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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4131-4143
Presenting White Blood Cell Count and Kinetics of Molecular Remission
Predict Prognosis in Acute Promyelocytic Leukemia Treated With
All-Trans Retinoic Acid: Result of the Randomized MRC Trial
By
Alan K. Burnett,
David Grimwade,
Ellen Solomon,
Keith Wheatley, and
Anthony H. Goldstone on behalf of the MRC Adult Leukaemia
Working Party
From the Department of Haematology, University of Wales College of
Medicine, Cardiff, UK; the Cancer Genetics Laboratory, Division of
Medical and Molecular Genetics, Guy's Hospital, London, UK; the
Clinical Trial Service Unit, Radcliffe Infirmary, Oxford, UK; and the
Department of Haematology, University College Hospital, London,
UK.
 |
ABSTRACT |
All-trans retinoic acid (ATRA) is an essential component of
the treatment of acute promyelocytic leukemia (APL), but the optimal timing and duration remain to be determined. Molecular characterization of this disease can refine the diagnosis and could be potentially useful in monitoring response to treatment. Patients defined
morphologically to have APL were randomized to receive a 5-day course
of ATRA before commencing chemotherapy or to receive daily ATRA
commencing with chemotherapy and continuing until complete remission
(CR). The chemotherapy was that used in current MRC
Leukaemia Trials. Outcome comparisons were by intention to treat with
additional analysis for relevant risk factors. Patients were
characterized by molecular techniques for the fusion products of the
t(15;17) and monitored by reverse transcriptase-polymerase chain
reaction (RT-PCR) during and after treatment. Two hundred thirty-nine
patients were randomized. Treatment with extended ATRA resulted in a
superior remission rate (87% v 70%, P < .001), due
to fewer early and induction deaths (12% v 23%, P = .02), and less resistant disease (2% v 7%, P = .03), which was associated with a significantly more rapid recovery of
neutrophils and platelets. Extended ATRA reduced relapse risk (20%
v 36% at 4 years, P = .04) and resulted in superior survival (71% v 52% at 4 years, P = .005).
Presenting white blood cell count (WBC) was a key
determinant of outcome. The 70% of patients who presented with a WBC
less than 10 × 109/L had a better CR (85% v
62%, P = .0001) and reduced relapse risk (22% v
42%, P = .002) and superior survival (69%
v 43%, P < .0001). Within the low count group,
extended ATRA resulted in a better CR (94% v 76%, P
= .001), reduced relapse risk (13% v 35%, P = .04), and improved survival (80% v 57%, P = .0009).
There was no evidence of benefit in patients presenting with a higher WBC (>10 × 109/L). Molecular monitoring after the third
chemotherapy course had a correlation with risk of relapse. The relapse
risk was 57% if the RT-PCR was positive versus 27% if the RT-PCR was
negative (P = .006). APL patients who present
with a low WBC derive substantial benefit from combining ATRA with
induction chemotherapy until remission is achieved, whereas patients
with a higher WBC did not benefit. Molecular characterization of
disease can improve diagnostic precision and a positive RT-PCR after
consolidation identifies patients at a higher risk of relapse.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
ACUTE PROMYELOCYTIC leukemia (APL) is
associated with the reciprocal translocation,
t(15;17)(q22;q21),1 leading to the formation of
PML-RAR and RAR-PML fusion genes,2
and is characterized by a unique sensitivity to the differentiating agent (All-trans retinoic acid [ATRA]). It has been
recognized for some time that this acute myeloid leukemia
(AML) subtype, even when only characterized
morphologically (as French-American-British [FAB] M3), has a more
favorable survival than other subgroups when treated with
chemotherapy.3 However, the coagulopathy associated with
induction was a significant cause of death4,5 that was
additional to the usual risks of cytopenia as a result of chemotherapy.
Although the risk of relapse was lower than in other groups, the
majority of patients still died of recurrent leukemia.3
The introduction of ATRA into clinical practice immediately offered the
potential to circumvent some of these obstacles. First, the associated
coagulopathy resolved promptly, ie, usually within the first 48 hours,
and remission could be achieved in a high proportion of patients
without inflicting marrow hypocellularity.6-8 However these
remissions were not durable and disease detected by reverse
transcriptase-polymerase chain reaction (RT-PCR) usually remained.9,10 Subsequent studies used ATRA to induce
remission and then introduced chemotherapy as
consolidation.11-14 This approach significantly improved
disease outcome, although retinoid treatment was not without
complications. ATRA can induce a proliferative response, resulting in a
rapidly increasing peripheral white blood cell count (WBC)
that can herald the retinoic acid syndrome that is characterized by
features of capillary leak.15 This syndrome, which is not
exclusively associated with an increasing WBC, can occur in up to 25%
of APL cases and is associated with a high mortality unless
energetically treated with steroids. Pre-emptive chemotherapy
administered as the WBC increases also can abort the development of the
syndrome.16
ATRA clearly has a crucial role to play in this disease, but the
optimal means of combining ATRA and chemotherapy remains to be
determined. In our experience, use of chemotherapy alone for this
disease17 was associated with an overall survival of 54%
at 5 years, but 13% of cases failed to achieve complete remission (CR)
because of fatal hemorrhage. In this study, we sought to determine the
relative benefit of using ATRA therapy for a 5-day period only before
commencing chemotherapy with the aim of minimizing hemorrhagic
deaths.6 This was compared with the coadministration of
ATRA with chemotherapy, in which the aim was to achieve effective cytoreduction without exposing patients to the risk of developing the
ATRA syndrome, which might occur if they were treated with ATRA alone.
