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National Cancer Institute

Post Date: Mar 4, 2024

Treatments for children with acute promyelocytic leukemia (APL) include tretinoin, arsenic trioxide, chemotherapy, gemtuzumab ozogamicin, and stem cell transplant. Other drug therapy and supportive care is also used. Get detailed information for APL in this clinician summary.

Treatments for children with acute promyelocytic leukemia (APL) include tretinoin, arsenic trioxide, chemotherapy, gemtuzumab ozogamicin, and stem cell transplant. Other drug therapy and supportive care is also used. Get detailed information for APL in this clinician summary.

Childhood APL Treatment

childhood acute promyelocytic leukemia (M3)

General Information About Childhood Acute Promyelocytic Leukemia (APL)

APL occurs in about 7% of children with acute myeloid leukemia (AML). APL is a distinct subtype of AML. Several factors that make APL unique include the following:

  • Clinical presentation of universal coagulopathy (disseminated intravascular coagulation) and unique morphological characteristics (French-American-British [FAB] M3 or its variants).
  • Unique molecular etiology as a result of the involvement of the RARA oncogene.
  • Unique sensitivity to the differentiating agent tretinoin and to the proapoptotic agent arsenic trioxide.

When these unique features of APL are discovered at diagnosis, it is important to initiate proper supportive care measures to avoid coagulopathic complications during the first few days of therapy. It is also critical to institute an induction regimen specific to the treatment of APL. This regimen minimizes the risk of coagulopathic complications and provides a much improved long-term relapse-free survival and overall survival, compared with outcomes for patients with the other forms of AML.

References

  1. von Neuhoff C, Reinhardt D, Sander A, et al.: Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J Clin Oncol 28 (16): 2682-9, 2010.
  2. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 17-34. Also available online. Last accessed August 11, 2022.
  3. Melnick A, Licht JD: Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93 (10): 3167-215, 1999.
  4. Sanz MA, Grimwade D, Tallman MS, et al.: Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113 (9): 1875-91, 2009.
  5. Sanz MA, Lo-Coco F: Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol 29 (5): 495-503, 2011.

Clinical Presentation

Clinically, acute promyelocytic leukemia (APL) is characterized by severe coagulopathy that is often present at the time of diagnosis. APL blasts induce coagulopathy by activation of the coagulation cascade (caused by the expression of tissue factor and other procoagulants) with concomitant increase in primary and secondary fibrinolysis, resulting from the expression of annexin II on the APL blasts. Coagulopathy is typically manifested with thrombocytopenia, prolonged prothrombin time and partial thromboplastin time, elevated d-dimers, and hypofibrinogenemia.

Coagulopathy and bleeding complications increase the risk of early death during induction therapy (particularly with cytotoxic agents used alone). Because of these complications, mortality was once more common in patients with APL than in patients with other French-American-British (FAB) or World Health Organization (WHO) AML types.

Patients at greatest risk of coagulopathic complications are those presenting with high white blood cell (WBC) counts, decreased platelet count, abnormal coagulation studies (hypofibrinogenemia, prothrombin time), high body mass index, molecular variants of APL, and the presence of FLT3 internal tandem duplication (ITD) mutations.

Scoring systems using clinical characteristics and laboratory values can help predict the risk of developing severe or lethal coagulopathy, as demonstrated in studies of both adult and pediatric patients. Aggressive supportive care to correct coagulopathy, even before clinical signs and symptoms of bleeding or thrombosis occur, is important to prevent early death.

Because tretinoin has been shown to ameliorate bleeding risk for patients with APL, tretinoin therapy is initiated as soon as APL is suspected on the basis of morphological and clinical presentation. A retrospective analysis identified an increase in early death resulting from hemorrhage in patients with APL in whom tretinoin introduction was delayed.

A multicooperative group analysis of children with APL who were treated with tretinoin and chemotherapy reported the following:

  • Early induction coagulopathic deaths occurred in 25 of 683 children (3.7%); 23 deaths resulted from hemorrhage (19 central nervous system [CNS], 4 pulmonary), and 2 resulted from CNS thrombosis.
  • A lumbar puncture at diagnosis should not be performed until evidence of coagulopathy has resolved. When current treatment regimens with tretinoin and arsenic trioxide are used, diagnostic and therapeutic lumbar punctures are limited to only a relatively small subset of patients who present with signs and symptoms concerning for CNS disease and/or CNS hemorrhage.

Tretinoin is administered early to address this emergent need, but participation in other AML clinical trials is not precluded should the diagnosis of APL prove to be incorrect. Additionally, initiation of supportive measures such as replacement transfusions to correct coagulopathy is critical during these initial days of diagnosis and therapy.

