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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1527-1535
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
A randomized study of interferon- versus interferon- and
low-dose arabinosyl cytosine in chronic myeloid leukemia
Michele Baccarani,
Gianantonio Rosti,
Antonio de Vivo,
Francesca Bonifazi,
Domenico Russo,
Giovanni Martinelli,
Nicoletta Testoni,
Marilina Amabile,
Mauro Fiacchini,
Enrico Montefusco,
Giuseppe Saglio, and
Sante Tura for the Italian Cooperative Study Group on Chronic
Myeloid Leukemia
From the L. and A. Seràgnoli Institute of
Hematology and Medical Oncology, S. Orsola Hospital, University of
Bologna, Italy; Division of Hematology, Udine University Hospital,
Italy; Division of Hematology, La Sapienza, Rome University, Italy; and
Division of Internal Medicine, University of Turin at Orbassano, Italy.
 |
Abstract |
Interferon- (IFN-) has significantly prolonged survival in
chronic myeloid leukemia (CML), but some patients do not respond and
many responses are not durable. To improve the results, IFN- has
been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the
response rate and to prolong survival. Here are
reported the results of a study of 538 Philadelphia
chromosome-positive CML patients who were assigned at random
to treatment with IFN-2a alone or in combination with LDAC.
The scheduled dose of IFN-2a was 56
IU/m2/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The
efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN--plus-LDAC arm versus 55% in the IFN-
arm; P = .11), major cytogenetic response (MCgR) rate at
24 months (28% versus 18%; P = .003), and overall survival (5-year survival, 68% versus 65%; P = .77).
Treatment did not affect overall survival within different prognostic
risk groups: low, intermediate, or high. Also the duration of MCgR was
identical. The results of this study confirm the results of a similar
French study only for the response rate, not for survival, suggesting
that the relationship between cytogenetic response and survival may be
extremely variable and that a meta-analysis of these and other studies
of IFN- versus IFN- plus LDAC is required to settle the issue of
the role of LDAC in the treatment of CML.
(Blood. 2002;99:1527-1535)
© 2002 by The American Society of Hematology.
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Introduction |
Interferon- (IFN-) became the treatment of
choice for chronic myeloid leukemia (CML) when it was shown that
IFN- was able to induce hematologic and cytogenetic
remissions,1 that some cytogenetic remissions were
stable,2 and that survival was prolonged by comparison
with conventional chemotherapy.3-8 However, not all
patients respond to IFN-, and not all patients have their survival
prolonged. In particular, only 70% of the patients achieve a complete
hematologic response (HR), and fewer then 50% of them achieve the
major and stable cytogenetic response that is associated with long
survival and, sometimes, with a clinical cure.3-11
Therefore, although the introduction of IFN- has marked a
significant advance, only a minority of the patients receive
substantial benefit, and there is still much need for improvement,
especially in the rate, quality, and duration of cytogenetic
response.12 For patients who do not achieve a complete HR
with IFN-, treatment with a conventional cytotoxic drug like
hydroxyurea (HU) is usually employed, although it is not clear if the
combination is more advantageous than conventional chemotherapy
alone.3,5,10,13-15 To improve the results, IFN- has
been systematically combined with arabinosyl cytosine
(AC),16-18 intensive chemotherapy,19,21 or
homoharringtonine22 and has been associated with autologous
bone marrow transplantation,20,21,23,24 with some
promising results but without firm evidence of benefit, except for AC.
The association with AC has been pursued because it was shown that at a
low concentration, AC was more toxic against leukemic cells than
against normal cells24 and that treatment with low-dose AC
(LDAC) was able to obtain hematologic and cytogenetic responses, also
in patients who had failed IFN- alone or who were in advanced phases
of the disease.26-29 A prospective randomized study of
IFN- alone versus IFN- and LDAC was performed in France and was
reported to show the combination to be superior in terms of hematologic
and cytogenetic response and survival.16 That study was
begun in 1991. Three years later, when the results of the French study
had not not yet been discovered, the Italian Cooperative Study Group on
CML undertook a similar study, with the aim of providing independent
data on the important issue that was being tested in the French study.
| |
Patients and methods |
This phase 3, prospective, open-labeled, randomized study was
designed to evaluate whether the addition of LDAC to IFN- increased and improved the hematologic and the cytogenetic response rates, prolonged the duration of the cytogenetic response, and increased overall survival. Patients were eligible for the study if they had
Philadelphia chromosome-positive (Ph+) CML in chronic
phase (CP) for fewer than 7 months; were younger than 66 years old; had
not been treated, or had been minimally pretreated, with HU (less than
50 g, total dose) or busulfan (less than 100 mg, total dose); and
were free of any concurrent disorder that could interfere with
treatment or become life threatening. Written informed consent was
required to participate in the study, which was planned and managed
according to the Helsinki declaration.
