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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2225-2229
Therapy of Molecular Relapse in Acute Promyelocytic Leukemia
By
Francesco Lo Coco,
Daniela Diverio,
Giuseppe Avvisati,
Maria C. Petti,
Giovanna Meloni,
Enrico M. Pogliani,
Andrea Biondi,
Giuseppe Rossi,
Carmelo Carlo-Stella,
Carmine Selleri,
Bruno Martino,
Giorgina Specchia, and
Franco Mandelli
From the Dipartimento di Biotecnologie Cellulari ed Ematologia,
Università "La Sapienza," Rome; Clinica Pediatrica and
Divisione di Ematologia, Ospedale S.Gerardo, Monza; Sezione Ematologia,
Spedali Civili, Brescia; Cattedra di Ematologia, Università di
Parma; Divisione di Ematologia, Università Federico II, Napoli;
Dipartimento di Ematologia, Azienda Ospedaliera di Reggio Calabria; and
Cattedra di Ematologia, Università di Bari, Bari, Italy.
 |
ABSTRACT |
Fourteen patients with PML/RAR -positive acute promyelocytic
leukemia (APL) were given salvage therapy at the time of first molecular relapse. All patients had achieved first molecular remission after the AIDA protocol (all-trans retinoic acid [ATRA] + idarubicin) and were being prospectively monitored by reverse
transcriptase-polymerase chain reaction (RT-PCR). Molecular relapse was
defined as reappearance of RT-PCR-positivity for the PML/RAR fusion
(sensitivity 10 4) in 2 successive marrow samples
collected during postconsolidation monitoring. The median duration of
first molecular remission was 7.5 months (range, 2 to 25). Salvage
therapy consisted of oral ATRA for 30 days followed by 4 daily courses
of chemotherapy (CHT) with cytarabine 1 g/m2/d and
mitoxantrone 6 mg/m2/d. Second molecular remission was
obtained in 12 of 14 patients (86%). Seven of these 12 attained
molecular remission after ATRA alone. Of the 2 patients who persisted
PCR+ after CHT, 1 died in remission and 1 progressed to
hematologic relapse. Of 12 patients PCR, 8 received
consolidation with autologous bone marrow transplantation (ABMT), and 4 received ATRA-containing maintenance. Ten patients in this group are in
sustained second molecular remission at a median time of 9.5+ months
(range, 4 to 22+) and 2 underwent hematologic relapse 6 and 13 months, respectively, after transient second molecular remission. The
2-year Kaplan and Meier survival estimate from time of relapse was 92%
(95% confidence interval [CI]: 61% to 98%) in this
series, and 44% (95% CI: 35% to 52%) in a previous series of 37 patients who received the same treatment at the time of hematologic
recurrence (P < .05, by log-rank test). This study suggests
that early administration of salvage therapy is advantageous in APL and
represents the first experience on therapy of molecular relapse in
acute leukemia.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
ACUTE PROMYELOCYTIC leukemia (APL) is
characterized by a specific chromosome translocation t(15;17) and a
unique response to the differentiating agent all-trans retinoic acid
(ATRA). Although combined treatment with anthracycline-based
chemotherapy and ATRA induces long-lasting remission and potential cure
in up to 70% of newly diagnosed patients, early death during induction
and occurrence of relapse still represent the major obstacles to final cure in this disease.1-4
At the molecular level, the t(15;17) results in a hybrid PML/RAR
gene, which is readily identified by reverse transcriptase-polymerase chain reaction (RT-PCR). Besides allowing a more rapid and refined diagnosis, this test has proven useful for minimal residual disease monitoring during follow-up.5-7 Using conventional RT-PCR
assays with sensitivity between 103 and 104,
several investigators have shown that detection of residual PML/RAR
transcript during remission predicts subsequent hematologic relapse.8-15 This was confirmed in a recently reported
study of the GIMEMA group (Gruppo Italiano Malattie
Ematologiche Maligne dell' Adulto) in which patients enrolled in the
AIDA (all-trans retinoic acid + idarubicin) trial were
prospectively monitored at preestablished time intervals.16
As a result of these findings, our group elected to anticipate salvage
therapy in those patients who, at any time after front-line induction
and consolidation, showed conversion from PCR to
PCR+ for PML/RAR while remaining in hematologic
remission. We report here a clinical and laboratory study on an initial
series of 14 APL patients treated at the time of first molecular relapse.
| |
MATERIALS AND METHODS |
Patients and previous therapy.
