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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2230-2235
Molecular Remissions Induced by Liposomal-Encapsulated All-Trans
Retinoic Acid in Newly Diagnosed Acute Promyelocytic Leukemia
By
Elihu H. Estey,
Francis J. Giles,
Hagop Kantarjian,
Susan O'Brien,
Jorge Cortes,
Emil J Freireich,
Gabriel Lopez-Berestein, and
Michael Keating
From the Departments of Leukemia and Biologic/Immunologic Therapy,
The University of Texas M.D. Anderson Cancer Center, Houston, TX.
 |
ABSTRACT |
All-trans retinoic acid administered orally (oral ATRA) may not
regularly lead to either molecular complete remissions (CRs) or
prolonged hematologic CRs (HCR) unless combined with
chemotherapy. Because serum tretinoin concentrations are higher, and
maintained longer, after use of liposomal-encapsulated ATRA (lipoATRA)
rather than oral ATRA, we investigated lipoATRA monotherapy in newly diagnosed acute promyelocytic leukemia (APL). Patients received lipoATRA 90 mg/m2 every other day for
remission induction. The same dose was given 3 times a
week until 9 months had elapsed from HCR date.
Treatment then stopped. Chemotherapy (idarubicin 12 mg/m2
daily days 1-2 for 2 courses) was to be added only if 2 polymerase chain reaction (PCR) tests, performed 2 weeks apart, were positive at
3, 6, or 9 months from HCR date. The sensitivity level of the PCR was
10 4. We treated 18 patients (median age,
54 years; median white blood cell [WBC] count 4,500/µL). The HCR
rate was 12/18 (67%, 95% confidence interval [CI], 41% to 87%).
This rate was similar to that we observed in a previous study using
oral ATRA + idarubicin. Nine of 10 patients studied at HCR date were
PCR-positive. Subsequently, however, overall (+/ idarubicin) rates
of PCR positivity were 0/12 at 3 months, 1/10 at 6 months, 1/7 at 9 and
12 months, and 0/4 at 15 to 17 months. Idarubicin has been added in 3 patients, with this addition occurring at 6 months in 2 patients and at
9 months in 1 patient. Among patients who had not received idarubicin
when the PCR was evaluated, 0 of 12 were PCR-positive at 3 months, 1 of
10 was positive at 6 months, 1 of 6 was positive at 9 months, 0 of 4 were positive at 12 months, and 0 of 3 were positive at 15 to 17 months. Morphologic APL has recurred in 1 patient, with a median
follow-up time of 13 months in the 11 patients remaining in first CR.
The median follow-up time is 91/2 months (range, 3 to 17) in the 9 patients who have received only lipoATRA and who remain PCR-negative
and in first CR. Our data suggest that lipoATRA is an effective means
of producing molecular CR in newly diagnosed APL.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
ALL-TRANS RETINOIC ACID (ATRA)
and anthracyclines are the mainstays in the treatment of newly
diagnosed acute promyelocytic leukemia (APL).1 Although
ATRA itself, when given by mouth, can induce hematologic remissions in
a high proportion of patients,1 it is not clear that the
drug can regularly produce molecular remissions.2 Such
remissions are operationally defined by the "absence" of the
PML-RAR rearrangement characteristic of APL, using the polymerase
chain reaction (PCR) at a sensitivity level of 104
to detect the rearrangement. This definition of molecular remission follows from the strong correlation between results of the PCR test
performed at this level and subsequent likelihood of disease recurrence.2,3 Accordingly, the goal of therapy of APL
should be to produce a persistently negative PCR test at
104.
Although ATRA is routinely given by mouth, several studies have
demonstrated that serum tretinoin concentrations decrease within a few
days after beginning daily oral ATRA.4,5 Some have
speculated that this phenomenon is responsible for the presumed inability to reproducibly induce molecular remissions and to maintain ATRA-induced hematologic remissions6,7 unless ATRA is
subsequently combined with chemotherapy. There are, however, data
indicating that APL cells obtained at hematologic relapse after oral
ATRA therapy are less sensitive to ATRA-induced differentiation than cells obtained from the same patients at diagnosis.8,9 In some cases, this may reflect an increase in cellular retinoic acid
binding protein levels (CRABPII).8 In other
cases, a mutation may occur during therapy in the RAR region of the
PML-RAR fusion gene.9 Thus, both genetic and
pharmacologic mechanisms may underlie resistance to ATRA in the
treatment of APL.
