to dose dependent Received 4 October 2013; accepted 13 December 2013. Address correspondence to Nathalie Rock, MD, Hemato-oncology Unit, Department of Pediatrics, University Hospital of Geneva, Geneva 1205, Switzerland. E-mail: [email protected]
N. Rock et al.
degradation or apoptosis of the APL cell [3–5]. Therefore ATO is increasingly described as first line treatment in combination with ATRA conventional treatment for newly diagnosed childhood APL [6–9]. ATO and ATRA combination is currently approved in North America and Europe for the treatment of relapsed adult APL [3, 10–12]. In pediatric relapsed APL, the use of ATO is described either on its own [13, 14] or in combination with ATRA in long-term treatment periods [15] or in combination with conventional chemotherapy [8–9].
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CLINICAL CASE A 6-year-old girl was referred to our oncology unit for follow up of an APL. Three years before, she was diagnosed in Brazil of an AML M3 with positive PML-RARα transcript. The only symptoms were multiple hematomas. Induction phase with daunorubicin and ATRA, lead to a complete remission, and was followed by a consolidation phase using daunorubicin, mitoxantrone, and ATRA. Treatment was completed with ATRA, methotrexate, and 6-mercatopurine during 1 year. The total dose of daunorubicine was 500 mg/m2 and for mitoxanthrone was 30 mg/m2 . The exact cumulative dose of ATRA is not known. Molecular remission was confirmed at the end of treatment. The total duration of treatment was 2 years and half. Then, she moved to Switzerland and a blood count performed two months later showed no signs of the disease. She was finally referred to our unit for the follow-up, 6 months after the end of treatment. While she did not present any symptoms, isolated neutropenia (0.35 G/L) was detected (Hb:11.2 g/dL; platelets: 242 G/L; Leucocytes 2.7 G/L). Bone marrow aspiration confirmed the APL relapse with a massive infiltration of PML-RARα positive promyelocytes on cytogenetic analysis. Coagulation tests and lumbar puncture were normal as were renal and cardiac function. Due to the good results reported in adult relapsed APL and also because she had already received a high dose of anthracyclines, we decided to treat her with ATO in combination associated with ATRA without chemotherapy [1, 3, 7, 8]. Treatment began with oral ATRA 25 mg/m2 /day for 10 days. Afterwards, the patient received 10 weeks of 0.15 mg/kg/day IV ATO (5 times per of week). A second treatment of ATRA was given for 3 weeks followed by 5 weeks of ATO IV. Three prophylactic intrathecal injections of cytarabine (40 mg) were performed (W8, W15, and W20) (Figure 1). The whole treatment lasted 5 months. She received a total of 75 doses of ATO and 25 of ATRA. Bone marrow aspiration performed after 8 weeks of treatment, showed only 5% of promyelocyte, with normal blood count (Hb 10 g/dL; platelets 331× G/L; Leucocytes 3.4 G/L). Complete remission was confirmed at the end of treatment with a negative PML-RAR PCR. PCR assays were still negative 2 months later,
FIGURE 1 Treatment schedule over a 20 weeks period: ATRA (0.25 mg/m2 /day was given for 10 days, following by 10 weeks of ATO (0.15 mg/kg/day 5 days a week), 3 weeks of ATRA and then 5 weeks of ATO at the same dosage. Three TIT of cytarabine (40 mg) were performed (IT). Complete remission was obtained after 8 weeks (CR1) and confirmed at the end of treatment with PML-RAR α PCR negative (MCR). (A) Interruption by herpes Zoster infection. (B) Interruption by febrile aplasia. Pediatric Hematology and Oncology
Treatment of Child APL Relapsed
confirmed again with PCR assays performed after 1 month. This is a predictive factor of long-term remission [1, 16, 17]. She is currently in complete remission 16 month after the end of treatment. ATO and ATRA treatments were very well supported and only interrupted between weeks 3 and 4 for ATO because of a thoracic herpes Zoster infection treated with acyclovir and between weeks 5 and 6 for ATO, due to double bacteremias (Enterobacter sp and Pseudomonas Putida) with febrile aplasia. At this time, cardiac evaluation (electrocardiogram and electro ultrasonography) remain normal and no other toxicities were observed (Figure 1).