Fourteen patients with PML/RAR-positive APL who were given salvage
therapy at the time of first molecular relapse are included in this
study. All cases were initially enrolled for front-line therapy in the
GIMEMA trial AIDA17 and were prospectively monitored by
RT-PCR of PML/RAR at the following preestablished time intervals: every 2 to 3 months during the first year, every 4 months during the
second and third year, and every 6 months thereafter. Median age was
39.5 years (range, 19 to 65), median white blood cell (WBC) count was
5.4 × 109/L (range, 0.6 to 165.7). As to the type of
PML/RAR fusion detected at diagnosis, 9 patients showed a bcr3 and 5 patients a bcr1 PML/RAR isoform. According to the AIDA study
design,17 after the end of consolidation, 12 patients were
randomized to receive some type of maintenance, and 2 patients to no
further therapy. In the former group, 5 patients were assigned to
ATRA-containing maintenance (ATRA alone in 1 case and ATRA plus
methotrexate and 6-mercaptopurine chemotherapy in 4 cases), and 7 patients to chemotherapy alone. Detailed doses and schedules of
maintenance treatments are reported elsewhere.17 The median
duration of first molecular remission was 7.5 months (range, 2 to 25 months).
Criteria for molecular relapse.
In patients showing no evidence of disease at the morphologic analysis,
molecular relapse was defined as the conversion from PCR to PCR+ for PML/RAR detected in 2 successive postconsolidation bone marrow (BM) samples collected 2 to 4 weeks apart. The practice of confirming PCR positivity in a separate BM
sample before administering salvage therapy was established by our
group based on 2 considerations: (1) transient PCR positivity not
resulting in clinical recurrence had been detected, although very
rarely, in our series (unpublished observations); (2)
this practice represents a further cautionary step, which may allow to
rule out false positivity due to contamination of the first sample.
Patients who converted to PCR+ while in morphological
remission in the BM, but showed simultaneous overt disease in the
central nervous system (CNS) or other extramedullary sites, are not included in this study.
RT-PCR of PML/RAR.
Sequential BM samples were collected in each patient at established
time intervals for identification of molecular relapse and to assess
response at the PCR level during and after salvage treatment.
Mononuclear cells from BM aspirates were prepared locally at the
participating institutions in the Italian multicenter AIDA study and
suspended in a 4-mol/L guanidium thiocyanate (GTC) solution as
reported.16,17 Cryopreserved GTC samples were sent in dry ice to 1 of 2 referral molecular biology laboratories (Hematology, University "La Sapienza" of Rome and Clinica Pediatrica,
University of Milano-Monza). Reagents and experimental conditions for
RT-PCR of PML/RAR, sensitivity level of the reaction, and
interlaboratory quality control experiments to assess results
reproducibility have been reported elsewhere.16,17
Therapy for molecular relapse.
After confirmation of molecular relapse, all patients received as
reinduction ATRA 45 mg/m2/d by mouth for 30 days. This was
followed, after 1 week of rest, by cytosine arabinoside 1 g/m2 days 1 through 4 (intravenous [IV] infusion over 6 hours) and 3 hours after the end of cytosine arabinoside, mitoxantrone
6 mg/m2 days 1 through 4 by IV bolus. Patients who
converted to PCR were consolidated with unpurged
autologous BM transplantation (ABMT). BM harvest was collected at the
time of second molecular remission. In 6 patients, the conditioning
regimen was based on the BAVC protocol (carmustine
[BCNU], cytarabine [Ara-C], amsacrine [m-AMSA], and etoposide
[VP16]),18 while patients no. 2 and 7 received busulfan and cyclophosphamide according to the schedule reported by Tutschka et al.19 Patients not eligible for
ABMT after reinduction were given maintenance therapy with intermittent ATRA, methotrexate, and 6-mercaptopurine, as reported.17
Survival was calculated from the time of molecular relapse according to the Kaplan and Meier life tables.20
| |
RESULTS |
Response to reinduction treatment.
Response to therapy was assessed by molecular analysis of BM samples
collected after ATRA alone, after chemotherapy, and at various time
points after ABMT and/or during follow-up. All samples used for
molecular studies were blindly analyzed in parallel by light microscopy
to confirm the status of hematologic remission. ATRA was always
administered on an outpatient basis and no relevant side effects were
recorded during this treatment. After reinduction with ATRA alone, 7 patients (50%) tested PCR for the PML/RAR
hybrid. After completing chemotherapy with cytosine arabinoside and
mitoxantrone, 12 of 14 (86%) tested PCR, while 2 (14%) persisted PCR+ and in hematologic remission. The
results of serial RT-PCR analyses are shown in
Table 1.