To test the possibility of overcoming pharmacologic resistance, we
conducted a phase I study of liposomal-incorporated ATRA (lipoATRA).10 Incorporation into liposomes allows ATRA to
be given intravenously, thus bypassing initial hepatic metabolism. Our
study indicated that serum tretinoin concentrations were higher and
could be maintained longer after lipoATRA than after oral ATRA.
Although lipoATRA produced hematologic complete remissions (CRs) in
cases of recurrent APL treated in the phase I study, it seemed possible
that these patients might also have responded to oral ATRA, based on
time from last ATRA administration, duration of first CR, and number of
prior reinduction attempts.7 Furthermore, the number of
patients with recurrent APL available to us was quite small (5 annually). This led to a study designed to assess the activity of
lipoATRA in newly diagnosed APL. Patients received lipoATRA as a single
agent for both remission induction and maintenance ("monotherapy"), with chemotherapy added only if PCR tests
remained positive, or reverted to positivity, after lipoATRA had been
administered for  3 months from the date of hematologic CR. Herein we
report results in the first 18 patients.
| |
MATERIALS AND METHODS |
Eligibility required that patients (1) have untreated APL, (2) not be
pregnant, and (3) be logistically capable of receiving lipoATRA for 10 months, this being the total treatment duration as described below.
Between August 21, 1997, when the first patient was enrolled on study,
and December 9, 1998, when the 18th was enrolled, we saw 20 patients
with untreated APL. One did not qualify because she was pregnant, and
the second did not qualify because she could not receive lipoATRA in
her native Venezuela. Both patients presented with white blood cell
(WBC) counts >10,000/µL; both received oral ATRA + idarubicin with
the first dying on day 4 of treatment of intracranial hemorrhage and
the second now remaining in CR for 4 months. The diagnosis of APL
required either cytogenetic or molecular (PCR test) evidence of the
(15-17) translocation. Such evidence was obtained in 17 of the 18 patients reported here. The 18th patient had typical microgranular APL,
accompanied by disseminated intravascular coagulation
(DIC), but specimens were not sent for cytogenetic or
PCR studies. The patient died on day 2 of intracranial hemorrhage and,
although technically ineligible, we include him in the results because
of the high probability that the (15-17) and/or PML-RAR
rearrangement was present.
Induction therapy consisted of lipoATRA 90 mg/m2
administered intravenously (IV) over 30 minutes every other day until
standard criteria for hematologic CR were met.11
Hematologic CR refers to a marrow with <5% blasts and <8%
promyelocytes without morphologically abnormal promyelocytes.
Additionally, the neutrophil and platelet counts must be above 1,000 and 100,000/µL, respectively. Patients received corticosteroids in
the event of suspected ATRA syndrome and were transfused to maintain
the platelet count >30,000/µL and the fibrinogen >180 mg/dL;
heparin was not administered. Once in hematologic CR, patients
continued to receive lipoATRA at 90 mg/m2, now every
Monday, Wednesday, and Friday. Twenty-five percent dose decreases were
mandated for grade 3 National Cancer Institute (NCI)
criteria toxicity. A PCR test, performed at a level of
104, was obtained 3, 6, and 9 months from CR date.
If these were negative, lipoATRA was continued until the 9-month time
point, when all therapy was discontinued. If the PCR test was positive at 3, 6, or 9 months, another PCR was performed at the same level 2 weeks later. If this test was also positive, idarubicin (12 mg/m2 daily × 2 days for 2 courses given 4 to 5 weeks
apart) was added and lipoATRA continued. If the repeat test was
negative, chemotherapy was not added. If after 2 courses of
idarubicin + lipoATRA the PCR remained positive, patients received
arsenic trioxide. In sum, patients were to receive chemotherapy only if
they were PCR-positive at 104 × 2 at 3, 6, or
9 months from hematologic CR date. Otherwise, they received only
lipoATRA, stopping therapy 9 months from this date. Thereafter, they
were followed with PCR tests every 3 months. To evaluate the accuracy
of our PCR test, we sent 7 samples (6 PCR-negative, 1 PCR-positive)
from patients on this study to Dr Francesco Lo Coco (University La
Sapienza, Rome, Italy) of the GIMEMA group, who
repeated the PCR analyses without knowledge of our results. Dr Lo Coco
confirmed our results in all 7 cases. Morphologic examination of the
bone marrow and routine complete blood counts (CBCs)
were performed when PCR tests were obtained. Pharmacology studies were
not performed.
