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Therapeutic research in untreated acute promyelocytic leukemia

Leukemia volume 19, pages 913–915 (2005)Cite this article

This commentary is motivated by Schlenk et al's1 interesting contribution to the discussion of two of the more debated issues in therapy of acute promyelocytic leukemia (APL): (1) the need for maintenance therapy, and (2) the possibility of improving therapy in high-risk patients. It is well known that use of all-trans retinoic acid (ATRA) together with anthracyclines, or mitoxantrone, ± ara-C produces long-term remissions in 90% of patients who present with WBC counts <10 000/μl, but only 60–70% of patients with initial WBC counts >10 000/μl; the latter patients accordingly are referred to as ‘high risk’. Given these results, it is natural to ask whether we can make therapy easier, at least for low-risk patients, for example, by shortening its duration or by eliminating chemotherapy altogether, and whether outcome in high-risk patients can be made similar to that in low-risk patients, in effect eliminating the prognostic significance of initial WBC count. Both questions lead to consideration of new therapeutic approaches, such as that employed by Schlenk et al on behalf of the German AMLSG1 and of statistical designs appropriate for a situation where the results are already quite good, as in, at least, low-risk APL.

There are, broadly speaking, two approaches to postremission therapy in APL. The first, used for example by the European APL and the Spanish PETHEMA groups, employs two or three courses of anthracycline-containing consolidation followed by 2 years of maintenance with ATRA, 6 mercaptopurine (6MP) and methotrexate. The rationale for such prolonged maintenance is the European APL group's demonstration, in their APL93 study,2 that 2 years of maintenance using both ATRA and chemotherapy was superior to either no maintenance, maintenance including only ATRA or maintenance using only 6MP+methotrexate. It is of course possible that 6 months of maintenance, or even less, would produce equivalent results as 2 years of maintenance. Indeed, the second approach to postremission therapy, exemplified by GIMEMA trials, relies solely on induction and three courses of consolidation. This approach derives from GIMEMA data suggesting no benefit from 6MP and methotrexate once consolidation is completed.3 Both the GIMEMA and European AML/PETHEMA approaches appear to produce similar long-term results, leading to the suggestion that prolonged maintenance may be unnecessary if the preceding therapy is sufficiently intense, with the implication that this was perhaps not the case in APL93. I must admit that I have had difficulty accepting this possibility; the consolidation given in the APL932 and GIMEMA3 studies just do not appear that different. Furthermore, the European APL Group's relative greater emphasis on ara-C appears supported by their APL2000 trial, which found that ara-C in doses used in APL93 has a role in improving outcome in APL (Ades et al. Blood 2004; 104, ASH abstract # 391). Schlenk et al's paper appears to lend credence to the GIMEMA policy of no maintenance, although this is accomplished by use of high-dose ara-C, as advocated by the European APL group. Schlenk et al, however, note that it is impossible to say whether their results reflect administration of two courses of high-dose ara-C (3 gm/m2 every 12 h days 1–3) and mitoxantrone (HAM) in CR, or of administration of a second induction course (ICE) on day 28 of the first course (AIDA). Regardless, Schlenk et al's results with four courses of therapy seem as good as those observed by others using considerably more treatment.

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References

  1. Schlenk R, Germing U, Hartmann F, Glasmacher A, Fischer J, del Valle y Fuentes F, et al., for the AML Study Group. High dose cytarabine and mitoxantrone in consolidation therapy for acure promyelocytic leukemia. Leukemia 2005; 19: 978–983.

    Article  CAS  PubMed  Google Scholar 

  2. Fenauax P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, et al., for the European APL Group. A randomized comparison of all trans-retinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. Blood 1999; 94: 1192–1200.

    Google Scholar 

  3. Avvisati G, Petti M, Lo-Coco F, Vegna M, Amadori S, Baccarani M, et al., for the GIMEMA Group. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood 2002; 100: 3141–3146.

    Article  CAS  PubMed  Google Scholar 

  4. Sanz M, Lo Coco F, Martín G, Avvisati G, Rayón C, Barbui T, for the Spanish PETHEMA and Italian GIMEMA Copeartive Groups. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000; 96: 1247–1253.

    CAS  PubMed  Google Scholar 

  5. Lo Coco F, Diverio D, Avvisati G, Petti M, Meloni G, Pogliani E et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood 1999; 94: 2225–2229.

    CAS  PubMed  Google Scholar 

  6. Estey E . Treatment options for relapsed APL. Best Pract Res Clin Haematol 2003; 16: 521–534.

    Article  CAS  PubMed  Google Scholar 

  7. Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, et al., for the GIMEMA and AEIOP Groups. Molecular remission in PML/RARα-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin therapy. Blood 1997; 90: 1014–1021.

    CAS  PubMed  Google Scholar 

  8. Sanz M, Martín G, González M, León A, Rayón C, Rivas C et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004; 103: 1237–1243.

    Article  CAS  PubMed  Google Scholar 

  9. Soignet S, Frankel S, Douer D, Tallman M, Kantarjian H, Calleja E et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19: 3852–3860.

    Article  CAS  PubMed  Google Scholar 

  10. Jurcic J, DeBlasio T, Dumont L, Yao T, Scheinberg D . Molecular remission induction with retinoic acid and anti-CD33 monoclonal antibody HuM195 in acute promyelocytic leukemia. Clin Cancer Res 2000; 6: 372–380.

    CAS  PubMed  Google Scholar 

  11. Fenaux P, Castaigne S, Chomienne C, Dombret H, Degos L . All trans retinoic acid treatment for patients with acute promyelocytic leukemia. Leukemia 1992; 6 (Suppl 1): 64–66.

    PubMed  Google Scholar 

  12. Shen Z-X, Shi Z-Z, Fang J, Gu B-W, Li J-M, Zhu Y-M 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: 5328–5335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ades L, Chevret S, De Botton S, Thomas X, Dombret H, Beve B, et al., for the European APL Group. Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience. Leukemia 2005; 19: 230–233.

    Article  CAS  PubMed  Google Scholar 

  14. Sanz M, Vellenga E, Rayón C, Díaz-Mediavilla J, Rivas C, Amutio E et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia. Blood 2004; 104: 3490–3493.

    Article  CAS  PubMed  Google Scholar 

  15. Estey E, Giles F, Beran M, O'Brien S, Pierce S, Faderl S et al. Experience with gemtuzumab ozogamycin (‘mylotarg’) and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 2002; 99: 4222–4224.

    Article  CAS  PubMed  Google Scholar 

  16. Lo Coco F, Cimino G, Breccia M, Noguera N, Diverio D, Finolezzi E et al. Gemtuzumab ozogamicin (mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 2004; 104: 1995–1999.

    Article  CAS  PubMed  Google Scholar 

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  1. Leukemia Department, University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Estey, E. Therapeutic research in untreated acute promyelocytic leukemia. Leukemia 19, 913–915 (2005). https://doi.org/10.1038/sj.leu.2403767

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