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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2039-2042
PERSPECTIVE
Chronic myeloid leukemia: current treatment options
John M. Goldman and
Brian
J. Druker
From the Imperial College School of Medicine, London,
United Kingdom, and the Oregon Health Sciences University, Portland.
 |
Abstract |
The choice of primary treatment for patients with chronic myeloid
leukemia (CML) diagnosed in chronic phase has become exceedingly difficult. There is little doubt that allogeneic stem cell
transplantation can eradicate the leukemia and that a
graft-versus-leukemia effect makes a major contribution to this result;
conversely, only a minority of patients are eligible for
transplantation, which still carries an appreciable risk for death or
protracted illness. For most patients, interferon- (IFN-)
prolongs life to some degree in comparison with hydroxyurea, but it is
associated with considerable toxicity. The newly introduced tyrosine
kinase inhibitor STI571 induces complete hematologic remission in
almost all patients and is associated with a very high rate of
cytogenetic response; its capacity to prolong life in comparison with
IFN- is not yet established. Here are reviewed some factors that
predict survival after nontransplantation therapy and after
allografting for CML in chronic phase. Two contrasting options are
considered for managing the patient with newly diagnosed disease, and
it can be concluded that, for now, allogeneic stem cell transplantation
soon after diagnosis should continue to be offered as an option for
selected patients. Further experience with the use of STI571 as a
single agent or in combination with other antileukemic agents may alter the picture in the near future.
(Blood. 2001;98:2039-2042)
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Introduction |
It is generally accepted that allogeneic stem cell
transplantation (allo-SCT) has the potential to cure selected patients with chronic myeloid leukemia (CML) and that cure depends on the contribution of a poorly defined graft-versus-leukemia
effect.1 However, there is a significant risk for illness
or death as a direct consequence of the procedure. The introduction of
interferon- (IFN-) in the 1980s complicated the decision about
whether to recommend allo-SCT, and early clinical experience with the
Abl signal transduction inhibitor STI571 has made the decision-making process yet more complex. Here we define the current problem in general
terms and suggest some tentative recommendations. We recognize that
these recommendations may be valid for only a limited period.
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Predicting survival with nontransplantation therapy |
The duration of survival after diagnosis is highly variable
in a given cohort of patients with CML in chronic phase treated by
nontransplantation methods; the reason for this heterogeneity is
largely unknown. Studies at the molecular and cytogenetic levels may
have some prognostic value. For example, it was thought at one time
that the precise position of the genomic breakpoint in the
BCR gene might correlate with duration of survival, but this notion has not been substantiated. Conversely, recent data suggest that
the presence of genomic deletions in the vicinity of the ABL-BCR gene on 9q+ may have prognostic
significance.2 Moreover, the speed of telomere shortening
in the leukemic clone may relate inversely to the duration of
survival.3 These last 2 findings must be validated in
larger clinical trials.
In the 1980s, Sokal et al4 devised a staging system based
on clinical and hematologic criteria at diagnosis that correlated with
duration of survival for subgroups of patients treated predominantly with busulfan. (For individual patients, the Sokal score can be calculated by accessing the Web site:
http://www.nrhg.ncl.ac.uk/cgi-bin/cml/sokal.pl). More recently, Hasford
et al5 introduced an analogous system for predicting
survival of patients treated with IFN- (go to http://www.pharmacoepi.de/cmlscore.html for an on-line calculator). Patients at low risk and treated with IFN- had a median survival of
100 months, whereas patients at high risk had a median survival of 45 months. This low-risk group of patients, who may expect relatively long
survival with IFN- treatment, are particularly difficult to advise
regarding treatment options.
In practice, one of the most effective ways of predicting
survival is to assess the hematologic response to IFN- at 6 months and the cytogenetic response at 1 year.6 The greatest
survival advantage is seen in IFN--treated patients who achieve a
major cytogenetic response (less than 35% Ph-positive metaphases),
though the median time to optimal cytogenetic response may be 1 to 2 years. However, patients who do not achieve complete hematologic response at 6 months or who fail to achieve even a minor cytogenetic response (less than 65% Ph-positive) at 1 year are unlikely to obtain
a major cytogenetic response. Thus, patients not achieving these
landmarks could be considered candidates for alternative therapies.