References

  1. Tallman MS, Hakimian D, Kwaan HC, et al.: New insights into the pathogenesis of coagulation dysfunction in acute promyelocytic leukemia. Leuk Lymphoma 11 (1-2): 27-36, 1993.
  2. Altman JK, Rademaker A, Cull E, et al.: Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death. Leuk Res 37 (9): 1004-9, 2013.
  3. Lehmann S, Ravn A, Carlsson L, et al.: Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 25 (7): 1128-34, 2011.
  4. Park JH, Qiao B, Panageas KS, et al.: Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 118 (5): 1248-54, 2011.
  5. Abla O, Ribeiro RC, Testi AM, et al.: Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)-positive acute promyelocytic leukemia treated with ATRA and chemotherapy. Ann Hematol 96 (9): 1449-1456, 2017.
  6. Breen KA, Grimwade D, Hunt BJ: The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia. Br J Haematol 156 (1): 24-36, 2012.
  7. Mitrovic M, Suvajdzic N, Bogdanovic A, et al.: International Society of Thrombosis and Hemostasis Scoring System for disseminated intravascular coagulation ≥ 6: a new predictor of hemorrhagic early death in acute promyelocytic leukemia. Med Oncol 30 (1): 478, 2013.
  8. Rajpurkar M, Alonzo TA, Wang YC, et al.: Risk Markers for Significant Bleeding and Thrombosis in Pediatric Acute Promyelocytic Leukemia; Report From the Children's Oncology Group Study AAML0631. J Pediatr Hematol Oncol 41 (1): 51-55, 2019.
  9. Sanz MA, Grimwade D, Tallman MS, et al.: Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113 (9): 1875-91, 2009.
  10. Visani G, Gugliotta L, Tosi P, et al.: All-trans retinoic acid significantly reduces the incidence of early hemorrhagic death during induction therapy of acute promyelocytic leukemia. Eur J Haematol 64 (3): 139-44, 2000.
  11. Kutny MA, Alonzo TA, Abla O, et al.: Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial. JAMA Oncol 8 (1): 79-87, 2022.

Molecular Variants and Therapeutic Impact

RARA Fusion Proteins

The characteristic chromosomal abnormality associated with acute promyelocytic leukemia (APL) is t(15;17)(q22;q21). This translocation involves a breakpoint that includes the retinoic acid receptor and leads to production of the PML::RARA fusion protein. Other more complex chromosomal rearrangements may also lead to a PML::RARA fusion and result in APL.

Patients with a suspected diagnosis of APL can have their diagnosis confirmed by detection of the PML::RARA fusion protein through fluorescence in situ hybridization (FISH), reverse transcriptase–polymerase chain reaction (RT-PCR), or conventional cytogenetics. Quantitative RT-PCR allows identification of the three common transcript variants and is used for monitoring response on treatment and early detection of molecular relapse. In addition, an immunofluorescence method using an anti-PML monoclonal antibody can rapidly establish the presence of the PML::RARA fusion protein based on the characteristic distribution pattern of PML that occurs in the presence of the fusion protein.

Uncommon molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., PLZF, NPM, STAT5B, and NuMA) to RARA. Recognition of these rare variants is important because they differ in their sensitivities to tretinoin and arsenic trioxide.

  • PLZF::RARA fusion gene variant. The PLZF::RARA variant, characterized by t(11;17)(q23;q21), represents about 0.8% of APL, expresses surface CD56, and has very fine granules, compared with t(15;17) APL. APL with the PLZF::RARA fusion gene has been associated with a poor prognosis and usually does not respond to tretinoin or arsenic trioxide.
  • NPM::RARA or NuMA::RARA fusion gene variants. The rare APL variants with NPM::RARA (t(5;17)(q35;q21)) or NuMA::RARA (t(11;17)(q13;q21)) translocations may still be responsive to tretinoin.
  • PML::RARA fusion gene variant. There are rare case reports of patients with PML::RARA fusion–negative APL. One such APL is the torque teno mini virus (TTMV) subtype. This is a newly described entity in which the TTMV genome is integrated into intron 2 of the human RARA gene, resulting in a TTMV::RARA gene fusion. The clinical and morphological features of this APL subtype are similar to those of PML::RARA fusion–positive APL.

FLT3 Mutations

FLT3 mutations (either internal tandem duplication or tyrosine kinase domain mutations) are observed in 40% to 50% of APL cases. The presence of FLT3 mutations correlates with higher white blood cell counts and the microgranular variant (M3v) subtype. The FLT3 mutation has previously been associated with an increased risk of induction death and, in some reports, an increased risk of treatment failure. Given the extremely high cure rates for children with APL who were treated with tretinoin and arsenic trioxide, FLT3 mutations are not associated with inferior outcomes.

