Blood Reviews
Volume 26, Issue 1 , Pages 15-23 , January 2012

Optimal management of older patients with chronic lymphocytic leukemia: Some facts and principles guiding therapeutic choices

  • Tamar Tadmor

      Affiliations

    • Hematology Unit, Bnai-Zion Medical Center, Haifa, Israel
    • Corresponding Author InformationCorresponding author at: Hematology Unit, Bnai-Zion Medical Center, 47 Golomb Street, Haifa, 31048, Israel. Tel.: +972 48359407; fax: +972 48359962.
    • ,
  • Aaron Polliack

      Affiliations

    • Department of Hematology, Hadassah University Hospital, Hebrew University Medical School, Jerusalem, Israel

References 

  1. Hallek M, FK , Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;1164–1174
  2. Howlader NNA, Krapcho M, et al. SEER cancer statistics review, 1975–2008. Bethesda, MD: National Cancer Institute; 2010;http://seer.cancer.gov/csr/1975_2008/based on November 2010 SEER data
  3. Brenner H, Gondos A, Pulte D. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood. 2008;4916–4921
  4. Abrisqueta P, Pereira A, Rozman C, et al. Improving survival in patients with chronic lymphocytic leukemia (1980–2008): the Hospital Clínic of Barcelona experience. Blood. 2009;2044–2050
  5. Bairey O, Ruchlemer R, Rahimi-Levene N, et al. Presenting features and outcome of chronic lymphocytic leukemia patients diagnosed at age 80years or more. An ICLLSG study. Ann Hematol: Springer Berlin/Heidelberg. 2011;1–7
  6. Yee KWL, O'Brien SM. Chronic lymphocytic leukemia: diagnosis and treatment. Mayo Clin Proc. 2006;1105–1129
  7. Institute . NC. SEER Stat Fact Sheets: chronic lymphocytic leukemia. http://seer.cancer.gov/statfacts/html/clyl.htmlNovember 11 2009;Accessed
  8. Kristinsson SY, Dickman PW, Wilson WH, Caporaso N, Bjorkholm M, Landgren O. Improved survival in chronic lymphocytic leukemia in the past decade: a population-based study including 11,179 patients diagnosed between 1973–2003 in Sweden. Haematologica. 2009;1259–1265
  9. Zent CS, KM , Evans R, Schichman SA. Chronic lymphocytic leukemia incidence is substantially higher than estimated from tumor registry data. Cancer. 2001;1325–1330
  10. Marti GE, Rawstron AC, Ghia P, et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol. 2005;325–332
  11. Rawstron AC. Monoclonal B-cell lymphocytosis. Hematology. 2009;430–439
  12. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;5446–5456
  13. Eichhorst B, Goede V, Hallek M. Treatment of elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2009;171–178
  14. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009;3382–3391
  15. Turesson ILM, Björkholm M, Kristinsson SY, Goldin LR, Caporaso NE, Landgren O. Ascertainment and diagnostic accuracy for hematopoietic lymphoproliferative malignancies in Sweden 1964–2003. Int J Cancer. 2007;2260–2266
  16. Eichhorst BHM. Treatment of chronic lymphocytic leukemia in the elderly patients. In: Hematology education: the education program for the 16th Congress of the European Hematology Association. 2011;p. 104–111
  17. Del Giudice IMF, Foà R. Chronic lymphocytic leukemia in less fit patients (“SLOW-GO”). Leuk Lymphoma. 2011;Sep 13. [Epub ahead of print]
  18. Hallek M. State-of-the-art treatment of chronic lymphocytic leukemia. Hematology. 2009;440–449
  19. Extermann M, Overcash J, Lyman G, Parr J, Balducci L. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol. 1998;1582–1587
  20. Zent CS. Chronic lymphocytic leukemia in the elderly: who should be treated?. In: ASCO Educational Book. 2010;p. 268–272
  21. Thurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2008;49–56
  22. Moreno CME. New prognostic markers in chronic lymphocytic leukemia. Blood Rev. 2008;211–219
  23. Shanafelt TD, Rabe KG, Kay NE, et al. Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia. Cancer. 2010;4777–4787
  24. Catovsky D, FJ , Richards S. Prognostic factors in chronic lymphocytic leukaemia: the importance of age, sex and response to treatment in survival. A report from the MRC CLL 1 trial. MRC Working Party on Leukaemia in Adults. Br J Haematol. 1989;141–149
  25. Josefsson P, Geisler CH, Leffers H, et al. CLLU1 expression analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia. Blood. 2007;4973–4979
  26. Döhner H, Stilgenbauer S, James MR, et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood. 1997;2516–2522
  27. Zenz T, MD , Döhner H, Stilgenbauer S. Importance of genetics in chronic lymphocytic leukemia. Blood Rev. 2011;131–137
  28. Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of Fludarabine, Cyclophosphamide, and Rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;4079–4088