Knowledge of the molecular details of the fusion genes created by this
translocation has opened the way to evaluate RT-PCR-based methods to
confirm diagnosis and to evaluate response to treatment. In association
with this trial, bone marrow samples were characterized at the
molecular level to compare diagnostic precision with morphology and
cytogenetics and during and after chemotherapy in an attempt to clarify
the place of RT-PCR analysis in predicting relapse.
| |
PATIENTS AND METHODS |
Between January 1993 and January 1997, 239 patients who were
morphologically considered by the local physicians to have APL and who
were entered into the current chemotherapy trials conducted by the MRC
Leukaemia Working Parties were randomized to receive ATRA at 45 mg/m2/d either as a 5-day course before commencing
chemotherapy (short ATRA) or to commence ATRA on the first
day of chemotherapy and continue daily until CR or a maximum of 60 days
(extended ATRA). For patients in the short ATRA arm in which an
arbitrary WBC threshold of 25 × 109/L or greater was
reached, it was recommended that chemotherapy should start immediately.
The chemotherapy for patients less than 55 years of age was the MRC AML
10 protocol, which was subsequently superseded by MRC AML 12 for
patients less than 60 years of age. Older patients were treated
throughout on the MRC AML 11 protocol. The chemotherapy schedule for
AML 10 has been described elsewhere17 and is summarized in
Fig 1. In AML 12, patients were randomized to receive
ADE or MAE (where Mitoxantrone was substituted) in the first 2 courses,
followed by MACE and MidAc as in AML 10 with or without ICE
(Idarubicin, Cytosine, Etoposide) as course 5. In AML 11, patients were
randomized to receive DAT, MAE, or ADE for the first 2 courses,
followed by DAT (2+7) with or without 3 further courses [COAP × 2, DAT (2+5)]. Patients in these three trials were eligible for
randomization to receive granulocyte colony-stimulating factor (G-CSF)
as supportive care after course 1. G-CSF treatment started on day +8
after the end of chemotherapy until recovery of neutrophils to 0.5 × 109/L. Thirteen patients in the MRC 10 trial
received transplantation, but these were equally divided between the
two arms: 6 short (4 allo and 2 auto) and 7 extended (3 allo and 4 auto). The date of last follow-up was August 1, 1998, when the median
follow-up was 41 months.
Cytogenetic and Molecular Characterization
Cytogenetic analysis was performed in accordance with ISCN
guidelines.18 Twenty metaphases were fully examined after
at least 16 hours of culture to detect clonal abnormalities. For patients with a detectable clonal abnormality, at least 10 metaphases were examined to exclude additional changes, in accordance with the UK
central quality control scheme guidelines (UK NEQAS-National External
Quality Assessment Schemes). Fluorescence in-situ hybridization (FISH) studies using PML and RAR probes (VYSIS,
IP) have been described elsewhere.19
RT-PCR.
To establish the frequency of PML/RAR rearrangements among
patients with a clinical diagnosis of APL, to determine whether PML
breakpoint is of any prognostic significance, and to evaluate the
role of minimal residual disease (MRD) monitoring in APL, nested RT-PCR
was performed using primers to detect both PML-RAR and
RAR-PML fusion transcripts, as fully described
previously.20 Sensitivity assays for this method using the
APL cell line NB4 (kindly provided by Michel Lanotte, Hôpital St
Louis, Paris, France), which exhibits a bcr 1 PML breakpoint
diluted in HL60 filler cells that are negative for the
PML/RAR rearrangement, show that the PML-RAR
assay can detect 1 APL cell in 104, whereas the
RAR-PML assay is more sensitive, with a detection limit of 1 in 105.21 Identical sensitivities were also
observed with serial dilutions of diagnostic bone marrow derived from a
case with a bcr 3 PML breakpoint. For both diagnostic and MRD
assays, a 1 in 1,000 dilution of NB4 was routinely included as a
positive control together with an HL60-negative control and water
controls for the RT and PCR steps. In all assays, normal RAR
and PML transcripts were detected as controls for RNA
integrity, as described previously.20-22 Negative results
were only considered to be reliable with successful amplification of
RAR and PML RNA controls and provided that
all other controls were satisfactory. All RT-PCR assays were performed
at least twice, and results as determined by gel electrophoresis were
routinely confirmed by hybridization with a junctional RAR
cDNA probe (H7b).21
There are two major breakpoints within PML: 5' (bcr 3)
breakpoints typically occur within intron 3, whereas breakpoints in the
3' region usually occur within intron 6 (bcr 1) and less commonly disrupt more proximal exonic sequence (bcr 2), most usually exon 6.20,23,24 In the present study, 5' (bcr 3) and
3' (bcr 1/2) PML breakpoints were distinguished on the
basis of characteristic band sizes shown by nested
RT-PCR.20 Bcr 1 and 2 3' PML breakpoints were
distinguished by a combination of RT-PCR using a PML exon 5 primer, PML/RAR junctional oligoprobe hybridization, and
sequence analysis as detailed in full previously.20 In 1 patient, APL was associated with t(11;17)(q12-q21), leading to the
detection of PLZF-RAR and RAR-PLZF fusion
transcripts.25
PML immunofluorescence.