Treatment protocol
Pretreatment with HU, 40 mg/kg daily for 15 days, was allowed
for all patients and was recommended in cases of a white blood cell
(WBC) count higher than 100 × 109/L or a splenomegaly
more than 10 cm below the costal margin. Subsequent treatment with HU
was also allowed at any time during the study if it was required to
control counts or symptoms, with the need for treatment as well as the
dose and schedule at the investigator's discretion. Study
treatment was randomly assigned and consisted of human recombinant
IFN-2a (Roferon-A) (Roche, Basel, Switzerland), alone or in
combination with LDAC. Roferon-A was given subcutaneously or
intramuscularly at a dose of 36 IU daily for the first 2 weeks, at 66 IU daily for the next 2 weeks, and at
56 IU/m2 daily thereafter (maximum dose). AC
was given at a dose of 40 mg daily for the first 10 days of each month
of treatment. The guidelines for treatment and dose adjustment were
specified in the protocol, for the various types and degrees of
toxicity. The adjustment was decided every month and was valid for 1 month, after which it was reviewed. In cases of hematologic toxicity or
in cases of nonhematologic toxicity of uncertain attribution, LDAC was
discontinued while Roferon-A was continued, since the conservation of
the dose of Roferon-A had priority over the conservation of the dose of
AC. The assigned treatment was continued, if tolerated and accepted,
until treatment failure. Failure was defined by (1) lack of an at least
partial HR after 6 months, (2) lack of any cytogenetic response (no
Ph metaphases) after 12 months, (3) lack of an at least
minor cytogenetic response (fewer than 33% Ph
metaphases) after 24 months, (4) loss of a complete HR, (5) loss of a
major cytogenetic response, or (6) progression to accelerated or blast
phase (ABP). In cases of treatment failure, the patients who had been
assigned to IFN- alone were transferred to the IFN--plus-LDAC arm, while the patients who had been assigned to IFN- plus LDAC went
off study treatment and were managed at the investigators' discretion.
In cases of progression to ABP, study treatment was always terminated
irrespective of the assigned arm. After 3 years of treatment, the
patients who were in cytogenetic response (at least minor) had to be
randomly assigned to continue IFN- at maximum tolerated dose or at a
low dose (3 MIU 3 times a week). However, no information on the results
of this second randomization will be disclosed in this report, since
the observation time is still too short. The option of allogeneic bone
marrow transplantation (alloBMT) was always open, irrespective of the
response to the treatment, at the patient's and investigator's discretion.
Definitions
The accelerated and blast phases were not separated; the ABP was
defined, as previously described,3 by at least 2 of the following 5 criteria: a peripheral blood sample containing more than
10% blast cells or more than 30% blast cells and promyelocytes; a
bone marrow aspirate containing more than 15% blast cells or more than
50% blast cells and promyelocytes; a spleen that could be palpated
more than 10 cm below the left costal margin and a WBC count lower than
25 × 109/L; the involvement of the central nervous
system, bone, lymph nodes, or other extrahematologic sites; and
cytogenetic evaluation revealing trisomy Ph, trisomy 8, or
isochromosome 17. The HR was defined as complete (CHR) if all the
following criteria were met: WBC count below 10 × 109/L;
platelet count below 450 × 109/L; a differential with no
promyelocytes or myeloblasts and fewer than 5% myelocytes or
metamyelocytes; and a nonpalpable spleen. The HR was defined as partial
(PHR) if any of the following criteria were met: WBC count between 10 and 20 × 109/L; platelet count between 450 and
1000 × 109/L; a differential with more than 5%
metamyelocytes and myelocytes, or with promyelocytes or myeloblasts;
and a spleen palpable less than 6 cm below costal margin. It should be
appreciated that PHR was defined only to decide if the treatment had to
be continued for more than 6 months. The degree of HR was assessed and
checked monthly during the first year, every 2 months during the second year, and every 3 months thereafter. The cytogenetic response (CgR) was
defined on the basis of the percentage of Ph metaphases:
complete CgR (CCgR) in cases of 100%; partial (PCgR) in cases of 66%
to 99%; minor in cases of 33% to 65%; minimal in cases of
1% to 32%; and none if no Ph metaphase was
detected. CCgR and PCgR were pooled and named major (MCgR). The CgR was
evaluated after 6, 9, and 12 months, and every 6 months thereafter.
