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Acute promyelocytic leukemia: evolving therapeutic strategies Martin S. Tallman, Chadi Nabhan, James H. Feusner, and Jacob M. Rowe Acute promyelocytic leukemia (APL) is
the relapse rate compared with treatment
plantation are effective treatments for pa-
now the most curable subtype of acute
with chemotherapy alone. However, ATRA
tients with APL who relapse after or are
myeloid leukemia in adults. All-trans reti-
is associated with unique toxicities not
refractory to ATRA-based therapy. As ex-
noic acid (ATRA), which induces differen-
observed with conventional cytotoxic che-
perience with ATRA and arsenic trioxide
tiation of the leukemic cells into mature
motherapy. A number of clinical trials
in patients with APL accumulates, a num-
granulocytes, represents the important
have been performed to define the opti-
ber of important questions arise that need
advance. The incorporation of ATRA in
mal role of ATRA in the treatment of
to be addressed. (Blood. 2002;99:759-767)
induction results in a high complete re-
patients. The therapeutic strategies have
mission rate, leads to rapid resolution of
rapidly evolved as a result of both single
the characteristic life-threatening coagu-
institution and large cooperative group
lopathy, and, most importantly, decreases
trials. Arsenic trioxide and stem cell trans-
2002 by The American Society of Hematology
Induction therapy
Role of cytarabine
Before 1992, induction therapy for patients with acute promyelo- and compared the current regimen of ATRA plus idarubicin with an cytic leukemia (APL) was similar to all other patients with acute earlier study of cytarabine with doxorubicin, amsacrine or daunoru- myeloid leukemia (AML) and included an anthracycline and bicin without ATRA. The CR rate was 77% among patients treated cytarabine. However, the leukemic cells from patients with APL are with ATRA and idarubicin, which was not different from the peculiarly sensitive to anthracyclines, perhaps because of signifi- historic cohort of patients. The Italian Cooperative group GIMEMA cantly lower P-glycoprotein expression and other resistance mark- and the Spanish Cooperative group PETHEMA each combined ers in APL cells compared with other subtypes of AML.1-3 ATRA with single-agent idarubicin given in conventional doses (12 Both daunorubicin and idarubicin as single agents induce mg/m2 per day on days 2, 4, 6, and 8) and showed CR rates in the complete remission (CR) in 55% to approximately 90% of patients (Table 1).4-10 Two retrospective comparisons showed no difference Nevertheless, the evidence appears compelling that cytarabine in the CR rate between patients treated with daunorubicin alone or can be omitted during induction when an anthracycline is given with daunorubicin and cytarabine.6,7 In addition, in a prospective with ATRA. The European APL Group is currently conducting a randomized trial comparing idarubicin plus cytarabine to idarubi- trial in which patients presenting with a white blood cell (WBC) cin alone, no difference in the CR rate was observed.10 In that trial, count of 10 000/␮L or fewer are prospectively and randomly the CR rate was 76.3% with the single agent alone compared with assigned to ATRA and daunorubicin or to ATRA plus daunorubicin 66.6% in the combination arm. The event-free survival (EFS) was and cytarabine. The results of this trial should provide important 35% in the idarubicin arm compared with 35% in the combination information on the role of cytarabine in the treatment of APL.
arm (P ϭ .0429). This finding suggests that omission of cytarabine Choice of anthracycline
may permit higher doses of anthracycline to be given. However, thedose of idarubicin in the single-agent arm was 72 mg/m2 compared There is no clear choice of anthracycline in induction in APL.
with 40 mg/m2 in the combination arm. Therefore, patients in the Fenaux et al16 prospectively randomized patients to either rubidi- monotherapy arm received 1.8 times as much anthracycline as in zone plus cytarabine or to amsacrine plus cytarabine, and the CR the combination arm. In a retrospective analysis, the Southwest rate was 86% without any difference between the anthracyclines.
Oncology Group showed excellent survival in patients with APL Berman et al17 published a retrospective analysis in a preliminary when a daunorubicin dose of 70 mg/m2 per day was used compared form investigating prognostic factors in APL and suggested that with the dose used in most studies of 45 to 50 mg/m2 per day, but idarubicin is associated with an improved outcome compared with daunorubicin or amsacrine. No prospective randomized trial has The introduction of all-trans retinoic acid (ATRA) has prompted compared daunorubicin and idarubicin in APL. Therefore, no clear several study groups to exploit this peculiar sensitivity to anthracy- evidence proves that one anthracycline is clearly superior to clines by omitting cytarabine during induction (Table 2). Estey et another in APL. Despite theoretic considerations suggesting idaru- al12 reviewed sequential studies at the MD Anderson Cancer Center bicin may be better such as its relatively long half-life and good Reprints: Martin S. Tallman, Division of Hematology and Oncology, Robert H.
Comprehensive Cancer Center, Northwestern University Medical School, Lurie Comprehensive Cancer Center, 676 N St Clair St, Suite 850, Chicago, IL Chicago, IL; Children’s Hospital of Oakland, CA; and the Department of 60611; e-mail:
Hematology and Bone Marrow Transplantation, Technion Israel Institute ofTechnology, Rambam Medical Center, Haifa, Israel.
Submitted July 20, 2001; accepted September 30, 2001.
2002 by The American Society of Hematology BLOOD, 1 FEBRUARY 2002 ⅐ VOLUME 99, NUMBER 3 Table 1. Anthracycline monotherapy in acute promyelocytic leukemia
cin 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 mainte- nance. The European APL group and the Japanese Adult Leukemia Study Group studies included standard-dose cytarabine as consoli- dation.23,32 However, just as there appears to be little role for cytarabine during induction, emerging data suggest that there is norole for high-dose cytarabine in consolidation. A prospective studypublished by the PETHEMA group suggests that patients do as well central nervous system penetration, daunorubicin and idarubicin without cytarabine in either induction or consolidation.14 However, appear equally effective. It appears that what may be critical is the this study was not a randomized trial comparing idarubicin with or without cytarabine. It has become routine to administer at least 2courses of postremission therapy after induction with ATRA and Combining ATRA with chemotherapy
anthracycline, although, as in all subtypes of AML, there are noprospective data establishing the number of courses of intensive Although early phase II trials showed a high CR rate with ATRA postremission consolidation.33 The most important goal of postre- alone, the remission durations were short.18-21 Furthermore, somepatients treated with ATRA alone developed a rapid increase in mission therapy is complete eradication of the leukemic clone as WBC count that in some, but not all, studies was associated with determined by the conversion to a polymerase chain reaction retinoic acid syndrome (RAS).22-27 Therefore, most cooperative (PCR)–negative status, because persistence of such minimal re- groups initiated trials combining ATRA with intensive antileuke- sidual disease (MRD) predicts relapse.30,34-37 mic chemotherapy. The European APL group has conducted a Role of maintenance therapy
prospective randomized trial in which concurrent ATRA pluschemotherapy was compared with a sequential approach of ATRA Before the introduction of ATRA, several studies suggested a role followed by chemotherapy as postremission therapy.28 The EFS at for maintenance chemotherapy in patients with APL.6,38,39 Two 2 years was 84% among patients receiving the concurrent approach large prospective randomized trials now suggest that maintenance compared with 77% in the sequential arm. This difference was therapy with ATRA is useful (Table 4).28,29,40 In the North American attributable to a significant decrease in the risk of relapse (at 2 Intergroup study, patients in CR after 2 courses of consolidation years, 6% in the concurrent group versus 16% in the sequential chemotherapy were randomly assigned to either a year of daily group, P ϭ .04). This benefit was observed even among patients maintenance ATRA at standard doses or to observation.29 This presenting with a low WBC (Ͻ 5000/␮L). Although the CR rate study showed a significant benefit when a year of daily mainte- has not clearly increased and early mortality rate has not clearly nance ATRA is administered to patients whether they were induced decreased with the concurrent approach, the combination of ATRA into remission with chemotherapy alone or with ATRA. The best plus chemotherapy as initial therapy has become an attractive outcome was observed in patients who received ATRA during both strategy for all patients. This approach has the additional benefit of induction and as maintenance with a 5-year disease-free survival of possibly reducing the incidence of RAS from approximately 25% 74%.40 The European APL 93 trial randomly assigned patients in with ATRA25,26 to approximately 10% with concurrent chemo- remission after anthracycline-based consolidation to one of 3 therapy and ATRA (Table 3).13,14 Whether more intensive postre- maintenance regimens or observation: ATRA in standard doses for mission chemotherapy with, for example, higher doses of anthracy- 15 days every 3 months, or 6-mercaptopurine (6-MP) 90 mg/m2 per cline than has been customarily administered would have a similar day plus methotrexate 50 mg/m2 per week, or the combination of effect on the relapse rate is not known. It appears reasonable to ATRA and 6-MP/methotrexate as above.28 Patients receiving both begin treatment first with ATRA for 2 to 4 days to ameliorate the ATRA and chemotherapy had the lowest relapse rate. In addition, coagulopathy before initiating chemotherapy, provided the WBC is overall survival (OS) was improved in patients receiving mainte- nance chemotherapy (P ϭ .01), and there was a trend toward bettersurvival in patients who received maintenance ATRA (P ϭ .22).
