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High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities

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Abstract

Abnormalities of the p53 gene are known to confer detrimental effects in chronic lymphocytic leukaemia (CLL) and are associated with short survival. We have used high dose methylprednisolone (HDMP) to treat 25 patients with advanced refractory CLL of whom 45% had p53 abnormalities shown by one or more methods: flow cytometry, fluorescent in situ hybridisation and direct DNA sequencing. Fifteen were resistant to fludarabine and 16 were non-responders to their most recent therapy. Methylprednisolone had a cytotoxic effect on lymphocytes from 95% of cases assessed by an ex vivo apoptotic drug sensitivity index (DSI). HDMP was given alone or in combination with other drugs: vincristine, CCNU, Ara-C, doxorubicin, mitoxantrone and chlorambucil, according to the results of DSI. Three patients were treated twice and each treatment was analysed separately. The overall response rate was 77% with a median duration of 12 months (range 7 –23+). Responders included 5/10 with abnormal p53, of which two achieved nodular PR. Patients with p53 abnormalities fared worse than those with normal p53. There were no differences in response according to whether HDMP was used alone or in combination. Nine of the 22 evaluable patients (3 NR and 6 PR) have died from progressive disease or transformation. Main toxicity was infection in 7/25 patients. Event free and overall survival were significantly better in responders vs non-responders (P>0.0001 and P=0.04 respectively). Patients with a DSI of 100% to steroids had a better overall and event free survival, but this was not statistically significant. This study demonstrates that HDMP alone or in combination with other agents is a useful treatment strategy in refractory CLL including patients with p53 abnormalities.

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References

  1. Adkins J, Peters D, Markham A (1997) Fludarabine an update of its pharmacology and use in the treatment of haematological malignancies. Drugs 6:1005–1037

    Google Scholar 

  2. O’Brien S, Kantarjian H, Beran H, Smith M, Koller T, Estey C, Robertson E, Lerner LE, Keating M (1993) Results of fludarabine and prednisolone therapy in 264 patients with chronic lymphocytic leukaemia with multivariate analysis-derived prognostic model for response to treatment. Blood 82:1692–1700

    Google Scholar 

  3. Bosanquet A, Cann SRM, Mills M, Catovsky D (1995) Methylprednisolone in advanced chronic lymphocytic leukaemia: Rationale for and effectiveness of treatment suggested by DiSC assay. Acta Haematol 93:73–79

    CAS  PubMed  Google Scholar 

  4. Bosanquet A, Copplestone JA, Johnson SAN, Smith AG, Povey SJ, Orchard JA, Oscier DG (1999) Response to cladrabine in previously treated patients with chronic lymphocytic leukaemia identified by ex vivo assessment of drug sensitivity by DiSC assay. Br J Haemat 106:474–476

    Article  CAS  Google Scholar 

  5. Bosanquet AG, Johnson SA, Richards SM (1999) Prognosis for fludarabine therapy of chronic lymphocytic leukaemia based on ex-vivo drug response by DiSC assay. Br J Haemat 106:71–77

    Article  CAS  Google Scholar 

  6. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Döhner K, Bentz M, Lichter P (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916

    PubMed  Google Scholar 

  7. Wattel E, Preudhomme C, Hequet B, Vanrumbeke M, Quesnel B, Dervite I, Morel P, Fenaux P (1994) p53 Mutations are associated with resistance to chemotherapy and short survival in haematological malignancies. Blood 84:3148–3157

    CAS  PubMed  Google Scholar 

  8. Döhner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G, Diehl D, Schlenk R, Coy J, Stilgenbauer S, Volkmann M, Galle PR, Poustka A, Hunstein W, Lichter P (1995) p53 Gene deletion predicts for poor survival and non-response to therapy with purine analogues in chronic B-cell leukaemias. Blood 85:1580–1585