Where availability of suitable diagnostic material permitted,
immunofluorescence studies were performed as previously
described.20 A polyclonal PML antiserum was used in cases
lacking molecular and cytogenetic evidence for the t(15;17) and also in
a group with documented t(15;17) as positive controls.
Study Endpoints
CR was defined as a normocellular bone marrow aspirate which was
usually performed 21 to 23 days from the end of allocated chemotherapy
containing less than 5% blast cells and showing evidence of maturation
in all lineages. Concurrent central morphological review of diagnostic
material was provided and CR was confirmed by the treating physician.
Remission failures were classified as early death (ED), induction death
(ID; ie, related to treatment and/or hypoplasia), or resistant disease
(RD; ie, failure to achieve CR and including partial remissions with
5% to 15% blasts). Where a clinician's evaluation of response was
not given, deaths within 10 days of study entry were classified as ED,
deaths between 10 and 30 days as ID, and deaths beyond 30 days as RD.
Overall survival (OS) is the time from randomization to death.
Disease-free survival (DFS) is the time from first remission to first
event (either relapse or death in CR). Relapse risk is the cumulative
probability of relapse, censoring at death in CR.
Statistical Methods
Randomizations were undertaken by telephone to a central office in
Oxford, UK. Minimization was used to ensure that approximately equal
numbers of patients were allocated to each arm, both overall and within
age group, type of AML (de novo/secondary), performance status, and
induction treatment. Remission rates and reasons for failure were
compared using the  2 test. For other endpoints,
Kaplan-Meier life-tables were constructed for each endpoint and were
compared by means of the log-rank test, with surviving patients being
censored at August 1, 1998 when follow-up was up to date for 97% of
the patients. In addition to overall analyses, analyses were performed
within potentially important prognostic risk groups, ie, age, WBC <10
or  10 × 109/L, additional cytogenetic changes, and
5' or 3' PML molecular breakpoints.
All P values are two-tailed. All point estimates quoted are at
3 years from randomization. All analyses are on the basis of intention
to treat with all randomized patients analyzed in their allocated arm
(short or extended ATRA) irrespective of whether they received the
allocated treatment.
| |
RESULTS |
Patient Characteristics
The characteristics of the 239 patients are shown in
Table 1. During the course of this trial,
some patients received G-CSF as supportive care from day +8 after the
end of chemotherapy.26 These patients were evenly
distributed between the arms.
Compliance with treatment.
Because of early death, 12 patients (7 short and 5 extended) did not
receive ATRA. Of those allocated to extended ATRA, 88% received the
drug on schedule, but 12% of patients violated the protocol by
commencing ATRA treatment 1 to 3 days before the chemotherapy. Of those
allocated to short ATRA, 64% started chemotherapy at day 5, 26%
started before day 5 because of an increasing WBC of greater than 25 × 109/L (as prescribed in the protocol), and 10%
started treatment before the 5-day course was completed due to protocol
violation. All analysis was undertaken on an intent-to-treat basis.
Cytogenetic and molecular characterization of disease.
Cytogenetic and molecular screening for PML/RAR
rearrangements was routinely performed. The presence of the
rearrangement was confirmed by cytogenetics and/or molecular analysis
in 216 of 239 patients, as shown in Fig 2.
In 187 of 216 patients, the t(15;17) was identified by conventional
cytogenetics, whereas in 29 of 216 patients, the PML/RAR
rearrangement was established by molecular techniques, including
RT-PCR (n = 28) and FISH (n = 1). Cytogenetic analyses in this latter
group were most commonly normal (n = 12) or failed (n = 11); in the
remaining 6 patients, other clonal abnormalities were detected, of
which 2 had chromosomes 15 and 17 of normal appearance. Among the 12 patients with normal karyotype and documented PML/RAR
rearrangements, PML-RAR and RAR-PML fusion
transcripts were both detected in 6, suggesting that the conventional
t(15;17) had occurred, but had been missed despite culture of marrow
cells for at least 16 hours before analysis. In the remaining 6 patients, PML-RAR was the sole fusion transcript detected
consistent with insertion events, as we have recently demonstrated by
further characterization of a series of such cases by FISH, including
those derived from the MRC ATRA trial.25
PML immunofluorescence demonstrated the classic microparticulate
nuclear staining indicative of the presence of the PML-RAR fusion protein in 14 of 14 patients with a documented
t(15:17)20,25 and in 16 of 19 patients with cryptic
PML/RAR rearrangements. The absence of the microparticulate
pattern in 3 cases was accounted for by technical failure (n = 1) or absence of leukemic cells in the peripheral blood (n = 2). In 21 of the entrants to the trial, no evidence was found for
the existence of a PML/RAR rearrangement (Fig 2). In 7 cases, another primary cytogenetic abnormality was found; in 12 cases,
RT-PCR, FISH, or a wild-type nuclear staining pattern on PML
immunofluorescence failed to confirm cryptic rearrangements; and 2 cases were excluded on morphological review. In 1 patient in whom
molecular methods failed, APL was confirmed by morphology review.