Furthermore, the combination of intermittent maintenance ATRA Postremission therapy
and continuous maintenance chemotherapy appeared to be particu-larly useful for patients presenting with a high WBC count.
Consolidation chemotherapy
Therefore, at the present time, it appears that patients benefit from It has become mandatory to administer consolidation chemo-therapy after CR because early studies showed early relapse after Table 2. Anthracycline monotherapy with all-trans retinoic acid
ATRA alone. In most studies, consolidation chemotherapy has been in acute promyelocytic leukemia
anthracycline based. Three trials have included high-dose (1-3 g/m2) cytarabine in consolidation.29-31 The North American Inter- group study administered one cycle of daunorubicin 45 mg/m2 perday 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 daunorubi- Table 3. Comparison of the incidence and outcome of the retinoic acid syndrome
maintenance ATRA with or without continuous low-dose chemo- GIMEMA (ATRA plus idarubicin) trial in which all patients therapy, particularly those at high-risk of recurrence such as those received concurrent therapy, the incidence of the syndrome was presenting with a high WBC count and older adults (Ͼ 60 years).
10%.13 As experience with concurrent ATRA plus idarubicin The combination appears to be associated with the lowest relapse accumulated, the incidence of the syndrome decreased to approxi- rate. However, the data on which these recommendations are made mately 4%.15,42 In the Japanese Adult Leukemia Study Group trial are based on small numbers of patients. The GIMEMA Cooperative in which chemotherapy was introduced early for the prevention of Group is currently assigning patients in a randomized manner to the hyperleukocytosis, the incidence of the syndrome was 6%.32 An identical 3 maintenance regimens or to observation, and the North overall incidence of 15% was reported by the European APL group American Intergroup is currently assigning patients in CR in a with a mortality rate of 8%.28 A review of the first North American randomized manner to either ATRA every other week with 6-MP Intergroup trial showed that 26% of patients treated with ATRA and methotrexate or to ATRA alone. The results of these studies developed the syndrome at a median of 11 days; however, none of will aid in determining the optimal maintenance regimen and the the patients who received ATRA as maintenance therapy developed patient population most likely to benefit. It is possible that higher the syndrome.26 No difference in the incidence of the syndrome doses of anthracyclines in induction or consolidation may obviate was observed among patients treated with concurrent versus the need for maintenance therapy for some patients.11 sequential ATRA and chemotherapy. The Australian LeukemiaStudy Group has explored the benefits of prophylactic corticoste- Prevention and management of RAS
roids in patients who develop leukocytosis (WBC Ͼ 10 000/␮L).
The major toxicity of ATRA is RAS, a cardiorespiratory distress In a small nonrandomized study, 87 patients received prophylactic syndrome manifested by fever, weight gain, respiratory distress, corticosteroids at a dose of 75 mg prednisone per day, and 16% of interstitial pulmonary infiltrates, pleural and pericardial effusion, patients developed the syndrome that was fatal in 3%.43,44 This episodic hypotension, and acute renal failure.41 Among patients approach cannot be routinely recommended for all patients because induced into remission with ATRA alone, the incidence is approxi- no prospective randomized trial has confirmed the benefits given mately 25% (Table 3).25,26,41 The mortality rate of patients with the the potential toxicities of several weeks of corticosteroids in this syndrome has declined over time (29% in the New York study setting. Therefore, it appears reasonable to evaluate the benefits of versus 5% in the North American Intergroup study), likely reflect- prophylactic corticosteroids in a prospective randomized fashion.
ing earlier recognition and institution of dexamethasone. It is also This evaluation can likely be done safely because a small study has possible that the risk factors for development of the syndrome were shown that dexamethasone did not unfavorably influence the variable in the different studies. No factors are clearly predictive of induction of terminal differentiation by ATRA in NB4 cells.45 the syndrome, including WBC count,26-29 although the presence of It has been suggested that development of the syndrome may be microgranular variant (M3v) morphology was protective in one associated with an increased incidence of extramedullary relapse.46 study.26 An additional important issue concerns the potential A number of reports have emerged, suggesting that the incidence of difficulty in establishing an accurate diagnosis of the syndrome extramedullary relapse in APL, particularly in the central nervous because patients may develop toxicities and complications of system, is higher among patients previously exposed to ATRA than therapy, such as pneumonia, congestive heart failure, and sepsis, historically observed in patients treated with chemotherapy alone.47-51 This incidence may be related to modulation of adhesion The concurrent administration of chemotherapy with ATRA may decrease the incidence of the syndrome. However, this Prognostic significance of a positive molecular test
decrease has not been clearly established. In the first report of the for the promyelocytic-retinoic acid receptor-fusion
transcript after chemotherapy

Table 4. Maintenance therapy in acute promyelocytic leukemia
Reverse transcriptase (RT)–PCR has been shown to be an effective method to detect MRD in patients with APL in apparent CR.53,54 It is now clear that approximately 95% of patients are molecularly negative after intensive consolidation chemotherapy.15,30 However, a negative PCR test does not guarantee the absence of relapse.30 Overall, there is general agreement that a positive promyelocytic- retinoic acid receptor-␣ (PML/RAR␣) test after consolidation reliably predicts subsequent hematologic relapse, whereas repeat- edly negative results are associated with long-term survival in most CT indicates chemotherapy (6-mercaptopurine plus methotrexate).
