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PERSPECTIVE
From the Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical
School, Chicago, IL; Children's Hospital of Oakland, CA; and the
Department of Hematology and Bone Marrow Transplantation, Technion
Israel Institute of Technology, Rambam Medical Center, Haifa, Israel.
Acute promyelocytic leukemia (APL) is now the most curable subtype
of acute myeloid leukemia in adults. All-trans retinoic acid (ATRA), which induces differentiation of the leukemic cells into
mature granulocytes, represents the important advance. The incorporation of ATRA in induction results in a high complete remission
rate, leads to rapid resolution of the characteristic life-threatening
coagulopathy, and, most importantly, decreases the relapse rate
compared with treatment with chemotherapy alone. However, ATRA is
associated with unique toxicities not observed with conventional
cytotoxic chemotherapy. A number of clinical trials have been performed
to define the optimal role of ATRA in the treatment of patients. The
therapeutic strategies have rapidly evolved as a result of both single
institution and large cooperative group trials. Arsenic trioxide and
stem cell transplantation are effective treatments for patients with
APL who relapse after or are refractory to ATRA-based therapy. As
experience with ATRA and arsenic trioxide in patients with APL
accumulates, a number of important questions arise that need to be addressed.
(Blood. 2002;99:759-767) Role of cytarabine
Both daunorubicin and idarubicin as single agents induce complete
remission (CR) in 55% to approximately 90% of patients (Table 1).4-10 Two
retrospective comparisons showed no difference in the CR rate between
patients treated with daunorubicin alone or with daunorubicin and
cytarabine.6,7 In addition, in a prospective randomized
trial comparing idarubicin plus cytarabine to idarubicin alone, no
difference in the CR rate was observed.10 In that trial,
the CR rate was 76.3% with the single agent alone compared with 66.6%
in the combination arm. The event-free survival (EFS) was 35% in the
idarubicin arm compared with 35% in the combination arm
(P = .0429). This finding suggests that omission of
cytarabine may permit higher doses of anthracycline to be given.
However, the dose of idarubicin in the single-agent arm was 72 mg/m2 compared with 40 mg/m2 in the combination
arm. Therefore, patients in the monotherapy arm received 1.8 times as
much anthracycline as in the combination arm. In a retrospective
analysis, the Southwest Oncology Group showed excellent survival in
patients with APL when a daunorubicin dose of 70 mg/m2 per
day was used compared with the dose used in most studies of 45 to 50 mg/m2 per day, but without a change in cytarabine
dose.11
The introduction of all-trans retinoic acid (ATRA) has
prompted several study groups to exploit this peculiar sensitivity to
anthracyclines by omitting cytarabine during induction (Table 2). Estey et al12 reviewed
sequential studies at the MD Anderson Cancer Center and compared the
current regimen of ATRA plus idarubicin with an earlier study of
cytarabine with doxorubicin, amsacrine or daunorubicin without
ATRA. The CR rate was 77% among patients treated with ATRA
and idarubicin, which was not different from the historic cohort of
patients. The Italian Cooperative group GIMEMA and the Spanish
Cooperative group PETHEMA each combined ATRA with single-agent
idarubicin given in conventional doses (12 mg/m2 per day on
days 2, 4, 6, and 8) and showed CR rates in the range of 70% to
95%.13-15
Nevertheless, the evidence appears compelling that cytarabine can be omitted during induction when an anthracycline is given with ATRA. The European APL Group is currently conducting a trial in which patients presenting with a white blood cell (WBC) count of 10 000/µL or fewer are prospectively and randomly assigned to ATRA and daunorubicin or to ATRA plus daunorubicin and cytarabine. The results of this trial should provide important information on the role of cytarabine in the treatment of APL. Choice of anthracycline There is no clear choice of anthracycline in induction in APL. Fenaux et al16 prospectively randomized patients to either rubidizone plus cytarabine or to amsacrine plus cytarabine, and the CR rate was 86% without any difference between the anthracyclines. Berman et al17 published a retrospective analysis in a preliminary form investigating prognostic factors in APL and suggested that idarubicin is associated with an improved outcome compared with daunorubicin or amsacrine. No prospective randomized trial has compared daunorubicin and idarubicin in APL. Therefore, no clear evidence proves that one anthracycline is clearly superior to another in APL. Despite theoretic considerations suggesting idarubicin may be better such as its relatively long half-life and good central nervous system penetration, daunorubicin and idarubicin appear equally effective. It appears that what may be critical is the dose of anthracycline.11Combining ATRA with chemotherapy Although early phase II trials showed a high CR rate with ATRA alone, the remission durations were short.18-21 Furthermore, some patients treated with ATRA alone developed a rapid increase in WBC count that in some, but not all, studies was associated with retinoic acid syndrome (RAS).22-27 Therefore, most cooperative groups initiated trials combining ATRA with intensive antileukemic chemotherapy. The European APL group has conducted a prospective randomized trial in which concurrent ATRA plus chemotherapy was compared with a sequential approach of ATRA followed by chemotherapy as postremission therapy.28 The EFS at 2 years was 84% among patients receiving the concurrent approach compared with 77% in the sequential arm. This difference was attributable to a significant decrease in the risk of relapse (at 2 years, 6% in the concurrent group versus 16% in the sequential group, P = .04). This benefit was observed even among patients presenting with a low WBC (< 5000/µL). Although the CR rate has not clearly increased and early mortality rate has not clearly decreased with the concurrent approach, the combination of ATRA plus chemotherapy as initial therapy has become an attractive strategy for all patients. This approach has the additional benefit of possibly reducing the incidence of RAS from approximately 25% with ATRA25,26 to approximately 10% with concurrent chemotherapy and ATRA (Table 3).13,14 Whether more intensive postremission chemotherapy with, for example, higher doses of anthracycline than has been customarily administered would have a similar effect on the relapse rate is not known. It appears reasonable to begin treatment first with ATRA for 2 to 4 days to ameliorate the coagulopathy before initiating chemotherapy, provided the WBC is not high (< 10 000/µL).