The use of lipoATRA monotherapy in a disease in which oral ATRA + anthracyclines produce a substantial long-term disease-free survival rate was controversial. To monitor the study and stop it
expeditiously if results were worse than in patients previously given
oral ATRA + idarubicin at M.D. Anderson,11 we used the multiple outcome statistical design of Thall et al.12 In
the formulation we used, the study would stop if, based on results as a
patient was about to be accrued, the probability was >.90 that the
hematologic CR rate with lipoATRA was less than the rate we had
observed with oral ATRA + idarubicin (34 of 44 = 77%). Early
termination would also occur if the probability was >.95 that, among
patients achieving hematologic CR, the percent remaining alive in such
CR 12 months from CR date was less than the comparable percent with
oral ATRA + idarubicin (28 of 34 = 82%). These stopping rules were such that if the true hematologic CR rate was in fact 57%
(20% lower than historical), there was 94% probability that the study
would stop after a median of 12 patients had been enrolled. Similarly,
if, among patients achieving hematologic CR, the true proportion
remaining alive in CR at 12 months was 62% (again 20% lower than
historical), there was 82% probability that the study would stop after
a median of 19 patients had entered CR. If early stopping did not
occur, we planned to accrue 50 patients. However, accrual of this
number would require another 3 years not counting follow-up time,
leading us to report our current results.
| |
RESULTS |
The median age of the 18 patients was 54 years (range, 11 to 72). Three
patients were largely bedridden (Zubrod performance status 3) at
presentation, 2 because of dyspnea associated with bilateral densities
on chest x-ray, and 1 because of a depressed level of consciousness due
to a cerebellar hemorrhage. The median WBC count at presentation was
4,500/µL (range, 400 to 54,000, 6 patients with >10,000), and the
median platelet count was 28,000/µL (range, 7 to
133,000). Fourteen of the 18 patients had the t(15;17) translocation on
standard (minimum of 20 metaphases counted) cytogenetic analysis;
additional changes were found in 4 of the 14. In 3 patients the
karyotype was normal, but the PCR test was positive. The final patient
had typical microgranular APL, but no samples for cytogenetic or PCR
testing were sent (see Materials and Methods). PCR testing was
performed at presentation in 16 patients: 7 had the "short," 8 the "long," and 1 the "variable" isoform.
Induction results.
The hematologic CR rate was 12/18 (67%; 95% CI, 41% to 87%).
Patients were generally treated as outpatients and did not have daily
blood counts once 2 to 3 weeks had elapsed from beginning therapy.
Bearing this in mind, the median time to achieve CR was 34 days (range,
22 to 64). Four of the 6 failures died of hemorrhage. Three died of
central nervous system (CNS) hemorrrhage in the first
4 days after starting lipoATRA, and the fourth died 26 days after
starting therapy of complications of pulmonary hemorrhage that also
occurred in the first week of therapy. The presenting WBC counts in the
4 who died of hemorrhage were between 16,800 and 54,000/µL; one of
the 4 had a cerebellar hemorrhage at presentation and died of a repeat
hemorrhage. The fifth patient who did not achieve CR presented with
bilateral lower limb venous thromboses. Because these appeared to
worsen during the first 3 days of treatment, he was given idarubicin
instead of lipoATRA, but died 3 weeks later. The final patient who
failed to attain CR developed acute myocardial failure, confirmed by
echocardiogram, 1 day after beginning therapy and died 1 day later. The
patient had a history of coronary artery disease and had been taking an
angiotensin converting enzyme inhibitor that had been discontinued when
lipoATRA began. Autopsy failed to show acute thrombosis or other causes
of acute myocardial failure. Nine patients began treatment with
significantly abnormal values for serum fibrinogen (<180 mg/dL).
Fibrinogen became consistently over this level in 7 of the 9 at a
median of 4 days after beginning lipoATRA (range, 1 to 11). In the
remaining 2 who died, one of hemorrhage, the fibrinogen remained <180
at death, which occurred on days 2 and 3, respectively. Eight patients
had significantly elevated prothrombin times (PT >15 seconds) before
treatment. The PT decreased below this value in 3 of the 8 at 2, 2, and
10 days into treatment. In the remaining 5, all of whom died, 4 of hemorrhage, the PT remained >15 seconds at death or last follow-up, which occurred at 2, 3, 3, 7, and 19 days, respectively.