patients.55 Diverio et al37 reported a prospective study in which 163 BLOOD, 1 FEBRUARY 2002 ⅐ VOLUME 99, NUMBER 3 patients were induced into remission by ATRA combined with ATRA at a lower dosage. Because of this predisposition, children chemotherapy and were tested at regular pre-established time on maintenance ATRA should have periodic ophthalmologic exami- intervals after the end of treatment.37 Of 21 patients, 20 who nations. This feature is not due to differences in the pharmacokinet- converted to a positive PCR relapsed within a median of 3 months, ics of ATRA in children compared with adults, because there are no whereas the 3-year estimate of relapse risk for patients who tested apparent significant differences in this regard.79 It is speculated that negative at least twice after consolidation was less than 10%. The the difference may be attributable to poorly understood enhanced molecular tests were carried out at similar time points from CR (at end-organ sensitivity to ATRA in younger pediatric patients.79 the end of consolidation, every 3 months during the first and second A final special circumstance for treating children with APL year, and then every 6 months during the third and fourth years), relates to a reluctance to expose children to daunorubicin doses and the duration of follow-up was similar. Because patients who larger than 400 mg/m2 because of the cardiomyopathy reported in convert to a positive PCR can be salvaged early with chemotherapy several studies.80-82 Because of this issue and the concern for before overt disease,56 this approach resulted in a significantly additional cardiac toxicity that may be incurred if a marrow improved outcome compared with delaying treatment until morpho- transplantation were required, the 2 major pediatric cooperative logic evidence of relapse. It is anticipated that therapy at the time of groups decided to limit the maximum daunorubicin exposure to molecular relapse will be associated with a lower mortality rate children enrolled on the current North American Intergroup trial to than that observed with reinduction of overt disease. Furthermore, a similar dose. In addition, frequent assessment of cardiac function aggressive chemotherapy such as high-dose cytarabine may be is required for children on that trial. Whether delivery of daunoru- effective for patients who fail to achieve molecular remission with bicin by prolonged continuous infusion might decrease cardiac ATRA and daunorubicin.57 It is currently accepted that the persis- toxicity, as has been demonstrated in adults,83 has not been tence of a negative PCR is associated with long-term survival.58 A adequately studied in children. Other possible solutions, such as reasonable schedule of testing is to obtain at least 2 successive liposomal daunorubicin or the use of the cardioprotectant agent marrow samples at the end of treatment, every 3 months for the first ICRF 187, require further study in children.
2 years of CR, and then every 6 months for the next 2 to 3 years.
The use of quantitative PCR in the future will likely improve the Should older adults with APL be treated differently
ability to predict relapse because it is more sensitive in detecting than younger patients?
Older adults, arbitrarily defined in various studies as 65 to 70 years Should children with APL be treated differently than adults?
and older, with APL treated with ATRA appear to have a lessfavorable prognosis than younger adults.24,28,30,32,84-87 Age appears APL constitutes 6.2% to 8.7% of AML in children in the United to be an important prognostic factor for both achievement of States61,62 and up to 31% in some areas of Italy.63 Why there is such CR14,32 as well as EFS14,28,32 and, in one study, early death and an extreme variation in incidence is unknown and suggests the need overall survival.28 Despite the omission of potentially toxic consoli- for an international epidemiologic investigation. It is possible that dation that includes cytarabine and the addition of maintenance the variability may be explained by the apparent increased inci- with both ATRA and low-dose chemotherapy, patients older than dence of APL in patients of Latino and Hispanic origin with 70 years still had an inferior EFS compared with patients younger AML.55 The typical clinical features of APL in adults, which than 70 years.14 Most trials do indicate an inferior outcome in older include low WBC count at diagnosis, lack of hepatosplenomegaly adults, and it may be that even less intensive chemotherapy than or adenopathy, high incidence of coagulation abnormalities and reported by the PETHEMA group can favorably influence the signs of clinical hemorrhage, rarity of central nervous system outcome of older adults treated with ATRA/anthracycline-based leukemia, and special features of the microgranular variant, are also therapy, because a high induction mortality appears to contribute to the inferior outcome in older adults. The death rate among patients The results of contemporary treatment of children with APL in CR in the European APL93 trial (ATRA with either concurrent or also appear similar to those reported in adults. The CR rates for sequential daunorubicin and cytarabine followed by daunorubicin combination ATRA and anthracycline-based therapy have been plus cytarabine consolidation) was 19%, significantly higher reported to be 79% to 88%68-71 and long-term EFS of 64% (P ϭ .01) than among patients aged 65 years or younger presenting with a WBC count less than 5000/␮L or among all patients presenting There are, however, some special considerations in treating with a WBC count more than 5000/␮L. It is not clear whether older children with APL. The first special feature concerns the difficulty age itself confers a worse prognosis or rather a biologic issue of some young patients to reliably swallow capsules. The pharma- unique to older adults that is as yet undefined. Because the major cokinetics of such delivery has not been studied, but there have cause of failure in older adults is death in CR rather than failure to been CRs in the few patients reported to have had nasogastrictreatment.73 An alternative approach might be the use of a relatively achieve CR, RAS, or relapse, alternative consolidation strategies newly developed liposomal ATRA compound.74-76 This agent may such as liposomal ATRA,74-76 arsenic trioxide, or anti-CD33 also be useful in intubated adult patients. It is given intravenously antibody–based approaches should be explored.88,89 and has shown promising early results, but the responses of Current role of arsenic trioxide in APL
children in these trials have yet to be reported separately.
A second problem with the use of ATRA in pediatric patients Investigators from China reported that arsenic trioxide induces CR (especially those younger than 10 years) is increased neurotoxicity.
in patients with relapsed and refractory APL (Table 5).90-93 Both headache and pseudotumor cerebri have been shown to be Preclinical studies suggested that arsenic has several mechanisms more frequent in children compared with adults.77,78 Special of action, including apoptosis and leukemic cell differentiation.94-97 recommendations are made for management of this problem that Soignet et al98 initiated a pilot study of 12 patients with relapsed may necessitate withholding ATRA for a period of time, use of APL who were treated with arsenic trioxide at doses ranging from dexamethasone and/or acetazolamide, and then reinstitution of 0.06 to 0.2 mg/kg per day until leukemic cells were eliminated Table 5. Patients with relapsed and refractory acute promyelocytic leukemia
leukemia-free survival (LFS) in patients who received transplants achieving complete remission after one course of arsenic trioxide therapy
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 chemo- therapy is potentially curative in 75% to 80% of newly diagnosedpatients, it is not justifiable to recommend alloBMT as a consolida- from the bone marrow as determined by light microscopy. Eleven tion strategy. There are no comparative trials of patients who were patients obtained CR, with 8 of the 11 patients who initially tested maintained on long-term therapy with ATRA compared with those positive for the PML/RAR␣ fusion transcript later becoming negative.98 This finding suggested a pivotal role for arsenic trioxide Meloni et al109 reported 15 consecutive patients with relapsed in patients with relapsed APL. A multicenter trial of 40 patients APL who underwent ASCT with unpurged marrow. Thirteen confirmed the high CR rate (85%).99 Furthermore, approximately patients received anthracycline-based chemotherapy as initial treat- 78% of patients had no evidence of the leukemic clone by PCR ment, and 2 were treated by combined ATRA and idarubicin. All after 2 courses of arsenic trioxide.99 The most important toxicities patients received 3 cycles of consolidation therapy. The first CR include prolongation of the QTc interval and the APL differentia- duration ranged from 6 to 40 months. Second CR was achieved in tion syndrome, a cardiorespiratory distress syndrome with pulmo- all patients with oral ATRA. All but 3 patients received consolida- nary infiltrates, reminiscent of the RAS, and responsive to dexameth- tion therapy with intravenous cytarabine at 1 g/m2 on days 1 asone.100 Two recent reports of sudden cardiac death with arsenic through 4 and intravenous mitoxantrone at 6mg/m2 on days 1 trioxide indicate that careful monitoring is warranted.101,102 through 4. The median time interval from the achievement of Currently, arsenic trioxide is considered the treatment of choice second CR to alloBMT was approximately 2 months. In this study, for patients with relapsed disease, particularly in patients exposed 6 (40%) of 15 patients remained alive and well, and they remain in to ATRA within the prior 12 months. Once patients achieve a molecular remission. All 7 patients who underwent alloBMT with second CR, the best postremission strategy is not known. Little data persistent PCR-detectable MRD in the transfused cells relapsed exist about the duration of remission and PCR negativity with within 9 months after transplantation, which confirms the value of arsenic alone in patients with relapsed APL. The disease-free PCR positivity during remission as a predictor of relapse in APL.
