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102 Chapter 5 · Signal Transduction Inhibitors in Chronic Myeloid Leukemia
Trang 36.1 Medical Treatment of CML 103
6.2 Imatinib Mesylate 103
6.2.1 Clinical Efficacy 103
6.2.2 Side Effects of Imatinib 106
6.2.3 Dosage of Imatinib 107
6.2.4 Imatinib in Combination 108
6.2.5 Imatinib Resistance 109
6.2.6 Prediction of Response 109
6.3 Novel Bcr-Abl Inhibitors in Clinical Trials 109
6.3.1 Nilotinib (AMN107) 109
6.3.2 Dasatinib (BMS 354825) 111
References 111
Abstract.Leukemias have traditionally served as model
systems for research on neoplasia because of the easy
availability of cell material from blood and marrow
for diagnosis, monitoring, and studies on
pathophysio-logy Beyond these more technical aspects, chronic
mye-loid leukemia (CML) became the first neoplasia in
which the elucidation of the genotype led to a rationally
designed therapy of the phenotype Targeting of the
pathogenetically relevant Bcr-Abl tyrosine kinase with
the inhibitor imatinib has induced remissions with
al-most complete disappearance of any signs and
sym-ptoms of CML This therapeutic success has triggered
an intensive search for suitable targets in other cancers
and has led to the development of numerous inhibitors
of potential targets now being studied in preclinical and
clinical trials worldwide Imatinib mesylate has been the
first selective inhibitor of Bcr-Abl employed in patients Its routine use has been considered a revolution in the treatment of CML
6.1 Medical Treatment of CML
The first drug reported to be active in CML was arsenic
in 1865 Currently, arsenic has been reintroduced into CML management as second-line treatment in combi-nation with imatinib Therapy remained palliative dur-ing most of the last century and included splenic irra-diation, various cytostatic agents, of which busulfan was standard for almost three decades, and intensive combination therapy The intention of the treatment be-came curative with the introduction of stem cell trans-plantation in the 1970s (Goldman and Melo 2003) At
hydroxyurea or low-dose cytarabine (ara-C) offered the prospect of prolonging survival, particularly in low-risk patients and in patients who achieve a cytoge-netic remission (Bonifazi et al 2001; Hehlmann et al
1994, 2003)
6.2 Imatinib Mesylate
6.2.1 Clinical Efficacy
In an effort to identify compounds which could selec-tively inhibit the aberrantly enhanced tyrosine kinase Bcr-Abl, imatinib mesylate, a 2-phenylaminopyrimidine derivative, was identified (see Chap 1, entitled Chronic Myeloid Leukemia – A Brief History) Imatinib
compet-Treatment with Tyrosine Kinase Inhibitors
Andreas Hochhaus
Trang 4itively inhibits the ATP binding site of Bcr-Abl tyrosine
kinase and, by inhibiting tyrosine phosphorylation
blocks the Bcr-Abl signal transduction cascade It is
highly selective for inhibiting Bcr-Abl, ABL, PDGF-R
al-pha and beta, ARG, and c-kit (Buchdunger et al 2000)
without inhibiting the proliferation of
BCR-ABL-nega-tive cells (Druker et al 1996)
Imatinib is well absorbed from the gut Peak plasma
levels are reached after 2–4 h and bioavailability is 98%
A single oral dose of 400 mg/day produces a steady state
plasma concentration which exceeds the minimal
re-quired concentration for inhibiting cellular
phosphory-lation and causes lysis of BCR-ABL-positive cell lines in
vitro The mean elimination half-time of imatinib is 13–
16 h Excretion is primarily via the feces (Druker et al
2001 b) Imatinib is 95% protein bound, predominantly
through the action of the cytochrome P450 (CYP)
iso-form CYP3A4 The main metabolite (N-demethylated
piperazine derivative) has similar in vitro potency to
the parent compound
In a phase I study 83 IFN refractory patients in
chronic phase (CP) were treated with imatinib (Druker
et al 2001 b) The median duration of IFN pretreatment
was 8.5 months (1 week to 8.5 years) and the median
duration of imatinib therapy was 310 days (17–607 days)
Complete hematologic response (CHR) was noted in 53
of 54 patients treated with more than 300 mg of imatinib
/lfor at least 4 weeks) Hematologic responses were at-
tained generally within the first 4 weeks of imatinib
ther-apy and were durable in 51 of 53 patients with a median
follow-up of 265 days (17–468 days) A major cytogenetic
remission (MCR, Ph+ metaphases < 35%) was noted in
17 (31%), being complete in 7 patients (13%) The median
time to best cytogenetic response was 148 days (48–331
days) The side effects (i.e., nausea, diarrhea, myalgias,
and periorbital edema) were relatively frequent (25–
43%) but mostly mild (WHO grades I and II) In some
patients abnormal liver function tests were noted An
initial drop of hemoglobin of 1–2 g/dl, which was dose
related, occurred frequently Leukopenia and
thrombo-cytopenia (WHO grade III) occurred in 14% and 16%,
respectively, and was not dose limiting The highest dose
of imatinib administered was 1000 mg daily and the
maximum tolerable dose was not defined
In a second phase I study 58 patients with myeloid
(n = 38) or lymphoid blast crisis (BC) or Ph-positive
acute lymphoblastic leukemia (ALL, n = 20) were treated
with 300–1000 mg of imatinib daily (Druker et al
2001 a) The median age was 48 years (range, 24 to76) Additional chromosomal abnormalities were noted
in 58% and 65%, respectively Twenty-one patients withmyeloid BC (55%) achieved a hematologic response,which was complete in four patients (11%) In 12 patients(32%) less than 5% blasts were noted in the bone marrow