  29. Binet JL, AA , Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;219–234
  30. Döhner HSS, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. NEJM. 2000;1910–1916
  31. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;1848–1854
  32. Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol. 2007;799–804
  33. Zent CS, Kay NE. Management of patients with chronic lymphocytic leukemia with a high risk of adverse outcome: the Mayo Clinic approach. Leuk Lymphoma. 2011;52(8):1425–1434
  34. Kröber A, Bloehdorn J, Hafner S, et al. Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia. J Clin Oncol. 2006;969–975
  35. Zenz T, Häbe S, Denzel T, et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood. 2009;2589–2597
  36. Wierda WG, O'Brien S, Wang X, et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood. 2007;4679–4685
  37. Badoux X, Al-Ameri AM, O'Brien S, et al. Comparison of the efficacy and toxicity of Fludarabine (F) in first line therapy of younger versus elderly patients (Pts) with advanced chronic lymphocytic leukemia (CLL): results of a meta-analysis of two Phase III trials of the German CLL Study Group (GCLLSG). Retrospective analysis of the experience with Rituximab and Methylprednisone in elderly patients with CLL. ASH Annu Meet Abstr. 2005;717
  38. Wierda WG, O'Brien S, Wang X, et al. Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J Clin Oncol. 2009;1637–1643
  39. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;230–239
  40. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of Fludarabine plus Cyclophosphamide compared with Fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007;793–798
  41. Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003;101(1):6–14
  42. Eichhorst BF, Busch R, Stauch M, et al. No significant clinical benefit of first line therapy with Fludarabine (F) in comparison to Chlorambucil (Clb) in elderly patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a Phase III study of the German CLL Study Group (GCLLSG). ASH Annu Meet Abstr. 2007;629
  43. Smolej LBY, Spacek M, et al. Low-dose fludarabin and cyclophosphamide combined with rituximab in the treatment of elderly/comorbid patients with chronic lymphocytic leukemia: project of Q-LITE of Czech CLL study group. Haematologica in press abstract 0105.
  44. Marotta G, Bigazzi C, Lenoci M, Tozzi M, Bocchia M, Lauria F. Low-dose fludarabine and cyclophosphamide in elderly patients with B-cell chronic lymphocytic leukemia refractory to conventional therapy. Haematologica. 2000;1268–1270
  45. Forconi F, Fabbri A, Lenoci M, et al. Low-dose oral fludarabine plus cyclophosphamide in elderly patients with untreated and relapsed or refractory chronic lymphocytic leukaemia. In: Hematological Oncology. John Wiley & Sons, Ltd; 2008;p. 247–251
  46. Mulligan SP, GD , Renwick WEP, et al. The safety and tolerability of oral Fludarabine, ±oral Cyclophosphamide and Iv Rituximab Therapy in previously untreated patients with chronic lymphocytic leukaemia (CLL) aged ≥65years — interim analysis from the Australasian Leukaemia and Lymphoma Group (ALLG) and CLL Australian Research Consortium (CLLARC) CLL5 Study. Blood, ASH Annu Meet Abstr. 2010;699
  47. Smolej L, Spacek M, Brychtova Y, et al. Low-dose Fludarabine and Cyclophosphamide combined with Rituximab in the treatment of elderly/comorbid patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): preliminary results of Project Q-Lite by Czech CLL Study Group. ASH annu meet abstr. 2010;2466
  48. Foon KA, Boyiadzis M, Land SR, et al. Chemoimmunotherapy with low-dose Fludarabine and Cyclophosphamide and high dose Rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27(4):498–503
  49. Robak T, Błasiłska-Morawiec M, Błołski JZ, Dmoszyłska A. 2-Chlorodeoxyadenosine (Cladribine) in the treatment of elderly patients with B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 1999;151–156
  50. Shanafelt TD, Lin T, Geyer SM, et al. Pentostatin, Cyclophosphamide, and Rituximab regimen in older patients with chronic lymphocytic leukemia. In: Cancer: Wiley Subscription Services, Inc., A Wiley Company; 2007;p. 2291–2298
  51. Robak T, Jamroziak K, Gora-Tybor J, et al. Comparison of Cladribine plus Cyclophosphamide with Fludarabine plus Cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a Phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010;28(11):1863–1869
  52. Catovsky D, Else M, Richards S. Chlorambucil—still not bad: a reappraisal. Clin Lymphoma Myeloma Leuk. 2011;11(s1):S2–S6
  53. Foa R, AA, Guarini A, et al. A phase II study of chlorambucil +rituximab (CLB-R) followed by R maintenance vs observation in elderly patients with previously untreated chronic lymphocytic leukemia(CLL): induction phase results. Haemato-logica in press abstract-0532.