The most obvious difference between the 12 patients who did and the 6 who did not achieve CR was the presenting WBC count (P = .002, Mann-Whitney test). The CR rate was 11/12 (92%) in patients with WBC < 10,000/µL and only 1/6 (17%) in patients with higher WBC. The
P value (Fisher exact test) for this comparison is .004, and
the 95% CI for the true difference in the 2 rates is (.24, 1.0). All 3 patients with a performance status = Zubrod 3 failed treatment versus a
CR rate of 12/15 (80%) in patients who had a performance status < 3 (P = .02, Fisher exact test). Neither age nor initial platelet
count affected CR rate. CR rates were 6/7 (86%) in patients with the
long isoform and 4/8 if the short isoform was present (P = .18); the patient with the variable isoform entered CR. The overall CR
rate of 12/18 compares with a CR rate of 34/44 in patients previously
given oral ATRA + idarubicin at M.D. Anderson (see Materials and
Methods). The P value for this comparison is .52, and the 95%
CI for the true difference in rates is (.39, .16). Reflecting
the statistical similarity between the historical treatment and
lipoATRA, the boundary for stopping the study if the CR rate was
unacceptably low was not crossed; stopping after 18 patients would have
required a CR rate of  10/18. PCR testing, at 104,
was performed at time of hematologic CR in 10 of the 12 patients who
achieved this outcome. The test was positive in 9 patients and negative
in only 1.
Results of postremission therapy.
Table 1 examines results of PCR tests
performed at the indicated times. All 12 patients were PCR-negative 3 months from hematologic CR date. The 3 of these 12 whose PCR was
negative at CR or not performed at CR were PCR-positive at diagnosis
(patients 1 and 9) or did not have PCR testing at diagnosis, but had
the t(15;17) on standard testing (patient 2). At 6 months from CR date,
8 patients were PCR-negative and 1 was positive on 2 occasions 2 weeks
apart (patient 3). As specified in the protocol, idarubicin was added to lipoATRA. The PCR at 9 months from CR date (3 months after beginning
idarubicin) was suboptimal, but a frank relapse occurred 1 year from CR
date (Table 1). In the final patient evaluated to date at 6 months from
CR date, the PCR was first positive, but was negative on repeat testing
(patient 7). Nonetheless, at the attending physician's discretion,
idarubicin was added to lipoATRA, of course making it impossible to
ascertain whether the negative PCR tests obtained 3 and 6 months later
would have been obtained had idarubicin not been added. At 9 months
from CR date, 6 patients have been evaluated having received only
lipoATRA monotherapy (patients 1, 2, 4, 5, 6, and 8). One was
PCR-positive × 2 and thus had idarubicin added to lipoATRA,
becoming PCR-negative again 3 and 8 months later (patient 1). The
remaining 5 were PCR-negative, and thus discontinued therapy. Four of
the 5 have been evaluated at 12 months from CR date. Each remains
PCR-negative (patients 2, 4, 5, and 6). Three of the 5 have been
evaluated at 15, 15, and 17 months, with each remaining PCR-negative
(patients 2, 5, and 6). Including all 12 patients (the 3 who did and
the 9 who did not receive idarubicin), PCR negativity rates are 12/12
at 3 months, 8/9 at 6 months (with the 1 additional patient being positive, then negative), 6/7 at both 9 and 12 months, and 0/4 at 15 months (Table 1). Four patients are PCR-negative 6 to 8 months after
stopping lipoATRA (patients 1, 2, 5, 6). Two additional patients are
PCR-negative 3 months after stopping the drug (patients 4 and 7). There
are insufficient data to assess whether a particular isoform is more
likely to revert to positivity on lipoATRA monotherapy. Of the 2 patients who reverted to PCR positivity on 2 occasions (patients 1 and
3), 1 had the short and the other the long isoform. There are examples
of continued negativity at 12 months with short or variable isoforms
and at 9 months with the long isoform. The only patient who entered CR
after presenting with a WBC count >10,000/µL was the patient whose
PCR test reverted to positive on 1 occasion at 6 months from CR date,
but was negative on repeat testing (patient 7, discussed above).
