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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4059-4065
Response at Three Months Is a Good Predictive Factor for Newly
Diagnosed Chronic Myeloid Leukemia Patients Treated by Recombinant
Interferon-
By
F.X. Mahon,
C. Fabères,
S. Pueyo,
P. Cony-Makhoul,
R. Salmi,
J.M. Boiron,
G. Marit,
C. Bilhou-Nabera,
A. Carrère,
M. Montastruc,
A. Pigneux,
Ph. Bernard, and
J. Reiffers
From Service des Maladies du Sang, Centre Hospitalier Universitaire
de Bordeaux, Hôpital Haut-Levêque, Pessac, France; and the
Département d'Informatique Médicale, Université
Victor Segalen, Bordeaux, France.
 |
ABSTRACT |
In a single institution, we have used recombinant interferon-
(IFN-) to treat 116 newly diagnosed Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients and
analyzed the predictive factors for response and survival. The patients
whose median age was 50.3 years (range, 9 to 70) were administered
IFN- (5 million units/m2/d) subcutaneously. The IFN-
dose was subsequently adjusted to maintain the white blood cell and
platelet counts between 1.5 and 5 × 109/L, 50 and 100 × 109/L, respectively. At diagnosis, the Sokal score was used
to classify the patients into three groups: low (n = 57),
intermediate (n = 42), and high risk (n = 16). A complete
hematological response (CHR) was achieved in 93 cases (80.2%). Of the
116 patients, 113 were available for cytogenetic evaluation. Fifty
patients (43%) achieved a major cytogenetic response (MCR) (=65%
marrow Ph cells), 37 of them having a complete
cytogenetic response (CCR). The estimated 5-year survival of the 116 patients was 68% ± 11% (95% confidence interval [CI]) with a
median follow-up of 42 months (range, 3 to 114) and 85% ± 11% (95%
CI) with a median follow-up of 30.9 (range, 3 to 111) when patients
were censored at the time of transplantation. Event-free survival at 5 years (adding death and transplant as event) was 46% ± 11% (95% CI). Using proportional hazards regression to study
time-dependent variables, we confirmed that the most significant factor
associated with survival was the cytogenetic response (MCR or CCR)
(P < .0001). This factor was independent compared with the
Sokal score and baseline variables used to calculate the Sokal score.
Moreover, using either univariate or multivariate analysis, the
achievement of CHR within 3 months was strongly correlated with MCR
(P < .0001). Minimum cytogenetic response (mCR, ie, at least
5% of Ph metaphases) at 3 months was also a significant
predictive factor for MCR (P < .0001). These results show
that IFN- can induce a high rate of hematological and cytogenetic
response when administered in doses leading to myelosuppression.
Factors such as the achievement of CHR and mCR within 3 months could be
useful to identify early those patients who will not respond to IFN-
and who need alternative treatments such as stem cell transplantation.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
CHRONIC MYELOGENOUS LEUKEMIA (CML) is a
clonal myeloproliferative disorder characterized by acquisition of the
Philadelphia chromosome (Ph) in leukemic stem cells and their
progeny.1,2 The abnormal Ph chromosome is the result of a
reciprocal translocation between chromosomes 9 and 22. The major
consequence of this translocation is the fusion of the ABL gene to the
BCR gene on chromosome 22.3 The BCR-ABL fusion gene, which
is transcribed into an 8.6-kb chimeric mRNA, encodes a
210-kD hybrid protein that is probably responsible for the
chronic phase of the disease, but its critical function has not yet
been defined.4 The cells belonging to the malignant clone
can be detected by either chromosome analysis or molecular techniques
designed to monitor (and amplify) the expression of the characteristic
Bcr-Abl message.5
The course of CML is characterized by a multistep process from a
chronic phase to accelerated and blastic phases with rapidly fatal
outcome. Marrow transplantation (BMT) is the only curative treatment
for CML patients under the age of 45 to 50 years .6,7 Autologous stem cell transplantation (ASCT) has more recently been
proposed as an alternative treatment, but its efficiency is still under
evaluation.8 Using recombinant interferon- (IFN-), it
has been shown that complete hematological remission (CHR) and a
cytogenetic response (minor, partial or even complete) can be achieved
in some patients with newly diagnosed CML, and that some of these
remitter patients have a prolonged survival.9-12 However,
the contrary was found in two other studies.13,14 Thus, it
would be useful to have a test to identify early those the patients who
will not respond to IFN-.
