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Chronic Lymphocytic Leukemia Clinical Presentation

  • Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
Updated: May 23, 2016

History and Physical Examination

Patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) present with a wide range of symptoms and signs. Onset is insidious, and it is not unusual for CLL to be discovered incidentally after a blood cell count is performed for another reason; 25-50% of patients will be asymptomatic at time of presentation.

Enlarged lymph nodes are the most common presenting symptom, seen in 87% of patients symptomatic at time of diagnosis. A predisposition to repeated infections such as pneumonia, herpes simplex labialis, and herpes zoster may be noted. Early satiety and/or abdominal discomfort may be related to an enlarged spleen.

Mucocutaneous bleeding and/or petechiae may be due to thrombocytopenia. Tiredness and fatigue may be present secondary to anemia; 10% of patients with CLL will present with an autoimmune hemolytic anemia.

Richter syndrome or Richter transformation refers to the transformation of CLL into an aggressive large B-cell lymphoma and is seen in approximately 3-10% of cases. Patients will often present with symptoms of weight loss, fevers, night sweats, muscle wasting, (ie, B symptoms) and increasing hepatosplenomegaly and lymphadenopathy. Treatment remains challenging and prognosis poor, with median survival in months.

Physical examination

In addition to localized or generalized lymphadenopathy, patients may manifest the following:

  • Splenomegaly (30-54% of cases)
  • Hepatomegaly (10-20% of cases)
  • Petechiae
  • Pallor
Contributor Information and Disclosures

Muhammad A Mir, MD, FACP Assistant Professor of Medicine (Hematology, Blood/Marrow Transplant) Milton S Hershey Medical Center, Pennsylvania State University College of Medicine

Muhammad A Mir, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Hematology, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology

Disclosure: Nothing to disclose.


Haleem J Rasool, MD, FACP Chair, Department of Oncology, Mayo Clinic Health System, La Crosse, WI

Haleem J Rasool, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Delong Liu, MD, PhD Professor of Medicine, Division of Oncology/Hematology, New York Medical College; Chief of Hematology, Phelps Memorial Hospital Center; Director of Non-ablative Allogeneic Stem Cell Transplantation Program, Westchester Medical Center; Editor-in-Chief, Journal of Hematology and Oncology

Delong Liu, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Samir C Patel, MD Fellow, Department of Hematology and Medical Oncology, Metropolitan Hospital, New York Medical College

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.


Michael Perry, MD, MS, MACP† Former Nellie B Smith Chair of Oncology Emeritus, Former Director, Division of Hematology and Medical Oncology, Former Deputy Director, Ellis Fischel Cancer Center, University of Missouri-Columbia School of Medicine

Clarence Sarkodee-Adoo, MD Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program

Disclosure: Takeda Millenium Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

  1. Elter T, Hallek M, Engert A. Fludarabine in chronic lymphocytic leukaemia. Expert Opin Pharmacother. 2006 Aug. 7(12):1641-51. [Medline].

  2. PDQ Adult Treatment Editorial Board. Chronic Lymphocytic Leukemia Treatment (PDQ®): Health Professional Version. PDQ Cancer Information Summaries. Bethesda, MD: National Cancer Institute; January 29, 2016. [Full Text].

  3. Klepfish A, Gilles L, Ioannis K, Eliezer R, Ami S. Enhancing the action of rituximab in chronic lymphocytic leukemia by adding fresh frozen plasma: complement/rituximab interactions & clinical results in refractory CLL. Ann N Y Acad Sci. 2009 Sep. 1173:865-73. [Medline].

  4. Badoux XC, Keating MJ, Wang X, et al. Fludarabine, cyclophosphamide and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 2011 Jan 18. [Medline].

  5. Zenz T, Benner A, Duhrsen U, Durig J, Dohner H, Siffert W, et al. BCL2-938C>A polymorphism and disease progression in chronic lymphocytic leukemia. Leuk Lymphoma. 2009 Sep 11. 1-6. [Medline].

  6. Nicoloso MS, Kipps TJ, Croce CM, Calin GA. MicroRNAs in the pathogeny of chronic lymphocytic leukaemia. Br J Haematol. 2007 Dec. 139(5):709-16. [Medline]. [Full Text].

  7. Hanlon K, Rudin CE, Harries LW. Investigating the targets of MIR-15a and MIR-16-1 in patients with chronic lymphocytic leukemia (CLL). PLoS One. 2009 Sep 25. 4(9):e7169. [Medline]. [Full Text].

  8. Fabbri M, Bottoni A, Shimizu M, et al. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA. 2011 Jan 5. 305(1):59-67. [Medline].

  9. Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011 Dec 29. 365(26):2497-506. [Medline].

  10. Slager SL, Kay NE. Familial Chronic Lymphocytic Leukemia: What Does it Mean to Me?. Clin Lymphoma Myeloma. 2009 Sep 1. 9:S194-S197. [Medline].

