Therapy of acute promyelocytic leukemia in Czechia: results and analysis of prognostic factors
Authors:
J. Schwarz 1; Z. Kořístek 2; J. Starý 3; P. Žák 4; T. Kozák 5; J. Marková 1; K. Michalová 6,7; D. Dvořáková 8; J. Mayer 2; P. Cetkovský 1
Authors‘ workplace:
Klinický úsek Ústavu hematologie a krevní transfuze Praha, přednosta doc. MUDr. Petr Cetkovský, Ph. D.
1; Interní hematoonkologická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Vorlíček, CSc.
2; Klinika dětské hematologie a onkologie 2. lékařské fakulty UK a FN Motol Praha, přednosta prof. MUDr. Jan Starý, DrSc.
3; Oddělení klinické hematologie II. interní kliniky Lékařské fakulty UK a FN Hradec Králové, přednosta prof. MUDr. Jaroslav Malý, CSc.
4; Oddělení klinické hematologie FN Královské Vinohrady Praha, přednosta doc. MUDr. Tomáš Kozák, Ph. D., MBA
5; Centrum nádorové cytogenetiky 1. lékařské fakulty UK a VFN Praha, přednosta prof. MUDr. Tomáš Zima, DrSc., MBA
6; Výzkumný úsek Ústavu hematologie a krevní transfuze Praha, vedoucí prof. Ing. Jan E. Dyr, DrSc.
7; Centrum molekulární biologie a genové terapie Interní hematoonkologické kliniky Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Vorlíček, CSc.
8
Published in:
Vnitř Lék 2008; 54(7-8): 757-770
Category:
Original Contributions
Overview
We have retrospectively evaluated a cohort of 144 patients (including 17 pediatric ones) with de novo acute promyelocytic leukemia registered in databases of institutions cooperating within the CELL group (The Czech Leukemia Study Group for Life). The patients were diagnosed according to WHO criteria from 1989 until 2006. The aim was to check how well fared the patients, the majority of whom was not included into clinical trials, in real life. Of 140 evaluable patients, 97 (69.3%) attained complete remission (CR). The projected overall survival (OS) 4 years after diagnosis was 58.9%, and 55.3% at 6 years. In 8 patients (6.0%), no antileukemic therapy at all was given (either they died shortly after admission to the ward or therapy was not feasible due to their clinical status). Of 125 patients with documented commencement of some kind of therapy, 96 (76.8%) achieved CR. Of 102 patients with induction treatment with a combination of anthracycline and tretino in (ATRA), 84 individuals (82.4 %) attained CR (typically, this cohort might have been subjected to clinical trials). This result was better than that of patients treated by chemotherapy only (n = 15; CR 46.7%; P = 0.003) or by ATRA monotherapy (n = 13; CR 62.5%; P = 0.17). Another parameter with a significant impact on attaining CR was the leukocyte (WBC) count at diagnosis: its median values in patients achieving and not achieving CR were 2.1 and 24.0 × 109/ l, respectively (P < 0.0001). The WBC counts affected OS as well (P = 0.0001). However, when only patients after attaining CR were evaluated, the initial WBC counts no longer affected OS (P = 0.18). Achieving CR was also influenced by the performance status (PS) 0– 1 (P = 0.005), which was in turn closely correlated to WBC counts (P = 0.0006). Additional factors (most likely connected with leukocytosis) influenced attaining CR with borderline statistical significance: e. g. FAB M3v morphology, LDH serum level, fibrinogen level, presence of internal tandem duplicati on (ITD) of the FLT3 gene (which was strongly associated with leukocytosis and also with the short PML/ RARα transcript resulting from the bcr3 bre ak in the PML gene). It may be speculated that FLT3‑ ITD is just one of the possible factors that lead to leukocytosis. The platelet counts at diagnosis had no impact on entering CR. Thus, we have not validated the current PETHEMA risk stratificati on in distinguishing intertermediate and low risk patients. Our study points to a significant difference of the results obtained in real life and of the results that could be achieved in patients who were fit to enter clinical trials. Among the prognostic factors, the most important one was the WBC co unt, the PS (which is highly affected by the WBC count), and feasibility of administration of the most potent induction therapy with anthracyclines and ATRA.
Key words:
acute promyelocytic leukemia – therapy – chemotherapy – tretino in (ATRA) – prognostic factors – PML/ RARα fusion gene – FLT3 gene – performance status
Sources
1. Bernard J, Mathé G, Boulay J et al. La leucose aiguë à promyélocytes. Etude portant sur vingt observations. Schweiz Med Wochenschr 1959; 89: 604–608.
2. Frankel SR. Acute promyelocytic leukemia. New insights into diagnosis and therapy. Hematol Oncol Clin North Am 1993; 7: 109–138.