Events (relapse by standard morphologic criteria or death in CR) have
occurred in 1 of the 12 patients in Table 1 (patient 3). As mentioned
above, there was morphologic reappearance of this patient's APL after
a CR of 1 year despite addition of idarubicin when the PCR reverted to
positivity 6 months from CR date. A second remission was induced and
has been maintained for 1 month on arsenic trioxide. Each of the
remaining 11 patients in Table 1 remains in first CR, with follow-up
times of 3, 3, 6, 6, 9, 13, 13, 15, 15, 17, and 17 months from
hematologic CR date (median, 13 months). Idarubicin has been added in 3 of the 12 patients in Table 1 (patients 1, 3, and 7). In both patients
1 and 3, drug was added because of 2 positive PCR tests, as prescribed
in the protocol, with these occurring, respectively, at 9 and 6 months
from CR date. In patient 7, the decision was made by the attending
physician, because of a single positive test. Among the 9 patients who
have received only lipoATRA and remain PCR-negative in first CR, the median follow-up time is 91/2 months (range, 3 to 17) from
hematologic CR date.
Toxicity.
Toxicity could not be evaluated in the 4 patients who suffered early
hemorrhage. Among the remaining 14, worsening thromboses in the patient
taken off lipoATRA and given idarubicin on day 4 could have been due to
lipoATRA, but of course, is also a feature of APL; indeed, the patient
presented with thromboses. Similarly, the case of fatal acute
myocardial failure could have been due to lipoATRA, but no other
stigmata of "ATRA syndrome," eg, pericarditis, noncardiogenic
pulmonary edema were present. Grade III (NCI criteria) toxicity more
definitely related to lipoATRA occurred in 4 of the 14 patients who did
not suffer early hemorrhage. Three of the 4 had the ATRA syndrome.
These 3 had fever, dyspnea, and joint pain without alternative
explanation. The fourth had pseudotumor cerebri characterized by
headache and papilledema accompanied by normal mental status and a
magnetic reasonance imaging (MRI) scan showing no
intracerebral or extracerebral masses. Steroids and 25% reduction in
the lipoATRA dose were therapeutically effective, and all 4 continued to receive lipoATRA. An additional 7 of the 14 patients had grade 2 or less toxicity characterized by headache, joint
pain, and dry skin. We could evaluate changes in WBC count in 13 patients. In these 13, the WBC count increased from a pretreatment median of 2,000/µL to a posttreatment median high of 15,300/µL (range up to 154,000/µL). Defining an increase as a doubling in the
WBC count and a peak value >10,000/µL, an increase occurred in 9 of
the 13 patients. The increase began in the first or second week of
therapy and the peak occurred in the second or third week. The count
returned to normal 1 to 2 weeks after the peak was reached. There was
no correlation between the amount of increase in the WBC count and the
occurrence of grade 3 toxicity.
| |
DISCUSSION |
Our study shows that lipoATRA as a single agent ("monotherapy")
has activity in newly diagnosed APL. In only 3 of 12 patients was
idarubicin added, at 6, 6, and 9 months into hematologic CR, because of
PCR positivity. In 1 of the 3, addition was based on 1 positive test
followed by a negative test. Focusing on patients who had not received
idarubicin when the PCR was evaluated in remission, 12 of 12 were
PCR-negative at 3 months from hematologic CR date, 8 of 9 were
PCR-negative at 6 months, 5 of 6 were negative at 9 months, 4 of 4 were
negative at 12 months, and 3 of 3 were negative at 15 to 17 months.
Because 9 of 10 patients tested at CR date were PCR-positive, the
development of PCR negativity occurred during the first 3 months of CR.
It would obviously be useful to compare rates of PCR negativity in
newly diagnosed patients after monotherapy with lipoATRA with similar
rates after monotherapy with oral ATRA. It has been reported that 83%
(39 of 47) of newly diagnosed patients given oral ATRA without
chemotherapy for induction remain PCR-positive at time of
CR,3 reminiscent of our data with lipoATRA. However, there
are no published results of PCR tests after continued oral ATRA
monotherapy in newly diagnosed patients. PCR data after oral ATRA
monotherapy in relapsed APL is available in the publication by Miller
et al.13 Thus, to compare the PCR data noted in Table 1
with those reported after oral ATRA monotherapy, we used this publication. Three of 13 patients in the study by Miller et
al13 had previously received ATRA, with chemotherapy
following in all 3. Table
2 shows that there is statistically significant evidence that the rates
of PCR negativity at both 3 and 6 months from CR are higher with
lipoATRA. The magnitude of the differences is also noteworthy. Thus,
even at 9 months from CR date, when the P value is
insignificant, the 95% exact CI for the true difference in rates is
(.30, .99), indicating that there is as much evidence for a true
difference of .70 in favor of lipoATRA as for no true difference, as
both 0 and .70 are equidistant from the midpoint of the CI (.35).