References

  1. Melnick A, Licht JD: Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93 (10): 3167-215, 1999.
  2. Sanz MA, Grimwade D, Tallman MS, et al.: Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113 (9): 1875-91, 2009.
  3. Falini B, Flenghi L, Fagioli M, et al.: Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML). Blood 90 (10): 4046-53, 1997.
  4. Gomis F, Sanz J, Sempere A, et al.: Immunofluorescent analysis with the anti-PML monoclonal antibody PG-M3 for rapid and accurate genetic diagnosis of acute promyelocytic leukemia. Ann Hematol 83 (11): 687-90, 2004.
  5. Dimov ND, Medeiros LJ, Kantarjian HM, et al.: Rapid and reliable confirmation of acute promyelocytic leukemia by immunofluorescence staining with an antipromyelocytic leukemia antibody: the M. D. Anderson Cancer Center experience of 349 patients. Cancer 116 (2): 369-76, 2010.
  6. Zelent A, Guidez F, Melnick A, et al.: Translocations of the RARalpha gene in acute promyelocytic leukemia. Oncogene 20 (49): 7186-203, 2001.
  7. Yan W, Zhang G: Molecular Characteristics and Clinical Significance of 12 Fusion Genes in Acute Promyelocytic Leukemia: A Systematic Review. Acta Haematol 136 (1): 1-15, 2016.
  8. Rego EM, Ruggero D, Tribioli C, et al.: Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR alpha, PLZF/RAR alpha or NPM/RAR alpha. Oncogene 25 (13): 1974-9, 2006.
  9. Licht JD, Chomienne C, Goy A, et al.: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85 (4): 1083-94, 1995.
  10. Guidez F, Ivins S, Zhu J, et al.: Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 91 (8): 2634-42, 1998.
  11. Grimwade D, Biondi A, Mozziconacci MJ, et al.: Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies". Blood 96 (4): 1297-308, 2000.
  12. Sukhai MA, Wu X, Xuan Y, et al.: Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha. Oncogene 23 (3): 665-78, 2004.
  13. Redner RL, Corey SJ, Rush EA: Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia 11 (7): 1014-6, 1997.
  14. Wells RA, Catzavelos C, Kamel-Reid S: Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet 17 (1): 109-13, 1997.
  15. Wells RA, Hummel JL, De Koven A, et al.: A new variant translocation in acute promyelocytic leukaemia: molecular characterization and clinical correlation. Leukemia 10 (4): 735-40, 1996.
  16. Umeda M, Ma J, Huang BJ, et al.: Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia. Blood Cancer Discov 3 (3): 194-207, 2022.
  17. Chen X, Wang F, Zhou X, et al.: Torque teno mini virus driven childhood acute promyelocytic leukemia: The third case report and sequence analysis. Front Oncol 12: 1074913, 2022.
  18. Sala-Torra O, Beppu LW, Abukar FA, et al.: TTMV-RARA fusion as a recurrent cause of AML with APL characteristics. Blood Adv 6 (12): 3590-3592, 2022.
  19. Callens C, Chevret S, Cayuela JM, et al.: Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 19 (7): 1153-60, 2005.
  20. Gale RE, Hills R, Pizzey AR, et al.: Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 106 (12): 3768-76, 2005.
  21. Arrigoni P, Beretta C, Silvestri D, et al.: FLT3 internal tandem duplication in childhood acute myeloid leukaemia: association with hyperleucocytosis in acute promyelocytic leukaemia. Br J Haematol 120 (1): 89-92, 2003.
  22. Noguera NI, Breccia M, Divona M, et al.: Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 16 (11): 2185-9, 2002.
  23. Tallman MS, Kim HT, Montesinos P, et al.: Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group. Blood 116 (25): 5650-9, 2010.
  24. Iland HJ, Bradstock K, Supple SG, et al.: All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 120 (8): 1570-80; quiz 1752, 2012.
  25. Kutny MA, Moser BK, Laumann K, et al.: FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (4): 662-7, 2012.
  26. Kutny MA, Alonzo TA, Abla O, et al.: Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial. JAMA Oncol 8 (1): 79-87, 2022.

Classification of Childhood APL

Childhood acute myeloid leukemia and other myeloid malignancies are classified according to the 2022 World Health Organization Classification system. For more information, see the Classification of Pediatric Myeloid Malignancies section in Childhood Acute Myeloid Leukemia Treatment.

Prognostic Factors Affecting Risk-Based Treatment

White Blood Cell (WBC) Count

The prognostic significance of WBC count is used to define high-risk and low-risk patient populations and to assign induction treatment. High-risk patients are defined by a WBC count of 10 × 109/L or greater. Patients with high-risk acute promyelocytic leukemia (APL) are given an anthracycline (idarubicin) along with induction therapy. Postinduction therapy is the same for both standard- and high-risk APL.

APL in children is generally similar to APL in adults, although children have a higher incidence of hyperleukocytosis (defined as a WBC count higher than 10 × 109/L) and a higher incidence of the microgranular morphological subtype. As in adults, children with WBC counts of less than 10 × 109/L at diagnosis have historically had better outcomes than patients with higher WBC counts. Presenting WBC count is still used to determine induction therapy. However, with modern tretinoin- and arsenic trioxide–based therapy, patients with high-risk APL have similar excellent survival rates as patients with standard-risk APL.

In the Children's Oncology Group (COG) AAML0631 (NCT00866918) trial, which included treatment with chemotherapy, tretinoin, and arsenic trioxide, patients were stratified on the basis of WBC count to standard risk or high risk. Risk classification primarily defined early death risk rather than relapse risk (standard risk, 0 of 66 patients vs. high risk, 4 of 35 patients). In the COG AAML1331 (NCT02339740) trial, patients were treated with tretinoin and arsenic trioxide along with aggressive supportive care measures. There was only 1 death (standard-risk APL) and 3 relapses (1 standard risk and 2 high risk) reported among 154 patients. Thus, no significant differences were seen between the risk groups. In the COG AAML0631 (NCT00866918) and AAML1331 (NCT02339740) trials, relapse risk after remission induction was 4% and 2% overall, respectively.

Minimal Residual Disease (MRD) and Molecular Remission

For APL, MRD detection at the end of induction therapy lacks prognostic significance, likely related to the delayed clearance of differentiating leukemic cells destined to eventually die. However, it is standard practice to document molecular remission after completion of two to four cycles of consolidation therapy.

