Treatment Options

The prognosis of patients with CML (chronic myeloid leukaemia) has changed considerably since the first treatment attempts with arsenicals. In the past, the median survival of patients with CML was 3 years; less than 20% of patients were alive at 5 years after diagnosis.

Currently, the median survival has doubled to 5 to 6 years and, in good-risk patients, it is up to 9 years. More than one half of patients are alive 5 years after diagnosis, and more than 30% are alive at 10 years. Reasons for this improved survival include:


  • Earlier diagnosis
  • Better supportive care
  • More effective therapies, most notably allogeneic SCT– and IFN-α —based treatment


Assessing Risk Groups and Response to Treatment

The clinical course of CML is variable and the treatment outcome depends on the phase of the disease and the risk characteristics of the patient.


A number of clinical factors have been associated with a worse prognosis:


  • Older age
  • The presence of symptoms at diagnosis
  • Poor performance status at diagnosis
  • Hepatomegaly and splenomegaly at diagnosis
  • Evidence of blasts or basophils on peripheral smear
  • Collagen or reticulin fibrosis in the bone marrow
  • Long time to haematological remission
  • Short remission duration
  • High doses of hydroxyurea or busulfan required to normalise cell counts


Because of the variability in clinical course, experts have developed different prognostic models and staging systems to help with the management of CML patients, particularly those in chronic phase. Three widely used staging systems are shown in Table 1. These systems are used for:


  • Defining individual prognosis
  • Assigning patients to different strategies based on their risk profile
  • Evaluating the effects of newer therapies
  • Comparing the relative benefits of therapies within risk groups



Table 1. Criteria for Response to Therapy in CML


Sokal 1984

Kantarjian 1990

Hasford 1998


•Platelet Count
•Spleen size
•% blood blasts

Poor-prognosis features:

•Age ≥ 60
•Speen 10 ≥ cm below rib cage
•Blasts ≥ 3% in PB/BM
•Basophils ≥ 7% in PB/3% in BM
•Platelets ≥ 700 x 109/L

•Platelet count
•Spleen size
•% PB blasts
•% PB eosinophils
•% PB basophils

Category definition

1: Low risk (<0.8)
2: Intermediate risk (0.8-1.2)
3: High Risk (>1.2)

1: 0 to 1 poor prognosis criteria
2: 2 poor-prognosis criteria
3: 3 poor-prognosis criteria
4: ≥ 1 accelerated-phase criteria

1: Low risk (score ≤ 780)
2: Intermediate risk (780-1479)
3: High Risk (≥ 1480)

CML stage and median survival in months

1: 57
2: 41
3: 35

1: 56
2: 45
3: 30
4: 30

1: 98
2: 65
3: 42

*See original paper for scoring algorithm. PB = Peripheral Blood, BM = Bone Marrow

The criteria developed by Hasford et al, in particular, have been used to estimate the survival of patients treated with IFN-α. In this population, the median survival times in the low-, intermediate-, and high-risk groups are 8, 5, and 3.5 years, respectively. Table 2 outlines criteria used to assess the response of patients with CML (chronic myeloid leukaemia) to therapy. These criteria are primarily applicable to patients in chronic phase. Note that different clinical studies may use different criteria to define a response. Moreover, other response criteria, generally those associated with acute leukaemia, are used to evaluate patients in blast crisis CML.

Table 2. Criteria for Response to Therapy in CML

Cytogenic response
(only in patients with CHR)
- Complete *
- Partial *
- Minor

- No Ph+ cells
- 1%-35% Ph+ cells
- 36%-95% Ph+ cells



Complete haematological response (remission) (CHR)

•Complete normalisation of peripheral blood (PB) counts
-WBC <10 x 109/L
-Platelets <450 x 109/L
•No immature cells in PB
•No signs/symptoms of disease;
dissapearance of splenomegaly

Partial haematological response (remission) (PHR)

•Same as CHR, except:
-Persistance of immature cells in PB, or
-Platelets <50% of pre-treatment levels,
but >450 x 109/L, or
-Persistant splenomegaly, but <50% of pre-treatment size

Source: Faderl 1999a; *as used in Novartis clinical trials, major cytogenetic response = complete + partial, i.e., 35% Ph+ cells.