  11. Berndt SI, Camp NJ, Skibola CF, Vijai J, Wang Z, et al. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia. Nat Commun. 2016 Mar 9. 7:10933. [Medline].

  12. Cancer Facts & Figures 2016. American Cancer Society. Available at Accessed: March 10, 2016.

  13. Rai KR, Keating HJ. Chronic lymphocytic leukemia. Holland JF, Bast RC, Morton DL, et al, eds. Cancer Medicine. 4th ed. Baltimore, Md: Williams and Wilkins; 1997. Vol II: 2697-728.

  14. Kristinsson SY, Dickman PW, Wilson WH, et al. 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 Sep. 94(9):1259-65. [Medline]. [Full Text].

  15. Maurer MJ, Cerhan JR, Katzmann JA, et al. Monoclonal and polyclonal serum free light chains and clinical outcome in chronic lymphocytic leukemia. Blood. 2011 Sep 8. 118(10):2821-6. [Medline]. [Full Text].

  16. 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 Jun 15. 111(12):5446-56. [Medline].

  17. Bouley J, Deriano L, Delic J, Merle-Béral H. New molecular markers in resistant B-CLL. Leuk Lymphoma. 2006 May. 47(5):791-801. [Medline].

  18. Abbott BL. Chronic lymphocytic leukemia: recent advances in diagnosis and treatment. Oncologist. 2006 Jan. 11(1):21-30. [Medline]. [Full Text].

  19. Zwiebel JA, Cheson BD. Chronic lymphocytic leukemia: staging and prognostic factors. Semin Oncol. 1998 Feb. 25(1):42-59. [Medline].

  20. [Guideline] National Comprehensive Cancer Network. Non-Hodgkin's Lymphomas Version 2. 2016. NCCN. Available at Accessed: March 11, 2016.

  21. Parikh SA, Strati P, Tsang M, West CP, Shanafelt TD. Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis. Blood. 2016 Feb 3. 39 (8A):935-7. [Medline].

  22. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007 Dec 10. 25(35):5616-23. [Medline].

  23. Montillo M, Tedeschi A, Miqueleiz S, et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol. 2006 May 20. 24(15):2337-42. [Medline]. [Full Text].

  24. Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005 May 1. 23(13):2971-9. [Medline]. [Full Text].

  25. Visone R, Veronese A, Rassenti LZ, et al. miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia. Blood. 2011 Sep 15. 118(11):3072-9. [Medline]. [Full Text].

  26. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug. 46(2):219-34. [Medline]. [Full Text].

  27. Bosch F, Ferrer A, Villamor N, et al. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008 Jan 1. 14(1):155-61. [Medline].

  28. Byrd JC, Gribben JG, Peterson BL, et al. Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol. 2006 Jan 20. 24(3):437-43. [Medline].

  29. Wierda WG, O'Brien S, Wang X, et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol. 2011 Nov 1. 29(31):4088-95. [Medline].

  30. 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 Oct 15. 114(16):3382-91. [Medline].

  31. Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015 Dec 17. 373 (25):2425-37. [Medline].

  32. 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 Apr 10. 28(11):1863-9. [Medline].

  33. Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011 Sep 10. 29(26):3559-66. [Medline].

  34. Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, et al. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol. 2012 Oct. 159(1):67-77. [Medline].

  35. Nabhan C, Coutré S, Hillmen P. Minimal residual disease in chronic lymphocytic leukaemia: is it ready for primetime?. Br J Haematol. 2007 Feb. 136(3):379-92. [Medline].

  36. Sayala HA, Rawstron AC, Hillmen P. Minimal residual disease assessment in chronic lymphocytic leukaemia. Best Pract Res Clin Haematol. 2007 Sep. 20(3):499-512. [Medline].

  37. Parikh SA, Keating MJ, O'Brien S, et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood. 2011 Aug 25. 118(8):2062-8. [Medline].

  38. Badoux XC, Keating MJ, Wang X, et al. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood. 2011 Aug 25. 118(8):2085-93. [Medline].

  39. Skoetz N, Bauer K, Elter T, Monsef I, Roloff V, Hallek M, et al. Alemtuzumab for patients with chronic lymphocytic leukaemia. Cochrane Database of Systematic Reviews. 2012.

  40. Lemery SJ, Zhang J, Rothmann MD, Yang J, Earp J, Zhao H. U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. Clin Cancer Res. 2010 Sep 1. 16(17):4331-8. [Medline].

  41. Nelson R. FDA Grants Full Approval to Ofatumumab (Arzerra) for CLL. Medscape Medical News. Available at Accessed: March 10, 2016.

  42. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13. 370(11):997-1007. [Medline]. [Full Text].

  43. van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, et al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015 Oct. 16 (13):1370-9. [Medline].

  44. Goede V, Fischer K, Humphrey K, Asikanius E, Busch R, Engelke A, et al. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): Final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol 31, 2013 (suppl; abstr 7004).