In patients with lymphoid BC, hematologic responserate was 70%, which was complete in 20% In 11 patients(55%) less than 5% blasts were noted in the bone mar-row Seven of 58 patients (12%) attained MCR, whichwas complete in five patients (3 and 2 patients, respec-tively from each group) Response rates were not closelyrelated to the administered doses Of the 21 patientswith myeloid BC who had attained a hematologic re-sponse, nine patients relapsed after a median of 84 days(42–194 days) All but one of the patients with lymphoid
BC relapsed after a median of 58 days The side-effectprofiles were comparable to the aforementioned study
in CP CML Overall, 16 patients died due to disease gression Phosphorylation of CRK-oncogene-like pro-tein (CRKL), a major substrate of Bcr-Abl kinase, wasmarkedly reduced in leukemic cells, demonstratingthe effect of imatinib on its target
pro-Phase II trials were conducted in BC (n = 260), erated phase (AP) (n = 235), and CP after IFN resistance
accel-or intolerance (n = 532) Accaccel-ording to the accel-original lications, in patients with BC hematologic response ratewas 52% (complete in 8%), MCR occurred in 16%, with7% of the responses being complete (Sawyers et al.2002) Time to progression and median survival weresignificantly shorter in pretreated patients In patientswith AP imatinib induced sustained hematologic re-sponses lasting at least 4 weeks in 69% (complete in34%) (Talpaz et al 2002) MCR rate was 24% Estimated12-month overall survival was 74% In IFN refractory orintolerant patients in CP CML imatinib induced CHR in95%, MCR in 60%, with 41% of the responses beingcomplete (Kantarjian et al 2002) The median time toonset of CHR was 0.7 months, of MCR 2.9 months.Updated results are provided in Table 6.1 (Silver et al.2004) Phase-II data were confirmed by a large ex-panded access program with more than 7,000 patients(Hensley et al 2003)
pub-A subsequent phase III randomized controlled trial(IRIS – International Randomized Study of Interferonand STI571) in 1,106 patients with newly diagnosedCML in CP recruited between June 2000 and January
2001, has shown the superiority of imatinib, 400 mg/
104 Chapter 6 · Treatment with Tyrosine Kinase Inhibitors
Trang 5day, over the combination of IFN and cytarabine in all
relevant endpoints At 18 months the hematologic and
cytogenetic response rates in the imatinib arm were
97% and 87%, respectively, which is much higher than
comparable figures for the IFN/cytarabine arm (69%
and 22%, respectively); the toxicity with imatinib was
lower Time to progression to blast phase, duration of
progression-free survival irrespective of the
prognos-tic-factor score at the time of study entry, and the
per-ceived occurrence of adverse events were advantageous
for primary imatinib therapy (O’Brien et al 2003) Due
to the large numbers of crossovers from IFN to imatinib,
a long-term comparison of both therapies is impossible
A 60-month update of the imatinib group showed
complete hematologic remissions in 98%, partial
cyto-genetic remissions in 92%, and complete cytocyto-genetic
re-missions in 87% of cases (Druker et al 2006) (Figs 6.1,
6.2) Annual rate of relapse was 3.3, 7.5 and 4.8% in the
first three years and decreased to 1.5 and 0.9% in the
fourth and fifth year after start of treatment The time
to complete hematologic remission was much shorter
with imatinib (about 90% after 3 months) than with
IFN Similar to the effects observed with IFN, the
achievement of complete cytogenetic remissions was
fol-lowed in most patients by a continuous decline of
BCR-ABL transcript levels which continues up to 42 months.
Major parameters with favorable prognostic impact were
any cytogenetic response after 6 months (Fig 6.3) and
major cytogenetic response (Fig 6.4) after 12 months
of therapy (Druker et al 2003; Hughes et al 2003)
Quality-of-life analysis has demonstrated advantages
of imatinib compared with IFN + cytoarabine as
first-line treatment of CP CML In addition, patients who
cross over to imatinib from IFN-based therapies
experi-ence a significant improvement in quality of life (Hahn et
al 2003)
There are a number of questions that have been
answered definitively by the IRIS study The study has
shown that in terms of hematologic and cytogenetic sponses, progression-free survival, and side effects, tol-erability, and quality of life, imatinib is superior to IFNplus low-dose cytarabine However, two important re-lated questions have not definitely been answered by this
Major cytogenetic response ( £35% Ph-positive metaphases) (%)
Complete cytogenetic response (%)
Fig 6.1 Estimated response to first-line imatinib CHR, complete hematologic response; MCR, major cytogenetic response (Ph+ £35%); CCR, complete hematologic response (Druker et al 2006; O’Brien et al 2003)
Fig 6.2 Estimated CCR to first-line Imatinib by Sokal Group (Guilhot 2004; O’Brien et al 2003)
Trang 6study, namely (1) is imatinib superior to IFN plus
cyta-rabine in terms of long-term survival? and (2) what will
be the outcome of imatinib-treated patients in the longer
term? By extrapolation from survival data of IFN-treated
CML patients who achieved complete cytogenetic
remis-sions, a 10-year survival rate of at least 51% was estimated
for imatinib-treated patients (Hasford et al 2005)
As-suming the relationship between CCR and survival with
IFN holds good for imatinib, the much higher CCR rates
with imatinib therapy will result in an estimated 6.23
life-years gained compared with treatment with IFN plus
low-dose cytarabine (Anstrom et al 2004)
It can be concluded that imatinib is superior to IFN
with regard to response rate, progression-free survival
and adverse effects Comparison with historic data
indi-cates a clear survival advantage of imatinib compared to