Cytogenetic evaluations were made on marrow cells, were performed in
different laboratories, and were not centrally reviewed. The minimum
required number of metaphases was 20, but data based on fewer
metaphases, down to a minimum of 10, were accepted if they were
congruent with prior or subsequent evaluations. The risk was calculated
by means of Sokal formulation,30 as it was originally
stated in the protocol. Subsequently, risk was also calculated by means
of the more recent Euro formulation, derived from an international
study of patients treated with IFN--based regimens.31
The variables contributing to the calculation of the risk are age,
spleen size, platelet count, and the percentage of blast cells in
peripheral blood. In addition, the Euro formulation also takes into
account the percentage of eosinophils and basophils in peripheral blood.
Statistical design and procedures
Randomization was required and obtained by fax at registration,
prior to any study treatment, in a ratio of 1:1 on the basis of lists that were computer generated for each participating center. The lists were blind to the investigators and to the secretariat. The
primary efficacy endpoint of the study was overall survival. It was
established that the first assessment of survival would be made at 5 years and that a difference of 25% or more between the test arm
(IFN- plus LDAC) and the control arm would be clinically relevant.
From a prior study,3 the 5-year survival probability in
the control study was settled at 60%. The number of cases that were
required to detect a change of 25% of the predicted 5-year survival
was 450, with a type I error (, 2 sided) of 0.05 and a power (1- )
of 80%, allowing a 20% loss for alloBMT. The number of patients who
were actually randomized was in excess of 450, simply because it was
decided to continue in the same randomized treatment policy even after
the required case number had been reached. Secondary efficacy endpoints
were the rate of CHR after 6 months and the rate of MCgR after 12 and
24 months. It was established that any calculations and any comparisons
would be based on all randomized cases according to the
intention-to-treat principle. Calculations for censored data were made
by the Kaplan-Meier method,32 with the use of the
randomization date as the starting time and the date of the relevant
event (first CHR, first MCgR, death, or progression) as the end time.
The patients who received alloBMT in first CP were censored at the date
of BMT (the results, however, did not change if the patients were not
censored). Patients who received alloBMT after progression to ABP and
patients who received autografts in any disease phase were not
censored. Comparisons were performed by the Student t test,
the  2 test, and the log rank test for trend and for
heterogeneity. All P values were 2 sided.
| |
Results |
Between February 1994 and March 1997, 688 patients were registered
in 64 university and general hospitals located throughout the country,
but only 538 were enrolled and randomized, because 20 patients were
already in ABP, 18 patients refused to be enrolled, and the remaining
112 patients were not eligible for various reasons, such as
prior treatment, being more than 6 months from diagnosis, other
diseases, or logistical problems. The 538 enrolled patients were
assigned to receive IFN- and LDAC (275 patients) or IFN- alone (263 patients). The main demographic, clinical,
and laboratory characteristics of these patients are reported in Table
1, showing that there was no difference
of case distribution in the 2 treatment arms. The median age was 45 years. Spleen was palpable in 58% of cases. The karyotype was mixed
Ph+ and Ph in 15% of cases. The transcript
was B3A2 in 59% of cases. Low-risk patients were 50% by both Sokal
and Euro formulation. High-risk patients were 20% by Sokal formulation
and 8% by Euro.
Hematologic response
At 6 months after randomization, 81% of cases in the
IFN--plus-LDAC arm and 74% of cases in the IFN- arm had
achieved and maintained a complete or partial HR and thus were eligible
to continue in the assigned treatment. At the same time point (sixth month), the CHR rate, one of the secondary efficacy endpoints of the
study, was 62% in the IFN--plus-LDAC arm versus 55% in the
IFN- arm (P = .11, 2 test). The time
that was required to achieve a CHR ranged between 1 and 7 months in the
IFN--plus-LDAC arm (median, 3.5 months) and between 1 and 12 months in the IFN- arm (median, 4 months).