In our institution, we have now treated 116 patients with IFN- as
first line treatment and obtained a high rate of CHR as well as a high proportion of cytogenetic responses.15 We
have analyzed the factors influencing survival and the response to IFN- to identify early the CML patients who could be proposed for
alternative treatments.
| |
PATIENTS AND METHODS |
Patients.
Between October 1986 and February 1997, 116 patients (males = 66;
females = 50) were entered into the study. All patients (median age,
50.2 years; range, 9 to 70) had Ph+ CML in chronic phase
without clinical or biological signs of acceleration or blast
crisis.16 According to Sokal's
classification,17 the patients were divided into three
categories: low risk (index < 0.8) (n = 57), intermediate risk (0.8 < index < 1.2) (n = 42), and high risk (index > 1.2) (n = 16)
(Table 1). One patient had undergone an
operation for splenectomy before diagnosis, so the Sokal index could
not be calculated. These 116 patients were treated with IFN- alone
(see below).
During the same period of time, 46 other patients with previously
untreated CML in chronic phase were treated differently: 13 patients
were treated using straight ASCT (n = 5) or allogeneic BMT as first
treatment (n = 8); 33 others were treated by hydroxyurea alone (n = 26)
or combined IFN- (n = 7), because they were more than 70 years old
or they were included in an open French multicenter study comparing
hydroxyurea and IFN-.18
Treatment.
After informed consent, the patients were given recombinant IFN- (5 million IU/m2/d, subcutaneously). All patients
received IFN- as first-line treatment. The median time between
diagnosis and IFN- was 36 days (range, 1 to 356). IFN- doses were
subsequently adjusted to maintain the white blood cell (WBC) count
between 1.5 × 109/L and 5 × 109/L
and the platelet count between 50 and 150 × 109/L.
IFN- was stopped when the WBC count was below 1.5 × 109/L or the platelet count below 50 × 109/L. Moreover, IFN- was interrupted when: (1) There
was no response to IFN- with an increase in WBC count or less than
25% WBC decrease compared with initial leukocytosis over a period of
14 weeks; (2) patients failed to achieve a CHR or a cytogenetic
response (complete, partial, or minor) after 6 or 12 months,
respectively; or (3) an initial response was followed by a subsequent
increase in WBC to more than 40 × 109/L uncontrolled
by continued IFN- therapy.
These patients were planned to undergo either allogeneic BMT (for
patients under 45 years when an HLA-identical donor was available) or
ASCT.19
Moreover, IFN- was stopped when a blast crisis developed or
unacceptable toxic reactions (grade 3) were observed.
For responding patients, the treatment was continued when there were no
extra-hematological toxic effects (see below).
Response criteria.
Hematological and cytogenetic responses were evaluated according to the
criteria reported by the Houston group.20 A CHR required
the normalization of the peripheral WBC count to less than 10 × 109/L with the disappearance of immature circulating cells
(blasts, promyelocytes, myelocytes, metamyelocytes), the normalization of platelet count (<450 × 109/L) and the
disappearance of all signs and symptoms of the disease (in particular,
palpable splenomegaly). A partial hematological remission (PHR) was
defined by a decrease in WBCs of at least 50% compared with the
initial leukocytosis to a value at least below 20 × 109/L. This included patients whose peripheral WBC counts
had become normal but who had persistent splenomegaly or immature
peripheral cells. Failure comprised nonresponders. Accelerated phase
was defined according to the criteria described by Kantarjian et
al16 and blast crisis was considered to be when more than
30% blast cells were present in the BM.
Cytogenetic evaluation.
BM karyotypes were performed using a routine cell synchronization
technique after a 24- to 48-hour culture. Twenty-five to 30 R-or
G-banded metaphases were photographed or video-printed. Neither
fluorescence in situ hybridization (FISH) nor polymerase chain reaction
(PCR) data were performed.
Cytogenetic response was classified according to the proportion of Ph
metaphases21: (1) No response when the Ph chromosome persisted in all metaphases; (2) minor response when the Ph chromosome persisted in 35% to 95% of metaphases; (3) partial response when the
Ph chromosome persisted in 1% to 34% of metaphases; (4) complete response when the Ph chromosome was not found in marrow metaphases on
at least one karyotypic study.