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DISCUSSION Physiopathology of APL is explained by a maturation arrest in the promyelocytic stage caused by the PML-RARα chimeric protein. In the 1970s, the high sensitivity of the APL cells to daunorubicine was demonstrated allowing anthracycline to be used in first line treatments in many adult and pediatric protocols [1–2]. Because of the risk of cardiotoxicity with cumulative dose, anthracycline is not always recommended to treat relapsed APL and especially in a case like ours [1, 2]. First described in 1980, ATRA induces differentiation of leukemic promyelocytes into mature granulocytes by ligation of the PML-RARα receptor [4, 7]. Otherwise, ATO binds to PML-RARα protein and leads to dose dependent degradation or apoptosis of the APL cell [8, 9]. A synergistic effect between ATO and ATRA, as used in this protocol has been was demonstrated, which leads to the acceleration of the differentiation and apoptosis of abnormal cells [16–18] and to the improve survival rate of APL patients [10]. An adult meta-analysis study demonstrated that the use of ATO and ATRA compared to single ATO agent increased the complete remission rate after induction therapy, shortened the time of obtaining remission and permitted a better remission rate after a year of follow-up [11–19]. In adults, the use of an ATO and ATRA combination is currently the approved treatment of relapsed APL, in association with conventional chemotherapy. The combination of ATO and ATRA alone could become a choice of treatment of newly diagnosed adult patients with APL in the years to come. [3, 10, 11, 12, 19, 20]. LoCoco published in 2013 a study observing that ATO and ATRA is no less inferior to ATRA with chemotherapy in cases of newly diagnosed adult APL [11]. ATO with or without ATRA is also increasingly described as first line treatment for newly diagnosed childhood APL. Zhou et al. treated 19 children newly diagnosed for APL with single ATO agent during induction and 3 years of maintenance therapy. Eighty-nine percent of the patient achieved hematologic complete remission with a 5-year event free survival (EFS) of 78% [8]. This result corresponds well to what was found by Georges et al. They treated 11 children with intravenous ATO, and showed a 5-year EFS of 81% [6]. In 2010, Zhang et al., had already reported the association of ATO and ATRA in children. They treated 37 newly APL patients with ATRA, intravenous chemotherapy with or without ATO [7]. No relapse was observed in the 10 patients treated with ATO while 4 cases of relapse were found in the 17 patients treated without ATO. However, there is still limited data available concerning this treatment in childhood relapsed APL. ATO and ATRA are only discussed as case reports or case series, and there is no consensus about schema of treatment or post remission consolidation treatment [21]. Fox et al. published a phase 1 trial that evaluated the tolerability of ATO in children with relapsed acute leukemia. Among this population, 13 children with APL received intravenous ATO with a morphologic complete response of 85%. They did not receive ATRA. For six of them, a stem cell transplant was performed C Informa Healthcare USA, Inc. Copyright
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N. Rock et al.