References

  1. Sanz MA, Martín G, González M, 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 103 (4): 1237-43, 2004.
  2. Lo-Coco F, Avvisati G, Vignetti M, et al.: Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 116 (17): 3171-9, 2010.
  3. Kutny MA, Alonzo TA, Abla O, et al.: Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial. JAMA Oncol 8 (1): 79-87, 2022.
  4. de Botton S, Coiteux V, Chevret S, et al.: Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. J Clin Oncol 22 (8): 1404-12, 2004.
  5. Testi AM, Biondi A, Lo Coco F, et al.: GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 106 (2): 447-53, 2005.
  6. Ortega JJ, Madero L, Martín G, et al.: Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. J Clin Oncol 23 (30): 7632-40, 2005.
  7. Guglielmi C, Martelli MP, Diverio D, et al.: Immunophenotype of adult and childhood acute promyelocytic leukaemia: correlation with morphology, type of PML gene breakpoint and clinical outcome. A cooperative Italian study on 196 cases. Br J Haematol 102 (4): 1035-41, 1998.
  8. Sanz MA, Lo Coco F, Martín G, 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 96 (4): 1247-53, 2000.
  9. Kutny MA, Alonzo TA, Gerbing RB, et al.: Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631. J Clin Oncol 35 (26): 3021-3029, 2017.
  10. Mandelli F, Diverio D, Avvisati G, et al.: Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 90 (3): 1014-21, 1997.
  11. Burnett AK, Grimwade D, Solomon E, et al.: Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood 93 (12): 4131-43, 1999.

The Central Nervous System (CNS) and APL

CNS involvement at the time of diagnosis is not ascertained in most patients with acute promyelocytic leukemia (APL) because of the presence of disseminated intravascular coagulation. The Children's Oncology Group (COG) AAML0631 (NCT00866918) trial identified 28 patients out of 101 enrolled children who had cerebrospinal fluid (CSF) exams at diagnosis. In 7 of these children, blasts were identified in atraumatic taps. None of the patients experienced a CNS relapse with intrathecal treatment during induction and prophylactic doses during therapy. In the COG AAML1331 (NCT02339740) study, CSF exams were deferred if the patient did not have CNS symptoms or hemorrhage. Only 5 of 141 children without a history of CNS hemorrhage were diagnosed with CNS involvement, whereas 2 of 13 patients with CNS hemorrhage met the criteria for CNS disease.

Overall, CNS relapse is uncommon for patients with APL, particularly for those with white blood cell (WBC) counts of less than 10 × 109/L. In two clinical trials enrolling more than 1,400 adults with APL in which CNS prophylaxis was not administered, the cumulative incidence of CNS relapse was less than 1% for patients with WBC counts of less than 10 × 109/L, while it was approximately 5% for those with WBC counts of 10 × 109/L or greater. In addition to high WBC counts at diagnosis, CNS hemorrhage during induction is also a risk factor for CNS relapse. A review of published cases of pediatric APL also observed low rates of CNS relapse.

Arsenic trioxide is an agent known to have excellent CNS penetration. Because patients with APL receive arsenic trioxide and there is a low prevalence of CNS relapses, CSF exams are not necessary at diagnosis. In addition, the use of intrathecal chemotherapy prophylaxis is not required unless CNS hemorrhage occurs. Two COG trials revealed similar low incidences of CNS relapses.

  • The COG AAML0631 study included treatment with two courses of arsenic trioxide along with prophylactic intrathecal chemotherapy. CNS disease was detected in 2 of 3 children whose disease relapsed.
  • In the COG AAML1331 trial, only one patient was found to have CNS involvement (CNS 2A) that occurred in conjunction with a marrow relapse. In this study, triple intrathecal chemotherapy was administered to those who had CNS disease at diagnosis and/or experienced a CNS hemorrhage early in their diagnosis. No patients experienced recurrent CNS disease.

References

  1. Kutny MA, Alonzo TA, Gerbing RB, et al.: Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631. J Clin Oncol 35 (26): 3021-3029, 2017.
  2. Kutny MA, Alonzo TA, Abla O, et al.: Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial. JAMA Oncol 8 (1): 79-87, 2022.
  3. de Botton S, Sanz MA, Chevret S, et al.: Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia 20 (1): 35-41, 2006.
  4. Montesinos P, Díaz-Mediavilla J, Debén G, et al.: Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis. Haematologica 94 (9): 1242-9, 2009.
  5. Chow J, Feusner J: Isolated central nervous system recurrence of acute promyelocytic leukemia in children. Pediatr Blood Cancer 52 (1): 11-3, 2009.
  6. Kaspers G, Gibson B, Grimwade D, et al.: Central nervous system involvement in relapsed acute promyelocytic leukemia. Pediatr Blood Cancer 53 (2): 235-6; author reply 237, 2009.

Treatment of APL

Modern treatment programs for acute promyelocytic leukemia (APL) are based on the sensitivity of leukemia cells to the differentiation-inducing and apoptotic effects of tretinoin and arsenic trioxide. APL therapy first diverged from the therapy of other non-APL subtypes of acute myeloid leukemia (AML) with the addition of tretinoin to chemotherapy. With the incorporation of arsenic trioxide into modern treatment regimens, the use of traditional chemotherapy in adults and children is restricted to only the induction phase for high-risk patients.

Treatment options for children with APL may include the following:

  1. Arsenic trioxide and tretinoin, with or without chemotherapy.
  2. Supportive care.

Arsenic Trioxide and Tretinoin, With or Without Chemotherapy

Given the very high level of activity with the combination of arsenic trioxide and tretinoin for adults with APL and data indicating that children with APL have a similar response to these agents, the use of these two agents is the optimal therapeutic approach for this disease.

Induction therapy for patients with standard-risk APL includes repeated cycles of tretinoin and arsenic trioxide alone. Patients with high-risk APL receive treatment similar to that for patients with standard-risk disease, but they also receive short courses of chemotherapy during induction therapy. Assessment of response to induction therapy in the first month of treatment using morphological and molecular criteria may provide misleading results because delayed persistence of differentiating leukemia cells can occur in patients who will ultimately achieve a complete remission (CR). Alterations in planned treatment based on these early observations are not appropriate because it is rare for APL to be resistant to tretinoin plus arsenic trioxide.