Cytogenetic response
The CgR rate is reported in Table 2.
There was a difference in the rate of the MCgR (complete plus partial,
66% through 100% Ph) in favor of IFN- plus LDAC both
at 1 year (21% versus 13%) and at 2 years (28% versus 18%). In
Table 2, the rates are calculated on the basis of all randomized cases,
according to the intention-to-treat principle. Several cases were not
cytogenetically evaluable for reasons other than treatment failure,
including inadequate cytogenetic examinations, treatment refusal, and
treatment discontinuation for side effects or for alloBMT. If these
cases were removed, the difference would remain the same. Figure
1 shows that the patients who were
assigned to IFN- plus LDAC not only achieved more responses, but
responded more rapidly than the patients who were assigned to IFN-
alone. The duration of the MCgR is shown in Figure
2. About two thirds of the major
responders have maintained the response, with no detectable difference
between the 2 treatment arms.
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| Figure 1.
Time to MCgR.
Time from randomization to the achievement of the first MCgR (complete
or partial) (66% to 100% Ph). The difference is
significant (P = .038, log rank test).
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| Figure 2.
Duration of MCgR.
Time from the first MCgR (complete or partial) (66% to 100%
Ph) to loss of MCgR (lower than 66% Ph)
(P = .97, log rank test). About two thirds of cases are
projected to maintain the response for more than 4 years.
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Survival and response duration
Survival by treatment arm was the primary efficacy endpoint of the
study. It is shown in Figure 3. There was
a trend in favor of the IFN--plus-LDAC arm during the first 3 years, but the 2 curves became almost identical (P = .77),
with a 5-year survival rate of 68% (95% confidence interval [CI],
60%-75%) in the IFN--plus-LDAC arm versus 65% (95% CI,
57%-73%) in the IFN- arm. The early trend in favor of IFN- plus
LDAC is accounted for by the observation that during the first 2 years
the rate of the progression from CP to ABP was less rapid in the
IFN--plus-LDAC arm than in the IFN- arm (Figure
4). However, after 3 years, the
progression rates became identical. The relationship between overall
survival, treatment, and prognostic risk score is illustrated in Table
3. With both formulations, Sokal and
Euro, survival duration was clearly and significantly related with the
risk score, but within each risk group there was no survival difference
between IFN- and IFN- plus LDAC.
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| Figure 3.
Survival.
Survival from randomization (P = .77, log rank test). The
patients who received alloBMT in first CP were censored at the date of
BMT. The number of cases at risk at 12, 24, 36, 48, and 60 months is
246, 217, 181, 111, and 53, respectively, in the IFN--plus-LDAC
arm, and 225, 178, 151, 100, and 49, respectively, in the IFN-
arm.
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| Figure 4.
Time to progression to ABP.
This shows the time lapsed from randomization to progression to ABP.
The early divergence disappeared after 30 months, and the 2 curves are
not different (P = .35, log rank test).
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Overall survival was also related to the achievement of a CgR, but the
survival of patients who had achieved the same degree of CgR was not
affected by the assigned treatment. This is shown in Figure
5, which is a landmark analysis of the
patients who were alive and in CP after 12 months; the analysis was
done according to the extent of the best CgR that had been obtained
during that period and according to treatment arm. We also examined
other variables that were not included in either prognostic
formulations and that might interact with treatment; these included
prior treatment, gender, symptoms, hemoglobin concentration, WBC count,
and transcript type. These variables did not influence the relationship
of treatment to survival. We also examined whether there was any
center-related effect in terms of the number of cases per center and
the compliance with treatment, but no effect could be detected.
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| Figure 5.
Landmark analysis of survival according to CgR and
treatment arm.
The calculation includes only patients who were alive and in CP after 1 year of treatment. Patients are divided into (1) those who during the
first year of treatment had achieved a MCgR (complete or partial) (66%
to 100% Ph) (upper curves, no difference between IFN-
plus LDAC and IFN-) (P = .33, log rank test) and (2)
those who during the same period had not achieved a MCgR (66% or lower
Ph, or Ph not available) (lower curves, no
difference between IFN- plus LDAC and IFN-)
(P = .15, log rank test).