survival appears to be better when patients in CR after arsenic are Only 1 of 8 patients with negative PCR relapsed, and 1 patient treated with arsenic plus chemotherapy compared with arsenic developed secondary leukemia. The patient with secondary leuke- alone (2 of 11 relapses versus 12 of 18 relapses; P Ͻ .01, mia, however, received a different preparative regimen. This study respectively).93 Although some patients do well with maintenance demonstrates that patients with negative PCR after their second CR arsenic trioxide with or without chemotherapy, others relapse and will fare favorably with ASCT and patients with positive PCR may be considered for either allogeneic bone marrow transplanta- should not routinely be offered ASCT. It is impossible to speculate, tion (alloBMT) or autologous stem cell transplantation (ASCT) in based on this study alone, what the outcome would be after second CR. As initial induction, arsenic trioxide has been associ- alloBMT, and whether the PCR results would have the same effect.
ated with hepatotoxicity but has been evaluated in only a limited In addition, these patients were treated before the routine use of number of patients.93 Although the number of patients is small, it ATRA as a primary therapy, or as a therapy for relapsed disease.
appears that arsenic trioxide is as effective for treatment of Sanz et al110 on behalf of the European Blood and Marrow refractory or relapsed APL in children as in adults with a CR rate of Transplantation group have reported an OS, LFS, relapse rate, and 81% to 100%.92,98,103,104 The role of arsenic during the induction TRM for patients in first CR undergoing alloBMT of 77%, 70%, phase of treatment for newly diagnosed patients is being studied in 15%, and 20%, respectively, and for ASCT of 73%, 70%, 24%, and the current North American Intergroup trial in which patients in CR 12%, respectively.110 For patients in second CR, the results for are assigned randomly or not to 2 courses of arsenic trioxide as a alloBMT were 58%, 57%, 15%, and 33%, respectively, compared first consolidation cycle before 2 cycles of daunorubicin with 1 with 40%, 45%, 44%, and 25% for ASCT, respectively.
week of ATRA. Ongoing trials are under way, combining arsenic Currently, there is little role for alloBMT in first CR because the trioxide with ATRA and chemotherapy in induction in newly outcome with current ATRA-based strategies is excellent.111 Most diagnosed patients and evaluating its role in consolidation, based patients in first relapse achieve a second CR with arsenic trioxide.
on potential synergism.105,106 Preliminary studies in a small cohort However, many patients relapse after arsenic-induced second CR, of patients testing lower doses of arsenic trioxide suggest similar and there may be a benefit for postarsenic chemotherapy.93 In efficacy as the standard dose with less toxicity.107 second CR it is acceptable to recommend transplantation. Theoutcome of ASCT with molecularly negative cells is excellent, and Stem cell transplantation in APL
the TRM associated with alloBMT may be obviated, but these In a survey from the European Bone Marrow Transplant Registry, strategies have not been directly compared. The ability to detect Mandelli et al108 reported 362 patients, 187 of whom had under- MRD by molecular studies provides the unique opportunity to gone ASCT and 175 alloBMT between 1979 and 1992. Most of collect minimally contaminated stem cells.
these patients received transplants in first CR before the routine use Prognostic factors in APL
of ATRA. The results of this retrospective study suggested thatapproximately 45% of patients undergoing a transplantation proce- The presenting WBC count has been the most important prognostic dure can be cured. However, there were no data comparing the factor in patients treated with ATRA plus chemotherapy. Various outcome of the transplantation in relation to the induction regimen, levels of WBCs have been reported to predict for outcome, with and whether initial exposure to ATRA had prognostic value. The thresholds including 10 000/␮L,32,84,85 5000/␮L,30 and 2000/␮L.40 BLOOD, 1 FEBRUARY 2002 ⅐ VOLUME 99, NUMBER 3 Table 6. Current recommendations for treatment of acute promyelocytic leukemia for patients not participating in a clinical trial
ATRA 45 mg/m2 per day until CR ϩ an anthracycline, either daunorubicin 50 to 60 mg/m2 per day for 3 days or idarubicin 12 mg/m2 per day every other day for 4 days.
One to 2 cycles of anthracycline-based chemotherapy, daunorubicin 50 to 60 mg/m2 per day for 3 days to PCR negativity, or alternatively anthracyclines/anthracenedione; idarubicin 5 mg/m2 per day on days 1 to 4 (first consolidation), mitoxantrone 10 mg/m2 per day on days 1 to 5 (second consolidation), idarubicin 12 mg/m2 on day 1 (third consolidation). High-dose cytarabine can be considered for patients who remain PCR positive after such consolidation.
ATRA 45 mg/m2 daily for 15 days every 3 months ϩ 6-MP 100 mg/m2 per day ϩ MTX 10 mg/m2 per week all for 2 years for all patients.
PCR for PML-RAR␣ every 3 to 6 months for 2 years then every 6 months for 2 years.
Arsenic trioxide 0.15 mg/kg per day or Monday through Friday to second CR followed by ASCT with reinfusion molecularly negative peripheral blood stem cells or allogeneic transplantation considered in younger patients if a suitable donor is available. For patients relapsing late (Ͼ 12 months), ATRA may be used.
MTX indicates methotrexate.
*For pediatric patients, although by an infusional schedule a dose of daunorubicin 405 mg/m2 may be exceeded, the total dose should not exceed 500 mg/m2.
