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The Treatment of Chronic Myeloid Leukaemia in the Era of Tyrosine Kinase Inhibitors
the patients play an important role in choosing the optimal treatment
option in each individual patient. As was the case with nilotinib and
dasatinib, bosutinib first proved its clinical efficacy in relapsing patients,
and then this drug was tested in the Bosutinib Efficacy and Safety in
Newly Diagnosed CML (BELA) trial, in which the efficacy of bosutinib
has been evaluated in the frontline setting. 11 However the primary end
point (which was complete cytogenetic response [CCyR] at 12 months)
was not different for bosutinib versus imatinib and the gastrointestinal
side effects (mainly diarrhoea) were more common with bosutinib – as a
result bosutinib was not approved in the frontline setting, but it remains
a reasonable option in the salvage setting. Ponatinib is a pan-BCR-ABL1
inhibitor retaining potency against all ABL mutations including T315I.
This extremely active drug was first used in resistant cases, and then
in the Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia (EPIC)
trial. 12 But this phase III trial was terminated early due to observation of
arterial thrombotic events.
If we ask ‘What is the best first-line treatment option for patients with
CML-CP?’ the answer for the time being is that the best first option
is between all three currently available TKIs (imatinib, nilotinib and
dasatinib). But the most important concern is balancing TKI toxicity
profiles and the patient comorbidities, as well as the cost of treatment.
European LeukemiaNet (ELN) suggests that if the level of BCR-ABL1 IS
is still >10 % by 6 months, switching the TKI might be needed, and in
patients who failed to achieve a CCyR by 12 months, an alternative
TKI treatment should be initiated. 13 From the DASISION and ENESTnd
trials, we know that both dasatinib and nilotinib could induce molecular
responses deeper and faster than imatinib, and achieving an early
molecular response (EMR) might translate into less disease progression
and a favourable outcome. So in patients who do not meet the criteria
for gaining an EMR (i.e. BCR-ABL1 IS ≤10 % at 3 months) under any TKI,
but particularly imatinib, although the current data on switching TKI
at 3 months is still controversial and not excepted by all, switching
to 2GTKIs can be a treatment option. Also knowing that the clinical
1. Sasaki K, Strom SS, O’Brien S, et al., Chronic myeloid leukemia
in chronic phase: Survival in the era of tyrosine kinase
inhibitors is similar to that of the general population in all age
groups, Blood, 2014;124:1801.
2. Experts in Chronic Myeloid Leukemia, The price of drugs
for chronic myeloid leukemia (CML) is a reflection of the
unsustainable prices of cancer drugs: from the perspective of
a large group of CML experts, Blood, 2013;121:4439–42.
3. Soysal T, Eskazan AE, Ar MC, Generics in chronic myeloid
leukemia: current arguments for and against and the
established evidence, Expert Rev Hematol, 2014;7:697–9.
4. Carella AM, Dellepiane C, Lovera, et al., Chronic Myeloid
Leukaemia – The Choice of Therapy and Future Perspectives,
Eur Oncol Haematol, 2015;11(1):25–9.
5. O’Brien SG, Guilhot F, Larson RA, et al., Imatinib compared
with interferon and low-dose cytarabine for newly diagnosed
chronic-phase chronic myeloid leukemia, N Engl J Med,
2003;348:994–1004. E u rop ean O n col ogy & Ha em atol og y
outcomes with imatinib are worse in high-risk patients, someone might
find it rational to use nilotinib or dasatinib among these patients in the
upfront setting. But still there is no solid data about this hypothetically
favourable treatment approach.
Continuous TKI treatment can attenuate an individual’s quality of
life. There are studies showing durable molecular responses after
discontinuation of imatinib and even 2GTKIs 4 and this can be an option
in a minority of the patients. But it should also be kept in mind that for
the time being, optimal responders to any TKI should continue therapy
indefinitely, with careful surveillance, and they can only be enrolled in
studies of treatment discontinuation. 12
The current prices of TKIs are high, and the launch of generics might
reduce healthcare costs. Generic imatinibs has been approved for CML
treatment in some countries, and after the original imatinib loses its
patent, generic imatinib will be used in many countries. Although there
are conflicting results, 3 our observations show that generics were at least
non-inferior to the original molecule regarding efficacy and tolerability
when used in the upfront setting, as well as when used subsequently in
the short run. 14,15 However, further monitoring is still warranted, and more
reliable and solid long-term data should be accumulated before making
any definitive conclusions about the efficacy and safety of generics.
Although TKIs are effective treatment options for CML, there is a group
of patients who will be resistant to these therapies and eventually fail.
There are many efforts targeting mainly the CML stem cell as overviewed
by Carella et al. 4 The results are promising but none of these treatment
approaches are used in the daily clinical practice.
In conclusion, TKIs are the mainstay of CML treatment, but some
patients are intolerant and resistant to them. Among these patients
alternative treatments including combining TKIs with immunotherapy
and targeting the stem-cell niche are explored offering new possibilities
maybe for ‘curing’ this disease in the future. n
6. Huang X, Cortes J, Kantarjian H, Estimations of the increasing
prevalence and plateau prevalence of chronic myeloid
leukemia in the era of tyrosine kinase inhibitor therapy,
7. Deininger M, International randomized study of interferon Vs
STI571 (IRIS) 8-year follow up: sustained survival and low risk
for progression or events in patients with newly diagnosed
Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated
with Imatinib, ASH 2009;Abstract 1126.
8. Yilmaz M, Abaza Y, Jabbour E, Selecting the best frontline
treatment in chronic myeloid leukemia, Curr Hematol Malig
Rep, 2015 [Epub ahead of print]
9. Saglio G, Kim DW, Issaragrisil S, et al., Nilotinib versus imatinib
for newly diagnosed chronic myeloid leukemia, N Engl J Med,
2010;362:2251–9. 10. Kantarjian H, Shah NP, Hochhaus A, et al., Dasatinib versus
imatinib in newly diagnosed chronic-phase chronic myeloid
leukemia, N Engl J Med, 2010;362:2260–70.
11. Cortes JE, Kim DW, Kantarjian HM, et al., Bosutinib versus
imatinib in newly diagnosed chronic-phase chronic
myeloid leukemia: results from the BELA trial, J Clin Oncol,
2012;30:3486–92. 12. Baccarani M, Deininger MW, Rosti G, et al., European
LeukemiaNet recommendations for the management of
chronic myeloid leukemia: 2013, Blood, 2013;122:872–84.
13. Lipton JH, Epic: a phase 3 trial of ponatinib compared
with imatinib in patients with newly diagnosed Chronic
Myeloid Leukemia in Chronic Phase (CP-CML), ASH 2014
Abstract 519. 2014.
14. Eskazan AE, Ayer M, Kantarcioglu B, et al., First line treatment
of chronic phase chronic myeloid leukaemia patients with
the generic formulations of imatinib mesylate, Br J Haematol,
2014;167:139–41. 15. Eskazan AE, Elverdi T, Yalniz FF, et al., The efficacy of generic
formulations of imatinib mesylate in the treatment of chronic
myeloid leukemia, Leuk Lymphoma, 2014;55:2935–7.