Consolidation chemotherapy It has become mandatory to administer consolidation chemotherapy after CR because early studies showed early relapse after ATRA alone. In most studies, consolidation chemotherapy has been anthracycline based. Three trials have included high-dose (1-3 g/m2) cytarabine in consolidation.29-31 The North American Intergroup study administered one cycle of daunorubicin 45 mg/m2 per day for 3 days and standard-dose cytarabine 100 mg/m2 per day for 7 days as a first consolidation course followed by high-dose cytarabine 2 g/m2 twice daily for 4 days with 2 days of daunorubicin 45 mg/m2 per day for 2 days.29 Patients in the Medical Research Trial younger than 60 years received consolidation with cytarabine 1 g/m2 twice daily on days 1 to 3.30 The German AML Cooperative Group administered intensified double induction therapy including high-dose cytarabine with ATRA to newly diagnosed patients.31 Patients in CR received standard-dose cytarabine, daunorubicin, and 6-thioguanine consolidation and 3 years of monthly maintenance. The European APL group and the Japanese Adult Leukemia Study Group studies included standard-dose cytarabine as consolidation.23,32 However, just as there appears to be little role for cytarabine during induction, emerging data suggest that there is no role for high-dose cytarabine in consolidation. A prospective study published by the PETHEMA group suggests that patients do as well without cytarabine in either induction or consolidation.14 However, this study was not a randomized trial comparing idarubicin with or without cytarabine. It has become routine to administer at least 2 courses of postremission therapy after induction with ATRA and anthracycline, although, as in all subtypes of AML, there are no prospective data establishing the number of courses of intensive postremission consolidation.33 The most important goal of postremission therapy is complete eradication of the leukemic clone as determined by the conversion to a polymerase chain reaction (PCR)-negative status, because persistence of such minimal residual disease (MRD) predicts relapse.30,34-37Role of maintenance therapy Before the introduction of ATRA, several studies suggested a role for maintenance chemotherapy in patients with APL.6,38,39 Two large prospective randomized trials now suggest that maintenance therapy with ATRA is useful (Table 4).28,29,40 In the North American Intergroup study, patients in CR after 2 courses of consolidation chemotherapy were randomly assigned to either a year of daily maintenance ATRA at standard doses or to observation.29 This study showed a significant benefit when a year of daily maintenance ATRA is administered to patients whether they were induced into remission with chemotherapy alone or with ATRA. The best outcome was observed in patients who received ATRA during both induction and as maintenance with a 5-year disease-free survival of 74%.40 The European APL 93 trial randomly assigned patients in remission after anthracycline-based consolidation to one of 3 maintenance regimens or observation: ATRA in standard doses for 15 days every 3 months, or 6-mercaptopurine (6-MP) 90 mg/m2 per day plus methotrexate 50 mg/m2 per week, or the combination of ATRA and 6-MP/methotrexate as above.28 Patients receiving both ATRA and chemotherapy had the lowest relapse rate. In addition, overall survival (OS) was improved in patients receiving maintenance chemotherapy (P = .01), and there was a trend toward better survival in patients who received maintenance ATRA (P = .22). Furthermore, the combination of intermittent maintenance ATRA and continuous maintenance chemotherapy appeared to be particularly useful for patients presenting with a high WBC count. Therefore, at the present time, it appears that patients benefit from maintenance ATRA with or without continuous low-dose chemotherapy, particularly those at high-risk of recurrence such as those presenting with a high WBC count and older adults (> 60 years). The combination appears to be associated with the lowest relapse rate. However, the data on which these recommendations are made are based on small numbers of patients. The GIMEMA Cooperative Group is currently assigning patients in a randomized manner to the identical 3 maintenance regimens or to observation, and the North American Intergroup is currently assigning patients in CR in a randomized manner to either ATRA every other week with 6-MP and methotrexate or to ATRA alone. The results of these studies will aid in determining the optimal maintenance regimen and the patient population most likely to benefit. It is possible that higher doses of anthracyclines in induction or consolidation may obviate the need for maintenance therapy for some patients.11
Prevention and management of RAS The major toxicity of ATRA is RAS, a cardiorespiratory distress syndrome manifested by fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, and acute renal failure.41 Among patients induced into remission with ATRA alone, the incidence is approximately 25% (Table 3).25,26,41 The mortality rate of patients with the syndrome has declined over time (29% in the New York study versus 5% in the North American Intergroup study), likely reflecting earlier recognition and institution of dexamethasone. It is also possible that the risk factors for development of the syndrome were variable in the different studies. No factors are clearly predictive of the syndrome, including WBC count,26-29 although the presence of microgranular variant (M3v) morphology was protective in one study.26 An additional important issue concerns the potential difficulty in establishing an accurate diagnosis of the syndrome because patients may develop toxicities and complications of therapy, such as