Our case was based on a 34 year old lady with a new diagnosis of CML.
CML in a proportion of patients is diagnosed on routine blood tests prior to onset of symptoms. However, symptoms can include:
- shortness of breath
- weight loss
- spontenous bruising or haemorrhage
- visual disturbance
- fever (rare in chronic phase)
- lymphanopathy (rare in chronic phase)
- Abdominal discomfort/mass secondary to splenomegaly. 50-70% present with splenomegaly at diagnosis
Patients can have a normal haemoglobin in the early phase of disease, but are often anaemic if splenomegaly is present. Leucocyte count can range from 20-200. The blood film shows a full spectrum of cells from blast forms to mature neutrophils. Basophil count is usually signifcantly raised, and there may also be an eosinophilia. Platelets are usually elevated, however the patient may also be thrombocytopenic. The most useful test to undertake in a patient with this presentaiton is the BCR-ABL PCR which can be performed on peripheral blood. The (9:22) translocation generates the BCR-ABL gene on the Ph (Philadelphia chromosome). This translocation in CML patients is present in all myeloid cell lineages, some B cells and a proportion of T cells.
Should we perform a bone marrow?
Bone marrow aspiration and trephine is not necessary for the diagnosis of CML. However it can be useful in determining the degree of marrow fibrosis, or transformation of CML, therefore more useful in patients who may be classified as accelerated or blastic phase. This would impact upon a patients prognosis, and potential management plan in which you may consider using second generation TKI, or potential for bridging of TKI prior to allogeneic transplant, providing a curative option for a patient with blastic phase CML.
In general patients with chronic phase CML can be diagnosed on peripheral blood. Spirit 3 trial will not perform bone marrow biopsies on patients classified according to the trials criteria of chronic phase CML.
Staging for trial
- <15% blasts in blood
- <30% blasts + promyelocytes in blood
- <20% basophils
- >100 platelets
- no evidence of extramedullary leukaemic involvement with the exception of hepatosplenomegaly
Our patient had < 15% blast on peripheral blood, but > 20% basophils and therefore technically would not have qualified for trial and would be classed as accelerated phase.
Staging of CML
Chronic phase – ability to reduce spleen size and restore and maintain ‘normal’ blood count with appropriate therapy.
Accelerated phase – ( one or more of the following features)
- Blasts 10-19% of white blood cells in peripheral blood and/or nucleated bone marrow cells
- Peripheral blood basophils >20%
- persistant thrombocytopenia <100, or persistant thrombocytosis >1000
- increasing spleen size, and increasing wcc unresponsive to therapy
- megakaryocyte proliferation in sheets or clusters in associated with marked reticulin or collagen fibrosis
Blastic phase (one or more of the following features)
- Blasts > 20% in peripheral blood or of nucleated cells of bone marrow
- extramedullay blast proliferation
- large foci or clusters of blasts on bone marrow biopsy
Imatinib – used as first line treatment. Toxicities include: myalgia, GI disturbance, and longstanding fatigue. Generally considered one of the safest TKI. NICE approved and due to come off patent, therefore reducing cost. However on the IRIS trial, 25-30% did not achieve the desired response (did not achieve CCyR, lost response or were intolerant of the medication.)
Second generation TKIs include nilotinib and dasatinib. Toxicities include;
- nilotinib – rash, pruritis, and headaches. Nilotinib should be avoided in patients with history of arterial disease, IHD, and cerebrovascular disease
- dasatinib – pleural effusion. Should be avoided in patients with history of pulmonary hypertension
ENESTnd, (imatinib vs nilotinib) and DANISION, (dasatinib vs imatinib) are two trials which have shown no difference in OS when comparing imatinib to second generation TKIS. However they do show that achievement of the key milestones was achieved quicker with 2nd generation TKIs, and fewer patients progressed to accelerated or blast phase CML.
Something at least to be considered when making treatment decisions? Take a look at this article for more info on this debate – its a really interesting read!
Using 2nd generation tyrosine kinase inhibitors in frontline management of chronic phase chronic myeloid leukaemia. South Asian Journal of cancer 2014, Jan-Mar, 3(1):87-91
Monitoring response -BCR-ABL 1 (international scale)
3 months – complete haematological response
6 months – at least a partial cytogenetic response (Ph <35%)
12 months – complete cytogenetic response
18 months – major molecular
Failure to reach these milestones suggests unreponsive disease to that specific TKI and would initiate discussion on changing treatment. Imatinib resistance may be primary or secondary. Evidence of resistance would prompt investigation for evidence of new mutations of the BCR-ABL oncoprotein. One specific mutation, T315I is resistant to imatinib and other TKIs and requires treatment with ponatinib (+ allogeneic transplant)
Our question of pregnancy in CML didn’t seem to spark much interest – or perhaps its because no-one really knows the impact of stopping TKI – therefore we’ll leave this subject for another case!!!
Postgraduate Haematology, sixth edition. Hoffbrand, A.V.
Using 2nd generation tyrosine kinase inhibitors in frontline management of chronic phase chronic myeloid leukaemia. South Asian Journal of cancer 2014, Jan-Mar, 3(1):87-91. Vishal, Jayakar
Clinical cancer research. Deep molecular response in chronic myeloid leukaemia: the new goal of therapy. Mahoni, F., Etienne, G http://clincancerres.aacrjournals.org/content/20/2/310.figures-only.