  45. B McCall. Obinutuzumab Active in Elderly Chronic Lymphocytic Leukemia. Medscape Medical News from the: 18th Congress of the European Hematology Association (EHA). June 21, 2013. Available at Accessed: November 11, 2013.

  46. Mougalian SS, O'Brien S. Adverse prognostic features in chronic lymphocytic leukemia. Oncology (Williston Park). 2011 Jul. 25(8):692-6, 699. [Medline].

  47. Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1. 28(10):1756-65. [Medline].

  48. Woyach JA, Ruppert AS, Heerema NA, Peterson BL, Gribben JG, Morrison VA, et al. Chemoimmunotherapy With Fludarabine and Rituximab Produces Extended Overall Survival and Progression-Free Survival in Chronic Lymphocytic Leukemia: Long-Term Follow-Up of CALGB Study 9712. J Clin Oncol. 2011 Apr 1. 29(10):1349-55. [Medline].

  49. Hallek M, Fischer K, 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 Oct 2. 376(9747):1164-74. [Medline].

  50. Nelson R. New Drug Combo Potentially 'Practice Changing' in CLL. Medscape [serial online]. Available at Accessed: December 16, 2013.

  51. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4. 369(1):32-42. [Medline]. [Full Text].

  52. Chustecka Z. Ibrutinib in CLL: indication expanded, benefit confirmed. July 28, 2014. [Full Text].

  53. Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17. 371 (3):213-23. [Medline]. [Full Text].

  54. Chustecka Z. Idelalisib (Zydelig) approved for CLL and lymphoma. Medscape Medical News. July 23, 2014. [Full Text].

  55. FDA news release: FDA approves Zydelig for three types of blood cancers. US Food and Drug Administration. July 23, 2014. Available at

  56. Molica S. Immunomodulatory drugs in chronic lymphocytic leukemia: a new treatment paradigm. Leuk Lymphoma. 2007 May. 48(5):866-9. [Medline].

  57. Boggs W. Chlorambucil Effective for Chronic Lymphocytic Leukemia in Elderly. Medscape Medical News. December 13, 2012. [Full Text].

  58. Woyach JA, Ruppert AS, Rai K, Lin TS, Geyer S, Kolitz J, et al. Impact of Age on Outcomes After Initial Therapy With Chemotherapy and Different Chemoimmunotherapy Regimens in Patients With Chronic Lymphocytic Leukemia: Results of Sequential Cancer and Leukemia Group B Studies. J Clin Oncol. 2012 Dec 10. [Medline].

  59. Gribben JG, Hosing C, Maloney DG. Stem cell transplantation for indolent lymphoma and chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2011 Jan. 17(1 Suppl):S63-70. [Medline].

  60. Michallet M, Dreger P, Sutton L, et al. Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood. 2011 Feb 3. 117(5):1516-1521. [Medline].

  61. Hodgson K, Ferrer G, Montserrat E, Moreno C. Chronic lymphocytic leukemia and autoimmunity: a systematic review. Haematologica. 2011 May. 96(5):752-61. [Medline]. [Full Text].

  62. Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis. Leuk Lymphoma. 2009 May. 50(5):764-72. [Medline].

  63. Koehrer S, Keating MJ, Wierda WG. Eltrombopag, a second-generation thrombopoietin receptor agonist, for chronic lymphocytic leukemia-associated ITP. Leukemia. 2010 May. 24(5):1096-8. [Medline].

  64. Borthakur G, O'Brien S, Wierda WG, et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab--incidence and predictors. Br J Haematol. 2007 Mar. 136(6):800-5. [Medline].

  65. Moulin B, Ronco PM, Mougenot B, Francois A, Fillastre JP, Mignon F. Glomerulonephritis in chronic lymphocytic leukemia and related B-cell lymphomas. Kidney Int. 1992 Jul. 42(1):127-35. [Medline].

  66. Chustecka Z. Ibrutinib (Imbruvica) Approved for CLL in US. Medscape [serial online]. Available at Accessed: February 19, 2014.

  67. FDA News Release. FDA approves Gazyva for chronic lymphocytic leukemia. Medscape [serial online]. Available at Accessed: November 4, 2013.

  68. FDA News Release. FDA approves Imbruvica to treat chronic lymphocytic leukemia. U.S. Food and Drug Administration. Available at Accessed: February 19, 2014.

  69. Nelson R. FDA Gives Arzerra Breakthrough Therapy Designation for CLL. Medscape Medical News. Available at Accessed: September 24, 2013.

  70. Shanafelt T, Lanasa MC, Call TG, et al. Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL). Cancer. 2013 Aug 6. [Medline].

  71. Venclexta (venetoclax) [package insert]. North Chicago, IL: AbbVie, Inc. April 2016. Available at [Full Text].

Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.
Peripheral smear from a patient with chronic lymphocytic leukemia, large lymphocytic variety. Smudge cells are also observed; smudge cells are the artifacts produced by the lymphocytes damaged during the slide preparation.
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