| |
Trial of therapy with interferon- |
It has been argued that patients at low risk could safely be
treated with IFN- for the first year, particularly given that the
risk for blast transformation in these patients is 1% to 2%, even
though they were otherwise eligible for allo-SCT. However, because
patients who undergo transplantation within the first year of diagnosis
have lower transplantation-related mortality rates than those who
undergo transplantation at longer intervals,7 this
strategy has been questioned in a decision-based
analysis.8 In addition, there has been much speculation
that prior treatment with IFN- might adversely affect the result of
a subsequent allograft procedure; in practice, a carefully performed
multicenter study in Germany implied that patients whose IFN-
treatment was discontinued at least 90 days before allografting fare no
worse than those who had never received IFN-.9
| |
Predicting survival after allogeneic stem cell transplantation |
The range of possible outcomes for a patient undergoing allo-SCT
varies widely. At one extreme, a patient may have an uneventful posttransplantation course and eventually be cured of CML. At the other
extreme, a patient may die within weeks of transplantation because of
acute graft-versus-host disease, opportunistic infection, or another
complication. Although the probabilities of complications and death can
be estimated for given patient cohorts, there is no reliable way of
predicting outcome for an individual patient.
Gratwohl et al10 made use of the database maintained by
the European Group for Blood and Marrow Transplantation (EBMT) to calculate a risk score that gives a probability of survival after allo-SCT. The risk score uses 5 specific pretransplantation
features phase of CML, duration of disease, patient age, degree of
donor-recipient histocompatibility, and donor-recipient gender match.
To this list may be added cytomegalovirus serostatus, which
correlates with survival, at least if the donor is not a family
member.11,12 Using the EBMT system,
transplantation-related deaths for patients with total scores of 0 or 1 were approximately 20%, whereas mortality rates were as high as
70% for patients with scores of 5 or 6. The International Bone Marrow
Transplant Registry is carrying out a similar analysis. This approach
does not, of course, take into account the possible independent effects
on transplantation-related mortality of procedure-related factors, such
as details of conditioning, stem cell dose, or approach used to prevent
graft-versus-host disease.
The notion that a graft-versus-leukemia effect plays a major role in
leukemia eradication has led to the introduction of reduced-intensity conditioning or nonmyeloablative stem cell transplantation (NMSCT). In
this procedure, the conditioning regimen is substantially reduced, and
reliance is placed on the donor-derived lymphocytes for eliminating the
patient's leukemia.13,14 Theoretically, this could
greatly reduce the toxicity and mortality associated with the
conventional procedure, allowing allografting to be offered to a wider
population of CML patients. Data from different centers using a variety
of reduced-intensity conditioning regimens show that some patients have
achieved Ph-negativity. The rate of molecular negativity and the
durability of these remissions must be determined from ongoing clinical
trials before one can recommend that NMSCT, also referred to as
minitransplants, should replace conventional allografting procedures
for patients deemed eligible for transplantation.
| |
STI571 |
STI571 is an Abl-specific tyrosine kinase inhibitor capable of
inhibiting the proliferation of CML cell lines and clonogenic CML
progenitor cells.15 It was first administered to patients with CML in the summer of 1998, and additional clinical trials accrued
patients rapidly. The drug is given orally, is well tolerated, and has
a manageable side-effect profile. Fifty-four patients with
chronic-phase CML either resistant or refractory to IFN- were
treated with STI571 at a dose of 300 mg/day or greater. Almost all
rapidly achieved complete hematologic responses17 (31%) achieved major cytogenetic responses, and 7 (13%) achieved complete cytogenetic remission.16 Although the durability of these responses
and the incidence of molecular remission cannot yet be assessed, an ongoing phase 2 study of 532 patients in chronic phase, for whom IFN- therapy failed, was designed to address this issue. Thus the
short-term results suggest that STI571 is a major advance in comparison
with the use of IFN- or IFN- plus cytarabine. This notion is
being tested in an international prospective study in which more than
1000 patients with newly diagnosed disease were randomized to receive
either STI571 or IFN- plus cytarabine. The definitive end-point will
be survival.
Although hematologic and cytogenetic responses to IFN- have
prognostic value, one cannot automatically assume that the same relations will apply for STI571. In other words, will the patient who
obtains good or complete cytogenetic response with STI571 survive as
well (or better) than a patient who obtains a comparable response with
IFN-? Will such responses be equally well maintained? Patients
treated with IFN- rarely achieve complete molecular remission when a
sensitive reverse transcription-polymerase chain reaction is
used.17 Will STI571-treated patients do better in this
regard? The ongoing randomized study comparing STI571 to IFN- plus
Ara-C is designed to address these questions, and these data are
essential before we can say with certainty that a particular patient
treated with STI571 is likely to gain substantial prolongation of life.