Almost all children with APL who were treated with tretinoin, arsenic trioxide, and modern supportive care achieved CR in the absence of coagulopathy-related mortality.

Results from the completed cooperative group trial (Children's Oncology Group [COG] AAML1331 [NCT02339740]) verified the benefit of treatment with tretinoin and arsenic trioxide for children with newly diagnosed APL, similar to results reported by other groups. The dramatic efficacy of tretinoin against APL results from the ability of pharmacological doses of tretinoin to overcome the repression of signaling caused by the PML::RARA fusion protein at physiological tretinoin concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis. Most patients with APL achieve a CR when treated with tretinoin, although single-agent tretinoin is generally not curative.

Arsenic trioxide, a proapoptotic and differentiation agent via binding to and the degradation of the PML::RARA fusion oncoprotein, is the most active agent in the treatment of APL. While initially used in patients with relapsed APL, it is now incorporated into the treatment of newly diagnosed patients. Data supporting the use of arsenic trioxide initially came from trials that included adult patients only, but its efficacy has now been seen in trials that included pediatric patients.

Based on the adult and pediatric experiences, consolidation therapy may include repeated cycles of tretinoin and arsenic trioxide without additional chemotherapy. Studies using arsenic trioxide–based consolidation have demonstrated excellent survival rates without cytarabine consolidation.

Based on data from adult trials and the COG AAML1331 (NCT02339740) trial, maintenance therapy is likely unnecessary for patients with APL who are treated with tretinoin and arsenic trioxide. Because of the favorable outcomes with tretinoin and arsenic trioxide, hematopoietic stem cell transplant is not recommended in first CR.

Before this approach was discovered, chemotherapy was used in all or most phases of therapy including induction, consolidation, and maintenance for pediatric trials like AAML0631 (NCT00866918). The regimens that use chemotherapy are now primarily of historical interest. They can also be used as a reference in refractory cases because of the findings from randomized clinical trials that compared regimens with the combination of tretinoin and arsenic trioxide with or without chemotherapy.

Evidence (arsenic trioxide and tretinoin, with or without chemotherapy):

  1. In children and adolescents with newly diagnosed APL treated on the COG AAML0631 (NCT00866918) trial, two consolidation cycles of arsenic trioxide were incorporated into a chemotherapy regimen with lower cumulative anthracycline doses compared with historical controls.
    • The 3-year overall survival (OS) rate was 94%, and the event-free survival (EFS) rate was 91%.
    • Patients with standard-risk APL had an OS rate of 98% and an EFS rate of 95%.
    • Patients with high-risk APL had an OS rate of 86% and an EFS rate of 83%. This lower survival compared with standard-risk patients was primarily caused by early death events.
    • The relapse risk after arsenic trioxide consolidation was 4% and was similar for standard-risk and high-risk APL.
  2. The concurrent use of arsenic trioxide and tretinoin in newly diagnosed patients with APL results in high rates of CR. Early experience in children with newly diagnosed APL showed high rates of CR to arsenic trioxide, either as a single agent or given with tretinoin.[Level of evidence C1] Results of a meta-analysis of seven published studies in adult patients with APL suggested that using a combination of arsenic trioxide and tretinoin may be more effective than using arsenic trioxide alone to induce CR.
    • In early trials in children, the impact of arsenic added to induction (either alone or with tretinoin) on EFS and OS had appeared promising.
  3. Arsenic trioxide was evaluated as a component of induction therapy with idarubicin and tretinoin in the APML4 clinical trial, which enrolled both children and adults (N = 124 evaluable patients). Patients received two courses of consolidation therapy with arsenic trioxide and tretinoin (but no anthracycline) and maintenance therapy with tretinoin, mercaptopurine, and methotrexate.
    • The 2-year freedom-from-relapse rate was 97.5%, the failure-free survival rate was 88.1%, and the OS rate was 93.2%.
    • These outcome results were superior to those reported for patients who did not receive arsenic trioxide in the predecessor clinical trial (APML3).
  4. The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.

    Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.

    • The median duration of induction therapy for all patients (standard risk and high risk) was 47 days which included a 14-day rest period before starting consolidation therapy. All standard-risk and high-risk patients who completed their induction therapy achieved a hematologic CR or a CR with incomplete hematologic recovery before day 70.
    • During induction therapy, one standard-risk patient died of complications from coagulopathy, differentiation syndrome, and subsequent organ failure. No high-risk patients died of complications.
    • All patients who received quantitative polymerase chain reaction (PCR) testing after completing their second round of consolidation therapy were in molecular remission.
    • No patients experienced a relapse while on therapy. One standard-risk patient (1%) and two high-risk patients (4%) experienced relapses after therapy completion. These patients were successfully salvaged.

    The AAML1331 and AAML0631 trials were compared and the following was reported:

    • Standard-risk patients had equivalent 2-year EFS rates (98% vs. 97%) and OS rates (99% vs. 98.5%).
    • High-risk patients who enrolled in the AAML1331 trial had a significantly improved 2-year EFS rate (96.4% vs. 82.9%; P = .05) and OS rate (100% vs. 85.7%; P = .02).
    • In the AAML1331 trial, only a few patients with CNS symptoms or hemorrhage were examined and treated using triple intrathecal chemotherapy, whereas in the AAML0631 study, all standard-risk patients received three prophylactic doses of intrathecal chemotherapy, and all high-risk patients received four prophylactic doses of intrathecal chemotherapy.
    • The length of therapy was significantly shorter in the AAML1331 trial (9 months) than in the AAML0631 trial (>2 years).
    • Hospitalizations during consolidation therapy were significantly reduced in the AAML1331 trial, when compared with the AAML0631 trial (0 days vs. 13 days, respectively; P< .001).
    • In the AAML1331 trial, early death was significantly lower in high-risk patients (0 vs. 4 in AAML0631; P = .02), and not significantly different for standard-risk patients (1 vs. 0 in AAML0631; P = .16).

