NB.
Heaney, TL. Holyoake
ATMU: Cancer Division, Section of Experimental
Haematology & Haemopoietic Stem Cells, University of Glasgow; UK.
Correspondence to: Professor Tessa Holyoake
Email: tlh1g@clinmed.gla.ac.uk
SMJ 2006 52(1): 36-41
Chronic myeloid leukaemia is a relatively rare
condition, though has stimulated widespread interest as a consequence of both
the stem cell basis and the success of rationally designed therapies.
This review will outline some of the issues involving the aetiology of
the disease and how this relates to current and future therapies.
Keywords
Chronic myeloid leukaemia (CML) is classified by
the World Health Organisation as a myeloproliferative disorder (MPD), one member
of a group of conditions including essential thrombocythaemia, polycythaemia
vera and chronic idiopathic myelofibrosis.
The MPD are all clonal disorders of the haemopoietic stem cell (HSC)
characterised by abnormal myeloid (i.e. granulocyte, erythroid and
megakaryocytic) proliferation. CML
(also termed chronic myelogenous or granulocytic leukaemia) is usually more
appropriately considered as a distinct entity as a consequence of the now well
characterised molecular biology of this disease. CML was first recognised in 18451, 2 with the
initial description of the characteristic Philadelphia chromosome published in
1960.3 Following this
the causative bcr-abl oncogene with its protein product were described in the
1980s.4, 5 This
stimulated the search for rationally designed therapies of which imatinib (IM,
Glivec®, STI571, Novartis Pharma), described in 1998, has achieved the most
widespread use.
CML accounts for approximately one-tenth of all new
leukaemia diagnoses. The reported
incidence in Scotland has varied little over the past decade at around 60 new
cases per year, with a median age at diagnosis of 68 years (statistics available
from Information Services Division Scotland, at website http://www.isdscotland.org).
This can be compared to the published estimates of incidence at 1-2 per
100000 population with a median age at diagnosis of 45-55 years.6
Pathogenesis
CML arises as a consequence of a reciprocal
translocation between the long arms of chromosomes 9 and 22 (t (9; 22)) in a HSC.
The shortened form of chromosome 22 is named the Philadelphia chromosome
(Ph), after the city in which it was discovered.
The only accepted causative insult from which this rare mutational event
may occur is exposure to high levels of radiation, such as in survivors of the
Hiroshima bomb and Chernobyl clean-up workers.7, 8
The majority of cases diagnosed worldwide are thought to arise
spontaneously with no clear evidence for environmental triggers.
The t(9;22) translocates the proto-oncogene abl from
chromosome 9 to 22 forming a chimeric oncogene bcr-abl.
This gene is responsible for the production of Bcr-Abl, an oncoprotein
with constitutive tyrosine kinase activity.
Bcr-Abl confers proliferative and anti-apoptotic properties to the cell
and is responsible for the pathogenesis of the disease.9
The HSC carrying t(9;22) (Ph+HSC) is capable of
performing the normal HSC functions of self renewal (allowing perpetuation of
the haemopoiesis) and differentiation to committed progeny, seen as mature
circulating cells – all of which carry the cytogenetic abnormality and fusion
oncogene. In the normal HSC pool,
the majority of cells are quiescent entering cell cycle only once every 1-3
months.10 This is in
contrast with the deregulated Ph+HSC population where the majority of cells are
in cycle at any one time. However,
a quiescent diseased population remains, constituting approximately 0.5% of the
affected HSC population.11, 12 This represents a potential reservoir
of disease in a cell group that by virtue of their inactivity may be less
susceptible to conventional therapy
The stem cell basis of CML has become a paradigm
for the mechanism of disease in a number of other malignancies.
These include acute myeloid leukaemia (AML), and non-haematological
malignancies including tumours of the central nervous system and breast - all of
which may arise of a consequence of deregulated stem cell activity.13
However, CML is the only malignancy for which a specific causative
cytogenetic abnormality has been identified.