Response to Treatment
Remission induction.
The extended ATRA arm had a significantly higher rate of CR (87%
v 70%, P  .001), less resistant
disease (2% v 7%, P = .03), and fewer early and
induction deaths (12% v 23%, P = .02;
Table 2). This difference was not
influenced by the chemotherapy schedule administered, whether they
received G-CSF or not, or by patient age, although there was an overall
effect of age on CR rate. However, the level of WBC (>10 or
<×109/L) was influential on treatment
outcome.
One hundred sixty-eight patients (70% of entrants) presented with a
WBC of less than 10 × 109/L, of whom 143 (85%)
entered CR, compared with 62% of those with a WBC greater than 10 × 109/L. Within this low count group, the extended
ATRA arm resulted in a superior CR rate (94% v 76%) due to
less deaths or resistant disease (Table 2), but no benefit was seen in
patients in the higher WBC group. A possible explanation for the
reduced induction deaths in the extended ATRA arm is the speed of
hematopoietic regeneration from induction treatment, which was
significantly more rapid for neutrophils and platelets in the extended
arm (Fig 3). However, the early and
induction deaths mostly occurred before they could be influenced by the
count recovery. No such regeneration differences were noted in
subsequent courses of chemotherapy. Confirmed or possible haemorrhagic
deaths occurred in 10 patients and infection occurred in 5 patients.
Four of 27 deaths in the short ATRA arm and 1 of the 14 deaths in the
extended ATRA were attributed to the retinoic acid syndrome; there were
2 and 1 other deaths, respectively, with respiratory complications that
were not recorded as RA syndrome. There were no important differences of response between the arms within the cytogenetic or molecular subgroups or in the 21 patients in whom APL was not confirmed.
Deaths in Remission
Of those in remission, 7 of 83 (8%) in the short ATRA arm and 7 of 104 (8%) in the extended ATRA arm died in CR during cytopenia after
subsequent courses of chemotherapy, giving an actuarial risk of death
of 10% at 4 years.
Relapse Risk
There were 42 relapses, including 3 in the central nervous system
(CNS), 2 of whom presented with a low WBC. There was an overall significant reduction in relapse risk for those on the extended
ATRA arm (20% v 36%, P = .04;
Table 3); however, this benefit was most
obvious in the low WBC group (13% v 35%, P = .04) and
not in the high WBC group (47% v 36%, P = .5; Table
3). There was no difference in this effect by age group or
molecular/genetic subgroup. There was no significant difference between
the arms in second remission rates (short 65% v extended 50%,
P = .5) or survival at 2 years from relapse (short 44%
v extended 43%, P = .5).
DFS
The patients who entered CR in the extended arm had a significantly
superior DFS compared with those on the short ATRA arm (72% v
59%, P = .07), but this advantage was limited to the low count
patients (77% v 59%, P = .02) and was not apparent in
those with a presenting WBC greater than 10 × 109/L
(53% v 58%, P = .6).
OS
The OS from diagnosis was significantly better in the extended ATRA
arm, being 71% compared with 52% in the short ATRA arm (Table 3), but
this benefit was also restricted to patients with a low WBC, where it
was 80% in the extended arm versus 57% in the short arm (P = .0009; test for heterogeneity of effect, P = .003), but with no
evidence of benefit in patients with a higher WBC
(Fig 4). This benefit was apparent over all
age groups and was unaffected by the presence of additional cytogenetic
abnormalities; however, it is noteworthy that all 4 patients whose
additional cytogenetic lesion was adverse in its own right (3 had 3q
abnormalities, 1 complex) relapsed. The survival in the 21 patients who
did not have APL was 57%, compared with the 40% achieved in the
similar age cohort with chemotherapy alone in the MRC AML 10 trial.17 Within the MRC AML 10 protocol, 185 patients
received the same chemotherapy as used in younger patients in this
study before ATRA was introduced. The survival for these patients was
54% at 4 years, which is the same as the result achieved with short
ATRA in this study. Thirteen patients were transplanted. They were evenly distributed between the arms, but censoring their follow-up at
time of transplant did not affect the results presented here.
Influence of Molecular Characterization by RT-PCR
Molecular characterization was achieved in 202 of 239 patients who
entered this trial, of whom 186 (92%) were confirmed to have the
PML/RAR rearrangement. Of these, only 158 (85%) were identified by cytogenetics. No significant differences in outcome were
seen between those confirmed cytogenetically (and molecularly) or the
28 cases confirmed molecularly only (CR, 78% v 81%; relapse risk, 25% v 8%; P = .1; OS, 63 v 82%;
P = .09). Because the protocol permitted patients to enter the
trial based on a morphological definition and 21 of the 239 entrants
were subsequently shown not to have APL, the outcomes were analyzed
separately. Of the 218 cases confirmed, 69% (short) and 86%
(extended) achieved CR, compared with 73% and 90%, respectively, of
the 21 non-APL cases. The respective DFS for confirmed cases at 4 years
was 58% (short) and 74% (extended), compared with 63% (short) and
56% (extended) for the non-APL cases. With respect to OS at 4 years,
the confirmed cases were 53% (short) and 73% (extended), compared
with 44% (short) and 50% (extended) in the unconfirmed cases.
