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Front Line Clinical Trials and Minimal Residual Disease Monitoring in Acute Promyelocytic Leukemia

  • F. Lo-Coco
  • E. Ammatuna
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 313)

Abstract

In spite of the very high cure rate (70%–80%) achieved in APL with combinatorial all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy regimens, a number of issues are still open for investigation in front-line therapy of this disease. These include, among others, improvements in early death rate, the role of arsenic trioxide (ATO) and maintenance treatment, and, finally, optimization of molecular monitoring to better identify patients at increased risk of relapse. The current consensus on the most appropriate induction therapy consists of the concomitant administration of ATRA and anthracycline-based chemotherapy. Although the antileukemic benefit provided by the addition of ATRA to consolidation therapy has not been demonstrated in randomized studies, historical comparisons of consecutive studies carried out by Spanish and Italian cooperative groups suggest that the combination of ATRA and chemotherapy for consolidation may also contribute to improving therapeutic results. While a variety of distinct treatments are being investigated for front-line therapy, most experts agree that a risk-adapted therapy represents the optimal approach, through the use of more intensive therapy in patients with initial hyperleukocytosis. Longitudinal RT-PCR of PML/RARα allows sensitive assessment of response to treatment and minimal residual disease (MRD) monitoring in APL. Achievement of negative PCR status or molecular remission at the end of consolidation is now universally accepted and recommended as a therapeutic objective in this disease. On the other hand, persistence of, or conversion to, PCR positive in the marrow during follow-up is associated with impending relapse. Preliminary studies on therapy of molecular relapse indicate a survival advantage as compared to administering salvage treatment at time of hematologic relapse. The more accurate and reproducible real-time PCR method to detect at quantitative levels the PML/RARα hybrid will likely provide better inter-laboratory standardization and trial results comparison in the near future.