pneumonia, congestive heart failure, and sepsis, with manifestations that mimic RAS.The concurrent administration of chemotherapy with ATRA may decrease the incidence of the syndrome. However, this decrease has not been clearly established. In the first report of the GIMEMA (ATRA plus idarubicin) trial in which all patients received concurrent therapy, the incidence of the syndrome was 10%.13 As experience with concurrent ATRA plus idarubicin accumulated, the incidence of the syndrome decreased to approximately 4%.15,42 In the Japanese Adult Leukemia Study Group trial in which chemotherapy was introduced early for the prevention of hyperleukocytosis, the incidence of the syndrome was 6%.32 An overall incidence of 15% was reported by the European APL group with a mortality rate of 8%.28 A review of the first North American Intergroup trial showed that 26% of patients treated with ATRA developed the syndrome at a median of 11 days; however, none of the patients who received ATRA as maintenance therapy developed the syndrome.26 No difference in the incidence of the syndrome was observed among patients treated with concurrent versus sequential ATRA and chemotherapy. The Australian Leukemia Study Group has explored the benefits of prophylactic corticosteroids in patients who develop leukocytosis (WBC > 10 000/µL). In a small nonrandomized study, 87 patients received prophylactic corticosteroids at a dose of 75 mg prednisone per day, and 16% of patients developed the syndrome that was fatal in 3%.43,44 This approach cannot be routinely recommended for all patients because no prospective randomized trial has confirmed the benefits given the potential toxicities of several weeks of corticosteroids in this setting. Therefore, it appears reasonable to evaluate the benefits of prophylactic corticosteroids in a prospective randomized fashion. This evaluation can likely be done safely because a small study has shown that dexamethasone did not unfavorably influence the induction of terminal differentiation by ATRA in NB4 cells.45 It has been suggested that development of the syndrome may be associated with an increased incidence of extramedullary relapse.46 A number of reports have emerged, suggesting that the incidence of extramedullary relapse in APL, particularly in the central nervous system, is higher among patients previously exposed to ATRA than historically observed in patients treated with chemotherapy alone.47-51 This incidence may be related to modulation of adhesion molecules by ATRA.52 Prognostic significance of a positive molecular test for the
promyelocytic-retinoic acid receptor- Overall, there is general agreement that a positive
promyelocytic-retinoic acid receptor- Should children with APL be treated differently than adults? APL constitutes 6.2% to 8.7% of AML in children in the United States61,62 and up to 31% in some areas of Italy.63 Why there is such an extreme variation in incidence is unknown and suggests the need for an international epidemiologic investigation. It is possible that the variability may be explained by the apparent increased incidence of APL in patients of Latino and Hispanic origin with AML.55 The typical clinical features of APL in adults, which include low WBC count at diagnosis, lack of hepatosplenomegaly or adenopathy, high incidence of coagulation abnormalities and signs of clinical hemorrhage, rarity of central nervous system leukemia, and special features of the microgranular variant, are also seen with this disease in children.63-68The results of contemporary treatment of children with APL also appear similar to those reported in adults. The CR rates for combination ATRA and anthracycline-based therapy have been reported to be 79% to 88%68-71 and long-term EFS of 64% to 76%.69-72 There are, however, some special considerations in treating children with APL. The first special feature concerns the difficulty of some young patients to reliably swallow capsules. The pharmacokinetics of such delivery has not been studied, but there have been CRs in the few patients reported to have had nasogastric treatment.73 An alternative approach might be the use of a relatively newly developed liposomal ATRA compound.74-76 This agent may also be useful in intubated adult patients. It is given intravenously and has shown promising early results, but the responses of children in these trials have yet to be reported separately. A second problem with the use of ATRA in pediatric patients (especially those younger than 10 years) is increased neurotoxicity. Both headache and pseudotumor cerebri have been shown to be more frequent in children compared with adults.77,78 Special recommendations are made for management of this problem that may necessitate withholding ATRA for a period of time, use of dexamethasone and/or acetazolamide, and then reinstitution of ATRA at a lower dosage. Because of this predisposition, children on maintenance ATRA should have periodic ophthalmologic examinations. This feature is not due to differences in the pharmacokinetics of ATRA in children compared with adults, because there are no apparent significant differences in this regard.79 It is speculated that the difference may be attributable to poorly understood enhanced end-organ sensitivity to ATRA in younger pediatric patients.79 A final special circumstance for treating children with APL relates to a reluctance to expose children to daunorubicin doses larger than 400 mg/m2 because of the cardiomyopathy reported in several studies.80-82 Because of this issue and the concern for additional cardiac toxicity that may be incurred if a marrow transplantation were required, the 2 major pediatric cooperative groups decided to limit the maximum daunorubicin exposure to children enrolled on the current North