| Accelerated Phase |
Blast
Crisis |
|
Blast
cells in blood or marrow 15-29% |
Blast
cells in blood or marrow ≥30% |
| Blast
cells + promyelocytes in blood or marrow >30% (blasts <30%) |
Extramedullary
disease* |
| Basophils
in blood ≥20% |
|
| platelets
<100 or >800x109/L (unrelated to therapy) |
|
| clonal
evolution† |
|
Clinical Features
The majority of patients diagnosed with CML are
asymptomatic, with the diagnosis an unexpected outcome of a routine full blood
count. The disease is divided into
3 recognised phases - chronic phase (CP), accelerated phase (AP) and blast
crisis (BC) (Table 1). At diagnosis
patients are commonly in CP, a state characterised by leucocytosis and
hepatosplenomegaly arising as a consequence of increased granulopoeisis and
leukaemic infiltration. It has been
shown that the presence of Bcr-Abl not only confers survival benefit, but
influences the cell-stromal interactions within the bone marrow environment,
leading to the release of more primitive cells into the circulation.6
This is reflected in the characteristic blood film of a patient with CML
as an elevated white cell count, with a shift in the myeloid line from mature to
immature precursors ('left shift'). There
are also typically an increased number of basophils and eosinophils.
The bone marrow appearance is also typical with hypercellularity, a
reversal of the normal ratio of erythroid to myeloid cells and a predominance of
less mature forms. Untreated, CP
will last a number of years and so it is suggested that the survival advantage
of the leukaemic line is subtle relative to more aggressive diseases such as
AML. The disease will then progress
to BC, either directly or through an intermediate AP.
Advanced stages (AP and BC) are characterised by a failure of maturation
of the leukaemic precursors with the consequent disease resembling acute myeloid
or lymphoblastic leukaemia. With
modern therapy the progression of CML appears to be significantly slowed,
however when advanced disease does occur it responds poorly to chemotherapy with
the median survival measured in months.
Initial assessment for the patient newly diagnosed
with CML includes a medical history and clinical examination to assess
performance status, spleen size and the presence or absence of extramedullary
disease. We would recommend as
baseline investigations peripheral blood including full blood count with an
accurate white cell differential and Bcr-Abl levels, by quantitative reverse
transcriptase polymerase chain reaction (qRT-PCR). A bone marrow aspirate is necessary, confirming disease phase
by assessment of morphology and allowing cytogenetic examination to quantify the
percentage presence of the Ph+ clone (at least 20 metaphases should be
examined). A small number of
patients with CML may be Ph-, with the formation of bcr-abl arising as a result
of more complex chromosomal translocations.
The diseased cells may have abnormalities in addition to Ph+, including
deletions of the derivative chromosome 9 (del(der)9).
This finding has been associated with a poorer prognosis, though with
newer therapies may be of less significance.14, 15
The baseline investigations serve to enable the clinician to determine
the patient's prognostic category. There
are 2 scoring systems accepted for use, both of which require information from
time of diagnosis: the Sokal score, utilising spleen size in centimetres below
the costal margin, the blast cell % (from a white cell differential count) and
the platelet count; and the Hasford score using the same information but adding
the basophil and eosinophil %. The
scoring systems allow assignment of the patient into one of high, intermediate
and poor prognostic groups.
The presence of the bcr-abl fusion gene transcript provides a mechanism for diagnosis and monitoring of minimal residual disease in CML. Initially this was done qualitatively using polymerase chain reaction (PCR) to detect only the presence or absence of transcripts. The evolution of the technology now allows quantitative monitoring of Bcr-Abl levels by real time PCR (RT-PCR). Results are expressed as a ratio of Bcr-Abl/Abl transcripts. The abl control gene data will provide an assessment of the quality and quantity of RNA being examined, providing an experimental sensitivity for each sample.16, 17 It has been demonstrated that the fall in levels with therapy reflects a reduction in disease burden. A major molecular response (MMolR) is defined as a greater than 3 log reduction in Bcr-Abl levels from baseline (or <0.1% Bcr-Abl level if the level at diagnosis is 100%).18 The test is however not standarised between laboratories and efforts are been made to correct this by use of an international standard, enabling patient groups to be compared more reliably when assessing therapeutic responses.18 Classification of responses can be made based on the full blood count, Bcr-Abl ratio and bone marrow cytogenetics as seen in Table 2.
|
Response |
Criteria |
|
Haematological
response Complete |
Platelets
<450x109/L White
cell count <10x109/L Normal
white cell differential Absence
of splenomegaly |
|
Cytogenetic
response Complete Partial Major* Minor Minimal None |
0%
Ph+ 1-35%
Ph+ ≤35%
Ph+ 36-65%
Ph+ 66-95%Ph+ >95%
Ph+ |
|
Molecular
response Complete Major |
Undetectable
transcript ≤0.1
Bcr/Abl control gene ratio |
The current recommendation is that patients on
therapy are monitored by Bcr-Abl measurements from taken peripheral blood every
3 months. A bone marrow aspirate is
required to assess for cytogenetic responses, though the frequency of routine
testing in the absence of evidence of altered disease activity is the subject of
some debate. Standard guidelines
recommend cytogenetic testing every 6 months until a complete cytogenetic
response (CCyR) is achieved and hence annually.18
There is no evidence that Bcr-Abl testing on marrow aspirate offers any
more information than results derived from peripheral blood and the low levels
of variation may lead to confusion in interpreting results.19
We would recommend that a consistent approach to testing is adopted,
allowing more reliable comparison of sequential results.
