t(9;22)(q34;q11) as part of a single or complex translocation, or BCR-ABL transcripts must be present in every case

Transcription

1 CHRONIC MYELOID LEUKAEMIA Diagnostic Criteria Chronic phase CML t(9;22)(q34;q11) as part of a single or complex translocation, or BCR-ABL transcripts must be present in every case Maximally cellular marrow with left shifted, myeloid series, monolobated megakaryocytes and suppressed erythroid series <5% blasts in bone marrow Prognostic Groups 5-10% blasts. The marrow should be repeated in 1 month to establish rate of change of blast cell population. Accelerated phase (AP): 10-19% blasts or >20% basophils in marrow or blood, associated with clinical progression or refractoriness to treatment (WHO criteria). Other features may include persistent thrombocytopenia (<100 x 109/l) unrelated to therapy, or persistent thrombocytosis (>1000 x 109/l) unresponsive to therapy; increasing WBC unresponsive to therapy; cytogenetic evidence of clonal evolution and excessive marrow fibrosis or dysplastic features. Blast crisis (BC): >20% myeloid blasts or >5% lymphoid blasts or solid extramedullary tumour deposit consisting mainly of blasts. Essential Investigations Full blood count with manual differential. Full examination with documentation of liver and spleen size. Ultrasound scanning of the abdomen to more accurately document spleen size may be considered. Routine biochemistry to include U&Es, LFTs, calcium, LDH and urate. Bone marrow aspirate and trephine with sample sent for cytogenetics Bone marrow and peripheral blood sample for RT-PCR All newly diagnosed patients should have either a Sokal or Hasford (Euro) score calculated. This can be done using simple web based programmes found at and Respectively

2 A full family history, in particular paying attention to potential sibling donor details, should be taken. As early as possible after diagnosis, tissue typing of the patient and siblings should be arranged. This should be mandatory in all patients under the age of 65. Primary Therapy Patients in Chronic Phase (CP) All new patients should be offered entry into the SPIRIT 2 study. This is a Prospective randomised study comparing imatinib with dasatinib. In the absence of published data to support the role of autologous stem cell transplantation in the treatment of CML, routine collection of autologous stem cells at diagnosis is not indicated. Patients who proceed to unrelated donor allogeneic transplantation may require a backup collection of autologous peripheral blood stem cells or bone marrow, but this can usually be scheduled later on in their disease management. In patients with symptoms of leucostasis consideration may be given to therapeutic leucopheresis All patients should be well hydrated and receive allopurinol 300mg daily. In non-trial patients, initial cytoreductive therapy should be with Imatinib 400 mg daily. Initial therapy with hyroxycarbamide 0.5g 2g daily can be considered for patients contemplating entry into SPIRIT 2 or other drug trials. Monitoring of therapy FBC, U&Es and LFTS weekly for 1st 4 weeks, then reduced frequency depending on response. Peripheral blood PCR should be carried out every every 3 months. 10ml of EDTA blood is required. Bone marrow (BM) examination with cytogenetics should be carried out in patients with an inadequate response according to the following crtiteria: At 3 months: If 1 log reduction in BCR-ABL not achieved (5.5% according to local reference range) (BM should be performed at 6 months). At 12 months: If <3 log reduction (>0.055%)