American Intergroup trial to a similar dose. In addition, frequent assessment of cardiac function is required for children on that trial. Whether delivery of daunorubicin by prolonged continuous infusion might decrease cardiac toxicity, as has been demonstrated in adults,83 has not been adequately studied in children. Other possible solutions, such as liposomal daunorubicin or the use of the cardioprotectant agent ICRF 187, require further study in children. Should older adults with APL be treated differently than younger patients? Older adults, arbitrarily defined in various studies as 65 to 70 years and older, with APL treated with ATRA appear to have a less favorable prognosis than younger adults.24,28,30,32,84-87 Age appears to be an important prognostic factor for both achievement of CR14,32 as well as EFS14,28,32 and, in one study, early death and overall survival.28 Despite the omission of potentially toxic consolidation that includes cytarabine and the addition of maintenance with both ATRA and low-dose chemotherapy, patients older than 70 years still had an inferior EFS compared with patients younger than 70 years.14 Most trials do indicate an inferior outcome in older adults, and it may be that even less intensive chemotherapy than reported by the PETHEMA group can favorably influence the outcome of older adults treated with ATRA/anthracycline-based therapy, because a high induction mortality appears to contribute to the inferior outcome in older adults. The death rate among patients in CR in the European APL93 trial (ATRA with either concurrent or sequential daunorubicin and cytarabine followed by daunorubicin plus cytarabine consolidation) was 19%, significantly higher (P = .01) than among patients aged 65 years or younger presenting with a WBC count less than 5000/µL or among all patients presenting with a WBC count more than 5000/µL. It is not clear whether older age itself confers a worse prognosis or rather a biologic issue unique to older adults that is as yet undefined. Because the major cause of failure in older adults is death in CR rather than failure to achieve CR, RAS, or relapse, alternative consolidation strategies such as liposomal ATRA,74-76 arsenic trioxide, or anti-CD33 antibody-based approaches should be explored.88,89Current role of arsenic trioxide in APL Investigators from China reported that arsenic trioxide induces CR in patients with relapsed and refractory APL (Table 5).90-93 Preclinical studies suggested that arsenic has several mechanisms of action, including apoptosis and leukemic cell differentiation.94-97
Soignet et al98 initiated a pilot study of 12 patients with
relapsed APL who were treated with arsenic trioxide at doses ranging
from 0.06 to 0.2 mg/kg per day until leukemic cells were eliminated
from the bone marrow as determined by light microscopy. Eleven patients
obtained CR, with 8 of the 11 patients who initially tested positive
for the PML/RAR Currently, arsenic trioxide is considered the treatment of choice for patients with relapsed disease, particularly in patients exposed to ATRA within the prior 12 months. Once patients achieve a second CR, the best postremission strategy is not known. Little data exist about the duration of remission and PCR negativity with arsenic alone in patients with relapsed APL. The disease-free survival appears to be better when patients in CR after arsenic are treated with arsenic plus chemotherapy compared with arsenic alone (2 of 11 relapses versus 12 of 18 relapses; P < .01, respectively).93 Although some patients do well with maintenance arsenic trioxide with or without chemotherapy, others relapse and may be considered for either allogeneic bone marrow transplantation (alloBMT) or autologous stem cell transplantation (ASCT) in second CR. As initial induction, arsenic trioxide has been associated with hepatotoxicity but has been evaluated in only a limited number of patients.93 Although the number of patients is small, it appears that arsenic trioxide is as effective for treatment of refractory or relapsed APL in children as in adults with a CR rate of 81% to 100%.92,98,103,104 The role of arsenic during the induction phase of treatment for newly diagnosed patients is being studied in the current North American Intergroup trial in which patients in CR are assigned randomly or not to 2 courses of arsenic trioxide as a first consolidation cycle before 2 cycles of daunorubicin with 1 week of ATRA. Ongoing trials are under way, combining arsenic trioxide with ATRA and chemotherapy in induction in newly diagnosed patients and evaluating its role in consolidation, based on potential synergism.105,106 Preliminary studies in a small cohort of patients testing lower doses of arsenic trioxide suggest similar efficacy as the standard dose with less toxicity.107 Stem cell transplantation in APL In a survey from the European Bone Marrow Transplant Registry, Mandelli et al108 reported 362 patients, 187 of whom had undergone ASCT and 175 alloBMT between 1979 and 1992. Most of these patients received transplants in first CR before the routine use of ATRA. The results of this retrospective study suggested that approximately 45% of patients undergoing a transplantation procedure can be cured. However, there were no data comparing the outcome of the transplantation in relation to the induction regimen, and whether initial exposure to ATRA had prognostic value. The leukemia-free survival (LFS) in patients who received transplants in first CR was 48% for ASCT and 42% for alloBMT. However, treatment-related mortality (TRM) was 19% and 42%, respectively. Patients who received transplants in second CR had an LFS of 32% for ASCT and 22% for alloBMT with a TRM of 23% and 41%, respectively. Despite the limitations of this study, the