Haematologica
HOME HELP FEEDBACK TABLE OF CONTENTS ARCHIVE SUBSCRIPTIONS
QUICK SEARCH:   [advanced]


     

Haematologica, Vol 92, Issue 3, 289-291 doi:10.3324/haematol.11226
Copyright © 2007 by Ferrata Storti Foundation
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lo-Coco, F.
Right arrow Articles by Sanz, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lo-Coco, F.
Right arrow Articles by Sanz, M. A.
Related Collections
Right arrowRelated Articles

Editorials and Perspectives

Current treatment of acute promyelocytic leukemia

Francesco Lo-Coco1, Emanuele Ammatuna1, Miguel A. Sanz2

1 Department of Biopathology, University Tor Vergata of Rome, Italy
2 Hematology Service, University Hospital La Fe, Valencia, Spain. E-mail: francesco.lo.coco{at}uniroma2.it

According to well established evidence, modern treatment of newly diagnosed acute promyelocytic leukemia (APL) should consist of all-trans retinoic acid (ATRA) and concomitant anthracycline-based chemotherapy. In fact, a number of large multi-center trials including high numbers of patients with prolonged follow-up have clearly shown that this approach allows cure of the disease in more than 75% of cases.1–7 Current consensus also indicates that APL should be managed by a risk-adapted approach essentially based on leukocyte number at presentation, whereby patients with leucocyte counts greater that 10x109/L should receive more intensive treatment including, for example, cytosine arabinoside.8–10 The type of anthracycline and whether it should be combined or not with other agents, such as cytosine arabinoside in standard risk patients remain controversial.11–12 Other issues which are still matter of investigation include the role of novel active compounds such as arsenic trioxide (ATO) and in particular its efficacy in the long-term, and the optimization of molecular monitoring of residual disease by reverse transcriptase polymerase chain reaction (RT-PCR), whose clinical relevance for better assessment of response to treatment is beyond question.13–15 Several prospective studies using qualitative RT-PCR of the disease-specific PML/RAR{alpha} hybrid gene have demonstrated that the achievement of molecular remission after completion of consolidation is associated with prolonged survival, whereas persistence of, or conversion to, PCR-positivity in bone marrow after consolidation correlates strongly with subsequent hematologic relapse.13–15 Thus, the achievement of molecular remission is nowadays considered as a therapeutic objective in the management of APL.16 The recent development of real-time quantitative PCR (RQ-PCR) techniques provides an opportunity to determine at the quantitative level the kinetics of PML/RAR{alpha} reduction or increase in the individual patient. Moreover, compared to the qualitative assay, RQ-PCR allows better identification of poor quality RNA and facilitates the standardized analysis of samples in multi-center clinical trials.15

Although the standard ATRA plus chemotherapy combination has dramatically improved the disease prognosis, treatments fails in about 25% of APL patients reported in most recent studies due to early death or relapse. Moreover, these conventional treatments are associated with significant hematologic toxicity due to myelosuppression, and with serious, though infrequent late complications such as the occurrence of secondary myelodysplastic syndromes and/or acute myeloid leukemias.11–12 Current investigations aimed at optimising treatment of newly diagnosed APL include the use of less toxic and highly effective agents such as ATO and the possibility of more accurate and stringent molecular monitoring of minimal residual disease (MRD) offered by the RQ-PCR technique.

In this issue of the journal, Santamaria et al. report on the longitudinal monitoring by RQ-PCR in APL patients.17 Considering the timing of sampling, the authors found no correlation between molecular status after induction and outcome. By contrast, RQ-PCR results obtained at the end of consolidation and successively during follow-up revealed significantly distinct risks of relapse according to RQ-PCR transcript levels, with the most significant correlation being found during follow-up (only three positive cases were detected at the end of consolidation time point). These data, which are in line with those reported in previous studies,15,18,19 further strengthen the clinical value of molecular monitoring in the post-consolidation phase, whereas early (post-induction) results are not informative for therapy adaptations. In fact, molecular data after consolidation and during follow-up not only to therapy to be anticipated in patients at risk of relapse, but also spare patients who are presumably cured or at very low risk of relapse from unnecessary toxicity. Using RQ-PCR, some degree of uncertainty remains on the significance of low PML/RAR{alpha} transcript numbers (between 1 and 10 normalized copy numbers). In these latter cases, running in parallel the conventional qualitative PCR test characterized by relatively low sensitivity (10–3–10–4 approximately) is helpful because it may provide more informative data as remarked by Santamaria et al.17