[14]. Bally et al. described the outcome of 26 pediatric patients of APL. And 12 of them under the age of than 4 years and with a higher risk of relapse compared to others. Our patient was within this group. One of these relapsed APL patients remains in complete remission 3.5 years after treatment with ATO and ATRA and consolidation with stem cell transplantation [22]. Wy et al. described the use of oral ATO in combination with ATRA in four children with relapsed APL. The induction phase was performed with oral ATO and ATRA or conventional chemotherapy, which was followed by consolidation with oral ATO, and ATRA for three patients and ARA-C for the fourth. The maintenance therapy contained oral ATO during 2 years. The four patients maintained long-term remission [15]. In 2008, Zhang et al. reported a retrospective analysis of 65 children with APL. Five out of seven patients who relapsed were treated with ATRA alone or in combination with ATO followed by a treatment with ATRA and chemotherapy. All remain in second complete remission [9]. Ebinger et al. described a case of an 8-year-old boy treated with a single arsenic single agent that resulted in long-term remission [13]. In contrast with these cases, the main advantage of the protocol described here is the possibility of avoiding hematopoietic stem cell transplantation (HSCT), of shortening the consolidation [3], and of avoiding long maintenance therapy. To this day, there is no evidence indicating which is the most appropriate consolidation therapy for relapsed APL in childhood [21]. HSCT has not provided better results compared than other treatment of consolidation. Thus the reason for why it was decided to try to avoid performing a HSCT [11]. Another benefit of ATO and ATRA treatments are the very little side effects, which are important in heavily pretreated APL children. Our patient presented only a few complications after treatment and no cardiac toxicity to this day. ATRA is principally known to induce side effects such as the development of pseudo-tumor cerebri in 5–16% of the cases [1, 2]. Different publications reported the safety of ATO compared to conventional chemotherapy, principally because of the shortness of exposure [18–20]. The most described ATO side effects are common and transitory, such as nausea; dizziness, skins rashes, headaches, muscle pain, and elevated liver enzymes [1, 3,18]. A risk of acute or chronic intoxication also exists such as dermatitis or chronic polyneuropathy or prolonged Qtc, fatal arrhythmia occurs rarely [3]. Due to the recent use of ATO in children, long-term follow up is needed. There is no consensus or randomized trials in pediatrics patient on the most suitable treatment for newly or relapse APL, because of the low patient numbers. The result of the case presented here is encouraging because it described a case of very short use of ATRA and ATO for relapsed APL and supports the existing data concerning the interest of using ATRA and ATO in pediatrics APL treatment for further improving the outcome and reducing the sides effects related to conventional chemotherapy. However, the efficacy of this association of ATO and ATRA in a relapsed APL child or in any newly APL cases needs to be prospectively evaluated in a randomized multicentric trial in order to understand which side effects are specific to children before constructing an adapted schema of ATRA/ ATO treatment for children. CONCLUSION Currently there is no consensus concerning the optimal schedule and the duration of treatment in relapsed APL in pediatric patients. We report a case of a relapsed APL pediatric patient treated with a combination of ATRA and ATO without other conventional chemotherapy during a period of only 5 months. While long term follow up is needed, 22 months post beginning of treatment; this patient is considered to be in complete clinical and molecular remission.
Pediatric Hematology and Oncology
Treatment of Child APL Relapsed
Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Marc Ansari is supported by a grant from the CANSEARCH Foundation and the Geneva Cancer League.
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REFERENCES [1] Mantadakis E, Samonis G, Kalmanti M. A comprehensive review of acute promyelocytic leukemia in children. Acta Haematologica. 2008;119:73–82. [2] Yoo ES. Recent advances in the diagnosis and management of childhood acute promyelocytic leukemia. Korean J Pediatr. 2011;54:95–105. [3] Lengfelder E, Hofmann W-K, Nowak D. Impact of arsenic trioxide in the treatment of acute promyelocytic leukemia. Leukemia. 2012;26:433–442. [4] Zhang X-W, Yan X-J, Zhou Z-R, et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science (New York, N.Y.). 2010;328:240–243. [5] Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood . 2006;107:3469– 3473. [6] George B, Mathews V, Poonkuzhali B, et al. Treatment of children with newly diagnosed acute promyelocytic leukemia with arsenic trioxide: a single center experience. Leukemia. 