ACUTE LEUKEMIAS (R STONE, SECTION EDITOR)

Contemporary Treatment of APL

Elizabeth H. Cull & Jessica K. Altman

# Springer Science+Business Media New York 2014

Abstract Acute promyelocytic leukemia (APL) is character-ized by coagulopathy, leukopenic presentation and sensitivityto anthracyclines, all-trans retinoic acid (ATRA) and arsenictrioxide (ATO). For the last 25 years, APL has been treatedwith a combination of ATRA and chemotherapy for inductionfollowed by consolidation and maintenance therapy. Thisgeneral treatment approach has resulted in cure rates of 80–90 %. ATO, originally approved in relapsed APL, has beenincorporated into contemporary upfront treatment regimenswith excellent response rates. Recent studies show that mostpatients with APL can be cured with ATRA and ATO alone,eliminating cytotoxic chemotherapy and resulting in superioroutcomes compared to standard treatment. We will hereinreview historical treatment of APL, treatment considerationsin specific patient populations, and therapeutic updates.

Keywords Acute promyelocytic leukemia .Arsenic trioxide .

All-trans retinoic acid . Early death rate

Introduction

Acute promyelocytic leukemia (APL) is a subtype of acutemyeloid leukemia (AML) characterized by leukopenia, coag-ulopathy and high cure rate. APL is a rare disease withapproximately 1,000 cases diagnosed yearly in the UnitedStates [1]. Patients typically present with pancytopenia andcomplications from coagulopathy [1, 2]. Over 95 % of casesare characterized by a balanced translocation of the PML geneon chromosome 15 and the RARA gene on chromosome 17,t(15,17). This results in a PML/RARA fusion protein thatinhibits transcription of genes necessary for differentiation.APL cells are sensitive to the differentiating effects of all-transretinoic acid (ATRA) and arsenic trioxide (ATO) [3].Differentiation of leukemic promyelocytes leads to rapid res-olution of coagulopathy, the major cause of early death inAPL patients. Studies with single agent ATRA began in the1980s [4–10], and since that time, ATRA and ATO in varyingcombinations with chemotherapeutic agents have resulted incure rates of 80–90 % [11]. Based on recent phase III datapresented by the Italian Group for Haematological Diseases inAdults (GIMEMA), there is now evidence to suggest thatchemotherapy can be eliminated completely for low and in-termediate risk patients [12••]. In this article, we will reviewthe historical data informing current APL treatment and dis-cuss clinical considerations in specific patient populations andrecent therapeutic updates.

Historical Overview

With efficacy first reported in the 1980s by investigators fromthe People’s Republic of China, single agent ATRA has beenfound to induce high complete remission (CR) rates in APL[4–10]. In the 1990s, European and American investigatorsadded ATRA to chemotherapy further improving survival

E. H. Cull : J. K. AltmanDivision of Hematology and Oncology, Department of Medicine,Northwestern University Feinberg School of Medicine andNorthwestern Memorial Hospital, Chicago, IL, USA

E. H. Cull (*)Division of Hematology/Oncology, Robert H. Lurie ComprehensiveCancer Center Northwestern University, Northwestern UniversityFeinberg School of Medicine, 676 N. St. Clair, Suite 850, Chicago,IL 60611, USAe-mail: e-cull@northwestern.edu

J. K. Altman (*)Division of Hematology/Oncology, Robert H. Lurie ComprehensiveCancer Center Northwestern University, Northwestern UniversityFeinberg School of Medicine, Lurie 5-111, 303 E. Superior Street,Chicago, IL 60611, USAe-mail: j-altman@northwestern.edu

Curr Hematol Malig RepDOI 10.1007/s11899-014-0205-6

rates [13–16]. The focus then shifted to risk-adapted strategiesfor APL treatment, partitioning patients into low, intermediateand high-risk groups based on white blood cell (WBC) countand platelet count [17–20]. Specifically, WBC over 10,000/μLwas found to correlate with increased induction death andhigher relapse rates [13–16].

ATOwas also found to be highly active in APL. ATO breaksdown the PML-RAR-∝ fusion transcript, allowing for transcrip-tion of genes necessary for differentiation of promyelocyticleukemia cells and apoptosis [21]. ATO was initially approvedfor use in the relapsed setting [22, 23]. Studies then transitionedto its use in the upfront setting in combination with chemother-apy and ATRA resulting in impressive outcomes [24, 25••,26••, 27, 28]. These studies led to the pivotal phase III random-ized trial (APL0406) in which ATRA/ATO was shown to benon-inferior to ATRA/chemotherapy for low/intermediate riskpatients [12••]. Tables 1 and 2 summarize the regimens andoutcomes data from significant APL trials conducted in the last20 years.