In this report, we have considered together partial and complete
cytogenetic response as "major cytogenetic response" (MCR). For
cytogenetic evaluation 3 months after starting IFN- therapy, we have
defined a minimal cytogenetic response (mCR) as at least 5%
Ph cells present.
Toxic effects.
According to the World Health Organization classification, toxic
effects were classified in four groups 1 to 4: mild, moderate, severe,
and life-threatening. The treatment was temporarily stopped when a
grade 3 or 4 toxicity appeared and definitively stopped when a grade 4 neurological toxicity occurred.
Statistical analysis.
Comparisons were made by the Log-rank method and the Chi-square test.
Survival curves and cumulative incidences of hematological and
cytogenetic responses were analyzed by the Kaplan and Meier method and
were compared using the Log-rank test. A multivariate analysis of
prognostic factors was performed according to the Cox model. We also
compared results of this analysis with landmark analysis looking at
survival in patients who had already survived 1 year. Cytogenetic
responses were included as a time-dependent covariate (coded 0 before
and 1 after the date of occurrence of the event).22 At any
fixed point during the study, the effect of these events was assessed
only on the basis of events that occurred before that point. Baseline
variables for which P = .05 in the log-rank model were also
included in this proportional hazards model using a stepwise procedure,
and were tested either with threshold or continuous variables.
| |
RESULTS |
Hematological response.
For the 116 patients, the median follow-up was 42 months (range, 3 to
114). All patients received IFN- therapy for a median duration of 24 months (range, 3 to 110).
CHR was achieved in 93 patients (80%), and the cumulative incidence of
CHR at 12 months was 84% ± 7% (95% confidence interval [CI])
(Fig 1). The median time to achieve CHR was
4.6 months. Among the 93 patients who achieved CHR, 41 (44%) did
within 3 months of treatment (early CHR), whereas 52 other patients
entered CHR later (3.5 to 9 months) (late CHR). A number of
disease-related variables were tested by univariate analysis for their
association with CHR. The initial individual prognostic factors (size
of spleen, leukocytosis, peripheral blast [PB] cells, platelet count)
and Sokal score did not influence the CHR rate.
For the 93 patients, the estimated chance of remaining in CHR at 3 and
5 years after achieving CHR was, respectively, 57.7% ± 11% (95%
CI) and 48% ± 12% (95% CI). The Sokal risk groups (P = .028), platelet count (>380¥ 109/L)
(P = .02), spleen size (P = .04), and PB blast cells
(P = .018) were found to influence significantly CHR duration
by univariate analysis. Using multivariate analysis only platelet count
was found to influence CHR duration (P = .006 and relative risk = 2.76).
Cytogenetic response.
Of the 116 patients, 113 were available for cytogenetic evaluation. The
cumulative incidence of complete cytogenetic response (CCR) at 12 and
24 months was 16% ± 7% and 38% ± 11% (95% CI), respectively (72 and 39 cases, respectively, were exposed to this probability at 12 and 24 months). Among the 93 patients who achieved CHR, 37 (32% of the whole population) subsequently achieved CCR. The
estimated probability of remaining in CCR 24 and 48 months after
achieving it was 81% ± 13% and 66% ± 18% (95% CI),
respectively.
Thirteen other patients had more than 65% Ph cells,
so the total number of patients achieving MCR was 50 (43% for the
whole population). Thus, the actuarial proportion of patients who
achieved MCR at 6, 12, and 24 months was 10% ± 5%, 33% ± 9%, and 56% ± 11% (95% CI), respectively
(Fig 2). For the 50 MCR patients, the median time to achieve the MCR was 9.6 months (range, 3 to 28). The
estimated chance of remaining in MCR 24 and 48 months after achieving
it was, respectively, 84% ± 11% and 70% ± 15% (95% CI).
Toxic effects.
A flulike syndrome was usual and disappeared spontaneously or with
paracetamol after a few weeks of treatment. In three patients, IFN-
could be continued despite clinical signs of thyroid insufficiency due
to autoimmune thyroiditis.
However, 12 cases of severe intolerance were observed and the treatment
had to be stopped. One patient developed hepatitis with very high
levels of transaminases and gamma glutamyl transpeptidase (10×).