2004;18: 1587–1590. [7] Zhang L, Zhu X, Zou Y, et al. Effect of arsenic trioxide on the treatment of children with newly diagnosed acute promyelocytic leukemia in China. Int J Hematol. 2011;93:199–205. [8] Zhou J, Zhang Y, Li J, et al. Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood. 2010;115:1697–702. [9] Zhang L, Zhao H, Zhu X, et al. Retrospective analysis of 65 Chinese children with acute promyelocytic leukemia: a single center experience. Pediatr Blood Cancer. 2008;51:210–215. [10] Beccia M, Lo-Coco F. Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease. Expert Opin Pharmacother. 2012;13:1031–1043. [11] Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acutepromyelocytic leukemia. N Engl J Med. 2013;369:111–121. [12] Huang H, Qin Y, Xu R, et al. Combination therapy with arsenic trioxide, all-trans retinoic acid, and chemotherapy in acute promyelocytic leukemia patients with various relapse risks. Leukemia Res. 2012;36:841–845. [13] Ebinger M, Schwarze CP, Feuchtinger T, et al. Long-term remission after first-line single-agent treatment with arsenic trioxide of relapsed acute promyelocytic leukemia in an 8-year-old boy. Pediatr Hematol Oncol. 2011;28:334–337. [14] Fox E, Razzouk BI, Widemann BC, et al. Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood. 2008;111:566–573. [15] Au WY, Li C, Lee V, et al. Oral Arsenic Trioxide for Relapsed Acute Promyelocytic Leukemia in Pediatric Patients. Pediatr Blood Cancer. 2012;58:630–632. [16] Visani G, Piccaluga PP, Martinelli G, et al. Sustained molecular remission in advanced acute promyelocytic leukemia with combined pulsed retinoic acid and arsenic trioxide. Clinical evidence of synergistic effect and real-time quantification of minimal residual disease. Haematologica. 2003;88: ELT15. [17] Jurcic J-G, Nimer S-D, Scheinberg D-A, et al. Prognostic significance of minimal residual disease detection and PML/RAR-a isoform type: long-term follow-up in acute promyelocytic leukemia. Blood 2001;98: 2651–2656. [18] Zhou G-B, Zhang J, Wang Z-Y, et al. Treatment of acute promyelocytic leukaemia with alltrans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy. Philosophical transactions of the Royal Society of London Series B, Biological Sci. 2007;362:959– 971. [19] Wang H, Chen X, Wang B, et al. The efficacy and safety of arsenic trioxide with or without all-trans retinoic acid for the treatment of acute promyelocytic leukemia: a meta-analysis. Leukemia Res. 2001;35:1170–1177.
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N. Rock et al.
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[20] Soignet SL, Frankel SR, Douer D, et al. United States Multicenter Study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–3860. [21] Breccia M, Lo-Coco F. Arsenic trioxide for managementof acute promyelocytic leukemia: current evidence on its role in front-line therap and recurrent disease. Expert Opin Pharmacother. 2012;13(7):1031–1043. [22] Bally C, Fadlallah J, Leverger G, et al. Outcome of acute promyelocytic leukemia in children and adolescents: an analysis in two consecutive trials of The European APL Group. J Clin Oncol. 30:1641–1646.
Pediatric Hematology and Oncology
ORIGINAL ARTICLE Myeloid Leukemias and Myeloproliferative Disease
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Treatment of an Acute Promyelocytic Leukemia Relapse Using Arsenic Trioxide and All-Trans-Retinoic in a 6-Year-Old Child Nathalie Rock,1 V. Mattiello,1 C. Judas,1 P. Huezo-Diaz,1,2 J.P. Bourquin,3 F. Gumy-Pause,1,2 and M. Ansari1,2 1
Hemato-Oncology Unit, Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland; 2 CANSEARCH Research Laboratory, Geneva University Medical School, Geneva, Switzerland; 3 Hemato-Oncology Unit, Department of Pediatrics, University Hospital of Zurich, Zurich, Switzerland
In adult therapy, arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) are recognized as active treatment of relapsed acute promyelocytic leukemia (APL). The efficacy of this combination in pediatric APL has not yet been well established. We report the case of a 6-year-old girl with relapsed APL, with a PML-RARα mutation, treated with a combination of ATO and ATRA. Over a period of 5 months, she received in total, 75 doses of intravenous ATO and 40 doses of oral ATRA. Currently, 22 months after relapse, she is still in complete remission. Here, we describe treatment of a relapsed APL in a child with limited treatment of ATO and ATRA and review the literature. Keywords relapse
acute promyelocytic leukemia, all-trans-retinoic acid, arsenic trioxide, children,