The PETHEMA and GIMEMA groups have identified risk based improved the outcome of this disease. With contemporary therapeu- on WBC and platelet counts for patients treated with ATRA plus tic strategies, it appears that a cure rate of 70% or higher is a idarubicin for induction and for ATRA plus 6-MP and methotrexate reasonable expectation. Chemotherapy remains critically important for maintenance after anthracycline-based consolidation.86 Patients in the management of APL, because most patients relapse with at low risk of relapse were those with a presenting WBC count less ATRA alone. In contrast to other subgroups of AML, the mainstay than 10 000/␮L and a platelet count of 40 000/␮L or more, of chemotherapy is with anthracyclines (Table 6). The addition of high-risk if the WBC count was more than 10 000/␮L, and cytarabine in induction may not be necessary and adds little benefit, intermediate risk if the WBC count was less than 10 000/␮L and if any, to postremission therapy. Consolidation with anthracycline- platelet count less than 40 000/␮L. Female sex has been shown in based chemotherapy is necessary. As with other subtypes of AML, several trials to confer a favorable outcome compared with male the optimal dose and required number of cycles are unknown. Also sex.40,84 The long and short PML-RAR␣ fusion transcripts have in contrast with other subtypes of AML, maintenance therapy been examined for prognostic importance. Although a less favor- appears to have a unique role. The addition of low doses of able outcome for the short form has been reported by several chemotherapy to ATRA maintenance may further improve the groups,25,112 others have not shown a difference.84,113,114 Few patients with the variable form have been studied to make Although the outlook for patients with APL has remarkably conclusions about its prognostic value.115 Expression of CD56, improved over the past decade, more than 20% of patients which reflects the neural crest adhesion molecule believed to be presenting with APL will still die of the disease. This percentage involved in trafficking of leukemia cells, has also been shown to be includes some patients who relapse even after achieving apparent an unfavorable prognostic factor.116,117 The importance of cytoge- eradication of the PML-RAR␣ fusion transcript after appropriate netic abnormalities in addition to the t(15;17) in ATRA-treated induction and consolidation therapy. Although alloBMT has no role patients is not clear, but, in one study reporting the results in a small in APL in first CR, ASCT has been prospectively studied in patients number of patients (all treated with maintenance ATRA plus with relapsed or refractory disease who have been successfully low-dose chemotherapy), no apparent adverse effect was ob- treated with ATRA and anthracyclines. One may speculate whether served.14 Among patients treated before the availability of ATRA, such therapy, using peripheral blood–derived stem cells with such changes have been reported to confer a poor prognosis, but associated low mortality, can further improve the long-term cure this observation has not been confirmed in all studies.118,119 A recent rate. However, such a prospective study would require a very large study suggested that HLA-B13 was significantly associated with number of patients and, therefore, is unlikely to be performed. RAS relapse.120 Patients at high risk such as those with a presenting remains a potentially fatal complication, although increased experi- WBC count more than 10 000/␮L and those expressing CD56 can ence with ATRA and early intervention have significantly reduced be considered for investigational strategies that may include the the magnitude of this problem. The outlook has also improved for anti-CD33 antibody HuM195, which has been used to treat patients patients with relapsed APL. Arsenic trioxide is clearly very effective in this setting. However, the optimal dose, schedule, andbenefits when combined with other therapies, such as ATRA,chemotherapy, or transplantation, remain to be defined. Although Conclusions
the last decade has seen the introduction into clinical use ofnumerous targeted therapies for hematologic malignancies, ATRA Historically, APL was fatal for most patients. However, the has most dramatically changed the clinical course of a disease from introduction of ATRA as targeted therapy for APL has dramatically one that was highly lethal to one that now appears highly curable.
1. Paietta E, Andersen J, Racevskis J, et al. Signifi- 2. Michieli M, Damiani D, Ermacora A, et al. P-gly- 3. Takeshita A, Shinjo K, Naito K, et al. Role of P- cantly lower P-glycoprotein expression in acute pro- coprotein (PGP), lung resistance-related protein glycoprotein in all-trans retinoic acid (ATRA) re- myelocytic leukemia than in other types of acute my- (LRP) and multidrug resistance-associated pro- sistance in acute promyelocytic leukaemia cells: eloid leukemia: immunological, molecular and tein (MRP) expression in acute promyelocytic leu- analysis of intracellular concentration of ATRA.
functional analyses. Leukemia. 1994;8:968-973.
kaemia. Br J Haematol. 2000;108:703-709.
4. Bernard J, Weil M, Boiron M, Jacquillat C, Retinoic acids in the treatment of acute promyelo- 37. Diverio D, Rossi V, Avvisati G, et al. Early detec- Flandrin G, Gemon MF. Acute promyelocytic leu- cytic leukemia. Nouv Rev Fr Hematol. 1990;32: tion of relapse by prospective reverse transcrip- kemia: results of treatment by daunorubicin.
tase-polymerase chain reaction analysis of the 22. Warrell RP Jr, Frankel SR, Miller WH Jr, et al. Dif- PML/RAR-alpha fusion gene in patients with 5. Collins AJ, Bloomfield CD, Peterson BA, Mc- ferentiation therapy of acute promyelocytic leuke- acute promyelocytic leukemia enrolled in the Kenna RW, Edson JR. Acute promyelocytic leu- mia with tretinoin (all-trans-retinoic acid). N Engl GIMEMA-AIEOP multicenter “AIDA” trial.
kemia: management of the coagulopathy during GIMEMA-AIEOP Multicenter “AIDA” Trial. Blood.
daunorubicin-prednisone remission induction.
23. Fenaux P, Castaigne S, Dombret H, et al. All- Arch Intern Med. 1978;138:1677-1680.
trans-retinoic acid followed by intensive chemo- 38. Kantarjian HM, Keating MJ, Walters RS, et al.
6. Marty M, Ganem G, Fischer J, et al. Acute promy- therapy gives a high complete remission rate and Role of maintenance chemotherapy in acute pro- elocytic leukemia: retrospective study of 119 pa- may prolong remissions in newly diagnosed myelocytic leukemia. Cancer. 1987;59:1258- tients treated with daunorubicin. Nouv Rev Fr He- acute promyelocytic leukemia: a pilot study on 26 39. Fenaux P, Pollet JP, Vanderbossche-Simon L, et 7. Petti MC, Avvisati G, Amadori S, et al. Acute pro- 24. Fenaux P, Le Deley MC, Castaigne S, et al. Effect al. Treatment of acute promyelocytic leukemia: a myelocytic leukemia: clinical aspects and results of all trans-retinoic acid in newly diagnosed acute report of 70 cases. Leuk Lymphoma. 1991;4:239- of treatment in 62 patients. Haematologica. 1987; promyelocytic leukemia: results of a multicenter randomized trial. European APL 91 Group. Blood.
40. Tallman MS, Andersen JW, Schiffer CA, et al. All- 8. Sanz MA, Jarque I, Martin G, et al. Acute promy- trans retinoic acid in acute promyelocytic leuke- elocytic leukemia: therapy results and prognostic 25. Vahdat L, Maslak P, Miller WH, et al. Early mortal- mia: long-term outcome results and prognostic ity and the retinoic acid syndrome in acute promy- factor analysis from Intergroup protocol 0129 [ab- elocytic leukemia: impact of leukocytosis, low- 9. Avvisati G, Mandelli F, Petti MC, et al. Idarubicin dose chemotherapy, PMN/RAR-alpha isoform, (4-demethoxydaunorubicin) as single agent for 41. Frankel SR, Eardley A, Heller G, et al. All-trans and CD13 expression in patients treated with all- remission induction of previously untreated acute retinoic acid for acute promyelocytic leukemia: trans retinoic acid. Blood. 1994;84:3843-3849.
promyelocytic leukemia: a pilot study of the Italian results of the New York Study. Ann Intern Med.
cooperative group GIMEMA. Eur J Haematol.
26. Tallman MS, Andersen JW, Schiffer CA, et al.
Clinical description of 44 patients with acute pro- 42. Avvisati G. AIDA Protocol: the Italian way of treat- myelocytic leukemia who developed the retinoic 10. Avvisati G. Event-free survival (EFS) duration in ing APL [abstract]. Br J Haematol. 1998;102:593a.
acid syndrome. Blood. 2000;95:90-95.
newly diagnosed acute promyelocytic leukemia 43. Wiley JS, Firkin FC. Reduction of pulmonary tox- (APL) is favorably influenced by induction treat- 27. De Botton S, Dombret H, Sanz M, et al. Inci- icity by prednisolone prophylaxis during all-trans ment with idarubicin alone: final results of the dence, clinical features, and outcome of all trans- retinoic acid treatment of acute promyelocytic leu- GIMEMA randomized study (LAP389) comparing retinoic acid syndrome in 413 cases of newly di- kemia. Australian Leukaemia Study Group. Leu- idarubicinϩAra-C in newly diagnosed APL [ab- agnosed acute promyelocytic leukemia. The 44. Firkin FC, Mathews JP, Bradstock KF, Wiley JS.