Seven patients exhibited neuropsychiatric toxicity (1 depression within
the context of manic-depressive psychosis, 1 case of
undetermined transitory encephalitis, and 5 neuropsychiatric
disorders). Three other patients had a cardiac dysfunction (acute
pericarditis, arythmia, and congestive heart failure). Finally, we also
observed a clinical symptom mimicking rhumatoid pseudo-arthritis. All
these complications disappeared after a few weeks when IFN- was
stopped.
Outcome and SCT.
Forty-four patients underwent either allogeneic (n = 17) or
ASCT (n = 26). Another patient was treated by autologous
then allogeneic SCT. The indications for transplantation were as
follows: no CHR at 3 months (4 cases), no CHR at 6 months (7 cases), no MCR at 12 months (7 cases), hematological relapse after CHR (10 cases),
cytogenetic relapse after MCR (5 cases), accelerated phase (10 cases),
patient request (1 case). After allogeneic (9 of 17) or autologous (8 of 27) SCT, 17 patients died: this was due to blastic transformation (4 cases); transplant-related complications, ie, veno-occlusive disease (2 cases); interstitial pneumonitis (4 cases); hemorrhage (2 cases);
infection (1 case); acute graft-versus-host disease (3 cases); and
multiple organ failure (1 case).
Ten other patients who did not undergo transplantation died: 9 nonresponders died before transplantation; 6 of them were in acceleration, 1 had cardiac failure, and the cause of death was undetermined for the other 2 patients. Finally, 1 patient died from
hepatitis encephalopathy while he was in CCR.
We analyzed the survival, taking into account the transplantation
outcome. In both cases the median survival was not
reached. When the patients who underwent transplantation were censored at the time of the transplant, the estimated 5-year survival was 85% ± 11% (95% CI) with a median follow-up of 30.9 (range, 3 to 111)
months. When the patients were not censored at the time of transplant,
the estimated 5-year survival was 68% ± 11% with 42 months of
median follow-up (38 patients are exposed to this probability). Taking
into account transplant or death as constituting events (event-free
survival [EFS]), the probability of survival at 5 years was 46% ± 11% (Fig 3).
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| Fig 3.
Survival of the IFN--treated CML patients. Median
survival was not reached at 110 months for the curve A but the number
of observations is relatively small past 48 months. EFS of
IFN--treated CML patients was calculated using transplant and death
as constituting events (curve B).
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IFN- was stopped in three CCR patients because of the toxic effects.
In all three patients CCR was sustained with a follow-up of,
respectively, 22, 42, and 66 months after cessation of IFN-. Minimum
residual disease was detected only by molecular analysis such as
reverve transcriptase-PCR (amplification of Bcr-Abl
mRNA).23
Achievement of cytogenetic response is the best predictive factor for
survival.
Different factors for predicting survival have been analyzed. Among the
patient-related and disease-related variables studied by univariate
analysis, Sokal score (P = .02) and platelet count (>700 × 109//L) (P = .16) were found to
significantly influence survival. However, the best predictive factors
for survival were the achievement of CHR (P < .0001), MCR (P < .0001), and CCR (P < .0001) (Table 2). The 5-year survival for MCR versus
other patients was, respectively, 93% ± 9% versus 44% ± 17% (95% CI) (Fig 4).
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| Fig 4.
Survival and cytogenetic response. Survival probability
among the patients who obtained a major cytogenetic response MCR and
other patients. Day 0 represents the date of starting IFN-.
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Using landmark analysis, all the patients remaining alive at 12 months
(88 patients) were also classified according to whether they had a MCR
(47 patients) as compared with the others (41 patients), and survival
was analyzed, which showed a significant advantage for MCR patients
(P < .0001) (Fig 5).
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| Fig 5.
Landmark analysis of survival. All patients remaining
alive at 12 months (88 patients) were classified according to whether
they had an MCR compared with the other patients.
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For the multivariate analysis, we included either the Sokal score or
the associated factors from the Sokal score (age, PB blast, spleen,
platelet count) and considered cytogenetic reponse CCR or MCR as
time-dependent variables. This multivariate proportional hazards
regression model showed that both MCR and CCR were significantly associated with survival independently of the other factors. Indeed, according to this model, the patients who achieved MCR or CCR were at,
respectively, 0.17 and 0.13 time the risk of dying of the remaining
patients (P = .0001) independently of the other factors (Table
3). Sokal scores alone
without the threshold were entered quantitatively into this model and
were excluded from the final model: Sokal score, P = .91, relative hazard (RH) = 1.0035; CCR, P =.0001, RH = 0.1273. Moreover, MCR was also confirmed to be strongly linked to survival
(P < .00001, RH = 0.16) independently of the Sokal score
(P = .94, RH = 0.9978).