IFN in patients with early CP CML (Kantarjian et al
2003)
Another critical issue of course is whether imatinibcan cure CML Current in vitro and in vivo data suggest
that dormant or “quiescent” nondividing
BCR-ABL-positive stem cells are not responsive to imatinib andmay produce relapse after withdrawal of imatinib (Dru-ker et al 2006; Graham et al 2002)
6.2.2 Side Effects of Imatinib
The majority of imatinib-treated patients experience verse events at some time Most events are of mild tomoderate grade The most frequently reported drug-re-lated adverse events are nausea, vomiting, edema, andmuscle cramps Edema is most frequently periorbital
ad-or in lower limbs and is manageable with diuretics.The frequency of severe edema in phase I–III trialswas 2–5% Some of the adverse events observed are at-tributable to local or general fluid retention includingpleural effusion, ascites, pulmonary edema, and rapidweight gain with or without superficial edema The in-cidence of edema was dose and age related; it was about20% higher for patients who received imatinib 600 mg/day vs 400 mg/day and for patients > 65 years of age(Table 6.2)
Myelosuppression is common in CML patientstreated with imatinib (more common in patients withadvanced disease and in the initial phase of therapy)
In the phase III randomized trial of newly diagnosed tients in the CP treated with imatinib at 400 mg/day,
/l) occurred in less than 1% of patients(O’Brien et al 2003)
Both in vitro and in vivo data indicate that inhibition
of normal hematopoiesis during imatinib treatment isminimal; it is seen primarily as neutropenia and is large-
ly restricted to high doses (Deininger et al 2003) Themuch lower rate of infectious complications observed
as compared to that expected in patients with a similarlevel of myelosuppression induced by conventional che-motherapy may be related to the lack of mucous mem-brane damage in patients on imatinib Most patients,even patients with advanced phase CML, experiencerecovery of normal blood counts during continuoustherapy with imatinib Interventions with hematopoieticgrowth factors are under investigation
106 Chapter 6 · Treatment with Tyrosine Kinase Inhibitors
Fig 6.3 Prognostic value of any cytogenetic response (CyR) at 6
months (Guilhot 2004; O’Brien et al 2003)
Fig 6.4 Progression-free survival on first-line imatinib by molecular
response (MR) at 12 months (Guilhot 2004; O’Brien et al 2003)
Trang 76.2.3 Dosage of Imatinib
The recommended dosage of imatinib is 400 mg/day for
patients in CP CML and 600 mg/day for patients with
AP or BC CML Consecutive cohorts of patients treated
with 400 mg and 600 mg imatinib demonstrated the
ad-vantage of 600 mg/day in advanced disease
Retrospec-tive analysis of prognostic factors showed that the 400
mg and 600 mg cohorts were well matched
Dose increases from 400 mg to 600 mg/day in
pa-tients with CP CML or from 600 mg to 800 mg/day in
patients with advanced disease may be considered for
patients with progressive disease, if a satisfactory
he-matologic response is not achieved after > 3 months of
treatment, if cytogenetic remission is not achieved after
6–12 months of treatment or if a previously achievedhematologic or cytogenetic remission is lost (in the ab-sence of severe nonleukemia-related neutropenia orthrombocytopenia)
The increase of imatinib dosage has been previouslyshown to improve response in patients with accelerateddisease Accelerated disease was found to have higher re-sponse rates with 600 mg imatinib than with 400 mg.Kantarjian et al (2004) have reported in a historicalcomparison that higher cytogenetic and molecular re-mission rates can be achieved in shorter time intervalswith an imatinib dosage of 800 mg daily as compared to
400 mg in CP CML The disadvantage of the higher tinib dose is a higher rate of adverse effects, in particularmyelosuppression and fluid retention It is unknown
Table 6.2 Management of side effects from imatinib (Garcia-Manero et al 2003)
Nausea and/or emesis Avoid taking imatinib on an empty stomach
Antiemetics (e.g., ondansetron at a dose of 8 mg orally or prochlorperazine at a dose
of 10 mg orally 30 min prior to intake of imatinib) Adequate fluid intake
Diarrhea Loperamide at a dose of 2 mg orally after each loose bowel movement (up to 16 mg
daily) or diphenoxylate atropine at a dose of 20 mg orally daily in 3–4 divided doses
Topical steroids (e.g., 0.1% triamcinolone cream topically as needed) Systemic steroids (e.g., prednisone at a dose of 20 mg orally daily for 3–5 days) Muscle cramps Electrolyte substitution
Tonic water (quinine)
Mg2+replacements Bone aches Cox-2 inhibitors (e.g., celecoxib at a dose of 200 mg orally daily or rofecoxib at a dose
of 25 mg orally daily) Liver function abnormalities Hold imatinib
Resume within 1–2 weeks Consider decreasing the dose (no less than 300 mg orally daily) Myelosuppression
Thrombocytopenia Hold if platelets £40´10 9
/L High-dose folic acid Interleukin-11 as needed Resume at lower dose level (no less than 300 mg orally daily)
Trang 8whether the effect of high-dose imatinib is sustained and
provides a survival benefit The dosage of imatinib
should be adjusted or treatment interrupted if severe
neutropenia or thrombocytopenia occurs
Dose increase is suggested in case of suboptimal
re-sponse, which is defined as:
1 Failure to achieve a complete hematologic response
after 3 months,
2 failure to achieve any cytogenetic response after 6
months, or
3 failure to achieve a major cytogenetic response after
12 months of imatinib therapy (Druker et al 2003;
Hughes et al 2003)
High-dose imatinib therapy was tested in CML patients