11. Head D, Kopecky KJ, Weick J, et al. Effect of ag- A phase II study of all-trans retinoic acid (ATRA) gressive daunomycin therapy on survival in acute 28. Fenaux P, Chastang C, Chevret S, et al. A ran- with prednisone prophylaxis in the treatment of promyelocytic leukemia. Blood. 1995;86:1717- domized comparison of all trans-retinoic acid acute promyelocytic leukemia (APL) [abstract].
(ATRA) followed by chemotherapy and ATRA plus Proc Am Soc Clin Oncol. 1999;94:4225a.
12. Estey E, Thall PF, Pierce S, Kantarjian H, Keating 45. de Ridder MC, van der Plas AJ, Erpelinck-Vers- therapy in newly diagnosed acute promyelocytic M. Treatment of newly diagnosed acute promy- chueren CA, Lo¨wenberg B, Jansen JH. Dexa- leukemia. The European APL Group. Blood.
elocytic leukemia without cytarabine. J Clin On- methasone does not counteract the response of acute promyelocytic leukaemia cells to all-trans 29. Tallman MS, Andersen JW, Schiffer CA, et al. All- 13. Avvisati G, Lo Coco F, Diverio D, et al. AIDA (all- retinoic acid. Br J Haematol. 1999;106:107-110.
trans-retinoic acid in acute promyelocytic leuke- trans retinoic acid ϩ idarubicin) in newly diag- 46. Ko BS, Tang JL, Chen YC, et al. Extramedullary mia. N Engl J Med. 1997;337:1021-1028.
nosed acute promyelocytic leukemia: a Gruppo relapse after all-trans retinoic acid treatment in 30. Burnett AK, Grimwade D, Solomon E, Wheatley acute promyelocytic leukemia—the occurrence of dell’Adulto (GIMEMA) pilot study. Blood. 1996;88: K, Goldstone AH. Presenting white blood cell retinoic acid syndrome is a risk factor. Leukemia.
count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia 14. Sanz MA, Martin G, Rayon C, et al. A modified 47. Weiss MA, Warrell RP Jr. Two cases of extramed- treated with all-trans retinoic acid: result of the AIDA protocol with anthracycline-based consoli- ullary acute promyelocytic leukemia: cytogenet- Randomized MRC Trial. Blood. 1999;93:4131- dation results in high antileukemic efficacy and ics, molecular biology, and phenotypic and clini- reduced toxicity in newly diagnosed PML/RAR- cal studies. Cancer. 1994;74:1882-1886.
alpha-positive acute promyelocytic leukemia.
31. Lengfelder E, Reichert A, Schoch C, et al. Double 48. Wiernik PH, DeBellis R, Muxi P, Dutcher JP. Ex- induction strategy including high-dose cytarabine tramedullary acute promyelocytic leukemia. Can- in combination with all-trans retinoic acid: effects 15. Mandelli F, Diverio D, Avvisati G, et al. Molecular in patients with newly diagnosed acute promyelo- remission in PML/RAR alpha-positive acute pro- cytic leukemia. Leukemia. 2000;14:1362-1370.
49. Liso V, Specchia G, Pogliano EM, et al. Ex- myelocytic leukemia by combined all-trans reti- tramedullary involvement in patients with acute noic acid and idarubicin (AIDA) therapy. Gruppo 32. Asou N, Adachi K, Tamura J, et al. Analysis of promyelocytic leukemia: a report of seven cases.
prognostic factors in newly diagnosed acute pro- dell’Adulto and Associazione Italiana di Ematolo- myelocytic leukemia treated with all-trans retinoic 50. Evans GD, Grimwade DJ. Extramedullary dis- gia ed Oncologia Pediatrica Cooperative Groups.
acid and chemotherapy. Japan Adult Leukemia ease in acute promyelocytic leukemia. Leukemia Study Group. J Clin Oncol. 1998;16:78-85.
16. Fenaux P, Tertian G, Castaigne S, et al. A ran- 33. Rowe JM. Uncertainties in the standard care of 51. de Botton S, Chevret S, Thomas X, et al. Inci- domized trial of amsacrine and rubidazone in 39 acute myelogenous leukemia. Leukemia. 2001; dence and outcome of central nervous system patients with acute promyelocytic leukemia. J Clin (CNS) relapses in acute promyelocytic leukemia 34. Lo Coco F, Avvisati G, Diverio D, et al. Molecular (APL) treated with all-trans retinoic acid (ATRA) 17. Berman E, Little C, Kher U, et al. Prognostic anal- evaluation of response to all-trans-retinoic acid and chemotherapy (CT) [abstract]. Blood. 1999; ysis of patients with acute promyelocytic leuke- therapy in patients with acute promyelocytic leu- 35. Grimwade D, Howe K, Langabeer S, Burnett A, 52. Brown DC, Tsuji H, Larson RS. All-trans retinoic 18. Huang ME, Ye YC, Chen SR, et al. Use of all- Goldstone A, Solomon E. Minimal residual dis- acid regulates adhesion mechanism and transmi- trans retinoic acid in the treatment of APL. Blood.
ease detection in acute promyelocytic leukemia gration of the acute promyelocytic leukemia cell by reverse-transcriptase PCR: evaluation of line NB-4 under physiologic flow. Br J Haematol.
19. Chen ZX, Xue YQ, Zhang R, et al. A clinical and experimental study on all-trans retinoic acid- ment in patients who ultimately relapse. Leuke- 53. Ikeda K, Sasaki K, Tasaka T, et al. Reverse tran- treated acute promyelocytic leukemia patients.
scription-polymerase chain reaction for PML-RAR 36. Miller WH Jr, Kakizuka A, Frankel SR, et al. Re- alpha fusion transcripts in acute promyelocytic 20. Castaigne S, Chomienne C, Daniel MT, et al. All- verse transcription polymerase chain reaction for leukemia and its application to minimal residual trans retinoic acid as a differentiation therapy for the rearranged retinoic acid receptor alpha clari- leukemia detection. Leukemia. 1993;7:544-548.
acute promyelocytic leukemia. I. Clinical results.
fies diagnosis and detects minimal residual dis- 54. Fukutani H, Naoe T, Ohno R, et al. Prognostic ease in acute promyelocytic leukemia. Proc Natl significance of the RT-PCR assay of PML-RARA 21. Castaigne S, Chomienne C, Daniel MT, et al.
transcripts in acute promyelocytic leukemia. The BLOOD, 1 FEBRUARY 2002 ⅐ VOLUME 99, NUMBER 3 Leukemia Study Group of the Ministry of Health come: a cooperative Italian study on 196 cases.
use of syndrome differentiation of traditional Chi- and Welfare (Kouseisho). Leukemia. 1995;9:588- 73. Bargetzi MJ, Tichelli A, Gratwohl A, Speck B. Oral 55. Douer D, Preston-Martin S, Chang E, et al. High all-trans-retinoic acid administration in intubated 91. Zhang P, Wang S, Hu X. Arsenic trioxide treated frequency of acute promyelocytic leukemia patients with acute promyelocytic leukemia.
