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REVIEW ARTICLE

Chronic Myelogenous Leukemia: A Concise Update

By Hagop M. Kantarjian, Albert Deisseroth, Razelle Kurzrock, Zeev Estrov, and Moshe Talpaz

HRONIC MYELOGENOUS leukemia (CML) is a

clonal myeloproliferative disorder of the primitive hematopoietic stem cell.-3It involves the myeloid, erythroid,
megakaryocytic, B-, and sometimes T-lymphoid elements,
but not the marrow fibrobla~ts.~,~
CML is characterized by
(1) the heterogeneity of the disease among patients, (2) a
biphasic or triphasic course, and (3) the presence of a chromosomal marker, the Philadelphia chromosome (Ph), in
the leukemic
Proliferation is a shared feature of
CML and other myeloproliferative disorders such as essential thrombocytosis, polycythemia vera, and myeloid metaplasia/myelofibrosis. Although these entities are usually distinct, overlap in presentation is occasionally observed,
resulting in diagnostic confusion. Thus, it is important to
confirm the diagnosis of CML by cytogenetic (Ph chromosome) or molecular studies, because the natural history and
treatment of the myeloproliferative disorders are different.
PROGNOSTIC FACTORS AND MODELS IN CML

The disease heterogeneity led to analyses of the prognostic factors in CML (Table 1)6-3and to the development of
prognostic models that categorize patients into good-, intermediate-, or poor-risk groups with different survival expectations (median survival 2, v 3 to 4, v 5 to 6 years, respectively). A synthesis prognostic model, based on these
studies, was p r o p o ~ e d(Table
~
2).
CML PHASES AND DEFINITIONS

CML initially presents in an indolent or chronic phase

course, easily controlled with therapy. With conventional
treatment, it progresses into an accelerated phase that lasts
for less than 1 to 1.5 years, and is followed by a blastic phase
resulting in the patients death within 3 to 6 months.
Twenty percent to 25% of patients die from complications
of accelerated phase, while another 20% to 25% develop a
blastic phase without the intermediate accelerated phase
events. The definition of accelerated phase is vague.15xL6
With more therapies reporting success in accelerated phase,
a standardized definition, within which different approaches could be compared, is needed (Table 3).
CURRENT PROGNOSIS IN CML

In the past, the prognosis of patients with CML was poor.

The expected median survival was 3 years, and less than
20% of patients were alive 5 years after diagnosis. Prognosis
has improved in recent cohorts of CML patients because of
(1) earlier diagnosis, (2) improved anti-CML therapy, and
(3) better supportive care. With routine screening tests,
more patients are detected in the asymptomatic phase of
CML, and with lesser degrees of tumor burden (Table 4). In
contrast to the previous limited number of effective antiCML agents (hydroxyurea or busulfan), several additional
active drugs and combinations are now available that may
improve patient prognosis. These include interferons, lowBlood, VOI 82,NO 3 (August 1). 1993:pp 691-703

dose cytosine arabinoside (ara-C), intensive chemotherapy,

and autologous bone marrow transplantation (BMT). Presently, the median survival in CML is about 60 to 65
months. The survival rates are 75% to 85% at 3 years, and
50% to 60% at 5 years (Fig I). With a interferon (IFN-a)
regimens, 20% to 25% of all patients remain alive with major durable cytogenetic responses on therapy, as discussed
later.
PHILADELPHIA CHROMOSOME, MOLECULAR
ABNORMALITIES, AND DISEASE PATHOPHYSIOLOGY

The Ph chromosome initially described a shorter long

arm of chromosome 22. It is the result of breaks on chromosomes 9 and 22, with a reciprocal translocation of the distal
genetic material, t(9;22)(q34;ql l).7,18This translocation
transposes the c-ab1 proto-oncogene from its normal location, on chromosome 9, to a new position on chromosome
22, in proximity to the breakpoint cluster region (bcr) (Fig
2). A new hybrid BCR-ABL oncogene is formed. It produces an abnormal 8.5-kb RNA that encodes for a 2 IO-Kd
(p210) fusion protein. The latter, presumably through its
increased tyrosine kinase activity, changes normal hematopoietic cells into CML cells.
In Ph-positive CML, the breakpoints within BCR have
been assigned to 3 or 5 locations. Depending on whether
the joinings are between exon 3 or exon 2 of the BCR and
exon 2 of ABL, two different RNA messages are formed:
b3a2 and b2a2. While the 3breakpoints often result in b3a2
and 5 breakpoints in b2a2 messages, some patients with 5
breakpoints (zone 3) produce the b3a2 message. These abnormalities at the DNA and RNA levels have been associated with different prognostic implications, but the findings remain contr~versiaI.@~~
In Ph-positive acute leukemia, 50% to 80% of patients
have a breakpoint proximal to the BCR region, which results in a smaller 7.5-kb RNA and 190-Kd (p190) mesThese changes have been associated with lymphoid
lineage-specific involvement (in contrast to multilineage involvement with p2 10 disease), and with shorter periods to
acute transformation in animal models. However, except
for the development of second chronic phase disease in
p2 10 Ph-positive acute leukemia, the clinical features and
prognoses are similar in p210 versus p190 acute leukemias.26

From the Sections of Leukemia and Biological Studies, the Division of Medicine, M.D. Anderson Cancer Center, Houston, TX.
Submitted February 5, 1993; accepted April 30, 1993.
H.M.K. is a Scholar of the Leukemia Society ofAmerica.
Address reprint requests to Hagop M . Kantarjian, MD. M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 61. Houston, T X
77030.
0 I993 by The American Society of Hematology.
0006-49 71/93/8203-0043%3.00/0
691