3 Bone marrow cytogenetics should also be performed on patients who have > 2-5 fold rise in BCRABL, confirmed on repeat sample taken at a six week interval. Mutation screening will also be performed Response Criteria Optimal response according to the revised European leukaemia Net Guidelines (Baccarani, et al 2009) are: Complete haematological response (CHR) at 3 months At least a partial cytogenetic response (PCyR - Ph +ve < 35%) after 6 months of therapy A complete cytogenetic response after 12 months of therapy (equivalent to at least a 2 log reduction in BCR-ABL) A major molecular response after 18 months of therapy. Failure is defined as: Lack of HR at 3 months No CHR or any CyR at 6 months Less than PCyR at 12 months No CCyR at 18 months Loss of CHR, CCyR or acquisition of mutation associated with imatinib insensitivity at any time Suboptimal response refers to levels of response between the above two categories at the relevant time points. Patients in Accelerated Phase (AP) Patients presenting in the accelerated phase of CML should receive Imatinib 600mg daily, which is associated with a reported progression-free survival rate of 67% at 12 months, and overall survival of 66% at 36 months. Patients in Blast Crisis (BC) Patients presenting in blast crisis present a difficult management problem. The best Responses have been reported to Imatinib mg daily, with reported 12 month survival rates of 32%.Major cytogenetic responses have been reported in 16% of patients, and complete cytogenetic responses in 7%. Dasatinib is also licensed for this indication, at a dose of 70mg bd. NICE do not recommend continued use of Imatinib in patients presenting in CP who progress to AP or BC after exposure to the drug. Management of such cases should be discussed with the MDT lead for Leukaemia, but a second generation tyrosine kinase inhibitor (2G TKIs, Nilotinib or Dasatinib) should be given while assessing BMT options. For patients in BC, options include acute leukaemia type therapy (as for AML or ALL depending on phenotype) and rarely, autologous stem cell transplantation.

4 Side effects of imatinib and their management Imatinib is well tolerated by the majority of patients. Nausea if it occurs often improved if the drug is taken with food, or split doses. Normal antiemetics and in the few patients who experience diarrhoea, antidiarrhoeal agents can be given Side effects include mild allergic type rashes, which may respond to simple antihistamines. Severe dermatological reactions have been documented which may require steroid therapy or in some cases the discontinuation of Imatinib. Arthralgia is seen in 60% of patients and usually responds to simple treatment with nonsteroidals, and usually settles after the first few months of treatment Fluid retention may be troublesome and occurs in the majority of cases often just as simple peri-orbital oedema. More severe oedema is often quite refractory to diuretic therapy and may require dose reduction or discontinuation. Reducing salt intake should be tried. Cytopenias may occur in up to 14% of patients. If thrombocytopenia (plts < 50 x 109/l) or neutropenia (neuts < 1 x 109/l) develop, imatinib should be stopped. If counts recover in two weeks, restart at 400mg/day. If not consider introducing at 300mg/day with G-CSF or platelet support as necessary. Symptomatic anaemia should be managed with blood transfusions as clinically indicated, but erythropoietin therapy may be effective. Management of Chronic Myeloid Leukaemia Patients who are resistant or intolerant to imatinib Intolerance Patients who are intolerant of imatinib should be treated with a second generations TKI, either nilotinib or imatinib. The choice would be influenced by the nature of the intolerance to imatinib, and also other pre-morbid conditions as per resistant patients. Sub-optimal response The following describes a reasoned approach to the patient with a sub-optimal response: Consider compliance (which may require use of plasma level monitoring)

5 If the patient has achieved a complete cytogenetic response but not a major molecular response, consider merely continuing at present dose and monitoring closely. CCyR is the most important prognostic factor for progression free survival and as long as the patient achieves a CCyR, OS and PFS are not affected by how long it takes to get there. However if CCyR has not been achieved by 18 months of therapy, consider dose escalation. Failure Patients failing imatinib should receive a 2nd generation tyrosine kinase inhibitor. Published efficacy data show little difference between the two licensed drugs, Nilotinib 400mg bd and Dasatnib 100mg od in this setting. Factors that may influence choice are: Presence of a kinase domain mutation: This information will only be informative in a minority of patients, where the presence of a so called breakthrough mutation will predict the response to one or other of the available TKIs. These are Y253H, E255K/V and F359C/V which will be resistant to Nilotinib, and F317L and V299L which will be resistant to Dasatinib. T315I is associated with resistance to both 2G TKIs as well as imatinib and such patients should not be treated with these agents, and be assessed for allogeneic SCT. Management of CML in Pregnancy There is little in the way of large published series about the management of chronic Myeloid leukaemia in pregnancy. However, a number of the concerns that are associated with myeloproliferativedisorders (MPD) in pregnancy will also apply to CML. There are two scenarios: 1. A patient presenting with CML in pregnancy 2. A patient on Glivec who becomes pregnant As regards the first scenario, there is little evidence that pregnancy itself adversely affects the natural course and prognosis of CML but any haematological disorder that may lead to hyperleucocytosis and possibly thrombocytosis is likely to affect fertility, and may lead to an adverse outcome of the pregnancy itself because of thrombotic or bleeding complications. This is certainly true in primary thrombocythaemia (PT) where first trimester abortion is the most frequent complication but increased perinatal mortality and premature delivery are also observed. Placental infarction due to thrombosis is the most consistent event. As regards management, it is desirable that some attempt to control the white cell count (and perhaps platelet count) in pregnancy should be attempted. However, Imatinib is teratogenic with a 25 % incidence of fetal abnormality in the only series collected (Pye, et al 2008).