There is prognostic significance in the serial monitoring of patient
responses to therapy, in particular the response to IM.
Imatinib (IM)
The recommended standard first line therapy for
patients with CML in CP is IM. This
drug was shown to be superior to interferon-alpha (IFN-A) and cytosine
arabinoside in the randomised prospective IRIS trial with initial data published
in 2003. When adopted as initial
therapy for those newly diagnosed with CP CML, IM led to a major improvement in
outcome, as assessed by haematological, cytogenetic, molecular responses,
progression free survival, side effects and quality of life.20
Recent updated long term data generated from this trial reveals that 82%
of patients achieve a CCyR with some late responses occurring in patients after
18 months treatment.21 Early
cytogenetic responses to IM are associated with improved outcome and can predict
later response. Those with a partial cytogenetic response (PCyR) at 3, 6 or
12 months have a 90%, 80% or 50% chance respectively of achieving a complete
cytogenetic response (CCyR) at 2 years. The
benefit of achieving a major cytogenetic response (CCyR or PCyR) by 12 months is
illustrated by recent data showing a 96% freedom from progression to advanced
stages in this group, as compared to 81% in those with less than a partial
response.21
Despite the impressive responses seen with IM there
are some concerns about the long term efficacy.
These have basis in the phenomena of disease persistence and IM
resistance. It is accepted that
despite the marked fall in Bcr-Abl measurements in those treated with IM
therapy, with the majority of patients demonstrating a MMolR, few patients
(<4%) will achieve a complete molecular response (i.e. undetectable Bcr-Abl).22
Various groups, including our team in Glasgow, have focused on the Ph+HSC
as the source of this minimal residual disease.
We have shown that the quiescent Ph+HSC is not susceptible to the
apoptotic effects of IM, even at concentrations greater than would be found
within a treated patient. We have
also demonstrated an accumulation of these quiescent cells with IM exposure of
bone marrow samples taken from patients at diagnosis of CML.23
This work is complemented by that of Bhatia et al who have shown that
patients who have confirmed CCyR on IM maintain a population of functional
Bcr-Abl+ HSC.24 It is
possible to reverse the quiescent state of these Ph+HSC and reconstitute
disease, shown by experiments where selected non-cycling diseased cells are
transplanted into immunocompromised host mice, which then develop transplanted
leukaemia.11 This
disease recrudescence is modeled in patients who discontinue IM therapy having
achieved apparent disease control. The
majority of patients rapidly relapse, though usually respond again to IM
therapy.25, 26, 27
Resistance to IM is now a well recognised
phenomenon. This may be primary,
the failure of a patient to achieve a significant haematological or cytogenetic
response, or secondary, manifest as reemergence of disease following an initial
response. Resistance may occur in
all phases of CML though is more common in AP and BC, where it may reflect the
presence of additional cytogenetic abnormalities characteristic of advanced
disease. Resistance may stem from:
Bcr-Abl dependent mechanisms, such as point mutations in Bcr-Abl affecting IM
binding, or amplification of the bcr-abl oncogene; and Bcr-Abl independent
mechanisms, such as altered influx or export of drug from the cell or
sequestration of IM by plasma proteins.28
IM binds to the inactive form of the Abl kinase and
once bound maintains the enzyme in an inert state by blocking phosphorylation, a
prerequisite for activation.29 The
most common mechanism of resistance identified in patients treated with IM
develops from mutations occurring within the Abl kinase domain of Bcr-Abl.28
Cells will then no longer be susceptible to the antiproliferative and
proapoptotic effects of the drug. This
will enable the resistant clone to multiply under selective pressure, which may
be reflected in disease recrudescence after a period of apparent control, with
rising Bcr-Abl levels.
Altered drug export from cells is another well
described mechanism of resistance to therapy in both solid organ and
haematological malignancies. This
forms the basis of the multidrug resistance (MDR) phenotype.
MDR is the simultaneous development of resistance to more than one
therapeutic agent and since it is not specific to the drug target, can
concurrently affect drugs with different mechanisms of action.