Based on several studies showing its striking activity in relapsed patients,20–24 ATO has been licensed for the treatment of relapsed and refractory APL. Although the mechanism of action of ATO in APL is complex and not yet known in detail, it induces apoptosis in vitro through caspase activation, while a lower ATO concentration produces partial differentiation of leukemic promyelocytes through PML/RAR{alpha} degradation.25,26 ATO is usually well tolerated, although its use is associated with a series of adverse events including hyperleukocytosis, the APL differentiation syndrome and prolongation of the QT interval.27 Remarkably, unlike ATRA, ATO alone is able to induce molecular remission in more than 85% of patients, thus representing the most effective single agent available in this disease.27 In keeping with this clinical observation, Zheng et al. report in this issue of the journal a study suggesting that ATO is able to eliminate the PML/RAR{alpha}-positive leukemic stem cells.28 Using murine Sca1+/lin- hematopoietic stem cells retro-virally transduced to express PML/RAR{alpha}, the authors show that these cells maintain their replating efficiency and capacity to engraft in vivo after exposure to ATRA, whereas the self renewal potential of Sca1+/lin- stem cells is abrogated following treatment with ATO.28 While this investigation gives further support to the notion that ATO as a single agent is potentially curative in APL, it is important to remember that ATO and ATRA have been shown to be synergic in vivo providing better results than either agent used as monotherapy in the clinical setting.29

Several investigators have recently reported promising, though preliminary, results using ATO in front-line APL therapy.29–33 These data need to be strengthened by analysis of larger series and by more prolonged observation in appropriately designed randomized trials for newly diagnosed APL.