In summary, survival rates for children with APL exceeding 90% are achievable using treatment programs that prescribe the rapid initiation of tretinoin with appropriate supportive care measures and combine arsenic trioxide with tretinoin for induction and consolidation therapy. Cytotoxic chemotherapy is required only for high-risk patients, and its use is restricted to induction therapy. For patients in CR for more than 5 years, relapse is extremely rare.[Level of evidence B1]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

Complications Unique to APL Therapy

In addition to the previously mentioned universal presence of coagulopathy in patients newly diagnosed with APL (further described below), several other unique complications occur in patients with APL as a result of treatment. The clinician should be aware of these complications. These include two tretinoin-related conditions, pseudotumor cerebri and differentiation syndrome (also called retinoic acid syndrome), and an arsenic trioxide–related complication, QT interval prolongation.

  • Pseudotumor cerebri. Pseudotumor cerebri is typically manifested by headache, papilledema, sixth nerve palsy, visual field cuts, and normal intracranial imaging in the face of an elevated opening lumbar puncture pressure (not often obtained in APL patients). Pseudotumor cerebri is known to be associated with tretinoin, presumably by the same mechanism of vitamin A toxicity that leads to increased production of cerebrospinal fluid.

    The incidence of pseudotumor cerebri has been reported to be as low as 1.7% with very strict definitions of the complication and as high as 6% to 16% in pediatric trials. Pseudotumor cerebri is thought to be more prevalent in children receiving tretinoin, leading to lower dosing in contemporary pediatric APL clinical trials. Pseudotumor cerebri most typically occurs during induction at a median of 15 days (range, 1–35 days) after starting tretinoin, but is known to occur in other phases of therapy as well. Pseudotumor cerebri incidence and severity may be exacerbated with the concurrent use of azoles via inhibition of cytochrome P450 metabolism of tretinoin.

    When a diagnosis of pseudotumor cerebri is suspected, tretinoin is withheld until symptoms abate and then is slowly escalated to full dose as tolerated.

  • Differentiation syndrome. Differentiation syndrome (also known as retinoic acid syndrome or tretinoin syndrome) is a life-threatening syndrome thought to be an inflammatory response–mediated syndrome manifested by weight gain, fever, edema, pulmonary infiltrates, pleuro-pericardial effusions, hypotension, and, in the most severe cases, acute renal failure. In the COG AAML0631 (NCT00866918) study, it was present in 20% of patients during induction. It was more prevalent in high-risk children (31%) than in low-risk children (13%), a risk factor also seen in adults with APL. There is a bimodal peak with this syndrome seen in the first and third weeks of induction therapy.

    Since differentiation syndrome occurs more often in high-risk patients, dexamethasone is given with tretinoin and/or arsenic trioxide to prevent this complication. Prophylaxis with dexamethasone and hydroxyurea (for cytoreduction) is also administered to standard-risk patients if their WBC count rises to greater than 10 × 109/L after the start of tretinoin or arsenic. If differentiation syndrome occurs, the patient's dexamethasone dose may be escalated with temporary withholding of tretinoin and arsenic trioxide and, similar to pseudotumor cerebri, restarted at a lower dose and escalated as tolerated. When this approach was used in the COG AAML1331 (NCT02339740) trial, 24.5% of standard-risk patients and 30.4% of high-risk patients presented with differentiation syndrome. Only one standard-risk patient died of differentiation syndrome and coagulopathy.

    Patients with standard-risk APL who are treated during induction with tretinoin and arsenic trioxide alone, without other cytotoxic chemotherapy, have a risk of hyperleukocytosis (WBC count >10 × 109/L). The differentiating effect of tretinoin and arsenic trioxide can cause a rapid and significant rise in the WBC count after initiation of therapy. While hyperleukocytosis is a risk factor for developing differentiation syndrome, it may occur without developing the signs or symptoms of differentiation syndrome. In the COG AAML1331 trial, 32 of 98 patients with standard-risk APL developed hyperleukocytosis. This was managed with the initiation of hydroxyurea for cytoreduction and prophylaxis with dexamethasone to prevent differentiation syndrome. Patients with high-risk APL did not require hydroxyurea because they received idarubicin doses in early induction, which were effective for cytoreduction.

  • Coagulopathy. Along with differentiation syndrome, coagulopathy complications result in a higher risk of death during induction therapy (early death in APL). For more information about the diagnosis and management of coagulopathy, see the Clinical Presentation section.
  • QT interval prolongation. Arsenic trioxide is associated with QT interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes). It is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at mid-reference ranges, as well as to be cognizant of other agents known to prolong the QT interval.

Minimal Residual Disease Monitoring

The current induction and consolidation therapies result in molecular remission in most patients, as measured by reverse transcriptase (RT)-PCR for the PML::RARA fusion protein. Only 1% or less of patients show molecular evidence of disease at the end of consolidation therapy. While two negative RT-PCR assays after completion of therapy are associated with long-term remission, conversion from negative to positive RT-PCR is highly predictive of subsequent hematologic relapse.