information provides some perspective. Because combined ATRA and chemotherapy is potentially curative in 75% to 80% of newly diagnosed patients, it is not justifiable to recommend alloBMT as a consolidation strategy. There are no comparative trials of patients who were maintained on long-term therapy with ATRA compared with those undergoing transplantation.Meloni et al109 reported 15 consecutive patients with relapsed APL who underwent ASCT with unpurged marrow. Thirteen patients received anthracycline-based chemotherapy as initial treatment, and 2 were treated by combined ATRA and idarubicin. All patients received 3 cycles of consolidation therapy. The first CR duration ranged from 6 to 40 months. Second CR was achieved in all patients with oral ATRA. All but 3 patients received consolidation therapy with intravenous cytarabine at 1 g/m2 on days 1 through 4 and intravenous mitoxantrone at 6mg/m2 on days 1 through 4. The median time interval from the achievement of second CR to alloBMT was approximately 2 months. In this study, 6 (40%) of 15 patients remained alive and well, and they remain in molecular remission. All 7 patients who underwent alloBMT with persistent PCR-detectable MRD in the transfused cells relapsed within 9 months after transplantation, which confirms the value of PCR positivity during remission as a predictor of relapse in APL. Only 1 of 8 patients with negative PCR relapsed, and 1 patient developed secondary leukemia. The patient with secondary leukemia, however, received a different preparative regimen. This study demonstrates that patients with negative PCR after their second CR will fare favorably with ASCT and patients with positive PCR should not routinely be offered ASCT. It is impossible to speculate, based on this study alone, what the outcome would be after alloBMT, and whether the PCR results would have the same effect. In addition, these patients were treated before the routine use of ATRA as a primary therapy, or as a therapy for relapsed disease. Sanz et al110 on behalf of the European Blood and Marrow Transplantation group have reported an OS, LFS, relapse rate, and TRM for patients in first CR undergoing alloBMT of 77%, 70%, 15%, and 20%, respectively, and for ASCT of 73%, 70%, 24%, and 12%, respectively.110 For patients in second CR, the results for alloBMT were 58%, 57%, 15%, and 33%, respectively, compared with 40%, 45%, 44%, and 25% for ASCT, respectively. Currently, there is little role for alloBMT in first CR because the outcome with current ATRA-based strategies is excellent.111 Most patients in first relapse achieve a second CR with arsenic trioxide. However, many patients relapse after arsenic-induced second CR, and there may be a benefit for postarsenic chemotherapy.93 In second CR it is acceptable to recommend transplantation. The outcome of ASCT with molecularly negative cells is excellent, and the TRM associated with alloBMT may be obviated, but these strategies have not been directly compared. The ability to detect MRD by molecular studies provides the unique opportunity to collect minimally contaminated stem cells. Prognostic factors in APL The presenting WBC count has been the most important prognostic factor in patients treated with ATRA plus chemotherapy. Various levels of WBCs have been reported to predict for outcome, with thresholds including 10 000/µL,32,84,85 5000/µL,30 and 2000/µL.40 The PETHEMA and GIMEMA groups have identified risk based on WBC and platelet counts for patients treated with ATRA plus idarubicin for induction and for ATRA plus 6-MP and methotrexate for maintenance after anthracycline-based consolidation.86 Patients at low risk of relapse were those with a presenting WBC count less than 10 000/µL and a platelet count of 40 000/µL or more, high-risk if the WBC count was more than 10 000/µL, and intermediate risk if the WBC count was less than 10 000/µL and platelet count less than 40 000/µL. Female sex has been shown in several trials to confer a favorable outcome compared with male sex.40,84 The long and short PML-RAR fusion
transcripts have been examined for prognostic importance. Although a
less favorable outcome for the short form has been reported by several
groups,25,112 others have not shown a
difference.84,113,114 Few patients with the variable form
have been studied to make conclusions about its prognostic
value.115 Expression of CD56, which reflects the neural crest adhesion molecule believed to be involved in trafficking of
leukemia cells, has also been shown to be an unfavorable prognostic factor.116,117 The importance of cytogenetic abnormalities
in addition to the t(15;17) in ATRA-treated patients is not clear, but,
in one study reporting the results in a small number of patients (all
treated with maintenance ATRA plus low-dose chemotherapy), no apparent
adverse effect was observed.14 Among patients treated before the availability of ATRA, such changes have been reported to
confer a poor prognosis, but this observation has not been confirmed in
all studies.118,119 A recent study suggested that HLA-B13
was significantly associated with relapse.120 Patients at
high risk such as those with a presenting WBC count more than 10 000/µL and those expressing CD56 can be considered for
investigational strategies that may include the anti-CD33 antibody
HuM195, which has been used to treat patients in CR who remain PCR
positive.121
Historically, APL was fatal for most patients. However, the
introduction of ATRA as targeted therapy for APL has dramatically improved the outcome of this disease. With contemporary therapeutic strategies, it appears that a cure rate of 70% or higher is a reasonable expectation. Chemotherapy remains critically important in
the management of APL, because most patients relapse with ATRA alone.