  54. Badoux XC, Keating MJ, Wen S, et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood. 2011;Jul 1. [Epub ahead of print]
  55. Montillo M, Ricci F, Tedeschi A, Vismara E, Morra E. Bendamustine: new perspective for an old drug in lymphoproliferative disorders. Expert Rev Hematol. 2010;131–148
  56. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of Bendamustine compared with Chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;4378–4384
  57. Weide R, MU , Friesenhahn V, et al. Bendamustine/mitoxantrone/rituximab: a short remission induction chemoimmunotherapy for elderly patients with relapsed or refractory chronic lymphocytic leukemia. Leuk Lymphoma. 2009;1468–1474
  58. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with Chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25(35):5616–5623
  59. Delmer A, Lepretre S, Cazin B, et al. Consolidation therapy with subcutaneous Alemtuzumab following induction treatment with oral FC (Fludarabine and Cyclophosphamide) in previously untreated patients aged 65–70Years with advanced stage chronic lymphocytic leukemia (CLL): a Phase II trial of the FCGCLL/MW. ASH annu meet abstr. 2006;2831
  60. Dungarwalla M, Evans SO, Riley U, Catovsky D, Dearden CE, Matutes E. High dose methylprednisolone and rituximab is an effective therapy in advanced refractory chronic lymphocytic leukemia resistant to fludarabine therapy. Haematologica. 2008;93(3):475–476
  61. Castro JE, James DF, Sandoval-Sus JD, et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009;23(10):1779–1789
  62. Badoux X, Al-Ameri AM, O'Brien S, et al. Retrospective analysis of the experience with Rituximab and Methylprednisone in elderly patients with CLL. ASH annu meet abstr. 2010;4636
  63. Hensel M, Zoz M, Ho A. Complementary and alternative medicine in patients with chronic lymphocytic leukemia. Support Care Cancer. 2009;17(1):47–52
  64. Ghosh AK, Kay NE, Secreto CR, Shanafelt TD. Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG. Clin Cancer Res. 2009;1250–1258
  65. Shanafelt TD, Call TG, Zent CS, et al. Phase I trial of daily oral Polyphenon E in patients with asymptomatic Rai Stage 0 to II chronic lymphocytic leukemia. J Clin Oncol. 2009;3808–3814
  66. Lucas DM, Edwards RB, Lozanski G, et al. The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. Blood. 2009;4656–4666
  67. Han S-S, Chung S-T, Robertson DA, Ranjan D, Bondada S. Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, C-myc, Bcl-XL, NF-[kappa]B, and p53. Clin Immunol. 1999;152–161
  68. Liu H-l, Chen Y, Cui G-h, Zhou J-f. Curcumin, a potent anti-tumor reagent, is a novel histone deacetylase inhibitor regulating B-NHL cell line Raji proliferation1. Acta Pharmacol Sin: Blackwell Publishing Asia. 2005;603–609
  69. Gururajan M, Dasu T, Shahidain S, et al. Spleen tyrosine kinase (Syk), a novel target of curcumin, is required for B lymphoma growth. J Immunol. 2007;111–121
  70. Pepper C, Thomas A, Hoy T, Milligan D, Bentley P, Fegan C. The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro. Blood. 2003;2454–2459
  71. Shanafelt TD, Drake MT, Maurer MJ, et al. Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia. Blood. 2011;1492–1498
  72. Goede V, Hallek M. Optimal pharmacotherapeutic management of chronic lymphocytic leukaemia: considerations in the elderly. Drugs Aging. 2011;28(3):163–17610.2165/11587650-000000000-00000
  73. Shvidel L, Shtalrid M, Bairey O, et al. Conventional dose Fludarabine-based regimens are effective but have excessive toxicity in elderly patients with refractory chronic lymphocytic leukemia. Leuk Lymphoma. 2003;1947–1950
  74. Pitini V, AC , Naro C, et al. Subcutaneous low-dose alemtuzumab as first line therapy for elderly CLL patients with deletion of 17p. J Clin Oncol. 2008;7048
  75. Ferrajoli A, OBS , Faderl S, Wierda WG, Schlette E, Jorgensen JL, et al. The combination of rituximab and GM-CSF in elderly patients with chronic lymphocytic leukemia (CLL). ASCO annual meeting proceedings part I J Clin Oncol. 2006;24(18S):6602;(June 20 Supplement)
  76. WM.P . Long-term clinical remission of a patient with chronic lymphocytic leukemia using alternative treatment option: cottonseed oil (gossypol). Phytomedicine. 2008;563–565
  77. Pan L, Kardono LBS, Riswan S, et al. Isolation and characterization of minor analogues of silvestrol and other constituents from a large-scale re-collection of Aglaia foveolata. J Nat Prod: Am Chem Soc. 2010;1873–1878

PII: S0268-960X(11)00067-1

doi: 10.1016/j.blre.2011.09.002

Blood Reviews
Volume 26, Issue 1 , Pages 15-23 , January 2012

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