Patients with persistent or relapsing disease on the basis of PML::RARA fusion protein RT-PCR measurement may benefit from intervention with relapse therapies. For more information, see the Treatment of Recurrent APL section.

References

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  2. Platzbecker U, Avvisati G, Cicconi L, et al.: Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol 35 (6): 605-612, 2017.
  3. Kutny MA, Alonzo TA, Abla O, et al.: Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial. JAMA Oncol 8 (1): 79-87, 2022.
  4. Creutzig U, Dworzak MN, Bochennek K, et al.: First experience of the AML-Berlin-Frankfurt-Münster group in pediatric patients with standard-risk acute promyelocytic leukemia treated with arsenic trioxide and all-trans retinoid acid. Pediatr Blood Cancer 64 (8): , 2017.
  5. Yang MH, Wan WQ, Luo JS, et al.: Multicenter randomized trial of arsenic trioxide and Realgar-Indigo naturalis formula in pediatric patients with acute promyelocytic leukemia: Interim results of the SCCLG-APL clinical study. Am J Hematol 93 (12): 1467-1473, 2018.
  6. Zhang L, Zou Y, Chen Y, et al.: Role of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all-trans retinoic acid and arsenic trioxide: a randomized controlled trial. BMC Cancer 18 (1): 374, 2018.
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  22. Kutny MA, Alonzo TA, Gerbing RB, et al.: Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631. J Clin Oncol 35 (26): 3021-3029, 2017.
  23. Shen ZX, Shi ZZ, Fang J, et al.: All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 101 (15): 5328-35, 2004.
  24. Ravandi F, Estey E, Jones D, et al.: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27 (4): 504-10, 2009.
  25. Hu J, Liu YF, Wu CF, et al.: Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 106 (9): 3342-7, 2009.
  26. Cheng Y, Zhang L, Wu J, et al.: Long-term prognosis of childhood acute promyelocytic leukaemia with arsenic trioxide administration in induction and consolidation chemotherapy phases: a single-centre experience. Eur J Haematol 91 (6): 483-9, 2013.
  27. Wang H, Chen XY, Wang BS, 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. Leuk Res 35 (9): 1170-7, 2011.
  28. 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 51 (2): 210-5, 2008.
  29. Zhou J, Zhang Y, Li J, et al.: Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood 115 (9): 1697-702, 2010.
  30. Iland HJ, Collins M, Bradstock K, et al.: Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial. Lancet Haematol 2 (9): e357-66, 2015.
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  32. Coombs CC, DeAngelis LM, Feusner JH, et al.: Pseudotumor Cerebri in Acute Promyelocytic Leukemia Patients on Intergroup Protocol 0129: Clinical Description and Recommendations for New Diagnostic Criteria. Clin Lymphoma Myeloma Leuk 16 (3): 146-51, 2016.
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  36. Unnikrishnan D, Dutcher JP, Varshneya N, et al.: Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 97 (5): 1514-6, 2001.
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Treatment of Recurrent APL

Historically, 10% to 20% of patients with acute promyelocytic leukemia (APL) relapsed. However, current studies that incorporated arsenic trioxide therapy showed a cumulative incidence of relapse of less than 5%.

In patients with APL who initially received chemotherapy-based treatments, the duration of first remission was prognostic. Patients who relapsed within 12 to 18 months of initial diagnosis had a worse outcome.

An important issue in children who relapsed is the exposure to anthracyclines received in previous trials, which ranged from 400 mg/m2 to 750 mg/m2. Thus, regimens containing anthracyclines were often not optimal for children with APL who relapsed.

Treatment options for children with recurrent APL may include the following:

  1. Arsenic trioxide with or without tretinoin.
  2. Gemtuzumab ozogamicin.
  3. Hematopoietic stem cell transplant (HSCT).

Arsenic Trioxide With or Without Tretinoin

For children with recurrent APL, the use of arsenic trioxide as a single agent or in regimens including tretinoin should be considered, depending on the therapy given during first remission. Arsenic trioxide is an active agent in adult patients with recurrent APL, with approximately 85% to 94% of patients achieving remission after treatment with this agent. More limited data in children suggest that children with relapsed APL have a response to arsenic trioxide that is similar to that of adults. Arsenic trioxide is well tolerated in children with relapsed APL, with a toxicity profile similar to that of adults.

Arsenic trioxide is capable of inducing remissions in patients who relapse after having received arsenic trioxide with or without other agents during initial therapy. However, APL cells may become resistant to arsenic trioxide through mechanisms that include mutation of the PML domain of the PML::RARA fusion oncogene.

Because arsenic trioxide causes QT-interval prolongation that can lead to life-threatening arrhythmias, it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.

Gemtuzumab Ozogamicin

In one trial, the use of gemtuzumab ozogamicin, an anti-CD33/calicheamicin antibody-drug conjugate, as a single agent resulted in a molecular remission rate of 91% (9 of 11 patients) after two doses and a molecular remission rate of 100% (13 of 13 patients) after three doses. These results demonstrate excellent activity of this agent in patients with relapsed APL.

HSCT

Retrospective pediatric studies have reported 5-year event-free survival (EFS) rates after either autologous or allogeneic transplant approaches to be similar, at approximately 70%.