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692

KANTARJIAN ET AL

Table 2. Synthesis Prognostic Staging System for CML

Table 1. Poor Prognostic Factors in CML

~~

A. Clinical
Older age
Symptoms at diagnosis
Significant weight loss
Hepatomegaly
Splenomegaly
Poor performance
Black race
B. Laboratory
Anemia
Thrombocytosis, thrombocytopenia, megakaryocytopenia
Increased blasts, or blasts promyelocytes in blood or marrow
Increased basophils in blood or marrow
Collagen or reticulin fibrosis grade 3-4
C. Treatment-associated
Longer time to achieve hematologic remission with busulfan
chemotherapy
Short remission duration
Total dose of busulfan or hydroxyurea therapy required in the first
year to control the disease
Lack of significant suppression of Ph-positive metaphases with
intensive chemotherapy or IFN-ol therapy
Poor initial response to IFN-a therapy

Stage

No of
Poor-Prognosis
Characteristics

0 or 1

RATIONALE FOR INVESTIGATIONAL TREATMENTS IN CML

In the 1970s, intensive chemotherapy was developed, as

for acute leukemia, to attempt elimination of the Ph-positive CML clones. The degree of Ph suppression, or cytogenetic response, was intense but brief. It was also argued that
the Ph-positive event was a late phenomenon, and that the
Ph-negative cells obtained were still clonal. Thus, suppressing Ph-positive cells would not be therapeutically benefiThis was later refuted by in vitro and in vivo studies
showing that the Ph-negative cells were normal, nonclonal
hematopoietic stem ~ e l l s . This
~ ~ , strengthened
~~
the rationale for attempts to suppress or eliminate the Ph-positive

Poor-Prognosis Characteristics
~

1. Age 2 6 0 yrs

2 . Spleen 2 1 0 cm below costal margin

3. Blasts 23% in blood or 23%

in marrow

23

Any accelerated
phase
characteristic

The mechanisms underlying the growth advantage of

CML over normal hematopoietic cells are unknown. The
Ph-associated molecular abnormalities reduce the adherence of CML cells to the stromal matrix, thus decreasing the
time of stroma: hematopoietic cell interaction.* This abrogates the normal maturation of cell surface signals (cytoadhesion molecules, HLA-DR)28,29required for the normal
proliferation-maturation sequence, allowing CML cells to
remain longer in the late progenitor proliferative phase before differentiation. A discordant nuc1ear:cytoplasmic maturation in CML may also provide a growth advantage over
normal hematopoietic cells.3o331
Although increased proliferation is proposed as the mechanism of CML growth advantage, CML cells may live longer than normal cells, and not
undergo programmed cell death, or apoptosis, to the same
degree. Thus, approaches that induce ( 1) suppression of Phpositive cells or (2) normalization of their behavior via adherence to the stroma, maturation of deficient cell surface
signals, differentiation of late progenitor cells, or induction
of apoptosis, may be helpful and should be investigated.

Prognostic Determinants

4. Basophils 27% in blood or 23%

in marrow
5. Platelets 2700 x 103/pL
Accelerated-Phase Characteristics
Cytogenetic clonal evolution
Blasts 2 15% in blood
Blasts promyelocytes 230% in blood
Basophils 220% in blood
Platelets <loo x i03/pL

CML cells. It was postulated that while the bone marrow of

patients with CML is overwhelmed by the growth advantage
of the Ph-positive CML cells, a suppressed normal stem cell
pool persisted, which could be exploited therapeutically.
Treatments that reversed the growth advantage in favor of
normal over Ph-positive cells would hopefully change the
course of CML, and improve patient prognosis.
Preclinical models have established the causal association
between the Ph-associated molecular events and the initiation and perpetuation of CML
In one such
model, c-DNA encoding p2 1 OBCR-ABLwas introduced into
mouse marrow cells, which were reinfused into lethally irradiated mice. After 2 to 8 weeks, some of the mice developed
CML-like disorders, including ( 1) leukocytosis and splenomegaly, ( 2 ) monocyte and macrophage extramedullary tu-

Table 3. Definitions of Accelerated and Blastic Phases of CML

A. Blastic phase CML
30% or more blasts in the marrow or peripheral blood
Extramedullary disease with localized immature blasts
B. Accelerated phase CML
1. Multivariate analysis-derived criteria
Peripheral blasts 15% or more
Peripheral blasts plus promyelocytes 30% or more
Peripheral basophils 20% or more
Thrombocytopenia <lo0 X 103/pL unrelated to therapy
Cytogenetic clonal evolution
2. Other criteria used in common practice
Increasing drug dosage requirement
Splenomegaly unresponsive to therapy
Marrow reticulin or collagen fibrosis
Marrow or peripheral blasts 210%
Marrow or peripheral basophils IT eosinophils 10%or greater
Triad of WBC >50 x 103/pL, hematocrit 125% and
platelets <lo0 x I 03/pL not controlled with therapy
Persistent unexplained fever or bone pains

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693

CHRONIC MYELOGENOUS LEUKEMIA

Table 4. Changing Presentation of Patients With Ph-Positive
Chronic Phase CML by Year of Referral
Percentage With Characteristic

Before
Characteristic

Category

Age Ws)
Asymptomatic diagnosis
Hepatomegaly
Splenomegaly
Hemoglobin (g/dL)
WBC count (X103/pL)
Platelet count (1 03/pL)
Peripheral blasts
Peripheral basophils (%)
Marrow blasts (%)
Marrow basophils (%)
Additional chromosomal
abnormalities other
than Ph within 4 wks
from diagnosis

260
Yes
Yes
Yes

<12
2100
2700
Yes

27
25
23

Yes

1983
(N = 336)

Since
1983
(N = 494)

18
15
46
76
58
69
28
65
17
16
40

12
37
18
54
48
56
19
56
14
9
35

P Value

.03
<.01
1.01
<.01
.01
<.01
1.01
.03
NS

<.01
NS

NS

Abbreviation: NS. not significant.