after IFN failure and in newly diagnosed patients
Cyto-genetic and molecular responses were achieved faster
with 800 mg imatinib/day (Cortes et al 2003; Kantarjian
et al 2004) The TIDEL multicenter study in Australia
examined the effect of 600 mg/day among newly
diag-nosed patients with CP CML Dose escalation to 800
mg/day was allowed if patients did not achieve a CHR
at 3 months, an MCR at 6 months, a CCR at 9 months,
or became PCR negative at 12 months Additionally,
pa-tients who did not achieve hematologic or cytogenetic
responses following dose escalation to imatinib 800
mg/day were allowed to add intermittent ara-C to their
regimen When compared with historical data from the
IRIS study, a significantly higher proportion of patients
in the TIDEL study achieved an MCR and CCR (Hughes
et al 2004)
6.2.4 Imatinib in Combination
Combinations of imatinib with other drugs have been
extensively analyzed in vitro and have shown that a
num-ber of drugs are synergistic with imatinib in vitro Of
particular interest were the combinations of imatinib
with IFN or low-dose ara-C The feasibility of the
com-binations of imatinib with IFN (Pegasys, Peg-Intron) and
low-dose cytarabine has been shown in phase I and II
studies (Baccarani et al 2004; Hochhaus et al 2002)
On the basis of these studies, randomized trials were
designed by national study groups in Germany, France,
UK, and USA to compare imatinib monotherapy at 400
mg with imatinib in various combinations (IFN,
cyt-arabine) and dosages (600 mg, 800 mg) The first of
these studies, the German CML Study IV, started
re-cruitment in July 2002 and compared imatinib
400 mg/d with imatinib + IFN, imatinib + cytarabineand imatinib after IFN failure in newly diagnosed pa-tients with CP CML By June 2006, 810 patients wererandomized According to the Hasford score, 35% of pa-tients were low risk, 54% intermediate risk, and 11%high risk Rate of progression was rare, within the firstyear 13/335 patients (6 low, 3 intermediate, 4 high risk;4%) progressed to BC, 4 of them revealed clonal evolu-tion (complex aberrant karyotype, n = 3; +8, n = 1), two
other BCR-ABL mutations Within the second year 3/232
patients progressed to BC During the first year of ment imatinib therapy was stopped due to side effects
treat-or resistance in 6% of patients in the imatinib 400 mgarm, in 2% of patients in the imatinib+IFN arm, and
in 2% of patients in the imatinib+cytarabine arm IFNwas stopped in 21% and cytarabine in 18% of patients.The interim analysis of a prospective randomized trialwith imatinib and imatinib in combination for newly di-agnosed patients with CML has proven the feasibility ofimatinib combinations in addition to high response andlow progression rates (Berger et al 2004)
In September 2003, the French study was startedwhich compares imatinib monotherapy at 400 mg vs.imatinib at 600 mg vs imatinib plus IFN (Pegasys) vs.imatinib plus low-dose cytarabine After an observationperiod, it is planned to reduce the study to two arms.The UK study compares imatinib monotherapy at 400
mg vs imatinib at 800 mg vs imatinib plus IFN gasys) The USA study is focusing on the comparison
(Pe-of 400 mg and 800 mg imatinib therapy only
The emergence of resistance to imatinib therapy has led to a search for downstream targets ofthe Bcr-Abl kinase that may mediate the altered growth
mono-properties of BCR-ABL-transformed cells Identification
of signaling pathways downstream of ABL tyrosine nase may increase our understanding of the pathogen-esis of CML and suggest strategies to improve clinicaltreatment of the disease
ki-Farnesyl transferase inhibitors enhance the
antipro-liferative effects of imatinib against
BCR-ABL-express-ing cells, includBCR-ABL-express-ing imatinib-resistant cells Cells
resis-tant to imatinib because of amplification of BCR-ABL
remain sensitive to tipifarnib and lonafarnib and treatment of these cells with imatinib plus farnesyltransferase inhibitors leads to enhanced antiprolifera-tive or proapoptotic effects even in cells that are resis-tant to imatinib based on the expression of a Bcr-Ablkinase domain mutation (T315I) that is completely in-
co-108 Chapter 6 · Treatment with Tyrosine Kinase Inhibitors
Trang 9sensitive to imatinib Although this mutant is sensitive
to lonafarnib, the addition of lonafarnib to imatinib
yielded no increase in antiproliferative effects These
re-sults raise critically important issues of how and when
to molecularly targeted agents should be combined for
optimal results Although the discussion that follows
will focus on CML and Bcr-Abl signal transduction, this
paradigm could be applied to any agent that targets
sig-naling pathways (Peters et al 2001)
Early clinical studies using a combination of
imati-nib and farnesyl transferase inhibitors in advanced
phase CML patients demonstrated feasibility but
showed only moderate activity, probably due to clonal
evolution with novel molecular or cytogenetic
aberra-tions in addition to BCR-ABL not responding to farnesyl
transferase inhibitors (Cortes et al 2003)
It is shown that the PI3-kinase/Akt pathway is a
cri-tical contributor to survival/proliferation of
BCR-ABL-transformed cells The serine/threonine protein kinase
mTOR (mammalian target of rapamycin) is a
down-stream component of the PI3-Kinase/Akt pathway, and
plays an important role in controlling cell growth and
proliferation The mTOR pathway is constitutively
acti-vated by Bcr-Abl in CML cells Two of its known
sub-strates, ribosomal protein S6 and 4E-BP1, are
constitu-tively phosphorylated in a Bcr-Abl-dependent manner
in BCR-ABL-expressing cell lines and CML cell lines.