The gene MDR1 (also known as ABCB1) encodes P-glycoprotein (Pgp) a
protein serving as a drug efflux pump. IM
is a substrate of this transporter and it has been shown in cell lines that
increased expression of Pgp correlates with IM-resistance.30 It
has also been seen using CML samples from patients resistant to IM, that
IM-sensitivity may be restored with use of Pgp inhibitors in vitro.31
This demonstrates the importance of
identifying such transporters, as inhibition of their activity may act as a
mechanism to overcome resistance and enhance effective intracellular drug
concentration. Other transporters
which may be involved in IM transport include ABCG2 (a drug exporter)32, 33
and Oct1 (involved in drug uptake).16
Newer Tyrosine Kinase Inhibitors
The qualified success of IM has stimulated the
search for more effective tyrosine kinase inhibitors.
Nilotinib (AMN107, Novartis) has been designed based on the molecular
framework of IM, though with adjustments to the molecular structure which allow
a better topographical fit with the target Bcr-Abl molecule.
Initial in vitro work has demonstrated the increased potency of this drug
for inhibiting proliferation of Bcr-Abl+ cells.34
This has been carried forward into phase 1 trials where Nilotinib has
been shown to be effective in those intolerant of, or resistant to IM.
Responses were gained in patients with all phases of CML, though as with
IM, significant responses were achieved more commonly in those with CP CML.35
Dasatinib (BMS-354825, Bristol-Meyer Squibb) is dual Src- and Abl- kinase
inhibitor which has also been shown in vitro to have potent effects on Bcr-Abl+
cell lines. Phase 1 trial data,
published concurrently with that of nilotinib, demonstrates the effectiveness of
this drug in the IM-resistant or intolerant population of CML patients in all
phases of the disease. Again
responses are more frequently seen in those with CP disease.36
Despite this promising data, as with IM the problem of disease resistance
and persistence may remain. Data
produced from cell line studies and phase 1 trials show that neither nilotinib
nor dasatinib has activity against the T315I mutation of Bcr-Abl.
We have also shown that dasatinib, which demonstrates potent
antiproliferative activity with enhanced cell kill in dividing Bcr-Abl+ cells,
does not appear to eradicate the quiescent Ph+HSC population.33
Similar data has been produced using nilotinib.37
It is hoped that both these drugs will obtain
licenses for UK use in the near future. They
will be useful additions to the treatment options available for patients, though
it is not thought that initially they will replace IM as first line therapy.
There will also be a small group of patients with the T315I mutation who
will not respond to either therapy. The
answer for these patients may be in the future development of drugs aimed at
other targets in the CML cell such as farnesyl transferase inhibitors,
proteasome inhibitors, heat shock protein 90 inhibitors and histone deacetylase
inhibitors all of which are under investigations either as single agent or
combination therapies.37, 38, 39, 40, 41, 42
Of particular interest is research using an aurora kinase inhibitor with
in vitro activity against cells expressing the T315I mutation.43 The potential of future targeted therapies may ultimately be
dependent on their ability to eliminate the Ph+HSC. A phase 1 trial which has completed recruitment in Glasgow is
the granulocyte colony stimulating factor (G-CSF) and IM intermittently (GIMI)
trial. This trial was designed
following in vitro work using CD34+ selected populations derived from the bone
marrow of patients newly diagnosed with CML.
Exposure of these cells to pulses of G-CSF with during times of IM
interruption appeared to significantly reduce the frequency of quiescent Ph+HSC
detected. An explanation for this
may be that the quiescent cells were stimulated by G-CSF to proliferate and so
were rendered susceptible to the effects of IM.37
Bone Marrow Transplant
Haemopoietic stem cell transplantation (HSCT) is
currently considered the only cure for CML.
However it is limited in application by donor availability and the
toxicity of conditioning regimes. The
use of HSCT in CML has declined recently and a likely explanation for this is
the advent of IM.18 Despite
the morbidity and mortality associated with standard myeloablative HSCT, it
remains an important treatment option for those with IM intolerance or
resistance.18 HSCT with
reduced intensity conditioning (RI-HSCT) is now an established treatment
modality for a variety of different haematological malignancies.
The procedure differs from standard myeloablative HSCT in the
chemotherapy received by the recipient prior to transplantation.
The regimes used are significantly less toxic and are therefore
appropriate for a broader patient age range and performance status.