mors, and (3) acute lymphoid leukemia.38These findings,

recapitulating the pathogenesis of human CML, ( 1) establish the cause-effect relationship between the BCR-ABL
events and CML, (2) suggest that the Ph abnormality is
sufficient, not only for development of the chronic phase,
but also for disease transformation, and (3) strengthen the
notion of improving prognosis in CML, and changing its
course, through treatments that suppress or eliminate Phpositive clones.
THERAPY OF CML

Conventional Therapy
Until 1980, hydroxyurea and busulfan were the two most
effective anti-CML agents. They were superior to irradiation or other drugs such as melphalan, 6 mercaptopurine,
and chlorambucil, provided excellent disease control with
minimal toxicity, were inexpensive, and were administered
orally. Busulfan provided longer periods of disease control,
but was associated with unpredictable prolonged myelosuppression (10% or less of patients); organ fibrosis (lungs,
heart, marrow); and Addisons-like disease. It is still frequently used in countries where socioeconomic considerations prevail, and in older patients who are not candidates
for BMT, and who do not want frequent follow-ups. Hydroxyurea has been the drug of choice in patients who are
candidates for BMT because of its better toxicity profile. It
is used in intermittent schedules to keep the white blood cell
(WBC)count between 10 and 50 X 103/pL,or in continuous
exposure schedules to control the WBC count at a range of 2
to 5 X 103/pL, ie, a minimal CML tumor burden.
Both agents produce hematologic remissions in 70% to
80% of patients with chronic phase CML. However, these
are pseudoremissions because cytogenetic studies in
treated patients show persistence of Ph-positive cells in the
majority (>90%) of marrow metaphases. Ph suppression

has been observed occasionally when unpredictable prolonged myelosuppression is induced by busulfan therapy.
With hydroxyurea therapy, the cytogenetic responses are
minor and transient. While these treatments offer effective
disease control and survival prolongation, they have not
altered the inexorable transformation of CML into the terminal phases.

IFN-(U
Therapy with the partially pure human leukocyte IFN,in
patients with chronic phase CML, demonstrated a complete
hematologic response (CHR) rate of 70%,and a cytogenetic
response rate of 40%.40This was followed by several trials
with the recombinant (Y interferons (IFN-a) alone: or in
combinations with other biologic agents (IFN-.I, DFMO),
with initial or later cyclic intensive chemotherapy, hydroxyurea, and low-dose ara-C. These studies have confirmed
that CHRs are achieved in 70% to 80% of patients, cytogenetic responses in 40% to 60%, and major cytogenetic responses (Ph suppression to <35%) in 30% to 40% (Table 5).
Cytogenetic responses were categorized as complete if Phpositive cells were 0%,partial if they were 1% to 34%, and
minor if they were 35% to 90%. The median survival of
patients treated with IFN-a regimens in early chronic phase
CML is shown in Fig 1.
Results of IFN-(Ytherapy in CML have now been reported by several investigator^^^-^^ (Table 6). Differences in
CHR and cytogeneticresponse rates in various trials may be
related to (1) the CML phase in which patients are treated,
(2) the patient risk group and pretreatment characteristics,
and (3) the dose-schedule of IFN-a (Table 7). Alimena et
al randomized patients to receive IFN-a 2 X lo6 U/m2
three times weekly, or 5 X lo6 U/m2 three times weekly.
Among 33 patients treated at the lower dose schedule, 8
(24%) achieved CHR, compared with 14 of 30 patients
(47%)treated at the higher dose schedule ( P = .06). Among
21 patients who failed to achieve a response at the lower
dose scheduleand who were treated at the higher dose schedule, 8 (38%)achieved CHR. On the daily dose schedule that
they used subsequently, 7 of the first 8 patients treated

100

80

\
(N = 313)

*O

t
0

24

40

72

96

120

Survlval from Start of Therapy (Months)

Fig 1. Survival of patients with Ph-positive CML treated with

IFN-a-based regimens in early chronic phase.

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694

KANTARJIAN ET AL

Chromosome 9

Chromosome 22

t(9;22) (q34;qll)

Chromosome 22

Chromosome 9

BCRABL hybrid oncogene

8.5 Kb mRNA (b3a2 message)
I

Fig 2. The Ph chromosome

in CML and associated molecular abnormalities.

210 KD protein

achieved CHR (87%). In early chronic phase CML, I M - a

at 5 X lo6 U/m2 daily, or at the lower maximally tolerated
individual dose, is associated with better hematologic and
cytogenetic response rates.
Side effects. I M - a is associated with early flulike side
effects (fever, chills, postnasal drip, anorexia, lack of appetite) in most patients, which ( I ) are not dose-limiting, (2)
can be managed symptomatically(bedtimedose,acetaminophen), and (3) are minimized by starting I M - a at 50% of
the dose for the first week. Reducing the initial WBC counts
to 10 to 20 X 103/pLwith chemotherapy also reduces the

Table 5. Results of IFN-UStudies in CML at MDACC

leukocytosis-associated side effects (fever, chills, musculoskeletal pains). Tachyphylaxisdevelops within 1 to 2 weeks.
Late side effects are dose-limiting in 10%to 25% of patients,
and include persistent fatigue; weight loss; neurotoxicity
(depression); a triad of depression, fatigue, and insomnia
(manageable with small doses of antidepressants at bedtime); and occasional immune-mediated complicati~ns?~.~~
These have included immune-mediated hemolysisor thombocytopenia, collagen vascular disorders such as rheumatoid arthritis and systemic lypus erythematosis, and immune-mediated nephrotic syndrome and hypothyroidism.
Rare cases of cardiac dysfunction (arrythmias, congestive
heart failure) have been reported and may be immune-mediated. These necessitate immediate discontinuation of
IFN-a,standardtreatment for heart failure,and steroid ther-

