Imatinib has proven efficacy in chronic, accelerated and blast phases of chronic myeloid leukaemia (CML).
CHRONIC PHASE (CP)
The evidence supporting this protocol is provided by a phase III multicentre international randomised trial (IRIS).r 1106 patients with untreated chronic phase Ph-positive CML were treated with imatinib or interferon alfa plus cytarabine. Between June 2000 and January 2001, 553 patients were randomised to receive imatinib 400 mg orally daily and 553 patients randomised to receive interferon alfa at a daily target dose of 5 million U/m2 plus 10-day cycles of cytarabine 20 mg/m2 daily every month. Patients receiving imatinib who did not have a complete haematological response within 3 months or whose bone marrow contained more than 65% Ph-positive cells at 12 months were able to increase the dose to 400 mg twice daily. The primary end point was event-free survival and secondary end points were the rate of complete haematological response, cytogenetic response, progression to the accelerated phase or blast crisis, overall survival, safety and tolerability. After a follow-up at 5 years, imatinib as initial therapy was found to induce durable responses in a high proportion of patients: the event-free survival was 83%, 93% of patients had no progression to AP or BP and the estimated overall survival was 95% for patients treated with imatinib (see Figure 4 below).r
© NEJM 2006
After a follow up at almost 11 years, imatinib as initial therapy proved to remain efficacious without significant late toxic or cumulative side effects.r The cumulative rate of major cytogenetic response (Ph+ cells 1-35%) with imatinib was 89%, and the rate of complete cytogenetic response (no detectable Ph+ cells) was 82.8%. Among 204 patients who had molecular assessments and could be evaluated at 10 years, 190 (93.1%) had a major molecular response and 129 (63%) had a MR4.5.r
Within the imatinib group, 38 patients (6.9%) progressed to AP or BP, compared with 71 patients (12.8%) in the IFN-α plus cytarabine group. This culminated in a 10 year event-free survival rate of 79.6% in the imatinib group compared to 56.6% in the IFN-α plus cytarabine group (See Figure 2 below). 260 patients (47%) were still alive at 10 years and receiving treatment, while 89 patients had died from any cause. The most common causes were CML, either without haematopoietic stem cell transplantation (n=37) or following transplantation (n=13), and second malignancies (n=11). This translates to a 10 year overall survival rate of 83.3% among those in the imatinib group. Those with a high Sokal score had a poorer 10 year overall survival (68.6%) compared to those with a low Sokal score (89.9%).r
© NEJM 2017
The TIDEL-II trial,r evaluated the effect of dose escalating imatinib and/or switching from imatinib to nilotinib in patients who had suboptimal molecular responses. 210 patients with CP-CML were divided into 2 equal and sequential cohorts across 23 Australasian centres. All patients started treatment with imatinib 600 mg/day and dose escalated to 800 mg/day if the imatinib trough levels were <1000 ng/mL. Time-dependent MR targets were set: BCR-ABL =10%, =1% and =0.1% (IS) at 3, 6 and 12 months. In Cohort 1, patients who failed to meet these targets were dose escalated to imatinib 800 mg/day. Patients who failed to have improved molecular response or were already on imatinib 800 mg/day switched to nilotinib 400 mg twice a day. In Cohort 2, patients who failed these targets switched to nilotinib directly. Also, patients who experienced severe toxicities switched from imatinib to nilotinib. The primary end-point was confirmed MMR at 12 months. This was achieved by 64% of all patients, with no significant difference between the two cohorts, and at 24 months it was 73%. At 3 years, overall survival was 96%.r Thirty percent of patients switched from imatinib to nilotinib, however an early switch to nilotinib did not overcome the adverse outcome for patients who failed to achieve early molecular response on imatinib. Furthermore, the study showed that treatment with optimised imatinib (involving a higher dose and blood tests every 28 days) upfront with a switch to nilotinib for toxicities achieved similar results to studies using second generation TKIs. Although 400mg is the approved starting dose, the TIDEL-II trial shows that a higher starting dose of 600mg has comparable efficacy to 2nd generation TKIs.r
The outcomes of patients treated with imatinib for CP-CML are summarised in Table 3 below.r A recent data review of imatinib as first line therapy reported no new clinically relevant late side effects or complications. Imatinib combination therapies were also reviewed and although some studies reported a higher MMR and MR rate, none of the combination studies reported a superior PFS or OS.r
© Blood 2013
More recently, due to the increase in literature and experience surrounding imatinib and second generation TKIs, the ELN 2009 recommendations were reviewed and updated. The ELN 2013 recommendations state that imatinib, nilotinib or dasatinib can be given as initial treatment. Furthermore, the responses that should be achieved at 3, 6 and 12 months were redefined (see cytogenetic and molecular tests in the clinical information section). In the case of treatment failure an alternate second generation TKI could be used second line.r
Successful stopping of imatinib therapy (for >5 years) was observed in a subgroup of patients who achieved a durable deep molecular response (molecular response 4, molecular response 4.5, or undetectable BCR-ABL1 transcripts), with approximately 39 to 45% of patients remaining in remission for 3 years or longer.r
ACCELERATED PHASE (AP)
Rea et al. conducted a multicentre retrospective analysis that reported on the benefit of imatinib in newly diagnosed accelerated phase (AP)-CML patients. 42 patients were treated with either 600 mg or 400 mg of imatinib daily for a median duration of 24 months. The rates of CHR, MCyR and CCyR did not differ significantly between patients who received 600 mg and 400 mg/day. However 64.3% patients who started on 400 mg/day underwent dose escalation to 600 mg/day. After a follow up of 24 months, favourable rates of OS 87.8%, PFS 87.2% and FFS 54.2% were achieved. Front-line imatinib for AP-CML is effective for patients with haematological acceleration without chromosomal abnormalities in addition to the Philadelphia chromosome and patients solely with additional chromosomal abnormalities (ACAs).r
© Leukemia 2012
BLAST PHASE (BP)
Palandri et al. conducted a phase II trial of imatinib 600 mg daily in patients with chronic myeloid leukaemia in blast crisis (BC-CML). From June 2000 to April 2001, 92 patients with confirmed Ph-positive BC-CML were enrolled into a prospective study. The primary end point was event-free survival or progression-free survival. Imatinib was effective and safe in the short-term treatment of BC-CML but did not significantly influence the longer-term outcomes (see Figure 1 below).r
© Haematologica 2008
After a median follow-up of 60 months, the most common adverse events experienced by patients receiving imatinib on the IRIS study were oedema (including peripheral and periorbital oedema; 60%), muscle cramps (49%), diarrhoea (45%), nausea (50%), musculoskeletal pain (47%), rash and other skin problems (40%), abdominal pain (37%), fatigue (39%), joint pain (31%) and headache (37%). Congestive heart failure was reported as being drug-related in one patient <1%.r Grade 3 and 4 events are summarised in ‘Table 2’ below.
© New England Journal of Medicine 2006
At the 11 year follow up analysis, 51 patients (9.3%) had a serious adverse event, most commonly abdominal pain. Serious adverse events related to imatinib were most common in the first year of treatment and then declined over time. Serious cardiac events of any cause were seen in 39 patients (7.1%) and secondary neoplasms (malignant or benign) were reported in 62 patients (11.3%). No new safety issues were identified since the 5 year interim analysis.r
The side effects of imatinib therapy have also been documented in randomised trials comparing imatinib with dasatinib or nilotinib.rr The tables below summarise the most common side effects.
© New England Journal of Medicine 2010
© New England Journal of Medicine 2010