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Table 3.
Effect of Baseline Variables From the Sokal Score and
Cytogenetic Response (MCR and CCR) Events on Survival in the 113 Patients Using a Proportional Hazards Regression Model
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CHR at 3 months is the best predictive factor for cytogenetic
response.
By univariate analysis a number of patient-related and disease-related
variables were tested (age, sex, WBC count, platelet count,
splenomegaly, PB cells, percentage Sokal score) for their association
with MCR and CCR. Percent of PB cells and Sokal categories were found
to influence the MCR (P = .007) and CCR (P = .01)
rates. The CHR rate was also found to be significantly
associated with CCR (P < .02) and MCR (P < .002).
However, the CHR rate at 3 months was the most significant factor for
predicting MCR (P < .0001) and CCR (P = .0001) (Fig 6). The probability of MCR for
patients who achieved CHR at 3 months was 79% ± 14% (95% CI),
whereas it was 44% ± 15% for the others. Consequently, CHR at 3 months was also a strong predictive factor for EFS (P = .005)
and overall survival (P = .006).
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| Fig 6.
Probability of MCR (n = 113) among the patients who
achieved a CHR within 3 months (n = 41) and the other patients
(n = 72).
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Of the 113 evaluable patients, 41 achieved CHR within 3 months (group
1), 29 patients between 3 and 6 months (group 2), and 43 had not
achieved CHR at 6 months (group 3). The clinical characteristics including Sokal score did not differ between the three groups (data not
shown). The actuarial rate of MCR was significantly higher for group 1 than for group 2 (P = .002), and higher for group 2 than for
group 3 (P = .002).
By multivariate analysis compared with the factors included in the
Sokal score, achieving CHR at 3 months (P < .00001, relative risk = 4.38) and PB blast (P = .03, relative risk = 0.78) were confirmed to be the best statistically significant factors for predicting MCR.
For 63 patients, a cytogenetic analysis was performed at 3 months and
mCR was found in 27 cases. mCR was a significant factor for predicting
MCR (P = .0001) and CCR (P = .024). For these 27 patients the probability to develop MCR was 82% ± 18%
(95% CI) compared with 30% ± 20% (95% CI) for the other 36 patients (Fig 7).
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| Fig 7.
Probability of MCR (n = 63) among the 27 patients who
obtained an mCR at 3 months ( 5% of Ph cells) and the
other 36 patients.
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| |
DISCUSSION |
In this unicentric study, we have confirmed that IFN- can induce
hematological and cytogenetic responses in a substantial proportion of
untreated patients with newly diagnosed CML, and we have analyzed the
factors that could predict the response to IFN- and prolong
survival. Among 116 patients with newly diagnosed Ph+ CML
treated only with IFN-, 80% achieved a CHR and 43% had an MCR. The
estimated median survival for the total study group was not reached at
110 months. We confirm that achievement of an MCR is statistically
associated with survival prolongation.
Our results are very close to those reported by Kantarjian et al in a
unicentric study from the MD Anderson Cancer Center in Houston. In 274 patients they obtained 80% CHR and 38% MCR rates.9 These
results, like ours, look better than those reported in other randomized
or nonrandomized multicentric studies.10-14 Several factors
may explain these differences. First, according to their Sokal
classification, most of our patients belong to the low- and
intermediate-risk groups, as most of the high-risk patients seen in our
institution usually underwent autologous or allogeneic
transplantation.19 The ratio of low- to high-risk patients,
which is useful to compare the different cohorts, was higher in our study and in the Houston series compared
with that of the other studies.24 Second, we used IFN-
at an initial dose of 5 mU/m2/d and tried to
maintain this to obtain a large myelosuppression to maintain the WBC
count around 2.5 × 109/L or 3 × 109/L rather than 5 × 109/L. This dose is
higher than that used in some studies and, as reported elsewere, we
think that the IFN- dose could influence the response
rate.25 Third, the mean number of patients treated in each
individual center was lower in the multicentric studies than in our
study or the Houston one, so the results of IFN- treatment might
have been influenced by the number of patients treated in each
individual center. Indeed it has been suggested that the response to
IFN- treatment is higher in unicentric studies than in multicentric
ones.26 For these reasons, we decided to pursue IFN- in
these patients, who had nevertheless been informed of the potential
benefit of continuing their treatment (in the light of our previous
findings).