In contrast to other subgroups of AML, the mainstay of chemotherapy is
with anthracyclines (Table 6). The
addition of cytarabine in induction may not be necessary and adds
little benefit, if any, to postremission therapy. Consolidation with
anthracycline-based chemotherapy is necessary. As with other subtypes
of AML, the optimal dose and required number of cycles are unknown.
Also in contrast with other subtypes of AML, maintenance therapy
appears to have a unique role. The addition of low doses of
chemotherapy to ATRA maintenance may further improve the long-term
outcome.
Although the outlook for patients with APL has remarkably improved over
the past decade, more than 20% of patients presenting with APL will
still die of the disease. This percentage includes some patients who
relapse even after achieving apparent eradication of the PML-RAR
Submitted July 20, 2001; accepted September 30, 2001.
Reprints: Martin S. Tallman, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, 676 N St Clair St, Suite 850, Chicago, IL 60611; e-mail: m-tallman{at}northwestern.edu.
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N. Asou, Y. Kishimoto, H. Kiyoi, M. Okada, Y. Kawai, M. Tsuzuki, K. Horikawa, M. Matsuda, K. Shinagawa, T. Kobayashi, et al. A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RAR{alpha} transcript after consolidation therapy: The Japan Adult Leukemia Study Group (JALSG) APL97 study Blood, July 1, 2007; 110(1): 59 - 66. [Abstract] [Full Text] [PDF]
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 G.-B. Zhou, J. Zhang, Z.-Y. Wang, S.-J. Chen, and Z. Chen Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy Phil Trans R Soc B, June 29, 2007; 362(1482): 959 - 971. [Abstract] [Full Text] [PDF]
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 A. Sassano, E. Katsoulidis, G. Antico, J. K. Altman, A. J. Redig, S. Minucci, M. S. Tallman, and L. C. Platanias Suppressive Effects of Statins on Acute Promyelocytic Leukemia Cells Cancer Res., May 1, 2007; 67(9): 4524 - 4532. [Abstract] [Full Text] [PDF]
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F. Lo-Coco, E. Ammatuna, and M. A. Sanz Current treatment of acute promyelocytic leukemia Haematologica, March 1, 2007; 92(3): 289 - 291. [Full Text] [PDF]
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X. Zheng, A. Seshire, B. Ruster, G. Bug, T. Beissert, E. Puccetti, D. Hoelzer, R. Henschler, and M. Ruthardt Arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RAR{alpha}-positive leukemic stem cells Haematologica, March 1, 2007; 92(3): 323 - 331. [Abstract] [Full Text] [PDF]
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D. Chen, R. Chan, S. Waxman, and Y. Jing Buthionine Sulfoximine Enhancement of Arsenic Trioxide-Induced Apoptosis in Leukemia and Lymphoma Cells Is Mediated via Activation of c-Jun NH2-Terminal Kinase and Up-regulation of Death Receptors Cancer Res., December 1, 2006; 66(23): 11416 - 11423. [Abstract] [Full Text] [PDF]
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P. Yoon, N. Giafis, J. Smith, H. Mears, E. Katsoulidis, A. Sassano, J. Altman, A. J. Redig, M. S. Tallman, and L. C. Platanias Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL-expressing cells. Mol. Cancer Ther., November 1, 2006; 5(11): 2815 - 2823. [Abstract] [Full Text] [PDF]
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 J. P. CAPLAN All-Trans Retinoic Acid (ATRA) Syndrome Can Mimic Panic Disorder Psychosomatics, October 1, 2006; 47(5): 450 - 451. [Full Text] [PDF]
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G. Cimino, F. Lo-Coco, S. Fenu, L. Travaglini, E. Finolezzi, M. Mancini, M. Nanni, A. Careddu, F. Fazi, F. Padula, et al. Sequential Valproic Acid/All-trans Retinoic Acid Treatment Reprograms Differentiation in Refractory and High-Risk Acute Myeloid Leukemia. Cancer Res., September 1, 2006; 66(17): 8903 - 8911. [Abstract] [Full Text] [PDF]
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P. Kannan-Thulasiraman, E. Katsoulidis, M. S. Tallman, J. S. C. Arthur, and L. C. Platanias Activation of the Mitogen- and Stress-activated Kinase 1 by Arsenic Trioxide J. Biol. Chem., August 11, 2006; 281(32): 22446 - 22452. [Abstract] [Full Text] [PDF]
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N. Giafis, E. Katsoulidis, A. Sassano, M. S. Tallman, L. S. Higgins, A. R. Nebreda, R. J. Davis, and L. C. Platanias Role of the p38 Mitogen-Activated Protein Kinase Pathway in the Generation of Arsenic Trioxide-Dependent Cellular Responses. Cancer Res., July 1, 2006; 66(13): 6763 - 6771. [Abstract] [Full Text] [PDF]