Keywords

Acute Myeloid Leukemia Acute Promyelocytic Leukemia Minimal Residual Disease Arsenic Trioxide Molecular Remission 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Alcalay M, Zangrilli D, Fagioli M, et al (1992) Expression pattern of the RAR alpha-PML fusion gene in acute promyelocytic leukemia. Proc Natl Acad Sci U S A 89:4840–4844PubMedCrossRefGoogle Scholar
  2. Asou N, Adachi K, Tamura J, et al (1998) Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group. J Clin Oncol 16:78–85PubMedGoogle Scholar
  3. Avvisati G (1999) Event-free survival (EFS) duration in newly diagnosed acute promyelocytic leukemia (APL) is favorably influenced by induction treatment with idarubicin alone: final results of the GIMEMA randomised study LAP0389 comparing IDA vs IDA+ARA-C in newly diagnosed APL. Blood 94Suppl 1:505aGoogle Scholar
  4. Avvisati G, Mandelli F, Petti MC, et al (1990) Idarubicin (4-demethoxidaunorubicin) as single agent for remission induction of previously untreated acute promyelocytic leukemia. A pilot study of the Italian cooperative group GIMEMA. Eur J Haematol 44:257–260PubMedGoogle Scholar
  5. Barbui T, Finazzi G, Falanga A (1998) The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia. Blood 91:3093–3102PubMedGoogle Scholar
  6. Bennett JM, Catowsky D, Daniel MT, et al (1976) Proposal for the classification of the acute leukemias. Br J Haematol 33:451–458PubMedGoogle Scholar
  7. Bennett JM, Catowsky D, Daniel MT, et al (1980) A variant form of hypergranular promyelocytic leukemia. Br J Haematol 44:169–170PubMedGoogle Scholar
  8. Bernard J, Weil M, Boiron M, et al (1973) Acute promyelocytic leukemia. Results of treatment with daunorubicin. Blood 41:489–496PubMedGoogle Scholar
  9. Burnett AK, Grimwade D, Solomon E, et al (1999) Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: results of the randomized MRC trial. Blood 93:4131–4134PubMedGoogle Scholar
  10. Candoni A, Damiani D, Michelutti A, et al (2003) Clinical characteristics, prognostic factors and multidrug-resistance related protein expression in 36 adult patients with acute promyelocytic leukemia. Eur J Haematol 71:1–8PubMedCrossRefGoogle Scholar
  11. Chen SJ, Wang ZY, Chen Z (1995) Acute promyelocytic leukaemia: from clinic to molecular biology. Stem Cells 13:22–31PubMedGoogle Scholar
  12. Cheson BD, Bennett JM, Kopecky KJ, et al (2003) Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642–4649PubMedCrossRefGoogle Scholar
  13. Diverio D, Pandolfi PP, Biondi A, et al (1993) Absence of RT-PCR detectable residual disease in acute promyelocytic leukemia in long term remission. Blood 85:3556–3559Google Scholar
  14. Diverio D, Rossi V, Avvisati G, et al (1998) Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARα fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter “AIDA” trial. Blood 92:784–789PubMedGoogle Scholar
  15. Estey E, Thall PF, Mehta K, et al (1996) Alterations in tretinoin pharmacokinetics following administration of liposomal all-trans retinoic acid. Blood 87:3650–3654PubMedGoogle Scholar
  16. Estey EH, Giles FJ, Beran M, et al (2002) Experience with gemtuzumab ozogamycin (“mylotarg”) and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 99:4222–4224PubMedCrossRefGoogle Scholar
  17. Falini B, Flenghi L, Fagioli M, et al (1997) Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (Anti-PML). Blood 90:4046–4053PubMedGoogle Scholar
  18. Fenaux P, Chomienne C, Degos L (1997) Acute promyelocytic leukaemia: biology and treatment. Semin Oncol 24:92–102PubMedGoogle Scholar
  19. Fenaux P, Chastang C, Chevret S, et al (1999) A randomized comparison of ATRA followed by chemotherapy and ATRA plus chemotherapy, and the role of maintenance therapy in newly diagnosed acute promyelocytic leukaemia. Blood 94:1192–1200PubMedGoogle Scholar
  20. Gallagher RE, Yeap BY, Bi W, et al (2003) Quantitative real-time RT-PCR analysis of PML-RAR alpha mRNA in acute promyelocytic leukemia: assessment of prognostic significance in adult patients from intergroup protocol 0129. Blood 101:2521–2528PubMedCrossRefGoogle Scholar
  21. Gomis F, Sanz J, Sempere A, et al (2004) Immunofluorescent analysis with the anti-PML monoclonal antibody PG-M3 for rapid and accurate genetic diagnosis of acute promyelocytic leukemia. Ann Hematol 83:687–690PubMedCrossRefGoogle Scholar
  22. Grignani F, Fagioli M, Alcalay M, et al (1994) Acute promyelocytic leukaemia: from genetics to treatment. Blood 83:10–25PubMedGoogle Scholar
  23. Grimwade D (1999) The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. Br J Haematol 106:591–613PubMedCrossRefGoogle Scholar
  24. Grimwade D, Lo-Coco F (2002) Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia 16:1959–1973PubMedCrossRefGoogle Scholar
  25. Grimwade D, Howe K, Langabeer S, et al (1996) Minimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR: evaluation of PML-RAR alpha and RAR alpha-PML assessment in patients who ultimately relapse. Leukemia 10:61–66PubMedGoogle Scholar
  26. Guglielmi C, Martelli MP, Diverio D, et al (1998) 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 102:1035–1041PubMedCrossRefGoogle Scholar