Treatment Considerations in Standard Risk APL

Eliminating Chemotherapy from Treatment

Treatment for low and intermediate risk APL, referred to hereas standard risk APL has been redefined based on results fromthe APL0406 trial. Shen initially reported the benefits ofATRA in addition to ATO in 2004. Sixty-one newly diag-nosed patients with APL were randomized to ATRAvs. ATOvs. ATRA/ATO, and CR rates of over 90 % were achieved inall arms; however, the combination arm had an improvedrelapse free survival (RFS) and shorter time to hematologicremission [28]. Estey confirmed a benefit for ATRA plusATO, achieving a CR rate of 95 % in low-risk patients and79 % in high-risk patients [24, 27]. The North AmericanLeukemia Intergroup Study C9710 also evaluated addingATO to consolidation with ATRA/chemotherapy and reportedimproved outcomes in the groups receiving ATO [26••]. TheAPML4 study added ATO to ATRA and anthracycline induc-tion and eliminated chemotherapy from consolidation, utiliz-ing two cycles of ATRA/ATO followed by two years ofmaintenance therapy. Investigators reported a 95 % hemato-logic CR following induction and a 2-year OS of 94 % [25••].An update presented at the 2013 Rome APL meeting reporteda sustained 5-year OS of 94 % [29]. The APL0406 trial builton data obtained from these previous studies. In this study,newly diagnosed patients with standard risk APL were ran-domized to ATRA/ATO for induction and consolidation ther-apy or induction therapy with ATRA/idarubicin followed byATRA/chemotherapy consolidation and two years of mainte-nance therapy. At 34.4-month follow-up, EFSwas 97% in theATRA/ATO group and 86 % in the ATRA/chemotherapy Ta

ble1

Cooperativ

egroupstudiesusingnon-ATObasedregimens

Group

Year

NInduction

Consolid

ation

Maintenance

CR

D(E)FS

(2year

unless

otherw

isespecified)

OS

(2year

unless

otherw

isespecified)

EuropeanAPL

9313

1999

413

ATRA→

DNR/AraCvs.

ATRA+DNR/AraC

DNR/AraC

Nonevs.A

TRAvs.

6-MP/MTXvs.A

TRA/6-M

P/MTX

92%

both

arms

ATRA→

chem

o:77

%ATRA+chem

o:84

%EFS

ATRA→

chem

o:81

%ATRA+chem

o:84

%OSalso

improved

inATRA/chemo

maintenance

group

GIM

EMA93

141997

253

Ida+ATRA

AraC/Ida/M

TZ/

etoposide/6-TG

Nonevs.A

TRAvs.6-M

P/MTX

vs.A

TRA/6-M

P/MTX

95%

79%

EFS

87%

PETHEMALPA

9415

1999

123

Ida+ATRA

Ida/MTZ

6-MP/MTX/ATRA

89%

79%

EFS

82%

PETHEMALPA

9919

2004

426

Ida+ATRA

Ida/MTZ

(+ATRAin

interm

ediate/high

risk

groups)

6-MP/MTX/ATRA

90%

87%

3yDFS

85%

at3y

EuropeanAPL

2000

202006

340

DNR+ATRA+/−

AraC

DNR+/−

AraC

6-MP/MTX/ATRA

+AraC:9

9%

NoAraC:9

4%

+AraC:9

3%

NoAraC:7

7%

EFS

+AraC:9

8%

NoAraC:8

9.6%

PETHEMALPA

2005

31

2010

404

Ida+ATRA

Ida/ATRA/M

TZ

(+AraCin

high

risk

group)

6-MP/MTX/ATRA

92.5

%92

%3yDFS

89%

at3y

Abbreviations:A

TRA:all-transretin

oicacid;D

NR:d

aunorubicin;

araC

:cytarabine;6-MP:

6-mercaptopurine;MTX:m

ethotrexate;Ida:idarubicin;M

TZ:m

itoxantrone;6

-TG:6

-thioguanine

Curr Hematol Malig Rep

group. Additionally, the ATRA/ATO group had improved OScompared to the ATRA/chemotherapy group (99 % vs. 91 %).This improvement in OS was mostly due to reduced treatmentrelated toxicity rather than death from relapse. Specifically,rates of neutropenia and infection were higher in theATRA/chemotherapy group; the incidence of hepatotoxicityand QTc prolongation were increased in the ATRA/ATOgroup, but in the majority of cases, these findings were revers-ible with ATO withdrawal. Therefore, not only was toxicityimproved with ATRA/ATO, relapse rates were similar be-tween groups as well implying that disease free survival wasnot compromised by less intensive therapy [12••].Additionally, with elimination of anthracyclines from the reg-imen, long-term side effects including cardiac toxicity andsecondary myeloid neoplasms may be reduced. Based on thisstudy, ATRA/ATO is now a recommended upfront regimenfor standard risk APL while previously it was recommendedin the relapsed setting or in patients unable to receiveanthracyclines [30]. Notably, the role of ATO based inductionin high-risk APL or in patients over age 70 was not addressedby this trial.