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D. W. Milligan, K. Wheatley, T. Littlewood, J. I. O. Craig, A. K. Burnett, and for the NCRI Haematological Oncology Clinical Stud Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial Blood, June 15, 2006; 107(12): 4614 - 4622. [Abstract] [Full Text] [PDF]
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P. Lunghi, A. Costanzo, L. Salvatore, N. Noguera, L. Mazzera, A. Tabilio, F. Lo-Coco, M. Levrero, and A. Bonati MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis Blood, June 1, 2006; 107(11): 4549 - 4553. [Abstract] [Full Text] [PDF]
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 A. Ghavamzadeh, K. Alimoghaddam, S. H. Ghaffari, S. Rostami, M. Jahani, R. Hosseini, A. Mossavi, E. Baybordi, A. Khodabadeh, M. Iravani, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy Ann. Onc., January 1, 2006; 17(1): 131 - 134. [Abstract] [Full Text] [PDF]
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M. A. Sanz Treatment of Acute Promyelocytic Leukemia Hematology, January 1, 2006; 2006(1): 147 - 155. [Abstract] [Full Text] [PDF]
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F. Lo-Coco and E. Ammatuna The Biology of Acute Promyelocytic Leukemia and Its Impact on Diagnosis and Treatment Hematology, January 1, 2006; 2006(1): 156 - 161. [Abstract] [Full Text] [PDF]
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 M. A. Sanz, M. S. Tallman, and F. Lo-Coco Practice Points, Consensus, and Controversial Issues in the Management of Patients with Newly Diagnosed Acute Promyelocytic Leukemia Oncologist, November 1, 2005; 10(10): 806 - 814. [Abstract] [Full Text] [PDF]
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 J. J. Ortega, L. Madero, G. Martin, A. Verdeguer, P. Garcia, R. Parody, J. Fuster, A. Molines, A. Novo, G. Deben, et al. Treatment With All-Trans Retinoic Acid and Anthracycline Monochemotherapy for Children With Acute Promyelocytic Leukemia: A Multicenter Study by the PETHEMA Group J. Clin. Oncol., October 20, 2005; 23(30): 7632 - 7640. [Abstract] [Full Text] [PDF]
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P. Hampson, H. Chahal, F. Khanim, R. Hayden, A. Mulder, L. K. Assi, C. M. Bunce, and J. M. Lord PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC Blood, August 15, 2005; 106(4): 1362 - 1368. [Abstract] [Full Text] [PDF]
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A. M. Testi, A. Biondi, F. L. Coco, M. L. Moleti, F. Giona, M. Vignetti, G. Menna, F. Locatelli, A. Pession, E. Barisone, et al. GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children Blood, July 15, 2005; 106(2): 447 - 453. [Abstract] [Full Text] [PDF]
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M. A. Sanz, M. S. Tallman, and F. Lo-Coco Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia Blood, April 15, 2005; 105(8): 3019 - 3025. [Abstract] [Full Text] [PDF]
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D. Douer and M. S. Tallman Arsenic Trioxide: New Clinical Experience With an Old Medication in Hematologic Malignancies J. Clin. Oncol., April 1, 2005; 23(10): 2396 - 2410. [Abstract] [Full Text] [PDF]
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R. Rotem, A. Heyfets, O. Fingrut, D. Blickstein, M. Shaklai, and E. Flescher Jasmonates: Novel Anticancer Agents Acting Directly and Selectively on Human Cancer Cell Mitochondria Cancer Res., March 1, 2005; 65(5): 1984 - 1993. [Abstract] [Full Text] [PDF]
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L. Lal, Y. Li, J. Smith, A. Sassano, S. Uddin, S. Parmar, M. S. Tallman, S. Minucci, N. Hay, and L. C. Platanias Activation of the p70 S6 kinase by all-trans-retinoic acid in acute promyelocytic leukemia cells Blood, February 15, 2005; 105(4): 1669 - 1677. [Abstract] [Full Text] [PDF]
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S. de Botton, A. Fawaz, S. Chevret, H. Dombret, X. Thomas, M. Sanz, A. Guerci, J. San Miguel, J. de la Serna, A.M. Stoppa, et al. Autologous and Allogeneic Stem-Cell Transplantation As Salvage Treatment of Acute Promyelocytic Leukemia Initially Treated With All-Trans-Retinoic Acid: A Retrospective Analysis of the European Acute Promyelocytic Leukemia Group J. Clin. Oncol., January 1, 2005; 23(1): 120 - 126. [Abstract] [Full Text] [PDF]
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J. R. Rigas and K. H. Dragnev Emerging Role of Rexinoids in Non-Small Cell Lung Cancer: Focus on Bexarotene Oncologist, January 1, 2005; 10(1): 22 - 33. [Abstract] [Full Text] [PDF]