The nature of the breakpoint was characterized in 186 patients and was
5' (bcr 3) in 72 (39%) and 3' (bcr 1/2) in 114 (61%). This relative proportion did not significantly differ whether the
t(15:17) was alone or was associated with other cytogenetic changes,
with age, or with WBC. Bcr1 and 2 breakpoints were distinguished in 100 patients, showing 12 bcr2 cases. PML breakpoint position made
no difference to initial response (bcr1/2, 82%; bcr3, 78%), but there
was a nonsignificant trend for a lower relapse risk in 3'
breakpoints (19% v 42%), but this did not translate into a
survival difference (bcr1/2, 67%; bcr3, 65%). Reciprocal
RAR-PML transcripts were expressed in 142 of 186 patients (76%) but had no effect on survival. The patient with the
PLZF/RAR rearrangement was treated with extended
ATRA achieving CR after course one, as reported
elsewhere.27
MRD Monitoring Studies
Molecular monitoring studies were performed on 105 patients with
documented rearrangements to determine the kinetics of achievement of
molecular remission after treatment. Detection rates of
PML-RAR and RAR-PML fusion transcripts in bone
marrow samples taken after hematopoietic recovery after each course of
chemotherapy are shown in Fig 5.
In patients expressing RAR-PML, disappearance of
these reciprocal derived transcripts was frequently found to lag behind PML-RAR, consistent with the increased sensitivity
associated with the RAR-PML assay previously noted in
dilution studies of the NB4 cell-line.21,28 Use of the
RAR-PML assay in addition to the more conventional method
for PML-RAR led to the detection of disease-related
transcripts in an additional 20% (21/105) of patients while in
morphologic CR and included 4 patients with 5' PML
breakpoints as well as 17 with 3' breakpoints.
None of the 35 patients from whom bone marrow was examined after the
fourth course of chemotherapy had detectable PML-RAR transcripts; nevertheless, 11 of 35 ultimately relapsed. The
RAR-PML assay had been informative at diagnosis
in 8 of the relapsing patients; however, reciprocal transcripts were
undetectable in 7 of these 8 patients after completion of therapy
(3' PML breakpoint, n = 3; 5' PML
breakpoint, n = 4), despite the increased sensitivity associated
with this method. Overall, 22 of 35 patients assessed at the end of
treatment had an informative RAR-PML assay at diagnosis; reciprocal transcripts were detected in 2 of these patients immediately after completion of therapy: 1 patient with a 3' PML
breakpoint subsequently tested PCR-negative in a further sample
received 24 months later with no intervening therapy and remains in
complete continuous remission (CCR) at 3.5 years after
completion of therapy, whereas the other patient with a 5'
PML breakpoint relapsed within 7 months. Twelve patients found
to express RAR-PML at diagnosis (3' PML
breakpoint, n = 9; 5', n = 3) and maintaining long-term remission were also evaluated for both fusion transcripts in the first
year after completion of therapy; none was found to be RT-PCR positive.
No difference was observed in the rate of disappearance of
PML-RAR and/or RAR-PML transcripts between
patients randomized to extended or short ATRA.
We then sought to determine whether there was a difference in RT-PCR
profiles between 26 patients who ultimately relapsed and 79 remaining
in CCR. The detection rate of disease-related transcripts after each
course of chemotherapy was greater among the group who ultimately
relapsed. Among the whole group, detection of transcripts at any stage
after induction or during consolidation therapy was associated with an
increased risk of relapse (Fig 6). This trend was found
to be most predictively useful after the third course of chemotherapy,
when most patients were evaluable, coinciding with the timing of bone
marrow harvesting in the AML 10 and 12 trials. Detection of
disease-related transcripts at this stage predicted a significantly
increased risk of relapse (Fig 6) and poorer OS (57% v 89%,
P = .02). Among 12 patients studied at relapse, no discrepancy
was observed in either PML breakpoint or RAR-PML
expression pattern in comparison to the time of initial presentation.
| |
DISCUSSION |
It is now accepted that retinoic acid plays a key role in the treatment
of APL. Although this subtype of AML has always tended to be more
sensitive to chemotherapy alone, this study and other studies have
shown that survival is significantly improved when chemotherapy is combined with retinoic
acid.11-14,29 A 5-day schedule used before
chemotherapy in the hope of reducing early deaths, particularly
associated with coagulopathy, was clearly inferior to a continuous
schedule of retinoid administered until CR was confirmed. Indeed, when
a cohort of 50 patients treated with short ATRA on the MRC AML 10 protocol included here are compared with an historical group of 185 patients with APL in that trial receiving the same chemotherapy at an
earlier stage of that trial without retinoid, no improvement in
remission rate, DFS, or OS was observed. The benefit of extended
retinoic acid was limited to the 70% of patients who presented with a
low WBC. We were unable to show any benefit for patients presenting
with a WBC greater than 10.0 × 109/L. This level was
chosen because patients treated in our pre-ATRA schedules with a WBC
greater than 10 × 109/L had a
lower CR (70% v 87%) and a poorer 5-year survival (43% v 55%) than those with lower counts, but others have also
shown that a WBC greater or less than 5 × 109/L is
influential on outcome.8 We found on analysis of this study
that there was little difference between using 5.0 or 10.0 as the
appropriate cut-off. Although there was an increased risk of relapse in
patients with a higher WBC who achieved CR, the main reason for the
difference in outcome was an excess of early deaths, ie, within 30 days
of diagnosis (27 v 14 events). In the extended arm of this
trial, patients received ATRA until CR or day 60, whichever came first.