Percent
Cytogenetic
Response
Study-Year
(reference)

Human IFN-a-1982 (40)

Recombinant IFN-a-1984 (41)
IFN-a + IFN-7-1985
IFN-a f cyclic intensive
chemotherapy-1 986
IFN-a + hydrea-1988
IFN-a + low-dose ara-C-1989
Total

NO.
Patients

cnR

Any

Table 6. Results of IFN-a Studies in CML

Major

51
35
36

71
80
68

41
54
47

18
40
31

68
79
44

82
86
70

66
62
55

43
41
32

313

77

56

35

No. (%)
No.
Study (reference)

Patients

cnR

Ph Suppression

M.D. Anderson Cancer

Center
Alimena et al(42)
Niederle et a1 (43)
Ozer et al(44)
Freund et a1 (45)
Montastruc et a1 (46)

313
63
41
107
27
38

240 (77)
29 (46)
23 (56)
63 (59)
10 (37)
32 (84)

175 (56)
27 (43)
14 (34)
3 1/80 (44)
5 (19)
2 4 (63)

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CHRONIC MYELOGENOUS LEUKEMIA

695

+ +

Table 7. Parameters Associated With Differences

in Resoonse to IFN-a in Ph-Positive C M L
Percent
Cytogenetic
Response
Parameter

Category

CHR

Any

Major

CML phase (IFN-a 5 x 10'

Early chronic
Late chronic
Accelerated
Blastic
Low
Intermediate
High
5 X 10' U/m2 daily
5 x 10' U/m2 Tiw
2 x 10' U/m2 Tiw
c2 X 10' U/m2 Tiw

60-80

40-50

20-30

50-60

10-20

30-40
20-30
80-90
50-60
20-60
80
70
30-40
20-30

cl0

<10
0
0

U/m2 daily)

Risk category in early

chronic phase
Dose of IFN-a

<10

60
40
10-20
50-60

40
20
c10

40
20-30
5-10

40
20
5-10
0

Abbreviation: Tiw, 3 times weekly.

apy if indicated. Immune-mediated hypothyroidism does

not require IFN-a discontinuation and is managed by replacement therapy.
Dose reductions are required for (1) grade 3 or 4 toxicity
(hold therapy until recovery then start at 50%),(2) persistent
grade 2 toxicity not improved with symptomatic support
(25%dose reduction), or (3) if the WBC count decreases to
below 2 X 103/pLor platelets below 60 X 103/pL(25%dose
reductions). Elderly patients (age 60 years or older) tolerate
therapy less well than younger patients.
Long-term follow-up of cytogenetic responses. To evaluate the long-term course of patients, and allow for maturation and follow-up of cytogenetic responses, patients treated
until 1988 were reviewed. Cytogenetic studies were performed every 3 months in the first 2 years, then every 4 to 6
months. The duration of cytogenetic response is calculated
from the time of the achievement of any cytogenetic response (Fig 3, A and B), or from the time of achievement of
the best cytogenetic response (Fig 3, C), until recurrence of
more than 90% Ph-positive cells. Durable cytogenetic responses were noted in about 30%of patients (Table 8, Fig 3).
Of the 49 patients achieving cytogenetic complete remission (CR), 45 (92%)have durable cytogenetic responses for
periods ranging between 2 and 8 years, whereas 4 have lost
their cytogenetic response (ie, reverted back to 90% or more
Ph-positive metaphases)(Table 8). Thirty-four of the 49 patients were in a continuous cytogenetic CR (ie, Ph status
0%) with repeated studies. Sixteen of the 34 patients were
taken off IFN-a because of toxicities (5 patients) or patient
or physician choice (1 1 patients; continuous cytogenetic CR
for more than 2 years): 7 of the 16 continue in cytogenetic
CR for 12+ to 56+ months (median 34 months); 6 had Ph
recurrence but went back to 0%Ph-positivity (3 patients) or
less than 35% Ph-positive (3 patients) with reinstitution of
IFN-a; and 3 had recurrence of Ph-positive metaphases but
are on observation off IFN-a therapy (cytogenetic but not
hematologic relapse). Among the remaining 11 patients, 6
fluctuate with Ph-positive metaphases of 0% to lo%,
whereas 5 have more than 10%Ph-positive metaphases, but
are in continuous cytogenetic response on IFN-a therapy (2
with less than 35%Ph-positive metaphases). Thus, currently

28 (18 7 3) of the 49 patients (57%)are in continuous

cytogenetic CR on or off IFN-a therapy; while 39 patients
(28 cytogenetic CR, 1 1 cytogenetic PR) (80%of total) are in
a durable major cytogenetic response.
Associations of cytogenetic responses with prognosis. Accounting for the time to achieve the best cytogenetic response (median time 22 months for complete, 18 months
for partial, 12 months for minor cytogenetic responses, respectively), the duration of cytogeneticresponse was longest
in patients achieving a complete cytogenetic response (Fig
3). This is not surprising because, in most other tumors, the
lowest detectable tumor burden achieved (ie, CR) is the only
response that is associated with durable remissions and with
prolongation of survival or disease-free survival. Once such
a low tumor burden is obtained in a substantial fraction of
patients (40% to 60%), significant survival prolongation
may be observed for the total population under treatment.
A similar significant association between the cytogenetic response at 12 months and survival was also reported by the
Italian Cooperative Study Group in CML.4' Using a landmark analysis, Ozer et alMdid not find a significant correlation between cytogenetic response and remission duration
or survival. However, their analysis combined cytogenetic
CR and PR as one category (which might have diluted the
association), and only 14 patients were in cytogenetic CR.44
Zuffa et aIs1 updated their comparative study that randomized patients to IFN-a at 5 X lo6 U/m2 daily (218 patients) or hydroxyurea (104 patients). The long-term followup showed major cytogenetic response at 4 years in 25% of
patients receiving IFN-a and in 0% of those treated with
hydroxyurea. The median survivalswere significantly better
in IFN-a-treated patients overall (not reached v 49 months,
P = .004), and within low-intermediate (not reached v 50
months, P = .04),and high-risk groups (56 v 38 months, P =
.02).5*
Investigatingthe long-term prognosis of patients, Lazzarino et a15' analyzed IFN-a as a treatment variable for prognosis, showing it to be significantly favorable in good- and
intermediate-risk patients, but not in those with poor-risk
disease.
Interpretation of the maturing experience. While the results of Zuffa" and Lazzarino et a15' support association
between IFN-a and improved survival, the fact that only
25% of patients have complete responses suggests that the
beneficial effect on survival in the total denonimator may
not be reproducible in other studies. In general, to observe
the effect in the whole population, at least 40% of patients
should achieve a minimal tumor burden (ie, CR for solid
tumors, cytogenetic CR for CML) if that response is associated with at least a 25% improvement in progn6,:is (10%
overall improvement; P = .05; power 80%; 100 patients in
study and control groups).
These findings have important therapeutic implications.
If the positive effect of IFN-a on survival of the total population is shown in other studies, the treatment recommendations might change to advise continuing IFN-a therapy in
all patients with CML, regardless of the cytogenetic response, aiming for the survival benefit. However, if the survival association is not solidly confirmed, then only patients

