Chronic Myeloid Leukaemia

Chronic myeloid leukaemia (CML) is a clonal malignant myeloproliferative disorder believed to originate in a single abnormal haemopoietic stem cell. The progeny of this abnormal stem cell proliferate over months or years, so that, by the time the leukaemia is diagnosed, the bone marrow is grossly hypercellular and the number of leucocytes is greatly increased in the peripheral blood. Normal blood cell production is almost completely replaced by leukaemia cells, which, however, still function almost normally.

CML has an annual incidence of 1–1.5/100 000 of the population (in the UK about 700 new cases each year), with no clear geographical variation. Presentation may be at any age, but the peak incidence is at 50–70 years, with a slight male predominance. This leukaemia is very rare in children. Because the disease evolves very slowly and ‘routine’ blood counts are carried out increasingly fre- quently, today, up to 50% of patients are diagnosed before showing any symptoms.

Most cases of CML occur sporadically. The only known predisposing factor is irradiation as shown by studies of Japanese survivors of the atomic bombs and in patients who have received radiotherapy for ankylosing spondylitis and various neoplastic conditions.

The clinical course of CML can be divided into a chronic or ‘stable’ phase and an advanced phase, the latter term covering both accelerated and blastic phases. Most patients present with chronic phase disease, which in the past lasted on average 4–5 years. However, since the introduction into clinical practice of the new tyrosine kinase inhibitors (see p. 24), the median duration of the chronic phase may prove to be much longer, even 10–20 years. In about two-thirds of patients, the chronic phase transforms gradually into an accelerated phase, characterized by a moderate increase in blast cells, increasing anaemia or thrombocytosis, or other features not compatible with chronic phase disease. After a variable number of months, this accelerated phase progresses to frank acute blastic transformation. The remaining onethird of patients move abruptly from chronic phase to an acute blastic phase (or blastic crisis) without an intervening phase of acceleration. 

Pathogenesis 

All leukaemia cells in patients with CML contain a specific cytoge- netic marker, described originally in 1960 by workers in Philadel- phia, and thus known as the Philadelphia or Ph chromosome (Fig. 5.1). The Ph chromosome is derived from a normal 22 chromosome that has lost part of its long arm as a result of a balanced reciprocal translocation of chromosomal material involving one of each pair of chromosomes 9 and 22; thus the translocation is t(9;22)(q34;q11). The Ph chromosome (also known as 22q–) therefore appears some- what shorter than its normal counterpart, and the 9q+ somewhat longer than the normal chromosome 9. 

The Ph chromosome carries a specific fusion gene known as bcr– abl, which results from juxtaposition of part of the abl proto-oncogene (from chromosome 9) with part of the bcr gene on chromosome 22. This fusion gene is expressed as a specific messenger (m) RNA, which in turn generates a protein called p210Bcr–Abl. This protein perturbs stem cell kinetics and associated myelopoiesis, resulting in the chronic phase of CML, although the exact mechanism remains unclear. The management of CML in the chronic phase was revolution- ized in 1998 by the introduction of imatinib mesylate, which kills

Figure 5.1  Formation of the Philadelphia chromosome resulting in a bcr–abl fusion gene that generates a fusion protein (p210) responsible for the chronic myeloid leukaemia (CML) phenotype.

Figure 5.2 Mechanism of action of imatinib.

leukaemia cells by blocking the enzymatic function of the Bcr–Abl oncoprotein and thereby permits regeneration of normal haemo- poietic cells (Fig. 5.2).

Chronic phase disease 

Presentation 

The characteristic symptoms of CML at presentation include fatigue, weight loss, sweating, anaemia, haemorrhage or purpura, and the sensation of a mass in the left upper abdominal quadrant (spleen) (Box 5.1). Often the disease is detected as a result of routine blood tests performed for unrelated reasons, and up to 50% of patients are totally asymptomatic at the time of diagnosis. The spleen may be greatly enlarged before the onset of symptoms. Treatment that reduces the leucocyte count to normal usually restores the spleen to normal size. Much rarer features at presentation include non-spe- cific fever, lymphadenopathy, visual disturbances due to leucostasis (a form of hyperviscosity caused by an extremely high white cell count) or retinal haemorrhages, splenic pain due to infarction, gout and occasionally priapism. The commonest physical sign at diagnosis is an enlarged spleen (Fig. 5.3), which may vary from being just palpable at the left costal margin to filling the whole left side of the abdomen and extending

Figure 5.3  Patient with massive splenomegaly  in chronic phase chronic myeloid leukaemia.

towards the right iliac fossa. The liver may be enlarged, with a soft, rather ill-defined lower edge. Spontaneous and excessive bruising in response to minor trauma is common. 