These data suggest that Bcr-Abl may regulate
transla-tion of critical targets in CML cells via mTOR
The effect of rapamycin in three different
imatinib-resistant Bcr-Abl mutant cell lines (Ba/F-BCR-ABL T315I,
G250E, M351T) has been described Rapamycin alone
in-hibited proliferation to a degree that would be predicted
if mTOR was a critical downstream effector of Bcr-Abl,
while the combination of low-dose rapamycin with
im-atinib markedly enhanced this growth inhibitory effect
The synergy between rapamycin and imatinib,
occur-ring at doses well below typical serum levels obtained
during monotherapy with each of these agents
repre-sents a strong argument in favor of investigating the
clinical activity of the combination (Ly Chi et al 2003)
6.2.5 Imatinib Resistance
Several questions remain open, notably those
concern-ing the development of imatinib resistance, which is
rare in early CP, but increases in frequency along the
course of the disease (Hochhaus and La Rosée 2004)
Essentially two mechanisms underlie the development
of the tyrosine kinase P-loop mutations have been ciated with an especially poor prognosis (Branford et al.2003), but cessation of imatinib therapy and alternativetherapy with other drugs seem to be able to improveprognosis Novel methods are available to screen forsmall clones of mutated leukemic cells, e.g., denaturinghigh-performance liquid chromatography (D-HPLC).The impact of the results of such assays needs to beexplored in prospective clinical trials (Soverini et al.2005)
asso-6.2.6 Prediction of Response
Attempts have been made to develop prognostic models
to predict the outcome of CML patients on imatinibtherapy In CP patients after IFN failure, a low neutro-phil count and poor cytogenetic response at 3 monthswere identified as independent factors by investigators
of the Hammersmith Hospital in London (Marin et al.2003), but data are conflicting and were not confirmed
by others (Lahaye et al 2005)
6.3 Novel Bcr-Abl Inhibitors in Clinical Trials
6.3.1 Nilotinib (AMN107)
Nilotinib (AMN107) is a novel aminopyrimidine, able as an oral formulation It is a competitive inhibitor
avail-of the protein tyrosine kinase activity avail-of Bcr-Abl and
Trang 10prevents the activation of Bcr-Abl-dependent mitogenic
and antiapoptotic pathways (e.g., PI-3 kinase and
STAT5), resulting in death of the Bcr-Abl-induced
phe-notype In cellular autophosphorylation assays and
mediated cell proliferation, nilotinib is a highly potent
inhibitor of the Bcr-Abl tyrosine kinase An important
feature of nilotinib is its ability to inhibit most
imati-nib-resistant mutant forms of BCR-ABL Based on this
activity, nilotinib may provide therapeutic benefit in
patients with CML who have developed resistance to
imatinib therapy due to mutations within the Bcr-Abl
kinase
The effects of nilotinib on Bcr-Abl
autophosphoryla-tion have been evaluated in K562 and KU-812F human
leukemia cell lines, which naturally express Bcr-Abl,
as well as with p190 or p210-BCR-ABL transfected
mu-rine hematopoietic 32D and p210-BCR-ABL transfected
Ba/F3 cells In addition, the compound has been
evalu-ated for effects on autophosphorylation in a panel of Ba/
F3 cells, expressing different mutant forms of the
Bcr-Abl kinase
Nilotinib potently inhibits the Bcr-Abl kinase in cell
lines derived from human leukemic CML cells and from
in the range of 20 nM to 60 nM Nilotinib also potently
inhibited most of the imatinib-resistant mutant forms of
BCR-ABL Thus, M237I, M244V, L248V, G250A (E, V),
Q252H, E255D (K), E275K, E276G, E281K, K285N,
E292K, F311V, F317L (C, V), D325N, S348L, M351T, E355
(G), A380S, L387F, M388L, F486S are inhibited with
200 nM and 800 nM, leaving only the T315I mutant affected by nilotinib at concentrations < 8000 nM.The selectivity of nilotinib as a protein kinase inhi-bitor has been demonstrated by its lack of appreciable
> 3000 nM) against a panel of Ba/F3 cells transfected
to express a variety of different kinases (Weisberg et
al 2005) Excellent efficacy in models of ative disease was observed In an acute model in whichNOD-SCID mice were injected with murine 32D cellsharboring the firefly luciferase gene and transfected to
myeloprolifer-be dependent upon p210 Bcr-Abl, nilotinib (100 mg/kgQD) markedly reduced tumor burden, as assessed bynoninvasive imaging Furthermore, nilotinib (75 mg/
kg p.o., QD) prolonged the survival and reduced tumorburden, as assessed by spleen weights, of mice havingeither p210 or mutant (E255V, M351T) Bcr-Abl myelo-proliferative disease Nilotinib was also evaluated in adisease model using primary hematopoietic cells, inwhich mice were transplanted with bone-marrow cellstransfected to express Bcr-Abl Treated animals showedreduced morbidity and had spleen weights within thenormal range Similar, although slightly reduced effi-cacy was observed in mice receiving bone-marrowtransplants after infection with either E255V or M351TBcr-Abl (Weisberg et al 2005)
A Phase I/II study of nilotinib is currently ongoing
in adult patients with imatinib-resistant CML in CP,
AP, or BC relapsed/refractory Ph+ acute lymphoblasticleukemia, and other hematological malignancies Thephase I portion of this study has completed its enroll-ment and the phase-II portion is currently ongoing.During the phase I part of this study, 119 patients wereinitially treated in dose cohorts from 50 mg to 1200 mg
on a once daily schedule with intrapatient dose tion, and subsequently a twice daily dosing schedulewith 400 mg and 600 mg cohorts For the phase II part
escala-of the study, the 400 mg BID dose was selected on thebasis of safety and acceptability; this improved serumexposure over once daily dosing in the phase I patients
In the Phase I study nilotinib was orally tered after a light breakfast and a 2-h fast in sequentialcohorts of patients at escalating once daily doses of 50,
adminis-100, 200, 400, 600, 800, and 1200 mg Since a limitedincrease in serum exposure to nilotinib occurred athigher dose levels, the protocol was amended to add atwice daily dosing schedule of 400 mg (800 mg/day)and 600 mg (1200 mg/day) Nilotinib doses, up to
1200 mg orally once per day or 400 mg orally twice
110 Chapter 6 · Treatment with Tyrosine Kinase Inhibitors
Fig 6.5 Chemical structure of imatinib, nilotinib, and dasatinib
(Shah et al 2004; Weisberg et al 2005)
Trang 11per day, were well tolerated with the majority of adverse
events reflecting those commonly seen in patients with
advanced leukemia Overall, 20% of patients
experi-enced thrombocytopenia, 13% experiexperi-enced neutropenia,
4% developed anemia, and bone marrow aplasia
oc-curred in 2% There was a higher incidence of
neutro-penia (22% vs 9%) in the 600 mg BID cohort compared
with the 400-mg BID cohort
Additional adverse events that were suspected to be