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KANTARJIAN ET AL

696

100

80

E
0

5 %

60

(n = 101)

c .o,

gz

E&

40

0
20
Fig 3. Duration of cytogenetic response (A)
overall; and by cytogenetic response from (E) start
of therapy, and (C) from time of achievina
the best
response in patients treated from 1982 to 1988
(M.D. Anderson data base in CML). RefertoTable8
and text for discussion.

24

48

96

72

120

Duration of Cytogenetic Response (Months)

Cytogenetic CR (n = 49)

100
.I
?I

::

:L

80

:
. II

5::

S,U

.* I
.: II
:I

60

*a--

:... I
i,CI

Ea -2

i.:

2e:,g,

Cytogenetlc PA (n = 14)

..... L -----_--------.
.........,. Cytogenetlc Minor (n
.........................

40

:.

Cytogenetic PR (n = 14)

L--------

20

cytogenetic Minor (n = 38)

..............................

= 38)

\.
0

24

48

72

96

120

who achieve a major cytogenetic response would continue

on IFN-a therapy (discussed later under Proposed Sequence of Treatments in CML). Future studies with IFN-a
combinations would then aim to achieve complete cytogenetic response rates of 40% or more before other randomized clinical trials are planned.
In summary, the maturing experience with IFN-a regimens (1) shows median survivals of 60 to 65 months with

Table 8. Long-Term Follow-up d Responses in Patients Treated

With IFN-a-Based Regimens (1982-1988)
No. (%)

Parameter

Total treated
Complete hematologic response
Cytogenetic response
Complete
Partial
Minor
Overall

190 (100)
141 (74)
No. (%)

49 (26)
14 (7)
38 (20)
101 (53)

No. Durable [%I

45 [92]
5 [361
6 [IS]
56 [29% of total;
55% of
cytogenetic
resoondersl

24

Duration

Duratlon of Cytogenetic Response (Months)

48

72

96

120

of Cytogenetlc Response (Months)

25% of patients being in durable cytogenetic remissions,

and ( 2 ) suggests the superiority of IFN-ar over conventional
therapy, as measured by cytogenetic response and survival.
Other IFNs
The promising results with IFN-a encouraged the search
for other IFNs or biologic agents with potential anti-CML
activity. IFN-y differs from a and j3 IFNs in its biologic
properties, mechanisms of action, and cell surface receptors. Studies investigating y-IFN in CML have shown definite but modest activity, with a CHR rate range of 20% to
30%.53Combining IFN-a with y-IFN in ( I ) a simultaneous
dose schedule using the full dose of IFN-a and a low (in
vitro synergistic) dose of IFN-7, or ( 2 ) in a sequential fashion using alternate-day or alternate-week schedules of the
two IFNs, has produced disappointing result^.^^^^' IFN-j3
has had limited investigation in CML with negative res u l t ~ Studies
. ~ ~ with the concensus IFN,a synthetized
molecule that presumably incorporates the active moieties
of different subspecies of ar IFWs, are underway.

Combinations of IFN-a and Other Agents

To improve the prognosis beyond that obtained with
IFN-a alone, investigations have combined it with other

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697

CHRONIC MYELOGENOUS LEUKEMIA

Table 9. Therapy With IFN-a Alone or With Low-Dose ara-C
in Late Chronic-Phase CML

genetic response rate (30% v 44%),and for disease control at

12 months (60% v 80%).

No. (%)

Allogeneic BMT
No.

CML Phase

Late chronic

Therapy
IFN-a
IFN-a

Accelerated (clonal IFN-a

evolution only)
IFN-a

+ ara-C
+ ara-C

Patients
40
39
16

CHR
22 (55)
11 (28)
P=.02
8 (50)
6 (66)

Cytogentic
3-yr
Response Survival (%I
6 (1 5)
2 (5)
P = .15
4 (25)

2 (22)