72 cases of acute promyelocytic leukemia. Chin among Latinos with acute myeloid leukemia.
Schweiz Med Wochenschr. 1996;126:1944-1945.
74. Estey EH, Giles FJ, Kantarjian H, et al. Molecular 92. Shen Z, Chen G, Ni J. Use of arsenic trioxide in 56. Lo Coco F, Diverio D, Avvisati G, et al. Therapy of remissions induced by liposomal-encapsulated the treatment of APL, clinical efficacy and phar- molecular relapse in acute promyelocytic leuke- all-trans retinoic acid in newly diagnosed acute macokinetics in relapsed patients. Blood. 1997; promyelocytic leukemia. Blood. 1999;94:2230- 57. Hoffman R, Haddad N, Sahar D, Rosenbaum H, 93. Niu C, Yan H, Yu T, et al. Studies on treatment of 75. Douer D, Estey E, Santillana S, et al. Treatment acute promyelocytic leukemia with arsenic triox- therapy induces a molecular remission in APL of newly diagnosed and relapsed acute promy- ide: remission induction, follow-up, and molecular patients who failed to achieve a complete re- elocytic leukemia with intravenous liposomal all- monitoring in 11 newly diagnosed and 47 re- sponse following treatment with ATRA and an- trans retinoic acid. Blood. 2001;97:73-80.
lapsed acute promyelocytic leukemia patients.
thracyclines [abstract]. Blood. 1998;92:2517.
76. Estey E, Koller C, Cortes J, et al. Treatment of 58. Lo Coco F, Diverio D, Falini B, Biondi A, Nervi C, newly-diagnosed acute promyelocytic leukemia 94. Chen GQ, Zhu J, Shi XG, et al. In vitro studies on Pelicci PG. Genetic diagnosis and molecular with liposomal all-trans retinoic acid. Leukemia cellular and molecular mechanisms of arsenic monitoring in the management of acute promy- trioxide (As2O3) in the treatment of acute promy- elocytic leukemia. Blood. 1999;94:12-22.
77. Smith MA, Adamson PC, Balis FM, et al. Phase I elocytic leukemia: As2O3 induces NB4 cell apo- 59. Cassinat B, Zassadowski F, Balitrand N, et al.
and pharmacokinetic evaluation of all-trans-reti- ptosis with downregulation of Bcl-2 expression Quantitation of minimal residual disease in acute noic acid in pediatric patients with cancer. J Clin and modulation of PML-RAR alpha/PML proteins.
promyelocytic leukemia patients with t(15;17) translocation using real-time RT-PCR. Leukemia.
78. Mahmoud HH, Hurwitz CA, Roberts WM, San- 95. Shao W, Fanelli M, Ferrara FF, et al. Arsenic tri- tana VM, Ribeiro RC, Krance RA. Tretinoin toxic- oxide as an inducer of apoptosis and loss of PML/ 60. Tobal K, Moore H, Macheta M, Yin Liu JA. Moni- ity in children with acute promyelocytic leukae- RAR alpha protein in acute promyelocytic leuke- toring minimal residual disease and predicting mia cells. J Natl Cancer Inst. 1998;90:124-133.
relapse in APL by quantitating PML-RAR␣ tran- 79. Adamson PC. Clinical and pharmacokinetic stud- 96. Chen GQ, Shi XG, Tang W, et al. Use of arsenic scripts with a sensitive competitive RT-PCR ies of all-trans-retinoic acid in pediatric patients trioxide (As2O3) in the treatment of acute promy- method. Leukemia. 2001;15:1060-1065.
with cancer. Leukemia. 1994;8(suppl 3):S22-S25.
elocytic leukemia (APL): I. As2O3 exerts dose- 61. Steuber CP, Civin C, Krischer J, et al. A compari- dependent dual effects on APL cells. Blood. 1997; 80. Silber JH, Jakacki RI, Larsen RL, Goldwein JW, son of induction and maintenance therapy for Barber G. Increased risk of cardiac dysfunction acute nonlymphocytic leukemia in childhood: re- after anthracyclines in girls. Med Pediatr Oncol.
97. Jing Y, Dai J, Chalmers-Redman RM, et al. Ar- sults of a Pediatric Oncology Group study. J Clin senic trioxide selectively induces acute promyelo- cytic leukemia cell apoptosis via a hydrogen per- 81. Godoy LY, Fukushige J, Igarashi H, Matsuzaki A, 62. Argyle JC, Benjamin DR, Lampkin B, Hammond oxide-dependent pathway. Blood. 1999;94:2102- Ueda K. Anthracycline-induced cardiotoxicity in D. Acute nonlymphocytic leukemias of childhood: children with malignancies. Acta Paediatr Jpn.
inter-observer variability and problems in the use 98. Soignet SL, Maslak P, Wang ZG, et al. Complete of the FAB classification. Cancer. 1989;63:295- remission after treatment of acute promyelocytic 82. Krischer JP, Epstein S, Cuthbertson DD, Goorin leukemia with arsenic trioxide. N Engl J Med.
AM, Epstein ML, Lipshultz SE. Clinical cardiotox- 63. Biondi A, Rovelli A, Cantu-Rajnoldi A, et al. Acute icity following anthracycline treatment for child- promyelocytic leukemia in children: experience of hood cancer: the Pediatric Oncology Group expe- 99. Soignet SL, Frankel SR, Douer D, et al. United the Italian Pediatric Hematology and Oncology rience. J Clin Oncol. 1997;15:1544-1552.
States multicenter study of arsenic trioxide in re- Group (AIEOP). Leukemia. 1994;8:1264-1268.
lapsed acute promyelocytic leukemia. J Clin On- 83. Legha SS, Benjamin RS, Mackay B, et al. Reduc- 64. Carter M, Kalwinsky DK, Dahl GV, Santana VM, tion of doxorubicin cardiotoxicity by prolonged Mason CA, Schell MJ. Childhood acute promy- continuous intravenous infusion. Ann Intern Med.
100. Camacho LH, Soignet SL, Chanel S, et al. Leuko- elocytic leukemia: a rare variant of nonlymphoid cytosis and the retinoic acid syndrome in patients leukemia with distinctive clinical and biologic fea- 84. Chou WC, Tang JL, Yao M, et al. Clinical and bio- with acute promyelocytic leukemia treated ar- logical characteristics of acute promyelocytic leu- senic trioxide. J Clin Oncol. 2000;18:2620-2625.
65. Engelhard D, Yatziv S, Rachmilewitz E, Polliack kemia in Taiwan: a high relapse rate in patients 101. Unnikrishnan D, Dutcher JP, Varshneya N, et al.
A. Acute promyelocytic leukemia in childhood.
with high initial and peak white blood cell counts Torsades de pointes in 3 patients with leukemia during all-trans retinoic acid treatment. Leukemia.
treated with arsenic trioxide. Blood. 2001;97: 66. Chan KW, Steinherz PG, Miller DR. Acute promy- elocytic leukemia in children. Med Pediatr Oncol.
85. Ohno R, Asou N, Kanamaru A, Miyawaki S, 102. Westervelt P, Brown RA, Adkins DR, et al. Sud- den death among patients with acute promyelo- 67. Rovelli A, Biondi A, Cantu-Rajnoldi A, et al. Micro- Study for newly diagnosed acute promyelocytic cytic leukemia treated with arsenic trioxide.
granular variant of acute promyelocytic leukemia leukemia (APL): analysis of prognostic factors to in children. J Clin Oncol. 1992;10:1413-1418.
increase cure rate in the next study [abstract].
