Chronic Myeloid Leukemia Knowledge Centre

Understanding CML

Clinical Presentation and Natural history of CML

Chronic myeloid leukemia typically progresses through 3 stages or phases. Most patients present in chronic phase, deteriorate during the subsequent accelerated phase, and finally progress to a brief terminal phase, blast crisis. Although the lengths of the phases were altered by previous therapies, the clinical course and natural history of CML had not been changed before the molecular era. Glivec is expected to have a marked effect on the natural history of CML^1,2, based on clinical studies demonstrating 89% overall survival at 5-year follow-up and low overall risk for progression to advanced phase disease.^3,4

Table 1. Clinical Presentation of Ph+ CML.^5-7

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Philadelphia chromosome-positive (Ph+) CML progresses through 3 phases of shortening duration, characterised by worsening clinical features and laboratory findings and by increasing resistance to therapy: chronic phase (CP), accelerated phase (AP) and blast crisis (BC) (Table 1).

Phase Specifics

• The chronic phase of CML is defined by an elevated WBC count at presentation (≥20 × 10⁸/L) and a relative lack of blasts (<10%) in peripheral blood and bone marrow (BM).⁹ This phase could last 5-6 years in the pre-Glivec era. Glivec is expected to have a marked effect on the natural history of CML^1,2, based on clinical studies demonstrating 89% overall survival at 5-year follow-up and low overall risk for progression to advanced phase disease.^3,4
• The accelerated phase of CML is the second and intermediate phase in the natural history of the disease.⁹ Although diagnosis may be made on the basis of the presence of any of the typical laboratory findings, the defining criterion is the presence of 10%-19% of blast cells in peripheral blood or BM^6,7
  • A panel of experts has outlined recommendations suggesting that accelerated-phase criteria be defined by 15%-29% blast cells in blood or BM (blast cells plus promyelocytes in blood or BM >30%, with <30% blasts present in blood or marrow).¹
  • The onset of the accelerated phase may be marked by thrombocytopaenia and progressive anaemia.^9,10 Symptoms in accelerated phase may worsen and include unexplained fever, bone pain, splenomegaly, and hepatomegaly. Basophilia and decreased platelet counts may be observed. This phase may last 6-9 months.²
• The blast-crisis phase of CML is marked by an increase in the percentage of blast cells in blood or BM (20%-30%) and increased symptomatology, including anaemia, infection, lymphadenopathy, and bleeding. Of those in blast crisis, 50% have myeloid blast crisis, 25% have lymphoid blast crisis, and 25% are mixed. This phase is associated with a poor prognosis and median survival of 3-6 months.¹¹ Several factors, including the cell lineage expanded in the blastic phase and type of therapy, may alter the range of median survival seen in blast crisis.²
  

The introduction of new treatments could change the boundaries between chronic phase, accelerated phase, and blast crisis and slightly modify the subdivision of CML in 3 phases.¹ CML in its chronic and advanced phases is diagnosed on the basis of symptoms, signs, and laboratory findings.

References:
1. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.
2. Cortes J. Natural history and staging of chronic myelogenous leukemia. Hematol Oncol Clin North Am. 2004;18:569-584.
3. Druker BJ, Guilhot F, O'Brien S, Larson RA, on behalf of the IRIS. Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): the 5-year update from the IRIS study [abstract]. J Clin Oncol. 2006;24:338s. Abstract 6506. Oral presentation.
4. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
5. Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology (Williston Park).1999;13:169-180; discussion 181, 184.
6. Kantarjian HM, Giles FJ, O'Brien SM, Talpaz M. Clinical course and therapy of chronic myelogenous leukemia with interferon-alpha and chemotherapy. Hematol Oncol Clin North Am. 1998;12:31-80.
7. Spiers AS. Clinical manifestations of chronic granulocytic leukemia. Semin Oncol. 1995;22:380-395.
8. Hoffbrand AV, Pettit JE, Moss PAH. Essential Haematology. 4th ed. Oxford, UK: Blackwell Science; 2001.
9. Silver RT. Chronic myeloid leukemia. Hematol Oncol Clin North Am. 2003;17:1159-1173, vi-vii.
10. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292-2302.
11. Quintas-Cardama A, Cortes JE. Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc. 2006;81:973-988.

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