Consolidation Therapy

Consolidation regimens in an anthracycline based inductionapproach vary and recent studies have focused on a risk-adapted strategy when choosing consolidation agents. TheLPA96 and LPA99 studies used the same AIDA(ATRA/idarubicin) induction regimen but varied the consoli-dation regimen based on risk of relapse [15, 18, 19]. The LPA99 study specifically confirmed the benefit of ATRA use inconsolidation (in addition to intensified chemotherapy), mostnotably in the intermediate and high-risk groups. The FrenchAPL 2000 study and the LPA 2005 study further defined therole of cytarabine in consolidation therapy [20, 31]. A com-parison of the LPA 99 trial and the French APL 2000 studyshowed that cytarabine given in induction/consolidation wasbeneficial in the high-risk group but did not benefit thestandard-risk group [17].

More recently, the question of ATO use in consolidationhas been explored. The APML4 study used ATO/ATRA/idarubicin in induction followed by two cycles ofATRA/ATO in consolidation in all risk patients and reporteda 2-year OS of 93.2 % [25••]. The North American Intergrouptrial C9710 confirmed a benefit of ATO use in consolidation inall patients [26••]. The APL0406 study also used ATO/ATRAfor consolidation in the study arm and reported EFS rates andOS rates superior to the standard chemotherapy arm [12••]. Insummary, several consolidation regimens are appropriate, anda risk-adapted strategy should be used when selecting therapyin APL. However, it should be emphasized that regimensshould generally not be mixed and matched but rather follow-ed in entirety per protocol from induction throughTa

ble2

StudiesusingATObasedregimens

Author

Year

NInduction

Consolid

ation

Maintenance

CR

D(E)FS

(2year

unless

otherw

ise

specified)

OS

(2year

unless

otherw

ise

specified)

Shenetal28

2004

611)

ATRA

2)ATO

3)ATRA+ATO

DNR/AraC/

HA

inallg

roups

1)ATRA/6-M

P/MTX

2)ATO/6-M

P/MTX

3)ATRA/ATO/6-M

P/MTX

>90

%in

allarm

s1)

13months

2)16

months

3)20

months

DFS

Not

reported

Ravandi

etal27

2009

82ATRA/ATO

(+GOin

high

risk

group)

ATRA/ATO

none

92%

~80%

EFS

~85%

Pow

elletal26

2010

481

ATRA/AraC/DNR

ATRA/DNRvs.

ATRA/DNR/ATO

ATRAvs.

ATRA/6-M

P/M

TX

90%

inboth

arms

90%

inATOarm

70%

innon-ATOarm

DFS

86%

inATOarm

at3y

81%

innon-ATOarm

at3y

Iland2

52012

124

ATRA/Ida/ATO

ATRA/ATO

6-MP/MTX/ATRA

95%

97.5

%DFS

93%

Lo-Coco1

22013

156

ATRA/ATOvs.

ATRA/Ida

ATO/ATRAvs.

Ida/ATRA/M

TZ

None(ATRA/ATOarm)vs.

6-MP/MTX/ATRA(ATRA/Ida

arm)

ATRA/ATO:1

00%

ATRA/chemo:

95%

ATRA/ATO:9

7%

ATRA/chemo:

86%

EFS

ATRA/ATO:9

9%

ATRA/chemo:

91%

Abbreviations:ATRA:all-transretin

oicacid;ATO:arsenictrioxide;DNR:daunorubigin;AraC:cytarabine;HA:homoharringtonine;6-MP:

6-mercaptopurine;

MTX:methotrexate;GO:gentuzum

abozogam

icin;Ida:idarubicin;

MTZ:m

itoxantrone;M

TX:m

ethotrexate

Curr Hematol Malig Rep

maintenance. This allows the possibility of optimal results asdemonstrated in the corresponding trials.