103. Bergstrom S, Gillan E, Quinn J, Altman A. Arsenic 68. Shimizu H, Nakadate H, Taga T, et al. Clinical trioxide in the treatment of a patient with multiply characteristics and treatment results of acute pro- 86. Sanz M, LoCoco F, Martin G, et al. Definition of recurrent, ATRA-resistant promyelocytic leuke- myelocytic leukemia in children. Children’s Can- relapse risk and role of nonanthracycline drugs mia: a case report. J Pediatr Hematol Oncol.
cer and Leukemia Study Group. Rinsho Ket- for consolidation in patients with acute promyelo- sueki—Jpn J Clin Hematol. 1993;34:989-996.
cytic leukemia: a joint study of the PETHEMA and 104. Jun M, Minghua J, Liying C, et al. Clinical obser- 69. Hirota T, Fujimoto T, Katano N, et al. Treatment GIMEMA Cooperative groups. Blood. 2000;96: vation on arsenic trioxide in the treatment of re- results of intermittent and cyclic regimen with lapsed acute promyelocytic leukemia [abstract].
ATRA and chemotherapy in childhood acute pro- 87. Latagliata R, Avvisati G, Lo Coco F. The role of myelocytic leukemia. Children’s Cancer and Leu- all-trans-retinoic acid (ATRA) treatment in newly- 105. Jing Y, Wang R, Xai L, et al. Combined effects of kemia Study Group. Rinsho Ketsueki—Jpn J Clin diagnosed acute promyelocytic leukemia patients all-trans retinoic acid and arsenic trioxide in acute aged Ͼ 60 years. Ann Oncol. 1997;8:1273-1275.
promyelocytic leukemia cells in vitro and in vivo.
70. Bapna A, Nair R, Tapan KS, et al. All-trans-reti- 88. Jurcic JG, Caron PC, Miller WH Jr, et al. Sequen- noic acid (ATRA): pediatric acute promyelocytic tial targeted therapy for relapsed acute promyelo- 106. Dombret H, Rousselot P, Hermine O, et al. Treat- leukemia. Pediatr Hematol Oncol. 1998;15:243- cytic leukemia with all-trans retinoic acid and anti- ment of relapsing acute promyelocytic leukemia CD33 monoclonal antibody M195. Leukemia.
(APL) with arsenic trioxide (As2O3) Ϯ all-trans 71. Mann G, Reinhart D, Ritter J, et al. Treatment retinoic acid (ATRA): The French As98 Study [ab- with all-trans retinoic acid in acute promyelocytic 89. Jurcic JG, DeBlasio T, Dumont L, Yao TJ, Schein- leukemia reduces early deaths in children. Ann berg DA. Molecular remission induction with reti- 107. Shen Y, Shen ZX, Yan H, et al. Studies on the noic acid and anti-CD33 monoclonal antibody clinical efficacy and pharmacokinetics of low- 72. Guglielmi C, Martelli M, Diverio D, et al. Immuno- HuM195 in acute promyelocytic leukemia. Clin dose arsenic trioxide in the treatment of relapsed phenotype of adult and childhood acute promy- acute promyelocytic leukemia: a comparison with elocytic leukaemia: correlation with morphology, 90. Sun H, Ma L, Hu X, Zhang T. Treatment of acute conventional dosage. Leukemia. 2001;15:735- type of PML gene break-point and clinical out- promyelocytic leukemia by Ailing-1 therapy with 108. Mandelli F, Labopin M, Granena A, et al. Euro- transcript is associated with poor survival. Leuk pression is an indicator of poor clinical outcome in pean survey of bone marrow transplantation in patients with acute promyelocytic leukemia acute promyelocytic leukemia (M3). Working 113. Fukutani H, Naoe T, Ohno R, et al. Isoforms of treated with simultaneous all-trans-retinoic acid Party on Acute Leukemia of the European Coop- PML-retinoic acid receptor alpha fused tran- and chemotherapy. J Clin Oncol. 2000;18:1295- erative Group for Bone Marrow Transplantation scripts affect neither clinical features of acute pro- (EMBT). Bone Marrow Transplant. 1994;14:293- myelocytic leukemia nor prognosis after treat- 118. Hiorns LR, Swansbury GJ, Mehta J, et al. Addi- ment with all-trans retinoic acid. The Leukemia tional chromosome abnormalities confer worse 109. Meloni G, Diverio D, Vignetti M, et al. Autologous Study Group of the Ministry of Health and Welfare prognosis in acute promyelocytic leukaemia. Br J bone marrow transplantation for acute promyelo- (Kohseisho). Leukemia. 1995;9:1478-1482.
cytic leukemia in second remission: prognostic 114. Gallagher RE, Willman CL, Slack JL, et al. Asso- 119. Slack JL, Arthur DC, Lawrence D, et al. Second- relevance of pretransplant minimal residual dis- ciation of PML-RAR alpha fusion mRNA type with ary cytogenetic changes in acute promyelocytic ease assessment by reverse-transcription poly- pretreatment hematologic characteristics but not leukemia—prognostic importance in patients merase chain reaction of the PML/RAR alpha fu- treatment outcome in acute promyelocytic leuke- treated with chemotherapy alone and association sion gene. Blood. 1997;90:1321-1325.
mia: an intergroup molecular study. Blood. 1997; with the intron 3 breakpoint of the PML gene: a 110. Sanz MA, Arcese W, de la Rubia J, et al. Stem Cancer and Leukemia Group B study. J Clin On- cell transplantation (SCT) for acute promyelocytic 115. Slack JL, Willman CL, Andersen JW, et al. Mo- leukemia (APL) in the ATRA era: a survey of the lecular analysis and clinical outcome of adult APL 120. Bolognesi E, Cimino G, Diverio D, et al. HLA European Blood and Marrow Transplantation patients with the type V PML-RAR-alpha isoform: class I in acute promyelocytic leukemia (APL): Group (EBMT) [abstract]. Blood. 2000;96:2246.
results from intergroup protocol 0129. Blood.
possible correlation with clinical outcome. Leuke- 111. Nabhan C, Mehta J, Tallman MS. The role of stem cell transplantation in acute promyelocytic 116. Murray CK, Estey E, Paietta E, et al. CD56 ex- 121. Jurcic JG, Caron PC, Miller WH Jr, et al. Sequen- leukemia. Bone Marrow Transplant. 2001;28:219- pression in acute promyelocytic leukemia: a pos- tial targeted therapy for relapsed acute promyelo- sible indicator of poor treatment outcome? J Clin cytic leukemia with all-trans retinoic acid and anti- 112. Albitar M, Chang KS, Pierce S, Kantarjian H, Es- CD33 monoclonal antibodies M195. Leukemia.
tey E. The short form of PML-RAR-alpha fusion 117. Ferrara F, Morabito F, Martino B, et al. CD56 ex-



Public Hearing “Review State law governing forfeiture of property associated with criminal activity, including the system for distribution of assets seized and accountability for their expenditure” LOCATION: MEMBERS OF COMMITTEE PRESENT: Senator Louis F. Kosco, Chairman Senator James S. Cafiero, Vice-Chairman Senator Joseph L. Bubba Senator John A. Girgenti Senator Edw

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