INTRODUCTION Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) and arises in less than 5–10% of childhood AML. Blasts have a morphology of French–American–British (FAB) M3 subtype and generally are characterized by a balanced translocation between the promyelocytic leukemia (PML) gene on chromosome 15q and the retinoic acid receptor alpha (RARα) gene on chromosome 17q [1, 2]. The underlying t(15;17) translocation leads to the production of the PML-RAR α fusion gene. The prognosis of APL was further improved after the discovery in the 1980s that all-trans-retinoic acid (ATRA) acts against PML-RARα. Newly childhood APL treatment is currently based on ATRA and conventional chemotherapy with a 90% remission rate [2]. Furthermore, APL relapse in children remains a challenge because of the lack of consensus over treatment and the risk of cardiotoxicity due to cumulative doses of anthracyclines. Arsenic trioxide (ATO) is known as a poison and also as a treatment agent for more than 1000 years in Chinese medicine. More recently, it was reported that ATO binds PML to PML-RARα protein and leads to dose dependent Received 4 October 2013; accepted 13 December 2013. Address correspondence to Nathalie Rock, MD, Hemato-oncology Unit, Department of Pediatrics, University Hospital of Geneva, Geneva 1205, Switzerland. E-mail: [email protected]
N. Rock et al.
degradation or apoptosis of the APL cell [3–5]. Therefore ATO is increasingly described as first line treatment in combination with ATRA conventional treatment for newly diagnosed childhood APL [6–9]. ATO and ATRA combination is currently approved in North America and Europe for the treatment of relapsed adult APL [3, 10–12]. In pediatric relapsed APL, the use of ATO is described either on its own [13, 14] or in combination with ATRA in long-term treatment periods [15] or in combination with conventional chemotherapy [8–9].
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
CLINICAL CASE A 6-year-old girl was referred to our oncology unit for follow up of an APL. Three years before, she was diagnosed in Brazil of an AML M3 with positive PML-RARα transcript. The only symptoms were multiple hematomas. Induction phase with daunorubicin and ATRA, lead to a complete remission, and was followed by a consolidation phase using daunorubicin, mitoxantrone, and ATRA. Treatment was completed with ATRA, methotrexate, and 6-mercatopurine during 1 year. The total dose of daunorubicine was 500 mg/m2 and for mitoxanthrone was 30 mg/m2 . The exact cumulative dose of ATRA is not known. Molecular remission was confirmed at the end of treatment. The total duration of treatment was 2 years and half. Then, she moved to Switzerland and a blood count performed two months later showed no signs of the disease. She was finally referred to our unit for the follow-up, 6 months after the end of treatment. While she did not present any symptoms, isolated neutropenia (0.35 G/L) was detected (Hb:11.2 g/dL; platelets: 242 G/L; Leucocytes 2.7 G/L). Bone marrow aspiration confirmed the APL relapse with a massive infiltration of PML-RARα positive promyelocytes on cytogenetic analysis. Coagulation tests and lumbar puncture were normal as were renal and cardiac function. Due to the good results reported in adult relapsed APL and also because she had already received a high dose of anthracyclines, we decided to treat her with ATO in combination associated with ATRA without chemotherapy [1, 3, 7, 8]. Treatment began with oral ATRA 25 mg/m2 /day for 10 days. Afterwards, the patient received 10 weeks of 0.15 mg/kg/day IV ATO (5 times per of week). A second treatment of ATRA was given for 3 weeks followed by 5 weeks of ATO IV. Three prophylactic intrathecal injections of cytarabine (40 mg) were performed (W8, W15, and W20) (Figure 1). The whole treatment lasted 5 months. She received a total of 75 doses of ATO and 25 of ATRA. Bone marrow aspiration performed after 8 weeks of treatment, showed only 5% of promyelocyte, with normal blood count (Hb 10 g/dL; platelets 331× G/L; Leucocytes 3.4 G/L). Complete remission was confirmed at the end of treatment with a negative PML-RAR PCR. PCR assays were still negative 2 months later,
FIGURE 1 Treatment schedule over a 20 weeks period: ATRA (0.25 mg/m2 /day was given for 10 days, following by 10 weeks of ATO (0.15 mg/kg/day 5 days a week), 3 weeks of ATRA and then 5 weeks of ATO at the same dosage. Three TIT of cytarabine (40 mg) were performed (IT). Complete remission was obtained after 8 weeks (CR1) and confirmed at the end of treatment with PML-RAR α PCR negative (MCR). (A) Interruption by herpes Zoster infection. (B) Interruption by febrile aplasia. Pediatric Hematology and Oncology
Treatment of Child APL Relapsed
confirmed again with PCR assays performed after 1 month. This is a predictive factor of long-term remission [1, 16, 17]. She is currently in complete remission 16 month after the end of treatment. ATO and ATRA treatments were very well supported and only interrupted between weeks 3 and 4 for ATO because of a thoracic herpes Zoster infection treated with acyclovir and between weeks 5 and 6 for ATO, due to double bacteremias (Enterobacter sp and Pseudomonas Putida) with febrile aplasia. At this time, cardiac evaluation (electrocardiogram and electro ultrasonography) remain normal and no other toxicities were observed (Figure 1).