In fact, the median duration was 28 days (range, 0 to 62 days), which
for most patients was with course 1 only. Whether the addition of
retinoid to consolidation treatment would reduce further the relapse
risk is a potential question for prospective trials, although there are
preliminary data that suggest that maintenance treatment with ATRA can
reduce relapse risk.13
The retinoic acid syndrome has been reported in up to 25% of cases
receiving ATRA alone.15 Because of the multi-institutional pattern of care in this trial (101 different institutions took part),
we were anxious to minimize the risk of this complication in the study
design either by limiting the period of exposure to ATRA as a single
agent to 5 days (with the proviso that, if the WBC increased,
chemotherapy would be initiated) or by starting the chemotherapy at the
same time. On reviewing the early death reports, 4 of 27 deaths in the
short ATRA were ATRA syndrome, with an additional 2 respiratory deaths
not so labeled. Only 1 ATRA syndrome and 1 respiratory death were
reported in the extended ATRA arm. Whether prophylactic steroids would
be beneficial in patients who present with a high count as a means of
circumventing this problem is not clear.30
We have previously demonstrated that there is nothing to be gained in
undertaking a transplant procedure in first remission in good
cytogenetic risk cases.31,32 The small number of
transplanted patients, who were equally divided between the arms, did
not influence the trial result in that the results did not change if
they were censored at time of transplant. The policy of delaying
transplant beyond CR1 becomes even clearer now in low count cases of
APL who receive extended ATRA treatment. For reasons that are not entirely clear, a relatively modest increase in WBC makes a major impact on outcome that is not changed by the use of extended ATRA, although the number of such patients who entered CR was small. Once in
CR, these patients have a 41% risk of an event (36% of relapse), but
it would be statistically difficult to show a benefit of allogeneic
bone marrow transplantation in this subgroup, because the procedure
itself carries a 15% to 20% risk, and even after relapse there is a
survival of 25% in this group. An autograft should have a lower
procedural risk, and we know from the results of our MRC AML 10 trial32 in the APL subgroup that it can reduce the risk of
relapse (25% v 49%). The Italian experience suggests that the
success of autograft depends on the patient being RT-PCR negative at
the time of transplant.33
Because retinoic acid is such an important component in the treatment
of APL, it is crucial that all useful techniques are deployed to
identify patients who will benefit. It has previously been shown that
the PML/RAR rearrangement characterizes such patients.9 In this study, we have demonstrated that, for a number of reasons (mostly technical failure), cytogenetics alone was
not optimal. It is of interest that 21 patients who entered this study
and received retinoid were subsequently shown not to have APL. When
these patients are excluded, the survival at 4 years is 73% for
extended versus 53% for short. Although RT-PCR is the most valuable,
not least because it defines targets for minimal residual disease
detection, it is helpful to use FISH and PML immunofluorescence, as we
have demonstrated. Only 85% of patients were identified by
conventional cytogenetics. Those positive by RT-PCR alone have a
similar survival, and it is therefore reasonable to accept this as a
basis on which to make clinic decisions, as already indicated by
others.14 The breakpoint frequency observed in our study is
similar to that in other recently published series,14,34 but we have not been able to find a relationship between breakpoint and
additional cytogenetic abnormalities as reported in a previous smaller
study.35 Whether PML breakpoint influences outcome
is a somewhat contentious issue,22,34,36,37 probably
reflecting relatively small sample sizes and interstudy and intrastudy
treatment variation. Our study is in accordance with the results
reported from Memorial Sloan Kettering,36 suggesting that
the presence of a 5' (bcr 3) PML breakpoint is associated
with an increased risk of relapse. In both studies, the increased risk
of relapse was at a borderline level of significance; indeed, in the
present study, there was no difference in overall survival. This would suggest that there are insufficient data at present to justify the use
of PML breakpoint pattern as a means of directing treatment approach in individual patients. Indeed, other groups have observed no
difference in outcome according to PML
breakpoint,34,37 suggesting that any such effect may
reflect therapeutic differences between the studies or the play of chance.