Goals of Therapy in CML

The initial goals of therapy for patients in chronic phase CML include


Lowering the elevated WB

Reducing the symptoms of concomitant splenomegal

Treating complications, such as gout, caused by the marrow hyperproliferation


Hyperuricaemia and gout, caused by increased nucleic acid synthesis, can occur before treatment is started and can worsen after therapy begins. Thus, patients with CML are often started on allopurinol before receiving cytotoxic therapy.


Unless the WBC count is extremely high and producing severe symptoms, such as CNS, pulmonary, or haemorrhagic events, it is not usually necessary to institute aggressive chemotherapy or other measures such as leukapheresis. As the disease progresses to the accelerated and blast phases, it becomes considerably more difficult to treat. Although CML in blast crisis generally resembles AML or ALL, it is much more difficult to induce a remission in these patients than it is in patients with classical AML or ALL.


The therapy of advanced CML (chronic myeloid leukaemia) may include hydroxyurea, the typical agents used for acute leukaemia, and experimental therapies.

Treating Advanced CML: CML In Accelerated Phase

Patients who have haematological changes suggesting accelerated phase CML (chronic myeloid leukaemia) have low cytogenetic response rates when treated with IFN-α. Therefore, most of these patients are referred for allogeneic SCT if a donor can be identified. Under these circumstances, long-term DFS rates are approximately 10%–30%. However, if the patient’s only defining characteristic of acceleration is clonal evolution, then DFS rates may be as high as 60% following allogeneic SCT. The prognosis for these patients is quite similar to chronic phase CML patients treated with SCT.


IFN-α is also more effective in patients whose only evidence of acceleration is clonal evolution. In such circumstances, IFN-α may lead to suppression of clonal evolution in about 50% of patients. These responses, however, are usually transient, with little chance of developing a complete cytogenetic response. Figure 1 presents a flowchart for choosing therapy for a patient with CML in chronic phase.

Figure 1. Treatment choices for patients with CML in chronic phase. The flow chart presents a simplified schema for choosing between SCT and IFN-α in patients with newly diagnosed cML in chronic phase. Also see Chronic Myeloid Leukaemia Trialists' Collaborative Group 1997 and Sawyers 1999 for additional discussion. Early chronic phase = ≤ 12 months after diagnosis, late chronic phase = > 12 months after diagnosis, TRM = transplant-related mortality for SCT, SCT = stem cell transplant, CG = cytogenic, CGR = cytogenic remission.

  • Other myeloproliferative disorders
    • Myelofibrosis
    • Polycythaemia vera
    • Essential thrombocythaemia

  • Atypical CML—a Ph- and Bcr-Abl-negative myeloproliferative disease (the following discussion will explain Bcr-Abl), which has a worse prognosis than classical Ph+ CML
  • Chronic neutrophilic leukaemia—a rare disease associated with a clonal abnormality confined to neutrophil precursors; the clinical course is hetero-geneous, but characterised by a more sustained, mature neutrophilic leukocytosis, thrombocytosis, and a more indolent behaviour, with less tendency to transform into the blast phase
  • Chronic myelomonocytic leukaemia—one of the myelodysplastic syndromes, which clinically may resemble CML, (chronic myeloid leukaemia), but is Ph-
  • Juvenile chronic myeloid leukaemia—a rare Ph- disease of children associated with WBC findings similar to CML, but with a clinical course more closely resembling AML
  • Leukaemoid reaction—a marked elevation in WBC count not due to a haematological malignancy; often due to an undiagnosed inflammatory process or toxic response, but occasionally due to an underlying solid malignancy