It is conceivable that continuation of oral ATRA monotherapy in newly
diagnosed APL might produce rates of PCR negativity similar to or
higher than those we observed after lipoATRA monotherapy. In this
context, Jurcic (personal communication, January 1999) has noted that 7 of 34 patients with newly diagnosed APL at Memorial Sloan-Kettering
Cancer Center who were PCR-positive at CR date and received oral ATRA
for 1 additional month before starting chemotherapy became PCR-negative
before beginning the chemotherapy. If continued oral ATRA monotherapy
produced a high rate of persistent PCR negativity, a low relapse rate
might be expected in patients treated in this fashion. Apparently, the
only studies reporting use of oral ATRA monotherapy, although without
PCR data, in newly diagnosed APL are early Chinese
studies.14-16 The median CR duration in such patients was 5 months, as quoted by Fenaux et al.6 Comparison of this
result with that in our patients given lipoATRA monotherapy is
confounded because the lipoATRA patients were given idarubicin if they
were PCR-positive in CR, whereas the Chinese patients were not.
Limiting the comparison to the lipoATRA patients who did not receive
chemotherapy obviously introduces bias because these patients did not
receive chemotherapy precisely because they were PCR-negative and thus
thought unlikely to relapse. We are also unable to compare the oral
ATRA and lipoATRA groups with respect to covariates (eg, WBC count)
other than treatment that could influence CR duration.
The CR rate observed after lipoATRA (12/18, 67%) appears low when
compared with the much higher rates (eg, 90%) reported in European
studies administering oral ATRA without chemotherapy in newly diagnosed
APL.17,18 However, the 67% CR rate was similar to the 77%
rate we observed with oral ATRA + idarubicin in our immediately
preceding study.11 In that study, we noted that the
predictors of outcome of induction therapy were initial WBC count and
platelet count. Based on these counts, 11 to 12 of the 18 patients
given lipoATRA in the current study would have been expected to enter
CR had they received oral ATRA + idarubicin, as given in the previous
study (see Fig 1 in Estey et al11), and 12, in fact,
entered CR after lipoATRA. A similar proportion of the patients in our
oral ATRA + idarubicin and lipoATRA studies had Zubrod performance
status >2, and although the patients given lipoATRA were older
(P = .05, Mann-Whitney test), we could not identify age as a
prognostic factor in either study. This, of course, may merely reflect
our small sample sizes, because older age has been associated with
poorer outcome in European studies.18 Elevated presenting
WBC count appears to be associated with a poor response to both oral
ATRA and lipoATRA. The lower CR rates observed in either our oral ATRA + idarubicin or lipoATRA studies compared with the European studies may
result from a higher proportion of patients with relatively high WBC
counts at M.D. Anderson. Regardless, our CR rates in either study are
consistent with the CR rate observed by the US Intergroup after oral
ATRA or chemotherapy.19
In conclusion, single agent lipoATRA can produce PCR negativity in a
high proportion of newly diagnosed APL patients induced into CR solely
with this drug. This result, together with the persistence of PCR
negativity, does not conform to the generally held view that addition
of chemotherapy is necessary to render patients PCR-negative if induced
into CR with only oral ATRA. Further follow-up will be needed to
ascertain the duration of PCR negativity in our patients. Thus, the
proportion of lipoATRA-treated patients who will ultimately require
chemotherapy remains unknown. However, even if use of lipoATRA cannot
totally obviate the need for chemotherapy in all patients, it might
permit a reduction in the amount of chemotherapy needed to cure newly
diagnosed APL. A randomized comparison of oral ATRA + chemotherapy,
lipoATRA + chemotherapy, and lipoATRA monotherapy, as given in the
current study, might be undertaken to address this issue.
| |
ACKNOWLEDGMENT |
The authors thank Soon Woo, Jacquie Burrell-Parish, and Patricia Reed
for their expert assistance, with respectively, secretarial and data
management functions.
| |
FOOTNOTES |
Submitted March 1, 1999; accepted June 1, 1999.
Supported in part by Grant No. R-000923-04-01 from the FDA to G.L.-B.
G.L.-B. is a consultant, director, and shareholder of Aronex
Pharmaceuticals, Inc, the supplier of liposomal ATRA.
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.
Address reprint requests to Elihu H. Estey, MD, Department of Leukemia,
Box 61, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: eestey{at}odin.mdacc.tmc.edu.
| |
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ABSTRACT
INTRODUCTION