In the Houston study, median survival was 89 months and achieving a
cytogenetic response was associated with a statistically longer
survival. By incorporating MCR as a time-dependent variable, it was
considered as an independent prognostic factor for
survival.9 In contrast, in the Cancer and Leukemia Group
B study, a positive relationship between cytogenetic
response and survival was not found, but the number of patients with
strict MCR was small.13 In the German study, cytogenetic
responders in the IFN- arm had no significant survival advantage
over cytogenetic nonresponders, and no beneficial effect of IFN- on
survival compared with hydroxyurea was found in this trial, unlike in
the Italian study.10,14 These discrepancies between trials
have been debated and explained.27 Other studies have
reported the survival benefit of IFN treatment even among patients with
no cytogenetic response.11 A meta analysis from the CML
Trialists Collaborative Group based on seven randomized trials showed a
survival advantage in the IFN- group compared with the chemotherapy
group.28 Recently, in a randomized trial, the French CML
study group showed an advantage of the combination of IFN- and
cytarabine as compared with IFN- alone.29 It reported that cytogenetic response was associated with a longer survival by
landmark analysis in both arms of the trial.30
In our study, the achievement of cytogenetic response (MCR or CCR) was
significantly associated with prolonged survival (P = .0001).
Using univariate analysis, the Sokal index and platelet count were also
found to influence survival, so we included the baseline variables of
the Sokal score in the proportional hazards regression model with MCR
and CCR as time-dependent covariates. In the final model, only MCR or
CCR were included (P < .0001), showing that cytogenetic
response is an independent factor for predicting survival, whatever the
Sokal score. It has already been emphasized that the
incidence of cytogenetic response parallels survival trials; in our
study we have obtained the longest estimated median survival (>110
months) and the highest rate of MCR (43%) reported to date. However,
46 other patients were deleted in our study because they were not
treated by IFN- alone during the same period. Moreover, we have to
adjust these results with the fact that follow-up of our study is
relatively short compared with the estimated median survival.
We have also attempted to determine the factors that could predict the
response to IFN- and particulary MCR. Kantarjian et al30
found that the percentage of PB blast cells and the degree of
thrombocytosis correlated with the response to IFN therapy. The Italian
Cooperative Study Group found that CHR at 8 months was also associated
with a good response rate.10 In our study with univariate
analysis, Sokal score and PB blast were found to influence MCR. These
variables are linked because Sokal score is calculated using the PB
blast percentage. Achievement of CHR within 3 months was also a
statistically significant factor for predicting MCR. So multivariate
analysis (including baseline variables from Sokal index) confirmed that
CHR at 3 months (P < .00001) and PB blast (P = .03)
were the most significant factors associated with survival. Therefore,
with a physical examination and blood cell count at 3 months, it would
seem to be possible to predict those patients who will respond to
IFN-. Moreover, in our study of a subset of patients, the appearance
of Ph mitosis at 3 months was also found to be
statistically significant for predicting MCR and CCR.
Despite the heterogeneous results of the different trials reported to
date and the insufficient follow-up in some studies, survival seems to
be related to cytogenetic response, so for those patients who do not
achieve an MCR, alternative treatments must be proposed. Moreover, the
recent report from the Seattle group on the deleterious influence of
pretransplant IFN- on the prognosis of transplantation from an
unrelated donor suggests that early prognostic factors are needed to
better determine the indication of alloBMT.31 In our
experience, response at 3 months (hematological and cytogenetic) is the
best predictive factor.
Therefore, it is possible to identify those patients who have very high
probability of achieving MCR or CCR and will survive longer (and do not
need a transplant). For those patients who did not respond at 3 months
a further evaluation at 6 months could be indicated.
| |
FOOTNOTES |
Submitted January 21, 1998;
accepted July 28, 1998.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Presented in part at the 38th annual meeting of the American Society of
Hematology, Orlando, FL, December 6-10, 1996.
Address reprint requests to J. Reiffers, MD,
Université Victor Segalen, Bordeaux 2, 146 rue Léo Saignat
33076 Bordeaux, France.
| |
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Abstract
Introduction