Role of Maintenance

In contrast to other subtypes of AML, consolidation has tradi-tionally been followed by two years of maintenance therapywith ATRA, 6-mercaptopurine and methotrexate [13]. Nowthat ATO is being used in induction and/or consolidation, needfor maintenance has been questioned. In the phase II studypublished by Estey, low risk patients received ATRA/ATO forinduction followed by intermittent ATRA/ATO for a total of28 weeks after CR was confirmed. High-risk patients alsoreceived gemtuzumab ozogamicin (GO). Maintenance therapywas eliminated [24, 27]. At a median follow-up of 99 weeks,OS was 85 %. Not only did this study suggest that chemother-apy may not be required to achieve cure in APL, it alsoquestioned the role of maintenance therapy. A phase IIISWOG study sought to examine the role of maintenancetherapy. In this trial, standard-risk patients received a standardinduction and consolidation regimen including ATO and werethen randomized (if in molecular remission) to one year ofmaintenance therapy vs. observation. Although the study wasclosed due to slow accrual, at 22.7-month follow-up, the OS inall patients was >93 % and no relapses were noted in eithergroup [32•]. The APL 0406 study of ATRA/ATO for inductionconfirmed that survival and relapse rates are not compromisedby deletion of maintenance therapy when ATO is used ininduction and consolidation. However, median follow-up wasonly 34.4 months and longer follow-up may be needed in all ofthese studies to ensure that maintenance therapy can indeed beeliminated [12••].

Complications and Management of High Risk APL

Increased Early Death Rate

There are 20–25 % of APL patients who present with WBCover 10,000/μL, and these high-risk patients have both ahigher early death rate (EDR) and an increased risk of relapse.They typically present with more severe coagulopathy andhave higher rates of life threatening bleeding [33]. Even in thepost-ATRA era, EDR has been reported between 5–20 % inthis subgroup of patients [13, 14, 19, 27, 33]. This rate mayeven be an underestimate as it only encompasses patientstreated at academic centers and/or stable enough for clinicaltrial enrollment. One single center study reviewed data ontheir APL patients not enrolled on clinical trials and foundan EDR of 21 % compared to 3 % in patients enrolled onclinical trials [34]. Patients not enrolled tended to have higherWBCs and lower platelet counts. Despite major advances inAPL therapies, the EDR remains high, mostly due to

hemorrhagic complications. In the Swedish APL registry,reported EDR was 29 % and death occurred more commonlyin elderly patients and patients with poor performance status.The majority of early deaths were due to bleeding, followedby cardiopulmonary failure and sepsis [35]. In a retrospectivestudy of APL patients treated at five centers, including ourinstitution, the death rate in the first 30 days was 11 % and61 % of these deaths were attributable to hemorrhage. Therewas an increase in hemorrhage following delay of ATRAadministration, resulting in increased EDR only in the highrisk group [36]. Other studies suggest that early ATRA maynot necessarily decrease the EDR, however [37]. Despite this,ATRA should still be administered at first suspicion of APL[38]. The importance of aggressive transfusion support is alsoimportant. We suggest maintaining a platelet count greaterthan 30,000–50,000/μL and fibrinogen level more than150 mg/dL [39]. Although ATRA does reverse the coagulop-athy generally in a few days, aggressive blood product supportis necessary in the days following suspicion and diagnosis ofAPL to decrease the EDR [40].

Additionally, the risk of developing APL differentiationsyndrome (DS) increases with risingWBC count and is anothercause of early death [41]. DS is characterized by fevers andrespiratory distress as well as interstitial pulmonary infiltrates,pleural effusions, weight gain and lower extremity edema [42].This syndrome is often mistaken for pneumonia, volume over-load or alveolar hemorrhage. Prophylaxis with high dose dexa-methasone was used in the APL 2000 trial and led to a decreasein DS related deaths to 3.9 % compared to 5.7 % reported in theearlier APL 93 trial [43]. If not used pre-emptively, steroidsshould be started at the earliest sign of DS. If symptoms are lifethreatening, ATRA or ATO should be temporarily discontinueduntil symptoms resolve. Prophylactic steroid use is recom-mended in high-risk patients and should be strongly consideredin patients treated with ATRA/ATO for induction as was usedpreemptively in patients treated with ATRA/ATO on theGIMEMA APL 0406 trial [30].

While most patients with APL present with lower WBCscompared to other AML subtypes, 20–25 % will present witha WBC over 10,000/μL and 5 % or fewer patients will presentwith a WBC greater than 50,000/μL [41]. Leukapheresis isgenerally not recommended in APL given early reports ofdeath following this procedure [44]. Additionally, placementof a central venous catheter necessary for leukapheresis is notrecommended given the underlying coagulopathy. Cytotoxicchemotherapy in combination with ATRA should beginpromptly in this high-risk group. Hydroxyurea can also beused as a temporizing measure to control leukocytosis [12••].