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DISCUSSION Physiopathology of APL is explained by a maturation arrest in the promyelocytic stage caused by the PML-RARα chimeric protein. In the 1970s, the high sensitivity of the APL cells to daunorubicine was demonstrated allowing anthracycline to be used in first line treatments in many adult and pediatric protocols [1–2]. Because of the risk of cardiotoxicity with cumulative dose, anthracycline is not always recommended to treat relapsed APL and especially in a case like ours [1, 2]. First described in 1980, ATRA induces differentiation of leukemic promyelocytes into mature granulocytes by ligation of the PML-RARα receptor [4, 7]. Otherwise, ATO binds to PML-RARα protein and leads to dose dependent degradation or apoptosis of the APL cell [8, 9]. A synergistic effect between ATO and ATRA, as used in this protocol has been was demonstrated, which leads to the acceleration of the differentiation and apoptosis of abnormal cells [16–18] and to the improve survival rate of APL patients [10]. An adult meta-analysis study demonstrated that the use of ATO and ATRA compared to single ATO agent increased the complete remission rate after induction therapy, shortened the time of obtaining remission and permitted a better remission rate after a year of follow-up [11–19]. In adults, the use of an ATO and ATRA combination is currently the approved treatment of relapsed APL, in association with conventional chemotherapy. The combination of ATO and ATRA alone could become a choice of treatment of newly diagnosed adult patients with APL in the years to come. [3, 10, 11, 12, 19, 20]. LoCoco published in 2013 a study observing that ATO and ATRA is no less inferior to ATRA with chemotherapy in cases of newly diagnosed adult APL [11]. ATO with or without ATRA is also increasingly described as first line treatment for newly diagnosed childhood APL. Zhou et al. treated 19 children newly diagnosed for APL with single ATO agent during induction and 3 years of maintenance therapy. Eighty-nine percent of the patient achieved hematologic complete remission with a 5-year event free survival (EFS) of 78% [8]. This result corresponds well to what was found by Georges et al. They treated 11 children with intravenous ATO, and showed a 5-year EFS of 81% [6]. In 2010, Zhang et al., had already reported the association of ATO and ATRA in children. They treated 37 newly APL patients with ATRA, intravenous chemotherapy with or without ATO [7]. No relapse was observed in the 10 patients treated with ATO while 4 cases of relapse were found in the 17 patients treated without ATO. However, there is still limited data available concerning this treatment in childhood relapsed APL. ATO and ATRA are only discussed as case reports or case series, and there is no consensus about schema of treatment or post remission consolidation treatment [21]. Fox et al. published a phase 1 trial that evaluated the tolerability of ATO in children with relapsed acute leukemia. Among this population, 13 children with APL received intravenous ATO with a morphologic complete response of 85%. They did not receive ATRA. For six of them, a stem cell transplant was performed C Informa Healthcare USA, Inc. Copyright
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N. Rock et al.