study-drug-related included rash and pruritus Various
descriptive terms of rash, including erythema and
ex-anthema, were described in 33% of patients, the
major-ity of which were mild (grades 1 and 2), and 11% at
grade 3 Pruritus was reported separately in 15% of
pa-tients, 2 (1.6%) of which were grade 3 These cutaneous
changes responded to topical corticosteroids in most
cases Nausea (grade 1 or 2) was reported in 7% of
pa-tients and emesis in 3% Fatigue (grades 1–3) has been
reported in 5% of patients Lipase elevations, the
ma-jority of which were asymptomatic, have been reported
usually during the first cycle of nilotinib therapy The
incidence of clinically recognized pancreatitis was
ap-proximately 3% Transient hyperbilirubinemia occurred
early during nilotinib therapy and affected
approxi-mately 20% of patients Most instances of
hyperbilirubi-nemia were due to the unconjugated fraction These
ab-normalities generally resolved without further
interven-tion and most patients continued therapy without
further recurrence (Kantarjian et al 2006)
The interim efficacy analysis of the phase-I/II study
revealed complete hematologic response in 92% of CP,
51% of AP, and 6% of BC patients Complete cytogenetic
response was achieved in 35%, 14%, and 6% of patients,
respectively (Kantarjian et al 2006)
6.3.2 Dasatinib (BMS 354825)
Dasatinib (BMS-354825) is a potent, orally active
inhi-bitor of the Bcr-Abl, c-KIT, and SRC family kinases It
belongs to the thiazolecarboxamides and is structurally
different from imatinib and nilotinib In preclinical
studies, dasatinib has been shown to be a more potent
inhibitor of Bcr-Abl (260-fold), c-kit (eightfold),
PDGFRb (60-fold), and SRC (>1000-fold) than imatinib
Dasatinib inhibits the Bcr-Abl kinase with an in
vi-tro IC50 of 3 nM In cellular assays, dasatinib killed or
inhibited the proliferation of all Bcr-Abl-dependent
leu-kemic cell lines tested In vitro results suggest that
dasa-tinib is effective in reducing the proliferation or survival
of both imatinib sensitive and resistant cells, and its hibitory activity is not solely dependent on Bcr-Abl Theonly imatinib-associated Bcr-Abl mutation resistant todasatinib is T315I (Shah et al 2004) Dasatinib is astrong inhibitor of the human CYP3A4 enzyme, so itmay reduce clearance of drugs that are significantly me-tabolized by that enzyme
in-A phase-I study with dasatinib in CML patients wasinitiated in November 2003 Complete hematologic re-mission was achieved in 92% of CP, 45% of AP, 35% ofmyeloid BC and 70% of lymphoid BC or Ph+ ALL pa-tients Complete cytogenetic response was seen in35%, 18%, 26% and 30% of patients, respectively (Talpaz
et al 2006) Overall hematologic and nonhematologictoxicities have been manageable in the context of thephase-I population In CP patients, hematologic toxicityconsisting mostly of thrombocytopenia was seen at alldose levels Nonhematologic adverse events usually con-sisted of grade 1 or 2 events such as pleural effusions,rash, nausea, or fever They occurred at any dose levelwithout evidence of dose effect
Pharmacodynamic data (CRKL-phosphorylation say) suggested a twice-daily schedule However, the best
as-in vivo schedule is beas-ing tested as-in two randomized
phase II studies with once-daily and twice-daily ules at different dose levels (Sawyers et al 2005).The advent of selective tyrosine kinase inhibitorshas significantly changed CML therapy However, de-spite promising results patients should be identified inwhom treatment requires optimization, either by doseescalation of imatinib or combination with other drugs
sched-In case of resistance, novel tyrosine kinase inhibitorsare available within clinical trials In addition to hema-tologic and cytogenetic monitoring, molecular surveil-lance of response and resistance is essential for thera-peutic decisions
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Trang 147.1 Introduction 116
7.2 Changes in Allogeneic Transplant Practice 116
7.3 Prognostic Features at Diagnosis 116
7.3.1 Response to First Treatment as an Indicator of Prognosis 117
7.4 Prognostic Indicators for Transplant Outcome 117
7.4.1 Disease Phase 118
7.4.2 Age at Transplant 119
7.4.3 Source of Allograft Donor 119
7.4.4 Source of Hematopoietic Stem Cells 120 7.4.5 Therapy Pretransplantation 120
7.4.6 Patient and Donor Gender 121
7.5 Reduced Intensity Conditioning Transplantation 121
7.6 Detection and Management of Residual Disease 125
7.6.1 Role of Qualitative RT-PCR for BCR-ABL 125
7.6.2 Quantitative Studies for BCR-ABL in CML 125
7.7 Indications for Allogeneic Transplantation 126
7.7.1 Primary Therapy 126
7.7.2 Allogeneic Transplantation after Imatinib Failure 126
7.7.3 Management of Persistent or Relapsed Disease Post Transplant 126 7.8 Summary 127
References 127
Abstract.The management of CML has changed drama-tically over the past 5–7 years The development of the specific tyrosine kinase inhibitor, imatinib, has resulted
in incidences of cytogenetic and molecular response that far exceed those achieved with interferon The med-ian duration of survival is predicted to increase and the role of allogeneic transplantation has correspondingly decreased However, the technology of allografting has also progressed in that developments in molecular typ-ing methodology and in the management of infection have resulted in an improvement in the outcome of un-related transplants The imatinib era has coincided with the development of reduced intensity conditioning reg-imens and early results suggest that this is an effective strategy in CML associated with low transplant-related mortality This chapter summarizes the data on the prognostic factors for both disease- and transplant-re-lated outcomes and outlines the current indications for allogeneic transplant in CML These indications for allografting will continue to evolve Although allo-geneic transplant is no longer the initial therapy in the majority of patients, it remains the strategy with the highest probability of achieving a molecular remis-sion and curing the disease As such it will continue to play a role in the management of CML
Allogeneic Transplantation for CML
Charles Crawley, Jerald Radich and Jane Apperley
Trang 157.1 Introduction
The decision to offer allogeneic hematopoietic stem cell
transplantation to a patient with CML in chronic phase
(CP) has always been difficult, with a balance to be
drawn between the short-term risks of transplantation
with the longer-term disease risks of medical therapy
The introduction of the selective tyrosine kinase
inhib-itor, imatinib (Glivec, Gleevec, STI571) has replaced
in-terferon and cytarabine as primary medical therapy
and while survival data remain immature, the data on
surrogate markers of cytogenetic and molecular