The picture is complicated further by the fact that patients treated
with STI571 in combination with other agents may survive longer than
those treated with STI571 alone. There are plans to launch a 3-arm
multicenter study comparing STI571 with STI571 plus IFN- and STI571
plus cytarabine in patients with newly diagnosed disease. The number of
possible permutations using other drugs is enormous. Moreover, the
results of allo-SCT could conceivably be improved by prior or
subsequent use of STI571. Conversely, as was required with IFN-, it
remains to be determined whether prior treatment with STI571 negatively
impacts survival after allo-SCT.
| |
Patient preference |
In most cases the hematologist will be asked for his or her
recommendation on primary management, though the preference expressed by the informed patient must logically be the final deciding factor. For example, if the patient is determined to be cured of his or her
disease, allo-SCT is the only approach clearly able to achieve this
aim. Conversely, a patient for whom an allo-SCT seems advisable may
deem the risks of the procedure unacceptable and may thus prefer
treatment with IFN- or STI571. These points notwithstanding, we
suggest below a basis for treatment recommendations for
individual patients.
| |
Choice of primary therapy |
There are 2 contrasting approaches to the treatment of patients
with newly diagnosed CML.
Option 1
One approach is to recommend that every patient with newly
diagnosed CML receive initial treatment with STI571, IFN-, or a
suitable combination, ideally in the context of a clinical trial (Figure 1). Patients in the appropriate
age range for whom this trial of therapy fails and who have
human leukocyte antigen (HLA)-identical siblings or HLA-matched
alternative donors would then be offered allo-SCT. The problems with
this approach relate in part to the difficulty in defining a meaningful
response or failure to STI571 (or the combination) and in part to the
risk that the inherent delay might permit time for the disease to
progress. Although it now seems unlikely that prior treatment with
STI571 would adversely influence the results of subsequent allograft,
it is at least possible that a delay in transplantation might adversely
affect the result independently of any particular prior
therapy.
View larger version (19K):
[in this window]
[in a new window]
| Figure 1.
Schematic representation of option 1 by which all
patients with newly diagnosed disease receive a "trial" of STI571.
Those who do not respond (as defined in the text) may proceed to
undergo allo-SCT if they are young enough and have a suitable stem cell
donor. NMSCT, nonmyeloablative stem cell transplantation.
|
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Option 2
The second approach would be to try to decide within a few weeks
of diagnosis whether a given patient is or is not a good candidate for
allo-SCT (Figure 2). Patients newly
diagnosed would likely fit into 1 of 3 categories: (1) Patients deemed
eligible for transplantation (for this purpose, one must set an
arbitrary level of risk for transplantation-related mortality above
which early transplantation should not be recommended; one might
possibly accept a risk of up to 15% or 20%); (2) Patients for whom
transplantation is thought to carry a higher risk; and (3) Patients for
whom transplantation could not reasonably be considered in any
circumstance.
View larger version (27K):
[in this window]
[in a new window]
| Figure 2.
Schematic representation of option 2, by which some
patients are offered treatment by allo-SCT soon after diagnosis if they
are young and have a suitable donor.
Others are deemed ineligible for allo-SCT. The intermediate group is
offered initial treatment with STI571 and may proceed to allo-SCT if
the trial of STI571 is deemed to have failed. A/G indicates
autografting.
|
|
In this scheme, patients in category 1 would proceed to transplantation
soon after diagnosis. Taking into account the various factors that
impact on transplantation-related mortality, one might assume that a
patient under the age of 40 with an HLA-identical sibling donor or a
patient under the age of 30 years with a molecularly matched volunteer
donor might be a good candidate for an early allograft. One could
speculate that these upper age limits for transplantation might be
reduced by 10 years for patients in the Hasford good-risk category. For
patients in category 2, it would be reasonable to offer a trial of
therapy with STI571 or a combination incorporating STI571 and then to
assess the response after 6 or 12 months. Patients who did not achieve
and maintain a reasonable degree of cytogenetic improvement would then
be offered an allograft. Patients in category 3 might be offered
primary treatment with STI571 or a combination of STI571 with IFN-
or cytarabine with STI571 or a combination of STI571 with IFN- or
cytarabine or an autograft procedure.
At the time of writing, we believe the best advice for the patient with
newly diagnosed CML is option 2. Relatively young patients with newly
diagnosed CML who have HLA-identical sibling donors or molecularly
HLA-matched unrelated donors should undergo conventional
transplantation within the first year of diagnosis. The role of NMSCT
cannot yet be reliably assessed.