Clinical and molecular outcome.
Of the 2 patients persistently PCR+ after reinduction, 1 (no. 14) died of intracranial hemorrhage during postchemotherapy
aplasia and 1 (no. 13) had hematologic relapse 10 months later, despite receiving additional chemotherapy. This latter patient is presently in
second hematologic (PCR+) remission after 1 cycle of IV
arsenic trioxide (kindly supplied by PolaRx Inc, New
York, NY). In the group of patients PCR after
reinduction, 2 patients (nos. 5 and 8) showed prolonged BM hypoplasia,
which was complicated by pulmonary infection in 1 case. These 2 patients as well as patients no. 6 (ABMT refusal) and 12 (on waiting
list for ABMT, not yet performed due to logistic problems), were given
after reinduction maintenance treatment with ATRA, methotrexate and
6-mercaptopurine as reported.17 The remaining 8 patients
who experienced no significant toxic effects after salvage treatment
underwent unpurged ABMT at a median time interval of 2 months (range, 1 to 5 months) from the achievement of second molecular remission. RT-PCR
analysis confirmed in all cases absence of PCR-amplifiable PML/RAR
transcripts in the BM harvest. No major toxic effects were recorded
during and after ABMT procedures.
Ten patients (no. 1, 2, 3, 5, 6, 7, 8, 9, 10, and 12 in Table 1) have
remained in sustained second molecular remission for a median time of
9.5+ months (range, 4 to 22+). This group included 6 of the 8 autografted and all the 4 nonautografted patients. Two patients (no. 4 and 11), both in the ABMT group, had hematologic relapse at 13 and 8 months from the achievement of second molecular remission. In case no.
4, overt disease recurrence was not predicted by RT-PCR monitoring,
which yielded persistently negative results up to 2 months before
relapse. This patient underwent second hematologic remission with oral
ATRA and third molecular remission after cytosine arabinoside and
mitoxantrone chemotherapy. In case no. 11, hematologic relapse was
preceded by a PCR+ test performed 2 months earlier (Table
1). This patient was resistant to further therapy with ATRA and is
currently receiving arsenic trioxide.
The 2-year Kaplan-Meier estimate of survival from the time of first
molecular relapse was 92% (95% confidence interval
[CI]: 61% to 98%). This was compared with survival
of 37 patients enrolled in the AIDA study who were treated with the
same reinduction approach at the time of hematologic recurrence
(historical controls). In this latter group, median age was 35.3 years
(range, 9.5 to 73.8), median WBC count at presentation was 2.3 × 109/L (range, 0.3 to 85.5) and median duration of first
hematologic remission was 12.2 months (range, 5.2 to 29.1). The median
duration of first molecular remission was 6 months (range, 2 to 23) in 23 patients of the historical group who were adequately monitored during follow-up; hematologic relapse was preceded by a positive PML/RAR test in 20 of these 23 cases. The 2-year estimate survival from the time of hematologic relapse for the historical series was 44%
(95% CI: 35% to 52%). The difference with survival of the 14 patients treated for molecular relapse was statistically significant
(P < .05, Fig 1).
View larger version (9K):
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| Fig 1.
Kaplan-Meier estimates of overall survival from relapse
in patients treated at the time of molecular relapse (dotted line) and
in the historical series of patients treated for hematologic relapse
(continuous line).
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| |
DISCUSSION |
The availability of a disease-specific and PCR-detectable molecular
marker has recently allowed a more refined assessment of response to
treatment and relapse risk in patients with APL. As a consequence,
several investigators have adopted the term molecular remission,
corresponding to therapy-induced conversion to PCR
for the PML/RAR in the BM, as a more advanced therapeutic goal in
this disease.17,21-24 On the other hand, a number of
monitoring studies have shown that reappearance during hematologic
remission of PCR+ cells almost invariably predicts
recurrence of overt disease.8-15 After confirmation of this
in a prospective monitoring study,16 we started considering
as having molecular relapse those patients who converted from
PCR to PCR+ during hematologic remission
and decided to early administer salvage treatment in such cases.