re-sponse are impressive The evidence to date suggests
that these responses will be followed by improvements
in survival (Hughes et al 2003) These data have led
to a major re-evaluation of the role of allogeneic
trans-plantation for this disease The algorithms devised in
the 1990s are no longer applicable and opinions remain
divided as to the role of allogeneic hematopoietic stem
cell transplantation in the management of CP disease
in particular
7.2 Changes in Allogeneic Transplant Practice
During the 1990s there was a steady rise in the use of
allogeneic transplant for CML, particularly in CP
dis-ease That trend dramatically reversed after 1999 with
a reduction in transplant activity reported to the EBMT
(European Group for Blood and Marrow
Transplanta-tion) of almost 40% This fall has been restricted to
pa-tients transplanted in first CP and has not been matched
by a change in the numbers of transplants performed
for more advanced disease (Gratwohl et al 2001 b,
2004) (Fig 7.1) The change in activity reflects the
in-creased use of imatinib and was in anticipation of any
demonstrable survival benefit It has prompted
sugges-tions that there may be little role for allogeneic
trans-plants in the management of CP disease
Concurrent with the introduction of imatinib, the
past 7 years have also witnessed significant changes in
allogeneic transplant practice These include the
intro-duction of reduced intensity conditioning (RIC)
regi-mens or nonmyeloablative transplants with the
asso-ciated reduction in procedural-related mortality RIC
accounted for less than 1% of transplants performed
in Europe in 1998 but had increased to 27% in 2002–
2003 (Gratwohl et al 2004) Other improvements
in-clude better supportive care, which is reflected in the
progressive reduction of infection-related deaths wohl et al 2005) Finally, advances in molecular HLAtyping methodologies have led to the outcome of unre-lated donor transplantation approaching that achieved
(Grat-in HLA matched sibl(Grat-ing transplantation (Davies et al.2001; Hansen et al 1998; Weisdorf et al 2002).The decision to recommend early transplant for pa-tients with CML can only be made after careful consid-eration of prognostic factors at diagnosis, includingthose predicting both response to medical therapy andtransplantation outcomes This assessment should beconducted based on current outcome data as outcomesreported in the 1980s and early 1990s do not reflect theresult of medical therapy or transplantation in the 21stcentury Alternatively, if imatinib is to be offered, theremust an attempt to develop criteria for molecular re-sponse and imatinib failure that would warrant a recon-sideration of treatment strategy
7.3 Prognostic Features at Diagnosis
There are a number of well-established prognostic els of survival for patients with CML that have been de-veloped based on cohorts of similarly treated patients.These models identify patients who present in CP withhigh- or lower-risk disease based on the clinical featurespresent at the time of diagnosis It is important to ap-preciate that the value of these models varies with dif-ferent treatments The best-known score (Sokal et al.1984) is a model that was based on patients treated pre-dominantly with busulfan and hydroxycarbamide (hy-droxyurea) and but is a less useful guide for patientstreated with interferon The Hasford score was devel-
mod-116 Chapter 7 · Allogeneic Transplantation for CML
Fig 7.1 Changes in transplant activity in CML between 1990 and
2003 as reported to EBMT
Trang 16oped for patients treated with interferon and confirmed
the value of interferon in lower-risk patients (Hasford et
al 1998) Treatment has now changed again and the
val-ue of the Hasford score in patients treated with imatinib
is uncertain However, the Sokal score may be of
prog-nostic value in this setting For patients enrolled in the
IRIS study and randomized to imatinib, the probability
of achieving cytogenetic remissions were 76% and 49%
for Sokal low-risk and high-risk disease, respectively
The Sokal score was also predictive for molecular
re-sponses with 66% of the low-risk patients and 45% of
high-risk patients achieving a 3 log reduction in
BCR-ABL transcript numbers (Hughes et al 2003)
The applicability of the Sokal and Hasford scores to
the outcome of transplantation has been less clear
Re-cently the International Blood and Marrow Transplant
Registry (IBMTR) has analyzed the impact of the two
scores on transplant outcome and found that they were
entirely nonpredictive for survival (Passweg et al 2004)
It is likely that prognostic scores based on clinical
variables will be surpassed by biological markers as
pre-dictors of disease course and response to therapy
Ex-amples include deletions of 9q, which occur in 15–
20% of patients and are associated with an inferior
out-come (Huntly et al 2001), although there is some
con-troversy as to whether the prognostic significance of
9q deletions is overcome with imatinib therapy (Huntly
et al 2003; Quintas-Cardama et al 2005) Recently, gene
expression profiling has identified candidate genes such
as CD7 and proteinase-3 which may be of greater
predic-tive value (Yong et al 2006) The next few years may see
the incorporation of these or other markers into the
treatment algorithms
7.3.1 Response to First Treatment
as an Indicator of Prognosis
Interferon represented a significant advance over
hy-droxycarbamide and busulfan in that a significant
min-ority (10–15%) of patients with CML achieved a
com-plete cytogenetic remission, albeit after 1–2 years This
group of patients showed the greatest survival
advan-tage Data from the phase 2 studies suggested and the
IRIS study confirmed that the complete cytogenetic
re-mission (CCyR) rate after imatinib is substantially
high-er (74%) than that achieved with inthigh-erfhigh-eron Howevhigh-er,
there has been concern over a number of case reports
of rapid progression of disease to blast crises despite
the achievement of CCyR (Avery et al 2004; Jabbour
et al 2006; Morimoto et al 2004) This has led to thequestion as to whether a CCyR achieved on imatinibcarries the same prognostic weight as a remissionachieved with interferon These case reports, however,appear to be the exception and in patients who haveachieved a CCyR, the depth of remission as measured
by molecular response appears better with imatinibthan with interferon Interferon (or hydroxycarbamide)
is now rarely considered as first-line therapy for CMLand it is therefore the response to imatinib that is beingused to predict outcome in general and progression-freesurvival in particular In those patients with a CCyR and