Finally, we sought to determine whether molecular monitoring could
provide independent prognostic information in patients treated with
ATRA and chemotherapy. Recent studies have demonstrated that monitoring
for PML-RAR fusion transcripts postconsolidation can predict
subsequent relapses as well as outcome after autologous bone marrow transplantation performed in second morphological CR.33,38 Early studies also suggested that PCR status after completion of therapy was of key prognostic significance and stressed the importance of achievement of molecular remission as a prerequisite for long-term survival, although persistent PCR positivity was found to
predict a poor prognosis.9,10 However, these early studies
included significant numbers of patients treated with ATRA as
single-agent therapy or individuals treated in relapse, in whom, in
retrospect, a high frequency of persistent PCR positivity associated
with a poor long-term prognosis was not unexpected. It is now clear
that combinations of ATRA and chemotherapy constitute the optimal
treatment approach for APL at present and, as shown in this study and
others, the majority of patients treated in this way ultimately achieve
molecular remission.14,21 However, recent studies
demonstrate that molecular monitoring strategies in which PCR status is
only determined immediately postconsolidation fails to predict relapse
in the majority of patients who ultimately do so.14,21,38
This phenomenon reflects the relative insensitivity of conventional
PML-RAR assays, although this lack of sensitivity belies its
highly predictive nature when MRD detection is performed regularly
postconsolidation.38 Given the increased sensitivity of the
RAR-PML assay, we sought to determine whether additional use
of this assay could more successfully detect residual disease in
patients who ultimately relapsed. However, RAR-PML
transcripts were detected in only 1 of the 8 informative relapsing
patients tested after completion of therapy, suggesting that this assay also lacks sufficient sensitivity using conventional methods to detect
residual disease in all patients who eventually relapse. However,
attempts to further increase sensitivity using conventional assays have
failed to achieve more clinically useful prognostic information,
serving merely to identify disease-related transcripts in a series of
patients in long-term remission.28,39
The advantage of the present study is the demonstration that molecular
monitoring during the treatment period can provide independent
prognostic information in the context of a relatively homogeneous
disease. This would suggest that newer technologies such as real time
PCR,40 which affords the opportunity to quantify disease-related transcripts relative to an internal control, may more
accurately establish subgroups of patients at particular risk of
relapse during consolidation therapy, who may benefit from more
intensive consolidation therapy, including transplantation procedures.
It remains to be established whether a policy of treatment of molecular
relapse is more advantageous than delaying intervention to the time of
clinical relapse. Preliminary data suggest that it is. The majority of
patients examined during consolidation in our study were molecularly
negative. Although such patients are at a lower risk of relapse,
because they are the majority, the absolute number of relapses is
larger in this group. Such patients may be best served by regular
monitoring after consolidation as a means of predicting impending
relapse, but this would require at least 3 monthly review marrows. Even
then, not all patients can be treated at the time when there is solely
molecular evidence of disease, due to false-negative PCR results
reflecting poor sample quality or rapid hematological relapses not
predicted by the preceding PCR result. For this reason, it may be
pragmatic for the smaller group of APL patients with delayed clearance
of disease-related transcripts in consolidation to be treated with more
intensive consolidation therapy. Given the improved prognosis of APL
patients treated with extended ATRA and chemotherapy, the resolution of
these important issues will require clinical trials, including even
greater numbers of patients, necessitating collaboration of
intranational and international study groups.
| |
APPENDIX |
Contributors.
A.K.B. was involved in trial design and trial coordination and wrote
the report. D.G. undertook the molecular studies and wrote the report.
E.S. supervised the molecular studies. K.W. was involved in trial
design, supervised the data collection, and undertook statistical
analysis and finalization of the report. A.H.G. was involved in study
design and trial coordination.
Trial participants.
Aberdeen Royal Infirmary (N.B. Bennett, D.J. Culligan, A.A. Dawson);
Addenbrooke's Hospital (R. Marcus); Alder Hey Children's Hospital (M. Caswell); Belfast City Hospital (Z.R. Desai, T.C.M. Morris); Birmingham
Heartlands Hospital (D.W. Milligan); Bradford Royal Infirmary (L.A.
Parapia, A.T. Williams); Bristol Royal Infirmary (G.L. Scott);
Cheltenham General Hospital (R.G. Dalton); Christchurch Hospital
(D.N.J. Hart); City Hospital NHS Trust (D. Bareford); Conquest Hospital
(J. Beard, S.G. Weston-Smith); Derbyshire Royal Infirmary (A. McKernan,
D.C. Mitchell); Derriford Hospital (A. Prentice); Dundee Teaching
Hospital NHS Trust (P. Cachia); Ealing Hospital (U.M. Hegde);
Eastbourne District General (R.J. Grace); Falkirk & Dist. Royal
Infirmary (A.D.J. Birch); Frimley Park Hospital (J. VanDePette); George
Eliot Hospital (M.N. Narayanan); Glan Clwyd District General Hospital
(D.R. Edwards); Gloucester Royal Hospital (J. Ropner); Grantham
District NHS Trust (V.M. Tringham); Great Ormond Street Hospital (J.M.
Chessells, I.M. Hann); Guy's Hospital (S.A. Schey); Halifax General
Hospital (A.J. Steed); Hammersmith Hospital (J. Apperley, J.M.
Goldman); Harrogate General Hospital (M.W. McEvoy); Hillingdon Hospital
(R. Jan-Mohamed); Hinchingbrooke Hospital (C.E. Hoggarth); Horton
General Hospital, NHS Trust (I.J. Durrant); Hospital for Sick Children,
Bristol (A. Oakhill); Hospital for Sick Children, Edinburgh (A. Thomas); Hospital for Sick Children, Glasgow (E. Chalmers, B. Gibson); Huddersfield Royal Infirmary (C. Carter); Ipswich Hospital (C.N. Simpson); King's College Hospital (G. Mufti); King's Mill Hospital (E. Logan); Kingston General Hospital (M.L. Shields); Law Hospital (T.L. Allan); Leeds General Infirmary (J.A. Child, D.R. Norfolk, G.M.
Smith); Leicester Royal Infirmary (C.S. Chapman, R.M. Hutchinson, J.K.