    CAS  PubMed  Google Scholar 

  9. Cordone I, Masi S, Mauro FR, Soddu S, Morsilli O, Valentini T, Vegna ML, Guglielmi C, Manchini F, Giuliacci S, Sacchi A, Mandelli F, Foa R (1998) p53 expression in B-Cell Chronic Lymphocytic Leukaemia: A marker of disease progression and poor Prognosis. Blood 91:4342–4349

    CAS  PubMed  Google Scholar 

  10. Lens D, Dyer MJ, Garcia-Marco JM, Schouwer PJ de, Hamoudi RA, Jones D, Farahat N, Matutes E, Catovsky D (1997) p53 abnormalities in CLL are associated with excess of prolymphocytes and poor prognosis. Br J Haemat 99:848–857

    CAS  Google Scholar 

  11. Begleiter A, Mowat M, Israels LG, Johnston J (1996) Chlorambucil in chronic lymphocytic leukaemia: Mechanism of action. Leuk Lymphoma 23:187–201

    CAS  PubMed  Google Scholar 

  12. Johnston JB, Daeninck P, Verberg L, Lee K, Williams G, Israels LG, Mowat MRA, Begleiter A (1997) p53, MDM 2, BAX and BCL-2 and drug resistance in chronic lymphocytic leukaemia. Leuk Lymphoma 26:435–449

    CAS  PubMed  Google Scholar 

  13. Gartenhaus RB, Wang P, Hoffman M, Janson D, Rai KR (1996) The induction of p53 and WAF1/CIP1 in chronic lymphocytic leukaemia cells treated with 2-chlorodeoxyadenosine. J Mol Med 74:143–147

    CAS  PubMed  Google Scholar 

  14. Pettitt AR, Sherrington PD, Cawley JC (2000) Role of Poly(ADP-ribosylation) in the killing of chronic lymphocytic leukaemia cells by purine analogues. Cancer Res 60:4187–4193

    CAS  PubMed  Google Scholar 

  15. Silber R, Degar B, Costin D, Newcomb EW, Mani M, Rosenberg CR, Morse L, Drygas JC, Canellakis ZN, Potmesil M (1994) Chemosensitivity of lymphocytes from patients with B-cell chronic lymphocytic leukaemia to chlorambucil, fludarabine and camptothecin analogs. Blood 84:3440–3446

    CAS  PubMed  Google Scholar 

  16. Rouby SE, Thomas A, Costin D, Rosenberg CR, Potmesil M, Silber R, Newcomb EW (1993) p53 Gene mutation in B-cell chronic lymphocytic leukaemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 82:3452–3459

    PubMed  Google Scholar 

  17. Newcomb EW (1995) p53 Gene mutations in lymphoid diseases and their possible relevance to drug resistance. Leuk Lymphoma 17:211–221

    CAS  PubMed  Google Scholar 

  18. Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A, Que TH, Catovsky D (1994) The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia 8:1640–1645

    CAS  PubMed  Google Scholar 

  19. Gruszka-Westwood AM, R.A. Hamoudi, Matutes E, Tuset E, Catovsky D (2001) p53 abnormalities in splenic lymphoma with villous lymphocytes. Blood 97:3552–3558

    Article  CAS  PubMed  Google Scholar 

  20. Bosanquet A, Bell P (1996) Enhanced ex vivo drug sensitivity testing of chronic lymphocytic leukaemia using refined DiSC assay methodology. Leuk Res 20:143–153

    Article  CAS  PubMed  Google Scholar 

  21. Keating MJ, Kantarjian H, Talpaz M, Redman J, Credie KB (1988) Fludarabine therapy in chronic lymphocytic leukaemia (CLL). Nouv Rev Fr Hematol 30:461–466

    CAS  PubMed  Google Scholar 

  22. Monserrat E, Lopez-Lorenzo JL, Manso F, Martin A, Prieto E, Arais-Sampedro J, Fernandez MN, Oyarzabal FJ, Odriozola J, Alcala A, Garcia-Conde J, Conde E, Guardia R, Bosch. F (1996) Fludarabine in resistant or relapsing B-cell chronic lymphocytic leukaemia. The Spanish group experience. Leuk Lymphoma 21:467–472