Although at present the curative potential of STI571 is unknown, it is
entirely possible that STI571 alone, in combination with other agents,
or in conjunction with a novel approach to immunotherapy could
eradicate CML. Because clinical trials that test the various
combinations will soon be initiated, patients not wanting to undergo
allo-SCT should be encouraged to enroll in one or other of these
studies. If 1 or 2 years from now it becomes clear that few, if any, of
the patients responding to STI571 progressed to advanced disease and
that the cytogenetic responses achieved are durable, then option 1 involving initial treatment with STI571 (or an STI571-containing
combination) will become the treatment of choice. This view will gain
additional support if some of the patients who achieve complete
cytogenetic responses also achieve durable molecular remissions.
| |
Footnotes |
Submitted February 14, 2001; accepted May 30, 2001.
@ 2001 by The American Society of Hematology.
Reprints: John M. Goldman, Department of Haematology,
Hammersmith Hospital, Imperial College School of Medicine, Ducane Rd,
London W12 0NN, United Kingdom; e-mail: jgoldman{at}ic.ac.uk.
| |
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Ann. Onc.,
June 1, 2003;
14(6):
813 - 816.
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E. A. Hahn, G. A. Glendenning, M. V. Sorensen, S. A. Hudgens, B. J. Druker, F. Guilhot, R. A. Larson, S. G. O'Brien, D. G. Dobrez, M. L. Hensley, et al.
Quality of Life in Patients With Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia on Imatinib Versus Interferon Alfa Plus Low-Dose Cytarabine: Results From the IRIS Study
J. Clin. Oncol.,
June 1, 2003;
21(11):
2138 - 2146.
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M. W.N. Deininger, S. G. O'Brien, J. M. Ford, and B. J. Druker
Practical Management of Patients With Chronic Myeloid Leukemia Receiving Imatinib
J. Clin. Oncol.,
April 15, 2003;
21(8):
1637 - 1647.
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S. G. O'Brien, F. Guilhot, R. A. Larson, I. Gathmann, M. Baccarani, F. Cervantes, J. J. Cornelissen, T. Fischer, A. Hochhaus, T. Hughes, et al.
Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia
N. Engl. J. Med.,
March 13, 2003;
348(11):
994 - 1004.
[Abstract]
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J. V. Melo, T. P. Hughes, and J. F. Apperley
Chronic Myeloid Leukemia
Hematology,
January 1, 2003;
2003(1):
132 - 152.
[Abstract]
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I. Ringshausen, F. Schneller, C. Bogner, S. Hipp, J. Duyster, C. Peschel, and T. Decker
Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cdelta
Blood,
November 15, 2002;
100(10):
3741 - 3748.
[Abstract]
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E. A. Copelan, J. M. Goldman, and B. J. Druker
Treatment options in chronic myelogenous leukemia
Blood,
April 15, 2002;
99(8):
3070 - 3071.
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M. O'Dwyer
Multifaceted Approach to the Treatment of Bcr-Abl-Positive Leukemias
Oncologist,
April 1, 2002;
7(90001):
30 - 38.
[Abstract]
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M. C. Heinrich, C. D. Blanke, B. J. Druker, and C. L. Corless
Inhibition of KIT Tyrosine Kinase Activity: A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies
J. Clin. Oncol.,
March 15, 2002;
20(6):
1692 - 1703.
[Abstract]
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H. Kantarjian, C. Sawyers, A. Hochhaus, F. Guilhot, C. Schiffer, C. Gambacorti-Passerini, D. Niederwieser, D. Resta, R. Capdeville, U. Zoellner, et al.
Hematologic and Cytogenetic Responses to Imatinib Mesylate in Chronic Myelogenous Leukemia
N. Engl. J. Med.,
February 28, 2002;
346(9):
645 - 652.
[Abstract]
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D. G. Savage and K. H. Antman
Imatinib Mesylate -- A New Oral Targeted Therapy
N. Engl. J. Med.,
February 28, 2002;
346(9):
683 - 693.
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M. J. Mauro, M. O'Dwyer, M. C. Heinrich, and B. J. Druker
STI571: A Paradigm of New Agents for Cancer Therapeutics
J. Clin. Oncol.,
January 1, 2002;
20(1):
325 - 334.
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B. J. Druker, S. G. O'Brien, J. Cortes, and J. Radich
Chronic Myelogenous Leukemia
Hematology,
January 1, 2002;
2002(1):
111 - 135.
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B. J. Druker, C. L. Sawyers, R. Capdeville, J. M. Ford, M. Baccarani, and J. M. Goldman
Chronic Myelogenous Leukemia
Hematology,
January 1, 2001;
2001(1):
87 - 112.
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Top
Abstract
Introduction