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Treatment discontinuation
The study protocol required the discontinuation of the assigned
treatment in cases of treatment failure, study failure, or alloBMT.
Treatment failure was a priori defined as failure of the patient to
achieve an HR, either complete or partial, after 6 months; failure to
achieve a CgR, at least minimal after 12 months and at least minor
after 24 months; loss of a CHR at any time; loss of an MCgR at any
time; and progression to ABP. Study failure included the patients who
died in CP and patients for whom study treatment was discontinued
for causes related to compliance with treatment, adverse events or
toxic or side effects, or refusal of the patient or the doctor to
continue in the assigned treatment. Table
4 shows the treatment discontinuation by
treatment arm, according to cause of treatment failure and study
failure. In the IFN--plus-LDAC arm, slightly more patients went
off treatment because they had failed to achieve a response or had lost
the response, while in the IFN- arm more patients discontinued the treatment for progression to ABP. However, when one considers total
treatment failures, the percentages were similar: 39% in the
IFN--plus-LDAC arm versus 35% in the IFN- arm. Also, the rate
of treatment discontinuation for study failure, for alloBMT, and for
other causes was the same (Table 4).
Treatment compliance, adverse events
The type and frequency of adverse events are reported in Table
5. There were 140 patients in the
IFN--plus-LDAC arm and 110 patients in the IFN- arm who
reported one or more adverse events of grade 2 or higher (51% versus
42%) (P = .0034, 2 test). The total number
of adverse events or toxic side effects grade 2 or higher was 214 in
the IFN--plus-LDAC arm versus 135 in the IFN- arm, for a
frequency of 0.78 (95% CI, 0.73-0.83) and 0.51 (95% CI, 0.45-0.57)
per patient, respectively. This difference is significant
(P = .008, 2 test). In the
IFN--plus-LDAC arm, there were more cases of psychiatric disorders, mainly depression (21 versus 11); hematologic toxicity (61 versus 21, but with no case of severe marrow aplasia recorded); oral
mucositis (12 versus 2); skin toxicity (13 versus 1); and vomiting (9 versus 2). Table 5 also lists the events that led to permanent
discontinuation of the assigned treatment. While adverse events were
more frequent in the IFN--plus-LDAC arm, the rate of treatment
discontinuation for adverse events was slightly higher in the IFN-
arm than in the IFN--plus-LDAC arm (16% versus 12%)
(P = .145, 2 test). These data confirm that
the addition of LDAC to the basic regimen of IFN- resulted in an
increased toxicity but suggest that the policy of treatment adjustment
that was devised and applied in this study, and which was based on the
priority of the conservation of IFN- over the conservation of AC,
prevented an increased loss rate from the IFN--plus-LDAC arm. In
fact, the events that motivated treatment discontinuation were similar
in the 2 arms, with a prevalence of autoimmune complications (5 cases
of autoimmune hemolytic anemia and 2 cases of thyroiditis) and
psychiatric or neurologic disorders (16 and 8 cases, respectively).
Table 5 also shows the adverse events that were fatal and were the
cause of a death in CP. There was one such case in the
IFN--plus-LDAC arm, consisting in a fatal cerebral ischemic
stroke. There were 4 such cases in the IFN- arm: namely, a case of
congestive heart failure, a case of myocardial infarction, a case of
infection with a septic shock, and a case of fatal traumatic bleeding.
Five cases of other cancers were detected during the study: 2 in the
IFN--plus-LDAC arm and 3 in the IFN- arm.
Treatment dose
The mean daily dose of IFN- was the same in either treatment
arm during the first quarter (3.76 IU/m2 in the
IFN--plus-LDAC arm versus 3.6 in the IFN- arm) and in any
subsequent period (3.9 and 4.1 in the second quarter, 3.6 and 3.7 during the second half year, and 3.4 and 3.3 during the second year).