It must be emphasized that such clinical correlations have been
established using relatively insensitive PML/RAR PCR assays (capable
of detecting beween 103 and 104
positive cells). By contrast, the use of techniques characterized by
greater sensitivity, including amplification of the reciprocal RAR/PML hybrid, have yielded prognostically less informative results, due to the detection of residual transcripts in some patients
in long-term remission.25
The present study has 2 main weaknesses, which prevent us from drawing
firm conclusions on the advantage of anticipating salvage treatment in
APL. First, our series includes a small number of patients whose
follow-up is relatively short. In addition, it was quite difficult for
us to find an adequate control group, such that a historical series of
patients treated with the same approach had to be used to compare
survival. Indeed, given the high risk of early mortality in APL
patients with overt disease, we considered unethical comparing early
versus delayed therapeutic intervention in a randomized study, even
though we realize that this would be the best methodologic approach to
test this issue. Despite the above limitations, this study represents,
to the best of our knowledge, the first report on the treatment of
molecular recurrence in acute leukemia, and we believe that it contains some interesting preliminary observations.
Early therapy of relapse, ie, intervening on a minimal tumor burden,
minimizes the most serious disease- and treatment-related risks of APL,
such as hemorrhagic death and the life-threatening ATRA syndrome. All
patients in the present study could be treated on an outpatient setting
for ATRA administration with no toxic effects being recorded.
Subsequent chemotherapy, however, was associated with important
toxicity in 3 cases, including 1 death in remission, which occurred
during marrow aplasia.
Second, most patients in this series had aggressive disease, as
indicated by the initial median WBC count (5.4 × 109/L), and by first molecular remission duration, which
was  12 months in 13 of 14 and extremely short (6 months) in 6 of 14 cases (Table 1). In addition, they all relapsed at the molecular level
after having received optimal front-line therapy including simultaneous
ATRA and anthracycline-containing chemotherapy, the only exception
being patient no. 2 who could not complete the programmed induction
schedule due to ATRA toxicity. This notwithstanding, a status of second
molecular remission could be achieved in 86% of patients. Furthermore,
half of the patients showed conversion to PCR after
ATRA alone, a phenomenon that is only occasionally observed in patients
receiving ATRA for clinically overt disease.8,10 Recently,
Grimwade et al26 also reported the achievement of molecular
remission in 2 patients who received ATRA as therapy for minimal
residual disease.
Given the relative insensitivity of the RT-PCR assay used, it is
presumable that the molecular remissions observed after ATRA alone
reflect the reduction of tumor burden below the PCR detection threshold, rather than eradication of leukemia. For that reason, we
decided to adopt as treatment for molecularly relapsed APL the same
intensive approach used by our group for patients in hematologic
relapse. In this latter subset, we recently reported the achievement of
prolonged second molecular remission with ATRA followed by chemotherapy
and ABMT for patients with PCR BM.27
However, all 4 patients who could not receive ABMT in the present study
had prolonged second molecular remission; thus, the advantage of using
ABMT in addition to ATRA and chemotherapy remains unclear.
Due to heterogeneity of potentially relevant prognostic factors (eg,
age, WBC count, PML/RAR isoform, type of maintenance and first
molecular remission duration), we were unable to do a pair-matched
comparative analysis between patients treated for molecular and
hematologic relapse. However, patients in the historical control group
had a significantly worse survival compared with those treated for
molecular relapse. In particular, 16 of 37 (43%) patients have died in
the former group, compared with 1 of 14 (7%) in the molecular relapse
category (Fig 1). Our results in patients treated for first hematologic
relapse are in line with those of the MRC group, who recently reported
a remission rate of 65% and 50% and 2-year survival rates of 44% and
43% for patients relapsing at the hematologic level after chemotherapy
plus short or extended ATRA,
respectively.28
While our preliminary observations suggest a benefit in anticipating
salvage therapy in APL, it is difficult to establish which is the best
treatment approach for minimal disease recurrence. Recent observations
with arsenic trioxide (As2O3) indicate that this agent is more potent than ATRA for inducing molecular
remission.21 Although long-term results of
As2O3 are not yet available, its use in the
particular setting of molecular relapse might be encouraged. However,
due to the relative infrequency of relapses in this disease, comparative (ie, phase III) studies aimed at evaluating different approaches will most likely require collaborative efforts at the multiinstitutional or even multinational level.
| |
FOOTNOTES |
Submitted April 9, 1999; accepted June 1, 1999.
Supported by grants from ROMAIL (Associazione Italiana contro le
Leucemie, sez. di Roma), AIRC (Associazione Italiana per la Ricerca sul
Cancro), and Fondazione Tettamanti (Monza).
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 Francesco Lo Coco, MD, Dipartimento di
Biotecnologie Cellulari ed Ematologia, Università "La
Sapienza" Via Benevento 6, 00161 Rome, Italy; e-mail:
lococo{at}bce.med.uniroma1.it.
| |
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TOP
ABSTRACT
INTRODUCTION