    CAS  Google Scholar 

  23. Rossi GD de, Mauro FR, Caruso R, Monarca B, Mandelle F (1993) Fludarabine and prednisolone in pretreated and refractory B-chronic lymphocytic leukaemia (B-CLL) in advanced stages. Haematologica 78:167–171

    PubMed  Google Scholar 

  24. Marotta G, Bigazzi C, Lenoci M, Tozzi M, Bocchia M, Lauria F (2000) Low-dose fludarabine and cyclophosphamide in elderly patients with B-cell chronic lymphocytic leukaemia refractory to conventional therapy. Haematologica 85:1268–1270

    CAS  PubMed  Google Scholar 

  25. Tallman MS, Hakiaman D, Zanzig C, Hogan DK, Rademaker A, Rose E, Variakojis D (1995) Cladrabine in the treatment of relapsed or refractory chronic lymphocytic leukaemia. J Clin Oncol 13:983–988

    CAS  PubMed  Google Scholar 

  26. Bowen AL, Zomas A, Emmett E, Matutes E, Dyer MJS, Catovsky D (1997) Subcutaneous Campath-1H in fludarabine resistant/relapsed chronic lymphocytic leukaemia and B-prolymphocytic leukaemia. Br J Haemat 96:617–619

    CAS  PubMed  Google Scholar 

  27. Fenaux P, Preudhomme C, Lai JL, Quiquandon I, Jonveaux P, Vanrumbeke M, Sartiaux C, Morel P, Loucheux-Lefebvre MH, Bauters F, Berger R, Kerckaert JP (1992) Mutations of the p53 gene in B-cell chronic lymphocytic leukaemia: A report on 39 cases with cytogenetic analysis. Leukaemia 6:246–250

    CAS  Google Scholar 

  28. McConkey D, Chandra J (1992) Protease activation and glucocorticoid- induced apoptosis in chronic lymphocytic leukaemia. Leuk Lymphoma 33:421–431

    Google Scholar 

  29. Masdehors P, Omura S, Merle-Beral H, Mentz F, Cosset J-M, Dumont J, Magdelenat H, Delic J (1999) Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteosome-specific inhibitor lactacystin. Br J Haemat 105:752–757

    Article  CAS  Google Scholar 

  30. King KL, Cidlowski JA (1998) Cell cycle regulation and apoptosis. Ann Rev Physiol 60:601–617

    Article  CAS  Google Scholar 

  31. Mori N, Yamate J, Stassen APM, Oka S, Okumoto M, Tsubura A, Akamtsu T, Sakuma S, Demant P (1999) Modulations of Glucorticoid-induced apoptosis linked to the p53 deletion and to the apoptosis susceptibility gene Rapop1 ( radiation-induced apoptosis1). Oncogene 18:4282–4285

    Google Scholar 

  32. Smets L, Salomons G, van den Berg J (1999) Glucorticoid induced apotosis in leukaemia. Adv Exp Med Biol 457:607–614

    CAS  PubMed  Google Scholar 

  33. Riccardi C, Zollo O, Nocentini G, Bruscoli S, Bartoli A, D’Adamio F, Cannarile L, Delfino D, Ayroldi E, Migliorati G (2000) Glucocorticoid hormones in the regulation of cell death. Pharmacol Exp 55:165–169

    CAS  Google Scholar 

  34. Bartik MM, Welker D, Kay NE (1998) Impairments in immune cell function in B cell chronic lymphocytic leukemia. Semin Oncol 25:27–33

    Google Scholar 

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Acknowledgements

This work was supported by a clinical fellowship from the The Leukaemia Research Fund, London. We would also like to thank Rifat Hamoudi, Institute of Cancer Research, for his help with the p53 gene sequencing.

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Correspondence to Daniel Catovsky.

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Thornton, P.D., Matutes, E., Bosanquet, A.G. et al. High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities. Ann Hematol 82, 759–765 (2003). https://doi.org/10.1007/s00277-003-0710-5

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  • DOI: https://doi.org/10.1007/s00277-003-0710-5

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