75
48
P<.O1
74

49

effective anti-CML agents including busulfan, hydroxyurea,

initial or cyclic intensive chemotherapy, and low-dose araC. Combining busulfan with IFN-a proved to be difficult
because of the cumulative effect on prolonged myelosuppression. Adding intensive chemotherapy to IFN-a was not
associated with better results than with IF"-(U alone, perhaps because of the short-term exposure of CML cells to the
effect of chemotherapy (only 3 initial courses, or once every
6 months) mandated by the serious myelosuppressive side
effects.57
The combination of IF"-a and hydroxyurea is attractive
in clinical practice because of its ease of administration.
This regimen provides (1) rapid disease control, ( 2 )a better
CHR rate, (3) a lower incidence of side effects attributed to
leukocytosis (fever, chills, musculoskeletal syndrome), and
(4)a longer duration of disease control. However, it is not
associated with improved cytogenetic response rates (overall, major, durable).
Ara-C was combined with IFN-a because of its selective
anti-CML effect in vitro, and its capacity to induce cytogenetic remissions in treated patient^.^^,^^ With low-dose araC therapy in chronic phase CML, Sokal and Bigner" and
Cannistra et a159 observed cumulatively Ph suppression
down to a median of 27% Ph-positive metaphases (range 0%
to 84%)in 6 of 8 patients. Low-dose ara-C is associated with
less myelosuppressive side effects than intensive chemotherapy, and provides longer exposure of CML cells to the treatment (about 1 week every month) and, hence, potentially
better suppressionof CML clonal evolution. In late chronicphase CML, the combination of IFN-a and low-dose ara-C
was associated with significantly higher CHR rates compared with IFN-a alone, a trend for better cytogenetic response rates, and with significantly longer survivalm(Table
9). It also induced suppression of clonal evolution in 5 of 20
patients (25%) treated in accelerated phase (16 patients with
clonal evolution only, see Table 11; 4 patients with other
accelerated phase features with or without clonal evolution).
In a randomized study, Guilhot et a16' treated patients
with early chronic-phase CML with IFN-a plus low-dose
ara-C (39 patients) or with IFN-a alone (36 patients). Both
groups had received hydroxyurea during remission induction to achieve rapid cytoreduction until CHR was obtained. Compared with IFN-or therapy alone, the combination of IFN-(Uplus low-dose ara-C was associated with a
higher complete cytogenetic response rate (8% v 28%; P <
.01) and with nonsignificant trends for a higher major cyto-

Allogeneic BMT is curative in CML, with significantly

better disease-free survival rates in chronic, compared with
accelerated or blastic phases (Table 10). Candidate patients
should be offered matched or one antigen-mismatched related allogeneic BMT in chronic phase, before disease transformation.
The timing of allogeneic BMT in chronic phase is more
controversial because of the risks of the procedure. In
chronic phase CML, better results are achieved (1) in
younger patients, (lower risk of early and graft-versus-host
disease [GVHDI-associated mortality), (2) when BMT is
performed in early chronic phase, and (3) in patients not
exposed to busulfan
A lower incidence of BMT
morbidity and mortality from GVHD has been observed
with T-cell-depleted BMT, which was counterbalanced by
the higher incidence of graft failure and leukemia reiapse.66,67
The lower disease-free survival rates with transplantation
later in chronic phase CML are not due to a higher incidence of leukemia relapse (ie, more resistant clones from
longer disease duration), but to a higher BMT mortality.
This suggests that host- (age, organ function) or treatmentrelated factors (prior busulfan exposure) are partly responsible for this difference. This difference in survival rates, while
statistically significant in the international BMT registry
(IBMTR) in over 1,000 patients evaluated, is in the range of
5% to 1096, and may not be relevant to individual patients,68
particularly when accounting for age and prior therapy considerations. In a subset analysis of patients receiving non-Tcell-depleted allogeneic BMT, Goldman et a169 reported
both the duration of chronic phase, and exposure to busulfan therapy, to be independent prognostic factors for patient
outcome. The European BMT Registry (EBMTR) has not
shown a survival difference by time to BMT, but patients

Table 10. Results of Allogeneic BMT in CML

Percent

CML Phase

A . Results by CML Phase

Chronic
Accelerated
Blastic

Disease-free
Survival

Leukemia
Relapse

40-60
15-25
15 or less

50-60
60-80

5-30

% With Parameter by Age of Patients (yrs)

Parameter
B. Results by Age in ChronicPhase CML
Early mortality
Late mortality
Leukemia relapse
Disease-free survival

t20

20-29

230

5-10
5-10
20

10-20
10-20
20

10-25
10-25

60-70

40-50

40

20

From www.bloodjournal.org by guest on July 20, 2015. For personal use only.

698

with worse expected prognosis may have received transplants earlier in chronic-phase CML.70The long-term follow-up studies from both registries show disease-free survival rates of 38% at 5 years, a figure lower than projections
from earlier reports, with a continuous pattern of late relapses (relapse rates 10%at 2 years, 25% at 5 years). This late
relapse pattern, not seen in acute leukemia, may be caused
by the more primitive stem cell involvement in CML. Both
of these updates have included patients who had undergone
T-cell-depleted allogeneic BMT, and the disease-free survival rates in non-T-cell-depleted BMT are higher. In the
EBMTR studies, patients with prior IFN exposure and
those who underwent splenectomy before BMT did not
have different outcomes compared with those who had
Allogeneic BMT with matched unrelated donors (MUD)
has yielded encouraging r e s ~ l t s . ~The
~ , ~median
'
time from
the start of the search to BMT was 8.4 months. The procedure was associated with ( 1 ) a higher incidence of graft failure (16%), and ( 2 ) higher incidences of grade I11 and IV
acute GVHD (54%)and of extensive chronic GVHD (52%).
Overall, the 2-year disease-free survival rate was 3 1%, and
ranged from 14%to 43% depending on the patient age and
degree of HLA-mat~hing.~'
Thus, while promising, MUD
allogeneic BMT is presently associated with significant morbidity and mortality, particularly in older patients. It is indicated in patients with a poor prognosis (acute leukemia in 2
first relapse, CML transformation). Its benefit versus risk
should be carefully weighed in chronic-phase CML, particularly among older patients, in relation to other investigational modalities, and to the natural course of the disease
with current treatments.