Diagnosis 

The diagnosis of CML in the chronic phase can be made from a study of the peripheral blood film (Fig. 5.4), which shows greatly increased numbers of leucocytes with many immature forms (promyelocytes and myelocytes) (Box 5.2); the marrow is usually examined to confirm the diagnosis (Box 5.3). 

Marrow examination shows increased cellularity. The distribution of immature leucocytes resembles that seen in the blood film. Red cell production is relatively reduced. Megakaryocytes, the cells giv-

Figure 5.4  Peripheral blood film from a patient  with chronic myeloid leukaemia showing many mature  granulocytes,  including two basophils (arrow); a blast cell is prominent (double arrow).

ing rise to platelets, are plentiful but may be smaller than usual and morphologically atypical. 

Reverse transcriptase polymerase chain reaction (RT-PCR) confirms the presence of a bcr–abl fusion. Cytogenetic study of marrow shows the presence of the Ph chromosome in all dividing cells. 

The patient’s blood concentrations of urea and electrolytes are usually normal at diagnosis, whereas the lactate dehydrogenase is usually raised. Serum urate concentration may be raised (Fig. 5.5).

Management 

After diagnosis, the first priority is a frank discussion with the patient. It is now customary to use the term leukaemia in this discussion and to explain to the patient that he or she may expect to live for many years with a normal lifestyle (Box 5.4). The clinician should explain the propensity of the disease to progress to an advanced phase. The options for initial treatment should be discussed, but in

Figure 5.5  Course of chronic myeloid leukaemia, showing progression  to blastic phase.

practice most patients are advised to start treatment with imatinib mesylate (Glivec ®; Novartis) or an imatinib-containing combination. Younger men should be offered cryopreservation of semen if necessary.

If CML is diagnosed in pregnancy, the woman should have the chance to continue to term. CML has no adverse effect on pregnancy and pregnancy has no adverse effect on CML.

The clinician may wish to mention at this point the existence of patient information booklets produced by the British Association of Cancer United Patients (BACUP) and by the Leukaemia Research Fund, which are extremely valuable, as many patients will not retain all that is said at this first interview. There are also a number of use- ful websites available on the Internet, although some of these are somewhat one-sided.

Imatinib mesylate 

Imatinib is the treatment of choice for CML presenting in chronic phase. It acts by specifically inhibiting the enhanced protein tyro-sine kinase activity of the Bcr–Abl oncoprotein and kills leukaemia cells by inducing apoptosis. The standard dose is 400 mg/day but it is possible that higher doses (i.e. 600 or 800 mg daily) may prove superior. It induces complete haematological remission in > 95% of previously untreated patients and 70–80% of these will achieve complete cytogenetic remission. The best way of monitoring the pa- tient’s response to imatinib is by regular assay of Bcr–Abl transcript numbers in the peripheral blood using the real-time quantitative RT–PCR technology. Results are best expressed as a ratio of Bcr–Abl transcript numbers to a control transcript or as ‘log reduction’ from a baseline value. The rationale for regular monitoring is based on the observation that the degree to which the residual leukaemia is reduced predicts the duration of progression-free survival.

There are various possibilities for managing the patient who cannot tolerate or becomes resistant to imatinib but whose disease is still in the chronic phase. There is a good case for proceeding to allogeneic stem cell transplantation if the patient is relatively young (<55 years) and has an HLA (human leucocyte antigen) identical sibling or a well matched volunteer donor from the general population. A very reason- able alternative and the best option for the patient without any possible transplant donor would be to switch from imatinib to a second genera- tion tyrosine kinase inhibitor, namely dasatinib (Sprycel, Bristol- Myers Squibb) or nilotinib (Tasigna, Novartis).