Published data confirms that patients have shorter in patient stays,
engraft sooner with reduced transplant-related mortality.44
Relapse of CML post transplant is a recognised
problem thought to occur in between 16 and 33% of patients.44, 45
Donor lymphocyte infusion (DLI) has been shown to be particularly
effective in eradicating CML post transplant with responses seen in 70-80% of
patients.46, 47 DLI may
be given as a response to high or rising Bcr-Abl measurements or the presence of
donor/host chimerism (indicating the likely presence of residual diseased host
cells). DLI is associated with a risk of graft versus host disease (GvHD),
a potentially significant accompaniment to the desired graft versus leukaemia (GvL)
effect and marrow aplasia. The
estimation of risk varies and may be minimised by the use of regimes involving a
stepwise increase in cell dose given at set intervals.
There is also some controversy surrounding the use
of IM in association with HSCT. IM
use prior to transplant appears to be safe and does not appear to adversely
affect outcome48, however the need for IM following transplant is
less clear. IM is effective in the
context of controlling relapsed disease of all phases49, 50, 51,
though it is not known if it is routinely necessary. It is our view that the
graft versus leukaemia effect of the RI-HSCT and subsequent DLI will enable
disease eradication, however some would claim that maximal control with minimal
risk of disease progression requires the sustained use of IM. This dilemma will hopefully be addressed following
publication of trials currently in progress.
CML is a rare disease but one which has become a
paradigm for the stem cell basis of a number of malignancies. The treatment of IM has also been a major success in rational
drug design. Despite recent
advances, there are a number of dilemmas remaining for the clinician treating
and monitoring patients with CML.
IM remains the standard first line therapy for CML
in CP, with many patients in the advanced stages of disease also responding to
this treatment. The problems of
IM-resistance and minimal residual disease remain. This contributes to the sustained risk of disease progression
and prevents safe interruption of therapy.
The mechanism of resistance may result in a disease that is also
insensitive to the more potent therapies currently in trial, as seen with the
T315I mutant. The options for such
patients are limited. For this
reason efforts continue to eradicate persistent disease.
This may be with the use of next generation tyrosine kinase inhibitors,
novel compounds with alternative targets or by the use of combinations of
existing therapies.
Despite the decline in popularity of HSCT in CML it
remains a valuable option. Those
intolerant or failing to respond to IM require HSCT to enable long term disease
control or cure. The role for
RI-SCT is not yet clearly defined. It
may be that patients with a matched donor who demonstrate features carrying risk
of disease progression should be offered transplant.
Should RI-SCT be offered up front to all patients with matched donors?
This could cure their disease without the need for lifelong therapy with
IM. The morbidity and mortality of
the procedure with the likely subsequent need for DLI and the long term relapse
risk require consideration and so this is currently considered an option for
selected patients in experienced centres only.
CML is a paradigm for stem cell based disease and
IM a successful example of rational drug design.
The unique molecular basis of this disease will undoubtedly fuel further
research with the aim of achieving a cure without the need for lifelong therapy.
Nicholas Heaney is a Leukaemia Research Fund
sponsored clinical research fellow.
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Questions
Select
the most appropriate answer(s) from the following:
Consider
the following statements referring to chronic myeloid leukaemia (CML)
progression:
1
CML may progress to acute myeloid leukaemia
2
CML may progress to acute lymphoblastic leukaemia
3
CML blast crisis (BC) may develop in patients with stable chronic phase
disease
4
Clonal evolution alone is a feature of accelerated phase (AP)
5
Hepatosplenomegaly is a feature of AP or BC disease only
The
following are well recognised chromosomal rearrangements found in chronic
myeloid leukaemia (CML):
1
t(2;5)
False
2
t(9;22)
True
3
t(1,19)
False
4
del(der)9
True
5
t(15;17)
False
Regarding
response to treatment with imatinib (IM)
1
the majority of patients achieve a complete haematological response
True
2
the majority of patients achieve a complete cytogenetic response
True
3
the majority of patients achieve a complete molecular response
False
4
resistance to IM occurs only following exposure to drug
False
5
Nilotinib is effective in vitro against
all IM-resistant Bcr-Abl mutations
False
Regarding
the role of haemopoietic stem cell transplant (HSCT) in CML
1
HSCT is considered the only cure for CML
True
2
The Hasford score is designed for risk assessment prior to transplant
False
3
Reduced intensity stem cell transplant (RI-SCT) involves the less
intensive conditioning chemotherapy and the infusion of fewer donor stem cells
False
4
Donor lymphocyte infusions (DLI) are usually required for disease control
post RI-SCT transplant
True
5
DLI are sourced from pooled HLA-matched volunteer donors
False