a 3 log reduction in BCR-ABL transcript levels as sured by quantitative RT-PCR, the progression-free sur-vival (PFS) at 2 years is 100% For patients who achieveCCyR but in whom the fall in the BCR-ABL/ABL ratiowas less than 3 logs, the PFS is 95% and in those withoutCCyR the PFS was only 85% (Hughes et al 2003) Atpresent, the follow-up is too short to demonstrate anoverall survival advantage, but given the very low rates
mea-of progression, the clear expectation is that this will beseen with time
7.4 Prognostic Indicators for Transplant Outcome
The most widely used risk assessment score to predicttransplant outcome was developed by Gratwohl et al.and is based on five prognostic features (age at trans-plant, disease stage at transplant, donor type, donor-re-cipient gender combination, and the interval from diag-nosis to transplant) (Table 7.1) Using 3142 patientstransplanted for CML from 1984–1994, the score wasvalidated for transplant-related mortality, survival, anddisease-free survival (Gratwohl et al 1998) More re-cently the IBMTR has confirmed the value of the Grat-wohl score using an independent data set comprising
3211 patients (Passweg et al 2004) The prognostic value
of additional factors such as CMV antibody status of tient and donor, donor age, donor/recipient ABO bloodgroup compatibility, and Karnofsky performance scorewas examined An initial impression that the Karnofskyscore gave useful additional discriminatory power wasnot confirmed in a validation set of patients and hasnot been included in subsequent analyses
Trang 177.4.1 Disease Phase
The disease phase at the time of transplant remains the
most important determinant of survival (Fig 7.2) (Clift
and Storb 1996; Horowitz et al 1996) Survival after
transplant in CP ranges from 60% to 90% at 5 years
(Clift et al 1999; Gratwohl et al 1998; Horowitz et al
1996) The use of chemotherapy preparative regimens,
as opposed to total body irradiation (TBI)-based
regi-mens, and improved supportive therapy (includingCMV and fungal prophylaxis) may improve survivalfurther For example, both an initial and a follow-up re-port of CP CML patients randomized to a preparativeregimen of TBI and cyclophosphamide or busulfanand cyclophosphamide (BU/CY) demonstrated similarefficacy of both regimens (Clift and Storb 1996; Clift
et al 1999) Subsequently, a pharmacological assay forblood busulfan levels revealed that patients with levelsabove 900 ng/ml had better survival and fewer relapses,compared to patients with a level < 900 ng/ml (Slattery
et al 1997) This has led to subsequent targeting of sulfan in all patients to a level > 900 ng/ml (which also
bu-118 Chapter 7 · Allogeneic Transplantation for CML
Table 7.1 a BMT transplant risk score
Original EBMT risk score
Table 7.1 b Survival probabilities according to EBMT score
Risk Score Number of % of patients Probability of outcome at 5 years (%)
Trang 18permits correction for patients with a high busulfan
lev-el to prevent potential toxicity) This strategy may have
contributed to the apparent improvement of survival in
CML CP patients transplanted using targeted BU/CY
In-deed, in 131 consecutive CP CML patients treated in
Seattle using a preparative regimen of
pharmacologi-cally targeted busulfan and cyclophosphamide, the
3-year survival was 85%, with a relapse rate of 8% (Radich
et al 2003) The wide interpatient variation in busulfan
pharmacokinetics can also be overcome with the use of
intravenous rather than oral busulfan (Kim et al 2003)
Whether this will allow the Seattle data to be
repro-duced without the need for pharmacokinetic
monitor-ing is an open question Unfortunately, advances that
may have improved outcomes in CP patients have not
been easily translated to accelerated phase (AP) and
blast crisis (BC) transplants Survival rates in these
phases have remained relatively static over the last
de-cade, so that survival in AP remains approximately
25–40%, and BC, approximately 10%
7.4.2 Age at Transplant
Regimen-related toxicity tends to climb with increasing
patient age (Gratwohl et al 1998) However, age limits
have gradually increased as the introduction of new
preparative regimens and supportive therapies have
im-proved outcomes For example, CP patients transplanted
with matched related donors after TBI-based regimens
experience a clear age effect, with superior outcomes
in younger patients (< 21 years of age), and a steady
drop off in survival by increasing decade of age (Cliftand Storb 1996) This age effect may be mitigated bythe use of non-TBI regimens (e.g., targeted BU/CY),
as recent data from the Fred Hutchinson Cancer search Center in Seattle no longer show an age effect
Re-in patients Re-in CP up to 65 years of age (Clift and Storb1996) Likewise, age does not appear to be an importantfactor with RIC transplants (Crawley et al 2005)
7.4.3 Source of Allograft Donor
For those who lack an HLA-identical sibling donor, theuse of unrelated donor transplants is limited by donoravailability, and the increased toxicity due to the effects
of GVHD its associated infectious complications Fullymatched unrelated donors are now available for over50% of Caucasian patients, but unfortunately, donorsfor patients from other ethnic groups are limited.For “younger” patients (age < 40 years), the results
in CP CML are similar for fully matched unrelatedand related transplants, especially for patients in “goodrisk” groups In a series of 226 patients transplanted infirst CP at the Hammersmith Hospital in London therewere no differences in the transplant outcomes betweenthose patients with unrelated and those with HLA iden-tical sibling donors (Fig 7.3) In a multicenter analysis
of National Marrow Donor Program (NMDP) data, ease-free survival of unrelated and related transplantsfor CML CP patients aged 30–40 years, transplantedwithin 1 year of diagnosis, was 67% vs 57%, respectively(Weisdorf et al 2002) Two other studies have observed
dis-a nedis-ar-equivdis-alence of disedis-ase-free survivdis-al for CP CMLusing either a fully matched unrelated or related donor(Davies et al 2001; Hansen et al 1998) Estimates of dis-ease-free survival of more than 70% were found for pa-tients less than 50 years of age transplanted within ayear of diagnosis (Hansen et al 1998) Recent data fromthe EBMT support this with evidence that the survivalafter unrelated transplant has more than doubled be-tween 1980–1990 and 2000–2003 from 29% to 63% at
2 years (Gratwohl et al 2006)
The improved outcomes with unrelated donors are
in a large part due to the use of sequence-based typingmethodologies for HLA A, B, C, DR, and DQ Transplantoutcomes in CP CML are particularly affected by even asingle antigen or allele mismatch (Petersdorf et al 2004)(Fig 7.4)
Fig 7.3 Overall survival of 178 sibling allografts compared to 48
unrelated transplants for CML in first CP (data from Hammersmith
Hospital London)