Therefore, the ratio of the administered to the scheduled dose of of
IFN- ranged from 0.72:1 and 0.68:1 during the first year
and from 0.66:1 to 0.68:1 during the second year (Table
6). This ratio was lower for AC, ranging
from 0.82:1 in the first quarter down to 0.26:1 in the second year,
mainly because an increasing number of patients skipped AC, from 5% in
the first quarter up to 40% in the second year. Note that maintaining
IFN- and skipping AC in cases of toxicity was dictated by the
protocol. The study protocol required that the patients who failed
IFN- alone were crossed over to the IFN--plus-LDAC arm. The
crossing over should have been done in 48 cases, but in 19 of these
cases it was not done because of toxicity, refusal, alloBMT, or other reasons. In the remaining 29 cases, crossing over to the combined treatment resulted in the gain of 4 CHRs out of 14 cases and of 1 MCgR
out of 15 cases.
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Table 6.
Ratio of the administered to the scheduled dose of IFN-
and arabinosyl cytosine in the first 2 years of study
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Bone marrow transplantation
There were 115 patients who went off treatment protocol to receive
alloBMT. Another 25 patients received alloBMT after their treatment had
been discontinued for other causes. Therefore, a total of 130 patients
received allografts in CP: 63 in the IFN--plus-LDAC arm and 67 in
the IFN- arm. The time from randomization to alloBMT ranged between
3 and 44 months, with a median of 12 months in each arm. The 5-year
survival of these patients was 68%, but in all the calculations that
were reported in this paper they were censored at the date of alloBMT.
Another 34 patients (16 in the IFN--plus-LDAC arm and 18 in the
IFN- arm) received alloBMT after progression to ABP, and another 19 patients (9 in the IFN--plus-LDAC arm and 10 in the IFN- arm)
received autografts in advanced CP or in ABP. The survival of these
patients was not censored at the date of the transplant.
| |
Discussion |
In this study, we have evaluated the overall survival at 5 years,
the CHR rate at 6 months, and the MCgR rate at 1 and 2 years in a
cohort of 538 patients with early chronic phase Ph+ CML who
were enrolled over a 3-year period and were assigned at random to
treatment with IFN- alone or in combination with LDAC. The
composition of the 2 treatment arms was identical. The CHR at 6 months
was slightly, but not significantly, higher in the IFN--plus-LDAC
arm. The MCgR rate at 1 and 2 years was significantly higher in the
IFN--plus-LDAC arm. The overall survival and the time to
progression to ABP were identical, with a slight and not significant
superiority of IFN--plus-LDAC arm during the first 2 years.
Overall survival was also identical when the comparison was made within
the same risk group by means of both the old Sokal formulation30 and the new Euro prognostic
score31 (Table 3). The duration of the MCgR was also
identical (Figure 2). The frequency of the adverse events was
significantly greater in the IFN--plus-LDAC arm than in the
IFN- arm, but overall the compliance with the assigned treatment did
not differ (Table 5). However, since treatment protocol was designed
with the intention of assigning priority to the continuation of IFN-
over the continuation of LDAC, in cases of toxicity, almost all
patients received the same amount of IFN- in the 2 arms,
corresponding to about 0.75 of the scheduled dose, while the amount of
AC that was actually given decreased from 0.82 of the scheduled dose in
the first quarter to 0.26 after 2 years (Table 6).
The results of this study provide only a partial support to a general
extension of the combination of IFN- and LDAC to the treatment of
CML. It is useful to remember that the therapeutic application of AC to
the treatment of CML was based on a study25 published in
1987 reporting a preferential inhibition by AC of granulomonocytic
colony-forming units (CFU-GMs) from patients with CML, by comparison
with CFU-GMs from normal controls and showing that the inhibition of
Ph+ CFU-GM could be achieved at a low AC concentration
(4.0 ± 0.9 ng/mL), in a range that is achievable in vivo with a
continuous infusion of a low dose of the drug.33
Subsequent reports suggested that LDAC was effective for treatment of
CML26,29 and that the combination of LDAC and IFN- could
achieve stable hematologic and cytogenetic responses, either in
CP27 or in more advanced phases.28 A national
French study, which was begun in 1991, enrolled 721 patients who were
assigned at random to receive IFN- alone at a daily dose of 5 MIU/m2, or the same dose of IFN- plus AC at a daily dose
of 20 mg/m2 for 10 days every month.16 The
current Italian study was begun in 1991, when the results of the French
study were not yet known, and enrolled 538 patients who were
randomly assigned to the same treatment. The main results of the 2 studies are summarized in Table 7. The
CHR rate at 6 months was identical in the IFN- arms of the 2 studies
(55%) while in the IFN--plus-LDAC arms it was slightly higher in
the French study (66%) than in the Italian one (62%).