6 Hydroxyurea is teratogenic in animals and one stillbirth and one malformed infant have been reported after exposure in pregnancy. It should generally be avoided, but there are several well documented cases of successful outcomes in PT with hydroxyurea given throughout pregnancy. Alternative treatments include -interferon, which has been well documented as being safe in the management of PT in pregnancy, and leucopheresis. This is the most common therapeutic manoeuvre cited in the literature with good control of the white cell count and a successful outcome for mother and baby in all reported cases. Based on the published evidence, a reasonable recommendation for the management of CML in first chronic phase diagnosed in pregnancy would be as follows: Initial leucopheresis to control the white cell count, together with allopurinol and Aspirin therapy, especially if there is associated thrombocytosis. Instigation of -interferon therapy to maximum tolerated dose to control the white cell count with intermittent leucopheresis to keep the white cell count below 20 x10 9 /l and platelets below 400 x10 9 /l until delivery. No particular precautions need to be taken at delivery, assuming stable peripheral blood parameters, and normal vaginal delivery should be possible. The management of accelerated phase or blast crisis occurring in pregnancy is much more difficult. Either of these situations should warrant consideration of early termination of pregnancy and the introduction of Imatinib therapy, but it is possible that hydroxyurea may control the situation at least until the baby is of a great enough gestational age to deliver safely. This policy would be associated with a relatively low risk of foetal abnormality. More specific therapy, including bone marrow transplantation could then be considered following parturition. In the second scenario, management will be influenced by to the patient s response thus far to imatinib, and its duration. Recently published data suggests that stopping imatinib in patients who have achieved a stable complete molecular response (greater than 2 years) can be done with only a small risk of disease progression, with re-establishment of control if progression occurs (Mahon, et al 2008). Consideration in such a patient could be given to discontinuing therapy and monitoring closely until delivery. In all other cases, interferon therapy as described above would be preferable Bone Marrow Transplantation Bone marrow transplantation remains the only proven curable treatment for patient with chronicmyeloid leukaemia. However, the emergence of Imatinib has led to a reappraisal of the appropriate timing of BMT. The current consensus is that all patients should have a trial of imatinib therapy with close monitoring of their haematological, cytogenetic and molecular responses. BMT remains an option for

7 patients failing IM therapy, but treatment with a 2G - TKI may be more appropriate in some patients. This should be discussed with the MDT lead. Autologous transplantation The role of autologous transplantation in CML is not established, and a recent meta analysis did not show any benefit for this approach. References Baccarani, M., Rosti, G., Castagnetti, F., Haznedaroglu, I., Porkka, K., Abruzzese, E., Alimena, G., Ehrencrona, H., Hjorth-Hansen, H., Kairisto, V., Levato, L., Martinelli, G., Nagler, A., Lamnng Nielsen, J., Ozbek, U., Palandri, F., Palmieri, F., Pane, F., Rege-Cambrin, G., Russo, D., Specchia, G., Testoni, N., Weiss-Bjerrum, O., Saglio, G. & Simonsson, B. (2009) Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: A European LeukemiaNet Study. Blood, 113, Mahon, F.X., Hayette, S., Lagarde, V., Belloc, F., Turcq, B., Nicolini, F., Belanger, C., Manley, P.W., Leroy, C., Etienne, G., Roche, S. & Pasquet, J.M. (2008) Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp or Src kinase overexpression. Cancer Research, 68, Pye, S.M., Cortes, J., Ault, P., Hatfield, A., Kantarjian, H., Pilot, R., Rosti, G. & Apperley, J.F. (2008) The effects of imatinib on pregnancy outcome. Blood, 111,