Proposed Sequence of Treatments in CML

All patients with CML transformed (accelerated, blastic)
phases and those with a syngeneic donor should be offered
allogeneic BMT ifthey are candidates for the procedure (age
less than 50 to 55 years, available matched or one antigen
mismatched related donor).
Younger patients (age cut-off defined by investigators according to their experience in different age subgroups)
would be offered related allogeneic BMT in early chronic
phase when possible, because of the high disease-free survival rates and low morbidity and mortality in these age
groups.
For the remaining patients, an initial trial of IFN-acontaining regimen may be indicated. If patients achieve a
significant response (any cytogenetic response at 6 months,
Ph-positive cells less than 50% to 65% at 12 months) they
will continue on therapy unless the response is lost. The
others will be offered allogeneic BMT from related donors,
or investigational treatments such as MUD allogeneic
BMT, autologous BMT, or new agents (homohamngtonine, others) or combinations (Fig 4).
Patients who achieve a complete durable cytogenetic response documented over a 6-month period should have an
autologous marrow storage. In them, IFN-a therapy should
be held for at least 1 month before autologous marrow preservation for ease of procedure and storage of an adequate

KANTARJIAN ET AL

if n z available

Early chronic phase CML

Cytogenetic response
Any
Ph <at50%
6 months
at 12 months

If not

Investigational approaches
HUD allogeneic BMT
BHT
.: Autologous
New agents or regimens

Fig 4. Proposedtreatment approach in patients with CML.

marrow for BMT (3 X 10' nucleated cells or more/kg, IO4 or

more GMCFC/kg).
IFN-a therapy was thought not to benefit patients in late
chronic-phase CML. Recent studies showing a survival ad. ~ ' of IFN-a plus lowvantage of IFN-a versus h ~ d r e a ~ 'and
dose ara-C in late chronic phase CMLm suggest otherwise.
Patients in late chronic-phase CML who are not candidates
for allogeneic BMT (related, MUD), should consider an investigational trial before deciding on maintenance with
IFN-atherapy (IFN-a plus low-dose ara-C or hydroxyurea)
for optimal benefit (Fig 4).

Autologous BMT
Autologous BMT in CML transformed phases was associated with a high rate of reestablishment of a short-lasting
second chronic phase. In chronic-phase CML, autologous
BMT with infusions of predominantly Ph-positive autologous stem cells (peripheral, marrow) produced transient cytogenetic remission^.^^,^^ Follow-up studies have suggested a
longer survival with autologous BMT. However, similar to
autologous BMT studies in other tumors (acute leukemia in
first CR, multiple myeloma, breast and lung cancers), it is
difficult to dissociate the effect of patient selection, and lead
time bias, from that of BMT. Comparative studies with patients treated with other modalities and matched for age,
organ function, and time to BMT may help clarify the issue.
Autologous stem cell transplant using in vivo (chemotherapy, IFN) or in vitro purging (chemotherapy, IFNs, longterm liquid cultures, positive selection for CD34-positive
normal stem cells, negative selection for CML
is
an exciting strategy. The purpose is to infuse stem cells maximally enriched with normal hematopoietic cells and depleted of Ph-positive clones.
Using long-term liquid (Dexter) cultures for in vitro purging of CML marrows, Barnett et a174screened 88 patients
and identified 33 (38%) to be suitable for the large-scale
purging procedure. Twenty of the 33 patients underwent
purged autologous BMT (14 in first chronic phase; 6 in later

From www.bloodjournal.org by guest on July 20, 2015. For personal use only.

CHRONIC MYELOGENOUS LEUKEMIA

phases). Graft failure was noted in 5 patients (20%). Of 14

evaluable patients by cytogenetic studies, 12 (86%; 60% of
total) achieved a cytogenetic CR, and the other 2 had a
cytogenetic PR. After a median follow-up of 15 months
(range 6 to 51 months), Ph-positive recurrence was observed in 8 of the 12 patients, and 6 received IFN-a therapy.
Five patients (20%of total) are currently disease free for 14,
28,29,32, and 5 1 months, the latter 2 with IFN-atherapy.74
Alimena75summarized the Italian experience in patients
with CML who underwent autologous BMT intensification
if they had not achieved a desirable cytogenetic response
with IFN-a therapy. Fifteen patients, whose median percent
of Ph-positive cells was 72% after a median duration of 20
months of IFN-a therapy, had marrow harvest and underwent autologous BMT: 5 remain in cytogenetic remission
(Ph-positive less than 35% in 2, and more than 35% in 3).75
In that same analysis, of a total of 48 patients undergoing
autologous BMT before (26 patients) or after IFN-a therapy
(22 patients), 11 (23%) achieved favorable cytogenetic response~.~~
These relatively mature studies, as well as others using
different forms of in vitro purging (IFN-7, CD34-positive
stem cell selection, negative selection of Ph-positive cells),
or in vivo purging (intensive chemotherapy), encourage further investigations of purged autologous BMT programs as
an intensification procedure to (1) to increase the rate of
durable cytogenetic responses and ( 2 ) to prolong survival.
The potential use of oncogene-targeted approaches (antisense oligonucleotides, conjugated toxins) for in vitro purging or in vivo therapy in autologous BMT are of interest.
Combinations of these approaches may result in selective
relatively nontoxic anti-CML therapies.