Therefore, the difference between the 2 arms was significant in the
French study (P = .003) but not in the Italian study
(P = .11). The MCgR rate was higher in the French than in
the Italian study, in each arm, but the difference in favor of the
IFN--plus-LDAC arm was significant in both studies. The 5-year
survival in the IFN- arm was slightly higher in the Italian study
(65% versus 62%), while in the IFN--plus-LDAC arm it was
slightly higher in the French study (70% versus 68%). In spite of the
smallness of these differences, the difference between the 2 arms,
which was measured with the same log rank method, was significant in the French study (P = .02) but not in the Italian one
(P = .77).
Since it is generally believed that with IFN- any substantial
survival benefit is related to cytogenetic
response,3,7,9-12,16,34 the main question is why the
advantage in terms of MCgR, which was significant in both studies, was
associated with a survival advantage only in the French study. A second
question, which may, however, be relevant to the first, is why the MCgR
rate was higher in the French than in the Italian study for both
treatment arms. Answers to these questions may be helped by a scrutiny
of the data in Table 8, which lists the
results of the main studies of IFN- alone or with LDAC. These
studies are ordered according to the MCgR rate, from the lowest value
of 6.0%, which was reported in the German multicenter prospective
study,4 up to the highest value of 45.1%, which was
recorded in a series of patients who were treated with IFN- and LDAC
at a single center in Houston.17 Table 8 also lists the
5-year survival rates, which range between 50% and 70%; this shows
that although there is a trend toward a relationship between the MCgR
rate and survival, there is great variability, and the relationship
between the MCgR rate and survival is neither linear nor constant.
Therefore, a reasonable conclusion is that the differences between the
French and the Italian study are not surprising and are within the
order of magnitude that would be expected to occur when many studies
are compared. Moreover, it should be noted that although the 2 protocols were very similar for several important issues, such as dose
and schedule of both drugs, priority to IFN- over AC in cases of
toxicity, and the criteria for the definition of HR and CgR, there
were also differences. To cite a few, the upper age was 69 in the
French study and 65 in this study, so the median (and mean) ages were
50 years and 45 years, respectively. In the French study, the
patients who were eligible for alloBMT were neither registered nor
enrolled, while in this study enrollment and randomization were not
dependent on the decision to perform alloBMT, and the option to receive alloBMT was open at any time. Moreover, the criteria for crossover or
discontinuation of treatment differed, and the Italian protocol did not
provide for any increase of AC dose. A joint study of the Italian and
the German Group has already shown that different results can be
explained by a careful comparative analysis of the protocols and the
individual data.15 The same methodology should be applied
to the French study and the present one in a meta-analysis that could
also include the data of another, smaller study that is being performed
in Austria.37 This is important, because a noncontrolled
study of IFN- plus LDAC has shown a possible benefit in terms of CgR
and survival,17 while a second smaller study has failed to
show any advantage.18 New prospective studies of IFN-
plus LDAC will not be designed, while it is urgent to settle
the relationship between the CgR rate and survival and to establish
which treatment should be used as a control to evaluate the efficacy of
other treatments, specifically by protein tyrosine kinase
inhibitors.38-40
View this table:
[in this window]
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|
Table 8.
Percentage of partial cytogenetic responses, complete
cytogenetic responses, and partial plus complete, or major, cytogenetic
responses, and 5-year survival in the main chronic myeloid leukemia
studies of interferon- alone or in combination with low-dose
arabinosyl cytosine
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|
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Acknowledgments |
Among the many persons who have contributed to this study, special
mention is made of the skilled cooperation of Dr Eliana Zuffa and Katia Vecchi.
| |
Footnotes |
Submitted May 29, 2001; accepted October 11, 2001.
Supported by the National Research Council (CNR) of Italy, by The
Italian Association for Cancer Research (AIRC), Milan, and by MURST,
COFIN 1999 (Regulation of Ph-positive leukemia).
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Michele Baccarani, Institute of Hematology and
Medical Oncology, L and A Seràgnoli, S Orsola Hospital,
Via Massarenti 9, 40138 Bologna, Italy; e-mail:
baccarani{at}med.unibo.it.
| |
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Abstract
Introduction