[14]. Bally et al. described the outcome of 26 pediatric patients of APL. And 12 of them under the age of than 4 years and with a higher risk of relapse compared to others. Our patient was within this group. One of these relapsed APL patients remains in complete remission 3.5 years after treatment with ATO and ATRA and consolidation with stem cell transplantation [22]. Wy et al. described the use of oral ATO in combination with ATRA in four children with relapsed APL. The induction phase was performed with oral ATO and ATRA or conventional chemotherapy, which was followed by consolidation with oral ATO, and ATRA for three patients and ARA-C for the fourth. The maintenance therapy contained oral ATO during 2 years. The four patients maintained long-term remission [15]. In 2008, Zhang et al. reported a retrospective analysis of 65 children with APL. Five out of seven patients who relapsed were treated with ATRA alone or in combination with ATO followed by a treatment with ATRA and chemotherapy. All remain in second complete remission [9]. Ebinger et al. described a case of an 8-year-old boy treated with a single arsenic single agent that resulted in long-term remission [13]. In contrast with these cases, the main advantage of the protocol described here is the possibility of avoiding hematopoietic stem cell transplantation (HSCT), of shortening the consolidation [3], and of avoiding long maintenance therapy. To this day, there is no evidence indicating which is the most appropriate consolidation therapy for relapsed APL in childhood [21]. HSCT has not provided better results compared than other treatment of consolidation. Thus the reason for why it was decided to try to avoid performing a HSCT [11]. Another benefit of ATO and ATRA treatments are the very little side effects, which are important in heavily pretreated APL children. Our patient presented only a few complications after treatment and no cardiac toxicity to this day. ATRA is principally known to induce side effects such as the development of pseudo-tumor cerebri in 5–16% of the cases [1, 2]. Different publications reported the safety of ATO compared to conventional chemotherapy, principally because of the shortness of exposure [18–20]. The most described ATO side effects are common and transitory, such as nausea; dizziness, skins rashes, headaches, muscle pain, and elevated liver enzymes [1, 3,18]. A risk of acute or chronic intoxication also exists such as dermatitis or chronic polyneuropathy or prolonged Qtc, fatal arrhythmia occurs rarely [3]. Due to the recent use of ATO in children, long-term follow up is needed. There is no consensus or randomized trials in pediatrics patient on the most suitable treatment for newly or relapse APL, because of the low patient numbers. The result of the case presented here is encouraging because it described a case of very short use of ATRA and ATO for relapsed APL and supports the existing data concerning the interest of using ATRA and ATO in pediatrics APL treatment for further improving the outcome and reducing the sides effects related to conventional chemotherapy. However, the efficacy of this association of ATO and ATRA in a relapsed APL child or in any newly APL cases needs to be prospectively evaluated in a randomized multicentric trial in order to understand which side effects are specific to children before constructing an adapted schema of ATRA/ ATO treatment for children. CONCLUSION Currently there is no consensus concerning the optimal schedule and the duration of treatment in relapsed APL in pediatric patients. We report a case of a relapsed APL pediatric patient treated with a combination of ATRA and ATO without other conventional chemotherapy during a period of only 5 months. While long term follow up is needed, 22 months post beginning of treatment; this patient is considered to be in complete clinical and molecular remission.
Pediatric Hematology and Oncology
Treatment of Child APL Relapsed
Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Marc Ansari is supported by a grant from the CANSEARCH Foundation and the Geneva Cancer League.
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[20] Soignet SL, Frankel SR, Douer D, et al. United States Multicenter Study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–3860. [21] Breccia M, Lo-Coco F. Arsenic trioxide for managementof acute promyelocytic leukemia: current evidence on its role in front-line therap and recurrent disease. Expert Opin Pharmacother. 2012;13(7):1031–1043. [22] Bally C, Fadlallah J, Leverger G, et al. Outcome of acute promyelocytic leukemia in children and adolescents: an analysis in two consecutive trials of The European APL Group. J Clin Oncol. 30:1641–1646.
Pediatric Hematology and Oncology