Wood); Lincoln County Hospital (M.A. Adelman); Lister Hospital (S.M.
Watkins); Manor Hospital (G.P. Galvin); Monklands District General
(E.J. Fitzsimons, W. Watson); Norfolk & Norwich Hospital (A.J. Black,
J. Leslie); North Staffs Hospital Centre (P.M. Chipping, R.M.
Ibbotson); Northampton General Hospital (J.R.Y. Ross, S.S. Swart);
Nottingham City Hospital (N.H. Russell); Oxford Radcliffe Hospital (P. Emerson, T.J. Littlewood, J.S. Wainscoat); Pembury Hospital (D.S.
Gillett); Peterborough District Hospital (S.A. Fairham, M. Sivakumuran,
J.A. Wimperis); Pilgrim Hospital (S. Sobolewski); Prince Philip
Hospital (R.V. Majer); Queen Alexandra Hospital (T. Cranfield, M. Ganczakowski); Queen Elizabeth Hospital, Birmingham (J.A. Holmes);
Queen Mary's Sidcup NHS Trust (S. Bowcock); Raigmore Hospital (C.J.
Lush); Royal Chesterfield Hospital (R. Collin); Royal Cornwall
Hospital, Treliske (M.D. Creagh, A.R. Kruger); Royal Devon & Exeter
Hospital (M.V. Joyner); Royal Hallamshire Hospital (J.T. Reilly, D.A.
Winfield); Royal Hants. County Hospital (W.O. Mavor); Royal Infirmary
of Edinburgh (A.C. Parker); Royal Liverpool University Hospital (J.C.
Cawley, R.E. Clark); Royal Manchester Children's Hospital (R.F.
Stevens); Royal Marsden Hospital (S.T. Meller); Royal Shrewsbury
Hospital (N. O'Connor), Royal Sussex County Hospital (J. Duncan);
Royal United Hospital NHS Trust (C.R.J. Singer); Royal Victoria
Hospital, Belfast (F.G.C. Jones, E.E. Mayne); Sandwell General Hospital
(S.I. Handa, P.J. Stableforth); Scunthorpe General Hospital (S. Jalihal); Selly Oak Hospital (J.A. Murray, W.N. Patten); Sheffield
Children's Hospital (J.S. Lilleyman); Southampton University Hospital
Trust (A. Duncombe, A.G. Smith); Southmead Hospital (R.R. Slade); St George's Hospital (D.H. Bevan); St. James's University Hospital (D.L.
Barnard, B.A. McVerry); St Thomas' Hospital (R. Carr); Staffordshire General Hospital (P. Revell); Stirling Royal Infirmary (D.M. Ramsay); Stobhill General Hospital (R.B. Hogg); Taunton & Somerset Hospital (M.J. Phillips); The North Hampshire Hospital (A.E. Milne); UCL Medical
School, London (D.C. Linch); University College Hospital, Galway (E.L.
Egan); University College Hospital, London (S. Devereux, A. Goldstone, K.G. Patterson); University Hospital of Wales (A.K. Burnett,
S.H. Lim, C. Poynton, J.A. Whittaker); Victoria Infirmary (P.J.
Tansey); Warwick Hospital (P.E. Rose); West Suffolk Hospital (P. Harper); Western General Hospital (P. Ganly); Western General Hospital
(M.J. Mackie); Western Infirmary (N.P. Lucie); Whipps Cross Hospital
(C. DeSilva); Whiston Hospital (J. Tappin); William Harvey Hospital
(D.G. Wells); Worcester Royal Infirmary (A.H. Sawers, R. Stockley);
Worthing Hospital (A.W.W. Roques); Wycombe General Hospital (S. Kelly);
York District Hospital (L.R. Bond); Ysbyty Gwynedd (H.E.T. Korn, D.H. Parry).
| |
ACKNOWLEDGMENT |
The Working Party is grateful to Dr Graham Fothergill and Roche
Pharmaceutical for providing ATRA for this trial. We thank the
clinicians who entered their patients into this trial; Dr David Swirsky
and Sameena Iqbal for performing FISH studies; Steve Langabeer for
handling trial samples; Helen Walker for supervising cytogenetic
reporting and the regional cytogeneticists; Georgina Harrison for data
retrieval; Siân Edwards for preparing the manuscript; and Dr
Francesco Lo Coco for constructive review of the manuscript.
| |
FOOTNOTES |
Submitted August 21, 1998; accepted February 17, 1999.
D.G. was supported by an MRC Clinical Training Fellowship and by ICRF
and is currently supported by the Leukaemia Research Fund. E.S. was
supported by EEC Grants No. BIOMED-CR92-0755 and Biotech
BI02-CT-930450. Molecular studies for the ATRA trial were supported by
the MRC and ICRF. Material for molecular analyses was derived from the
MRC AML Trial Tissue bank at University College Hospital, which is
supported by the Kay Kendall Leukaemia Fund.
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 Alan K. Burnett, MD,
Department of Haematology, University of Wales College of Medicine,
Heath Park, Cardiff CF4 4XN, UK; e-mail: BurnettAK{at}Cardiff.ac.UK.
| |
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TOP
ABSTRACT
INTRODUCTION
)
PML-RAR
; (
) PML-RAR