Dasatinib

This second generation tyrosine kinase inhibitor is active against both Abl and Src oncogenes and in vitro studies show it to be about 300 times more active than imatinib. It has demonstrated considera-ble efficacy in patients resistant to imatinib and patients who respond well should probably be continued on the drug indefinitely. The recommended dose is currently 100 mg daily. 

Nilotinib 

This agent, also a second generation tyrosine kinase inhibitor, is also active in patients whose leukemia appears resistant to imatinib. The currently recommended dose is 800 mg daily. At present there is no clear reason for preferring dasatinib to nilotinib or vice versa.

Hydroxyurea 

Hydroxyurea is a ribonucleotide reductase inhibitor, which is remarkably effective at controlling symptoms and reducing the leucocyte count in chronic phase CML. It does not reduce the proportion of Ph-positive cells in the bone marrow and there is little evidence that it prolongs life to any extent. It is useful as a short-term measure for newly diagnosed patients or as an interim measure for patients resistant to imatinib while other more definitive treatments are being considered. The standard dose is 2.0 g daily. Toxicity includes rashes, gastrointestinal upset and mouth ulceration, but side effects are actually very rare at standard dosage.

Interferon-α 

Interferon-α is a member of a family of naturally occurring glycoproteins with antiviral and antiproliferative actions. Side effects include short-term fever and flu-like symptoms and sometimes also persisting anorexia, weight loss, depression, alopecia, rashes, neuropathies, autoimmune disorders and thrombocytopenia. Currently, interferon-α should be considered for chronic phase patients resistant to imatinib mesylate.

Allogeneic stem cell transplantation 

Patients younger than 60 years who prove resistant to imatinib at maximum dosage and who have siblings with identical HLA types

Figure 5.6  Possiblr scheme for managing patients  presenting with CML in chronic phase.  (See Baccarani, et al. 2006 for response  criteria.)

may be offered treatment by high-dose cytoreduction (chemotherapy and radiotherapy) followed by transplantation of haemopoietic stem cells collected from the donor’s bone marrow or peripheral blood. With the typical family size in western Europe, about 30% of patients will have matched sibling donors. In selected cases, trans- plants may also be performed with HLA-identical unrelated donors. Allogeneic stem cell transplants are associated with an appreciable risk of morbidity and mortality, and, in general, older patients (40– 60 years) fare less well than younger patients (Fig. 5.6). Nevertheless, the projected cure rate after allogeneic stem cell transplantation is about 60–70%.

Advanced phase disease 

Presentation 

Advanced phase disease may be diagnosed incidentally as a result of a blood test at a routine clinic visit. Alternatively, the patient may have excessive sweating, persistent fever, or otherwise unexplained symptoms of anaemia, splenic enlargement or infarction, haemorrhage, or bone pain. In most cases the blast crisis is myeloid (that is, resembling acute myeloid leukaemia), and in a fifth of cases lymphoid blast crisis occurs (Fig. 5.5). 

Occasionally patients progress to a myelofibrotic phase of the disease, in which intense marrow fibrosis predominates, blast cells proliferate less aggressively, and the clinical picture is character- ized by splenomegaly and pancytopenia consequent on marrow failure. 

Management Patients who present in accelerated phase may derive considerable short-term benefit from imatinib, which can re-establish chronic phase disease and even Ph-negative haemopoiesis in some cases. Conversely, imatinib has no role in the management of patients who received the drug for treatment of prior chronic phase disease. Such patients may still respond to hydroxyurea or busulfan if they have not previously received these agents. Splenectomy may be useful to improve thrombocytopenia or symptoms due to splenominib, although it may be reasonable to start their treatment with within a few weeks by use of appropriate combination chemotherapy (see below), although the possibility of treating localized pain or resistant splenomegaly by radiotherapy should not be forgotten. For those patients with myeloid transformations, drugs suitable proliferation for a time. About 30% of patients will achieve a second chronic phase compatible with a normal lifestyle for months or years. Patients with lymphoid transformations should be treated with drugs appropriate to adult acute lymphoblastic leukaemia. Second chronic phase may be achieved in 40–60% of cases, more commonly in those who had a short interval from diagnosis to transformation. Patients restored to second chronic phase should receive prophylaxis against neuroleukaemia, comprising five or six intrathecal injections of methotrexate, but there is no indication for cranial or craniospinal irradiation.