3. Lemež P, Schwarz J, Jelínek J et al. Pozdní a pomalá diagnostika akutních promyelocytárních leukemií – hlavní příčina časných smrtí. Vnitř Lék 1994; 40: 654–659.
4. Tallman MS, Nabhan C, Feusner JH et al. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002; 99: 759–767.
5. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008; 111: 2505–2515.
6. Fenaux P. Management of acute promyelocytic leukemia. Eur J Haematol 1993; 50: 65–73.
7. Mandelli F, Diverio D, Avvisati G et al. Molecular remission in PML/RARα‑positive acute promyelocytic leukemia by combined all‑trans retinoic acid and idarubicin (AIDA) therapy. Blood 1997; 90: 1014–1021.
8. Sanz MA, Martín G, Rayón C et al. A modified AIDA protocol with anthracycline‑based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARα‑positive acute promyelocytic leukemia. Blood 1999; 94: 3015–3021.
9. Asou N, Adachi K, Tamura J 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.
10. 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 1999; 93: 4131–4143.
11. 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 2000; 96: 1247–1253.
12. Schwarz J, Peková S, Protivánková M et al. FLT3 gene internal tandem duplications in APL: correlation with leukocytosis and outcome. In: Joint International Congress on APL and Differentiation Therapy; 2001. Rome 2001.
13. Mistry AR, Pedersen EW, Solomon E et al. The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease. Blood Rev 2003; 17: 71–97.
14. Schwarz J, Peková S, Cermák J et al. Prognosis in AML and APL: the role of FLT3 gene internal tandem duplications (ITDs) and other prognostic markers. Leuk Lymphoma 2003; 44 (Suppl): S64.
15. Au WY, Fung A, Chim CS et al. FLT-3 aberrations in acute promyelocytic leukaemia: clinicopathological associations and prognostic impact. Br J Haematol 2004; 125: 463–469.
16. Kiyoi H, Naoe T, Yokota S et al. In-ternal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia 1997; 11: 1447–1452.
17. 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 2002; 16: 2185–2189.
18. Brunning RD, Bennett J, Matutes E et al. Acute myeloid leukaemia with recurrent genetic abnormalities. In: Jaffe ES, Harris NL, Stein H et al. World Health Organization classification of tumours. Pathology and genetics. Tumours of haematopoietic and lymphoid tissues. Lyon: IARC 2001: 81–87.
19. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–655.
20. Bennett JM, Catovsky D, Daniel MT et al. A variant form of hypergranular promyelocytic leukaemia (M3). Br J Haematol 1980; 44: 169–170.
21. Biondi A, Rambaldi A, Pandolfi PP et al. Molecular monitoring of the myl/retinoic acid receptor-alpha fusion gene in acute promyelocytic leukemia by polymerase chain reaction. Blood 1992; 80: 492–497.
22. Cross NC, Melo JV, Feng L et al. An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders. Leukemia 1994; 8: 186–189.
23. Gabert J, Beillard E, van der Velden VHJ et al. Standardization and quality control studies of ‚real-time‘ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer program. Leukemia 2003; 17: 2318–2357.
24. Xu F, Taki T, Yang HW et al. Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children. Br J Haematol 1999; 105: 155–162.
25. Chen SJ, Zhu YJ, Tong JH et al. Rearrangements in the second intron of the RARA gene are present in a large majority of patients with acute promyelocytic leukemia and are used as molecular marker for retinoic acid‑induced leukemic cell differentiation. Blood 1991; 78: 2696–2701.
26. Warrell RP Jr, Frankel SR, Miller WH Jr et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all‑trans‑retinoic acid). N Engl J Med 1991; 324: 1385–1393.
27. Lo Coco F, Nervi C, Avvisati G et al. Acute promyelocytic leukemia: a curable disease. Leukemia 1998; 12: 1866–1880.
28. Fenaux P, Le Deley MC, Castaigne S et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. Blood 1993; 82: 3241–3249.
29. Tallman MS, Andersen JW, Schiffer CA et al. All‑trans‑retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997; 337: 1021–1028.
30. 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 2004; 103: 1237–1243.
Labels
Diabetology Endocrinology Internal medicineArticle was published in
Internal Medicine
2008 Issue 7-8
Most read in this issue
- An urgency in hematology: acute promyelocytic leukemia – principles of diagnosis
- Coagulopathy and differentiation syndrome: the main complications of the initial treatment of acute promyelocytic leukemia
- Brief case reports illustrate various initial courses in acute promyelocytic leukemia
- Leukemogenesis and therapy of acute promyelocytic leukemia: from the worse to the most favorable subtype of acute myeloid leukemia