Other Investigational Modalities

New agents such as homoharringtonine have shown
promising anti-CML e f f i ~ a c y . ~ ' ,Homoharringtonine,
~~
used in a low-dose prolonged-infusion schedule in patients
with late chronic-phase CML, resulted in CHR in 68% of
patients, and in cytogenetic responses in 3 1% ( 1 7% major)." Its activity in combination with IFN-a in early
chronic-phase CML is under i n ~ e s t i g a t i o n Other
. ~ ~ approaches of interest include differentiating agents (retinoids), agents that block cytokines that may mediate CML
progression (interleukin- 1 [IL- 13 receptor antagonists; I L 1
soluble receptors),80and new chemotherapeutic drugs.
QUESTIONS OF INTEREST IN THE MANAGEMENT OF CML

Ph Chromosome-Negative CML
About 10% of patients with a morphologic picture of
CML do not have the Ph chromosome by cytogenetic analysis. One third of them will have BCR rearrangement by
Southern blot molecular analysis (Ph-negative BCR-positive CML) and have a similar clinical picture, response to
therapy, and outcome as Ph-positive CML.'' The remaining patients have a spectrum of disorders including myelodysplastic syndrome with a myeloproliferative component,
chronic myelomonocytic leukemia, and true "Ph-negative,
BCR-negative CML." The latter, unlike Ph-positive CML,

699

may have a low propensity for blastic transformation (25%

to 50%), and an intermediate prognosis between chronic
myelomonocytic leukemia (CMML) and Ph-positive CML.

Thrombocytosis in CML
Thrombocytosis in CML is a poor prognostic feature, and
may be associated with thromboembolic or bleeding complications. In most patients, thrombocytosis responds to the
regimen used in controlling CML. IFN-ais effective in controlling thrombocytosis in more than three quarters of patientsS2Anagrelide, an agent that prevents megakaryocytic
maturation, also reduces the platelet counts, but has no effect on marrow megakaryocytosi~.~~
In patients refractory
or intolerant to the above treatments, thiotepa is effective at
doses of 75 mg/m2 intravenously every 2 to 3 weeks until
response occurs.
CML and Pregnancy
Pregnant women with CML may be managed with repeated leukophereses during the first one or two trimesters
of pregnan~y.'~
Leukopheresis may be performed when the
WBC count exceeds 70 to 100 X 103/pL, or in symptomatic
conditions. Hydroxyurea has been used in the later stages of
pregnancy without untoward or teratogenetic effects on the
fetus. IFN-a is teratogenic in animal models. Two of our
patients became pregnant while undergoing IFN-a therapy;
the treatment was discontinued, and both delivered normal
babies. However, patients on IFN-a therapy should have
adequate contraception, because the treatment has the potential of inducing serious complications in the newborn
(underweight babies, malformations).
Role of Splenectomy in CML
The spleen may be an initial site of CML transformation
in a minority of patients (? less than
These may be
the patients with persistent significant splenomegaly despite
adequate disease control in the BM and blood. Studies randomizing patients to splenectomy or no splenectomy in
early chronic phase,86 or before allogeneic BMT have not
Splenectomy before allogeshown a survival ad~antage.'~,~'
neic BMT may result in earlier hematopoietic recovery, but
is associated with a higher incidence of GVHD in patients
without palpable splenomegaly. Based on current knowledge, splenectomy in chronic-phase CML may be considered for persistent significant splenomegaly on optimal therapy, particularly with evidence of hypersplenism, or with
suboptimal treatment delivery because of anemia or thrombocytopenia. Splenectomy in CML transformation may be
associated with increased morbidity and mortality without
an obvious therapeutic benefit.
When Should Molecular Studies Be Performed in CML?
In patients with a morphologic picture of CML but no
Ph-positive metaphases, Southern blot analysis for BCR rearrangement will identify the subset of Ph-negative, BCRpositive CML patients. This will help directing their therapy
(as for Ph-positive CML) and prognosticating on the course
of the disease.

From www.bloodjournal.org by guest on July 20, 2015. For personal use only.

KANTARJIAN ET AL

700

The value of molecular studies to detect 3 versus 5breakpoints, or b3a2 versus b2a2 messages, is controversial. It
should be pursued in investigational studies, but not as routine tests in clinical practice.
In the follow-up of patients on treatment, BCR rearrangement quantification has not yet been standardized in relation to cytogenetic studies. Once the equivalence of the two
studies for measuring the degree of Ph-suppression is established, serial follow-ups with BCR quantification may be
easier, faster, and less expensive. The test is currently useful
to monitor the effect of therapy in patients with Ph-negative
BCR-positive disease. Southern blot analysis is equivalent,
but not superior, to cytogenetic studies in assessing minimal
residual disease (ie, Ph-positive 0%).
Polymerase chain reaction (PCR) studies to detect residual disease at
to
level is an important investigational tool in Ph-positive CML. In our experience, PCR
studies for BCR-ABL were positive in all 40 patients who
had 0% Ph-positive metaphases by cytogenetic studies after
IF%-a therapy. Other groups have reported some cases
with P C R - n e g a t i ~ i t y Detection
.~~~
of residual disease at
this level may not be clinically relevant because it has not
predicted consistently for subsequent relapse. Among patients studied after allogeneic BMT, more than 75% will
have at least one PCR-positive test within 12 months post
BMT, and 40% to 53% will be positive at 12 month^.^^-^*
Only 25% of the latter group will have CML relapse. Consequently, PCR studies for BCR-ABL should be pursued in
investigational studies of therapeutic interventions in CML,
but not in current community practice.
FUTURE DIRECTIONS

Future investigations should aim at improving and maximizing the intensity and duration of cytogenetic responses
in CML, ie, suppressing the Ph-positive clones responsible
for disease propagation and progression. This could be
achieved through (1) optimizing IFN-a combination regimens (with low-dose ara-C, homohamngtonine, or other
agents); (2) investigating new approaches in allogeneic BMT
that improve the efficacy and safety of the procedure; (3)
pursuing the leads in purged autologous BMT as an intensification procedure, followed by IFN-a or other maintenance therapies; (4)developing selective antioncogene targeted therapies; and (5) discovering new agents with specific
anti-CML efficacy. The sum of such programs will hopefully improve significantly the prognosis in CML over the
next decade.
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1993 82: 691-703

Chronic myelogenous leukemia: a concise update

HM Kantarjian, A Deisseroth, R Kurzrock, Z Estrov and M Talpaz

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