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S. Gettinger, I. Shapira, N. Scheinfeld, and M. Grossbard Complications of Therapy in Cancer Patients: CASE 2. Scrotal Ulceration During All-Trans-Retinoic Acid Therapy for Acute Promyelocytic Leukemia J. Clin. Oncol., November 15, 2004; 22(22): 4648 - 4649. [Full Text] [PDF]
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F. Lo-Coco, G. Cimino, M. Breccia, N. I. Noguera, D. Diverio, E. Finolezzi, E. M. Pogliani, E. Di Bona, C. Micalizzi, M. Kropp, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia Blood, October 1, 2004; 104(7): 1995 - 1999. [Abstract] [Full Text] [PDF]
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 M. Battistella, L. D Burry, and J. T Seki Retinoic acid syndrome after one dose of all-transretinoic acid Journal of Oncology Pharmacy Practice, September 1, 2004; 10(3): 149 - 154. [Abstract] [PDF]
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M. Levis, R. Pham, B. D. Smith, and D. Small In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects Blood, August 15, 2004; 104(4): 1145 - 1150. [Abstract] [Full Text] [PDF]
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P. Lunghi, A. Costanzo, M. Levrero, and A. Bonati Treatment with arsenic trioxide (ATO) and MEK1 inhibitor activates the p73-p53AIP1 apoptotic pathway in leukemia cells Blood, July 15, 2004; 104(2): 519 - 525. [Abstract] [Full Text] [PDF]
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M. A. Sanz, G. Martin, M. Gonzalez, A. Leon, C. Rayon, C. Rivas, D. Colomer, E. Amutio, F. J. Capote, G. A. Milone, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group Blood, February 15, 2004; 103(4): 1237 - 1243. [Abstract] [Full Text] [PDF]
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D. G. Gilliland, C. T. Jordan, and C. A. Felix The Molecular Basis of Leukemia Hematology, January 1, 2004; 2004(1): 80 - 97. [Abstract] [Full Text] [PDF]
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R. M. Stone, M. R. O'Donnell, and M. A. Sekeres Acute Myeloid Leukemia Hematology, January 1, 2004; 2004(1): 98 - 117. [Abstract] [Full Text] [PDF]
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S. Schnittger, M. Weisser, C. Schoch, W. Hiddemann, T. Haferlach, and W. Kern New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts Blood, October 15, 2003; 102(8): 2746 - 2755. [Abstract] [Full Text] [PDF]
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S. Kambhampati, Y. Li, A. Verma, A. Sassano, B. Majchrzak, D. K. Deb, S. Parmar, N. Giafis, D. V. Kalvakolanu, A. Rahman, et al. Activation of Protein Kinase C{delta} by All-trans-retinoic Acid J. Biol. Chem., August 29, 2003; 278(35): 32544 - 32551. [Abstract] [Full Text] [PDF]
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W.-Y. Au, C. R. Kumana, M. Kou, R. Mak, G. C. F. Chan, C.-W. Lam, and Y.-L. Kwong Oral arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia Blood, July 1, 2003; 102(1): 407 - 408. [Full Text] [PDF]
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L. C. Platanias Map kinase signaling pathways and hematologic malignancies Blood, June 15, 2003; 101(12): 4667 - 4679. [Abstract] [Full Text] [PDF]
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W. Y. Au, A. K. W. Lie, C. S. Chim, R. Liang, S. K. Ma, C. H. Chan, Y. K. Mak, Y. T. Chen, C. C. So, Y. M. Yeung, et al. Arsenic trioxide in comparison with chemotherapy and bone marrow transplantation for the treatment of relapsed acute promyelocytic leukaemia Ann. Onc., May 1, 2003; 14(5): 752 - 757. [Abstract] [Full Text] [PDF]
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A. Verma, M. Mohindru, D. K. Deb, A. Sassano, S. Kambhampati, F. Ravandi, S. Minucci, D. V. Kalvakolanu, and L. C. Platanias Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to Arsenic Trioxide J. Biol. Chem., November 15, 2002; 277(47): 44988 - 44995. [Abstract] [Full Text] [PDF]
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 L. M. Kelly, J. L. Kutok, I. R. Williams, C. L. Boulton, S. M. Amaral, D. P. Curley, T. J. Ley, and D. G. Gilliland PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model PNAS, June 11, 2002; 99(12): 8283 - 8288. [Abstract] [Full Text] [PDF]
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F. J. Giles, A. Keating, A. H. Goldstone, I. Avivi, C. L. Willman, and H. M. Kantarjian Acute Myeloid Leukemia Hematology, January 1, 2002; 2002(1): 73 - 110. [Abstract] [Full Text]
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Top
Abstract
Induction therapy
the occurrence of retinoic acid syndrome is a risk factor.
Leukemia.
1999;13:1406-1408