  27. Jurcic JG, Nimer SD, Scheinberg DA, et al (2001) Prognostic significance of minimal residual disease detection and PML/RARα isoform type: long term follow-up in acute promyelocytic leukaemia. Blood 98:2651–2656PubMedCrossRefGoogle Scholar
  28. Lengfelder E, Reichert A, Schoch C, et al (2000) Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects inpatients with newly diagnosed acute promyelocytic leukemia German AML Cooperative Group. Leukemia 14:1362–1370PubMedCrossRefGoogle Scholar
  29. Lo-Coco F, Diverio D, Avvisati G, et al (1999a) Therapy of molecular relapse in acute promyelocytic leukaemia. Blood 94:2225–2229PubMedGoogle Scholar
  30. Lo-Coco F, Diverio D, Falini B, et al (1999b) Genetic diagnosis and molecular monitoring in the management of acute promyelocytic leukemia. Blood 94:12–22PubMedGoogle Scholar
  31. Mandelli F, Diverio D, Avvisati G, et al (1997) Molecular remission in PML/RARa positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood 90:1014–1021PubMedGoogle Scholar
  32. Marty M, Ganem G, Fischer J, et al (1984) Leucémie aigue promyélocitaire: étude retrospective de 119 malades traités par daunorubicine. Nouv Rev Fr Hematol 26:371–378PubMedGoogle Scholar
  33. McKenna RW, Parkin J, Bloomfield CD, et al (1982) Acute promyelocytic leukemia a study of 39 cases with identification of a hyperbasophilic microgranular variant. Br J Haematol 50:201–214PubMedGoogle Scholar
  34. Miller WH Jr, Kakizuka A, Frankel SR, et al (1992) Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor alpha clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci U S A 89:2694–2698PubMedCrossRefGoogle Scholar
  35. Paietta E (2003) Expression of cell-surface antigens in acute promyelocytic leukaemia. Best Pract Res Clin Haematol 16:369–385PubMedCrossRefGoogle Scholar
  36. Paietta E, Andersen J, Racevskis J, et al (1994) Significantly lower P-glycoprotein expression in acute promyelocytic leukemia than in other types of acute myeloid leukemia: immunological, molecular and functional analyses. Leukemia 8:968–973PubMedGoogle Scholar
  37. Pandolfi PP, Alcalay A, Fagioli M, et al (1992) Genomic variability and alternative splicing generate multiple PML-RARα transcripts that encode aberrant PML proteins and PML-RARα isoforms in acute promyelocytic leukemia. EMBO J 11:1397–1407PubMedGoogle Scholar
  38. Reiter A, Lengfelder E, Grimwade D (2004) Pathogenesis, diagnosis and monitoring of residual disease in acute promyelocytic leukaemia. Acta Haematol 112:55–67PubMedCrossRefGoogle Scholar
  39. Samoszuk MK, Tynan W, Sallash G, et al (1998) An immunofluorescent assay for acute promyelocytic leukemia. Am J Clin Pathol 109:205–210PubMedGoogle Scholar
  40. Sanz M, Martin G, Gonzalez M, et al (2004) Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 103:1237–1243PubMedCrossRefGoogle Scholar
  41. Sanz MA, Jarque I, Martin G, et al (1988) Acute promyelocytic leukemia. Therapy results and prognostic factors. Cancer 61:7–13PubMedCrossRefGoogle Scholar
  42. Sanz MA, Martin G, Rayon C, et al (1999) A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARa positive acute promyelocytic leukemia. Blood 94:3015–3021PubMedGoogle Scholar
  43. Sanz MA, Lo-Coco F, Martín G, et al (2000) Definition of relapse risk and role of non-anthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 96:1247–1253PubMedGoogle Scholar
  44. Sanz MA, Tallman M, Lo-Coco F (2005) Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood 105:3019–3025PubMedCrossRefGoogle Scholar
  45. Seale JR, Varma S, Swirsky DM, et al (1996) Quantification of PML-RAR alpha transcripts in acute promyelocytic leukaemia: explanation for the lack of sensitivity of RT-PCR for the detection of minimal residual disease and induction of the leukaemia-specific mRNA by alpha interferon. Br J Haematol 95:95–101PubMedCrossRefGoogle Scholar
  46. Shen ZX, Shi ZZ, Fang J, et al (2004) All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 101:5328–5335PubMedCrossRefGoogle Scholar
  47. Tallman MS, Hakimian D, Snower D, et al (1993) Basophilic differentiation in acute promyelocytic leukemia. Leukemia 7:521–526PubMedGoogle Scholar
  48. Tallman MS, Andersen JW, Schiffer CA, et al (2002) All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 100:4298–4302PubMedCrossRefGoogle Scholar
  49. van Dongen JJ, Macintyre EA, Gabert JA, et al (1999) Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia 13:1901–1928PubMedCrossRefGoogle Scholar
  50. Villamor N, Costa D, Aymerich M, et al (2000) Rapid diagnosis of acute promyelocytic leukemia by analyzing the immunocytochemical pattern of the PML protein with the monoclonal antibody PG-M3. Am J Clin Pathol 114:786–792PubMedCrossRefGoogle Scholar
  51. Warrell RP Jr (1996) Pathogenesis and management of acute promyelocytic leukaemia. Annu Rev Med 47:555–565PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  • F. Lo-Coco
    • 1
  • E. Ammatuna
    • 1
  1. 1.Dipartimento di Biopatologia e Diagnostica per ImmaginiUniversità Tor Vergata via MontpellierRomeItaly

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