Evidence (autologous HSCT):

  1. A study in adult patients treated with an autologous transplant demonstrated the following:
    • There was an improved 7-year EFS rate (77% vs. 50%) when both the patient and the stem cell product had negative PML::RARA fusion transcripts by polymerase chain reaction (molecular remission) before transplant.
  2. Another study demonstrated that among seven patients undergoing autologous HSCT and whose cells were minimal residual disease (MRD) positive, all relapsed in less than 9 months after transplant. However, only one of eight patients whose autologous donor cells were MRD negative relapsed.
  3. An additional report demonstrated a difference in survival based on the treatment received during relapse.
    • The 5-year EFS rate was 83.3% for patients who underwent autologous HSCT in second molecular remission.
    • The 5-year EFS rate was 34.5% for patients who received only maintenance therapy.
  4. Another retrospective report found an improved survival for patients treated with HSCT after achieving a molecular remission.
    • Ninety-four percent of pediatric and adult patients (64 of 67) with relapsed APL, after primarily receiving single-agent arsenic trioxide, achieved a molecular remission after treatment with arsenic-containing reinduction regimens.
    • For patients who received postremission consolidation with HSCT (n = 35), the 5-year overall survival (OS) rate was 90.3% (± 5.3%), and the EFS rate was 87.1% (± 6.0%). These outcomes were significantly superior to the outcomes of patients who received an arsenic-containing maintenance regimen, which resulted in a 5-year OS rate of 58.6% (± 10.4%) and an EFS rate of 47.7% (± 10.3%).

Such data support the use of autologous transplant in patients who are MRD negative in second complete remission and have MRD-negative stem cell collections.

Because of the rarity of APL in children and the favorable outcome for this disease, clinical trials in relapsed APL to compare treatment approaches are likely not feasible. However, an international expert panel provided recommendations for the treatment of relapsed APL on the basis of the reported pediatric and adult experiences.

References

  1. Platzbecker U, Avvisati G, Cicconi L, et al.: Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol 35 (6): 605-612, 2017.
  2. Kutny MA, Alonzo TA, Gerbing RB, et al.: Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631. J Clin Oncol 35 (26): 3021-3029, 2017.
  3. Kutny MA, Alonzo TA, Abla O, et al.: Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial. JAMA Oncol 8 (1): 79-87, 2022.
  4. Marjerrison S, Antillon F, Bonilla M, et al.: Outcome of children treated for relapsed acute myeloid leukemia in Central America. Pediatr Blood Cancer 61 (7): 1222-6, 2014.
  5. Lengfelder E, Lo-Coco F, Ades L, et al.: Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia 29 (5): 1084-91, 2015.
  6. Holter Chakrabarty JL, Rubinger M, Le-Rademacher J, et al.: Autologous is superior to allogeneic hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission. Biol Blood Marrow Transplant 20 (7): 1021-5, 2014.
  7. Sanz MA, Grimwade D, Tallman MS, et al.: Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113 (9): 1875-91, 2009.
  8. 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 111 (2): 566-73, 2008.
  9. Niu C, Yan H, Yu T, et al.: Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 94 (10): 3315-24, 1999.
  10. Shen ZX, Chen GQ, Ni JH, et al.: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89 (9): 3354-60, 1997.
  11. Shen ZX, Shi ZZ, Fang J, et al.: All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 101 (15): 5328-35, 2004.
  12. Avvisati G, Lo-Coco F, Paoloni FP, et al.: AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 117 (18): 4716-25, 2011.
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  15. Lu J, Huang X, Bao L, et al.: Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all-trans retinoic acid and arsenic compound-based combined therapies. Oncol Lett 7 (1): 177-182, 2014.
  16. Zhu HH, Qin YZ, Huang XJ: Resistance to arsenic therapy in acute promyelocytic leukemia. N Engl J Med 370 (19): 1864-6, 2014.
  17. Unnikrishnan D, Dutcher JP, Varshneya N, et al.: Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 97 (5): 1514-6, 2001.
  18. Barbey JT: Cardiac toxicity of arsenic trioxide. Blood 98 (5): 1632; discussion 1633-4, 2001.
  19. Lo-Coco F, Cimino G, Breccia M, et al.: Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 104 (7): 1995-9, 2004.
  20. Dvorak CC, Agarwal R, Dahl GV, et al.: Hematopoietic stem cell transplant for pediatric acute promyelocytic leukemia. Biol Blood Marrow Transplant 14 (7): 824-30, 2008.
  21. Bourquin JP, Thornley I, Neuberg D, et al.: Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood. Bone Marrow Transplant 34 (9): 795-8, 2004.
  22. de Botton S, Fawaz A, Chevret S, et al.: Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 23 (1): 120-6, 2005.
  23. Meloni G, Diverio D, Vignetti M, et al.: Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene. Blood 90 (3): 1321-5, 1997.
  24. Thirugnanam R, George B, Chendamarai E, et al.: Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 15 (11): 1479-84, 2009.
  25. Abla O, Kutny MA, Testi AM, et al.: Management of relapsed and refractory childhood acute promyelocytic leukaemia: recommendations from an international expert panel. Br J Haematol 175 (4): 588-601, 2016.

Latest Updates to This Summary (03/05/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This is a new summary.

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute promyelocytic leukemia. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Acute Promyelocytic Leukemia Treatment are:

  • Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
  • Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Jessica Pollard, MD (Dana-Farber/Boston Children's Cancer and Blood Disorders Center)
  • Michael A. Pulsipher, MD (Children's Hospital Los Angeles)
  • Rachel E. Rau, MD (Texas Medical Center)
  • Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)
  • Sarah K. Tasian, MD (Children's Hospital of Philadelphia)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Promyelocytic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq/childhood-apl-treatment-pdq. Accessed .

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

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