References

  1. Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, et al. Molecular remission in PML/RAR{alpha} positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood 1997;90:1014-21.[Abstract/Free Full Text]
  2. Soignet S, Fleischauer A, Polyak T, Heller G, Warrell RP Jr. All-trans retinoic acid significantly increases 5-year survival in patients with acute promyelocytic leukemia: long-term follow-up of the New York study. Cancer Chemother Pharmacol 1997;40:S25-S29.[CrossRef][ISI][Medline]
  3. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, et al. All-trans retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997;337:1021-8.[Abstract/Free Full Text]
  4. Asou N, Adachi K, Tamura J, Kanamaru A, Kageyama S, Hiraoka A, et al. 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 1998;16:78-85.[Abstract/Free Full Text]
  5. Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. 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 1999;93:4131-4.[Abstract/Free Full Text]
  6. Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, et al. A randomized comparison of all-trans retinoic acid (ATRA) followed by chemotherapy and ATRA+ chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. Blood 1999;94:1192-200.[Abstract/Free Full Text]
  7. Sanz MA, Marti G, Rayon C, Esteve J, Gonzalez M, Diaz-Mediavilla J, et al. 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 1999;94:3015-21.[Abstract/Free Full Text]
  8. Sanz MA, Martin G, Gonzalez M, Leon A, Rayon C, Rivas C, Colomer D, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA Group. Blood 2004;104:3490-93.[Abstract/Free Full Text]
  9. Lo Coco F, Avvisati G, Vignetti M, Fioritoni G, Liso V, Ferrara F. Frontline treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation: results of the AIDA-2000 trial of the Italian GIMEMA group. Blood 2004;104:392a.
  10. Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, et al. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol 2006;24:5703-10.[Abstract/Free Full Text]
  11. Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002;99:759-67.[Abstract/Free Full Text]
  12. Sanz MA, Tallman MS, Lo-Coco F. Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood 2005;105:3019-25.[Abstract/Free Full Text]
  13. Lo Coco F, Diverio D, Falini B, Biondi A, Nervi C, Pelicci PG. Genetic diagnosis and molecular monitoring in the management of acute promyelocytic leukemia. Blood 1999;94:12-22.[Free Full Text]
  14. Grimwade D. The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. British Journal of Haematology 1999;106:591-613.[CrossRef][ISI][Medline]
  15. Grimwade D, Lo Coco F. Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia 2002;16:1959-73.[CrossRef][ISI][Medline]
  16. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003;21:4642-9.[Abstract/Free Full Text]
  17. Santamaria C, Chillon MC, Fernandez C, Martin-Jimenez P, Balanzategui A, Garcia-Sanz R, et al. Relapse-risk stratification in acute promyelocytic leukemia patients by PML-RAR· transcript quantification. Haematologica 2007;92:316-23.
  18. Gallagher RE, Yaep BY, Bi W, Livak KJ, Beaubier N, Rao S, et al. Quantitative rela-time RT-PCR analysis of PML/RAR· mRNA in acute promyelocytic leucemia: assessment of prognostic significance in adult patients from intergroup protocol 0129. Blood 2003;101:2521-8.[Abstract/Free Full Text]
  19. Lee S, Kim YJ, Eom KS, Min CK, Kim HJ, Cho SG, et al. The significance of minimal residual disease kinetics in adults with newly diagnosed PML/RAR aplha-positive acute promyelocytic leucemia: results of a prospective trial. Haematologica 2006;91:671-4.[Abstract/Free Full Text]
  20. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 1997;89:3354-60.[Abstract/Free Full Text]
  21. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852-60.[Abstract/Free Full Text]
  22. Lazo G, Kantarjian H, Estey E, Thomas D, O’Brien S, Cortes J. Use of arsenic trioxide (As2O3) in the treatment of patients with acute promyelocytic leukemia: the M.D. Anderson experience. Cancer 2003;97:2218-24.[CrossRef][ISI][Medline]
  23. Raffoux E, Rousselot P, Poupon J, Daniel MT, Cassinat B, Delarue R, et al. Combined treatment with arsenic trioxide and all-trans retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 2003;21:2326-34.[Abstract/Free Full Text]
  24. Shigeno K, Naito K, Sahara N, Kobayashi M, Nakamura S, Fujisawa S, et al. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol 2005;82:224-9.[CrossRef][ISI][Medline]
  25. Shao W, Fanelli M, Ferrara FF, Riccioni R, Rosenauer A, Davison K, et al. Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR· protein in acute promyelocytic leukemia cells. J Natl Cancer Inst 1998;90:124-33.[Abstract/Free Full Text]
  26. Miller WH, Schipper HM, Lee JS, Singer J, Waxman Sl. Mechanisms of action of arsenic trioxide. Can Res 2002;62:3893-903.[Abstract/Free Full Text]
  27. Sanz MA, Fenaux P, Lo-Coco F. Arsenic trioxide in the treatment of acute promyelocytic leukemia: A review of current evidence. Haematologica 2005;90:1231-5.[Abstract/Free Full Text]
  28. Zheng X, Seshire A, Ruster B, Bug G, Beissert T, Puccetti E, et al. Arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RAR{alpha}-positive leukemic stem cells. Haematologica 2007;92:324-31.
  29. Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, 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 USA 2004;101:5328-35.[Abstract/Free Full Text]
  30. George B, Mathews V, Poonkuzhali B, Shaji RV, Srivastava A, Chandy M. Treatment of children with newly diagnosed acute promyelocytic leukemia with arsenic trioxide: a single center experience. Leukemia 2004;18:1587-90.[CrossRef][ISI][Medline]
  31. Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, Rostami S, Jahani M, Hosseini R, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol 2006;17:131-4.[Abstract/Free Full Text]
  32. Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, et al. Single agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood 2006;107:2627-32.[Abstract/Free Full Text]
  33. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, et al. Use of all-trans retinoic acid + arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006;107:3469-73.[Abstract/Free Full Text]

Related Articles

Using quantification of the PML-RAR{alpha} transcript to stratify the risk of relapse in patients with acute promyelocytic leukemia
Carlos Santamaría, Maria Carmen Chillón, Carina Fernández, Patricia Martín-Jiménez, Ana Balanzategui, Ramón García Sanz, Jesús F. San Miguel, Marcos-Gonzalez González
Haematologica 2007 92: 315-322. [Abstract] [Full Text] [PDF]

Arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RAR{alpha}-positive leukemic stem cells
Xiaomin Zheng, Anita Seshire, Brigitte Rüster, Gesine Bug, Tim Beissert, Elena Puccetti, Dieter Hoelzer, Reinhard Henschler, Martin Ruthardt
Haematologica 2007 92: 323-331. [Abstract] [Full Text] [PDF]




This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lo-Coco, F.
Right arrow Articles by Sanz, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lo-Coco, F.
Right arrow Articles by Sanz, M. A.
Related Collections
Right arrowRelated Articles

HOME HELP FEEDBACK TABLE OF CONTENTS ARCHIVE SUBSCRIPTIONS