Increased Relapse Rates

Relapse rates are also greater in the high-risk group. Severalstudies have shown cytarabine-containing regimens used

Curr Hematol Malig Rep

during induction or consolidation lead to higher OS and lowerrelapse rates in high-risk APL [17, 31]. Additionally, mainte-nance therapy is recommended in the high-risk group. TheAPL 93 trial showed a clear benefit for combinedmaintenancetherapy, most noticeable in high-risk patients [13]. A compar-ison of the APL 93 trial and APL 2000 trial showed thatsystematic maintenance therapy as received in the APL 2000trial was the strongest factor associated with improved OS inthe high-risk group [43].

The role of ATO is less well-defined and is not routinelyrecommended for induction therapy in high-risk groups, apartfrom in the APML4 regimen. Its use in consolidation is betterstudied. The North American Intergroup trial C9710 random-ized patients to consolidation with ATO following standarddaunorubicin/ATRA/cytarabine induction and showed a ben-efit in all risk groups receiving ATO. Notably, DFS wassimilar between the standard risk group that did not receiveATO and the high-risk group that received ATO suggestingthat addition of ATO may partially overcome the negativeprognosis associated with high-risk disease [26••].

In regards to CNS relapse, the cumulative rate of CNSrelapse in high-risk APL patients is 5 % [45]. Outcomes inpatients with CNS relapse are poor and given the increasedincidence in high-risk APL, some authors are proponents forprophylactic intrathecal therapy; however, others do not con-sider this a standard recommendation, given that the number totreat to have a benefit is quite large [38, 45–47]. Furthermore,cytarabine andATO both cross the blood–brain barrier andmayobviate the need for prophylactic intrathecal therapy.

Considerations in Elderly Patients with APL

APL is relatively uncommon in patients over age 60,representing only 15–20 % of patients diagnosed [48]. TheEDR is higher in this cohort due to greater comorbiditiescompared to their younger counterpart. In a SwedishLeukemia registry study, the EDR was 29 % in all age groupsbut 50 % in patients over age 60 [35]. Similarly, a study usingthe Surveillance, Epidemiology, and End Results (SEER) datafrom the United States reported an EDR of 24 % in APLpatients over age 55 [49]. Although EDR and treatment relat-ed mortality are higher in this subgroup, patients tend topresent with lower risk disease and have lower rates of relapse.The European APL group reviewed outcomes in elderly pa-tients from the APL 93 trial and reported a 4-year OS of57.8 % in elderly patients compared to 78 % in youngerpatients. Elderly patients achieved lower rates of CR (86 %vs. 94%) and more died in CR (18.6 % vs. 5.7 %), mostly as aresult of complications during consolidation and maintenancetherapy. However, 4-year relapse rates were lower in theelderly group compared to the younger cohort (15.6 % vs.23.2 %) [50]. Results from other studies report similar

findings in their elderly cohorts: lower CR rates, higher deathrates while in CR, mostly as complications frommyelosuppression, resulting in worse OS [51, 52]. In anattempt to decrease these treatment related deaths, theGIMEMA group amended their AIDA protocol to decreasethe consolidation courses in elderly patients from three cyclesto one [53]. This resulted in an improved OS in the amendedprotocol cohort compared to the original cohort due to adecrease in treatment related death.

ATO has a more favorable side effect profile compared toconventional chemotherapy and is an attractive option in thiselderly cohort that is particularly susceptible to treatment relatedtoxicities.Most studies that useATO+/−ATRA in the upfront orrelapsed setting do not report specifically on outcomes in theelderly. The Chinese group used single agent ATO for remissioninduction and post-remission therapy for up to four years inpatients over age 60. Of these patients, 88 % achieved CR andhad a 10-year rate of relapse, OS and cause-specific survivalwere 10.3 %, 69.3 % and 84.8 %, respectively. Post-remissiontherapywithATOwaswell tolerated, and noATO-related deathsoccurred. The main side effect from therapy was leukocytosiswith resulting DS, which was successfully managed in all pa-tients. On ten-year follow up, there was no increased rate ofmalignancy or arsenic poisoning identified [54].

GO has also been studied in elderly patients and shown tobe efficacious [27, 55, 56]; however, its approval was with-drawn from the US market and the ability to utilize GO isseverely limited. The APL 0406 trial showing superiority ofATRA/ATO over ATRA/chemotherapy is particularly rele-vant for elderly APL patients; however, the upper limit ofage enrollment was 71 years old. The original publication didnot stratify patients by age but the authors recently submitted aletter addressing outcomes in patients ages 60–70. They reportsimilar findings seen in the younger cohort including im-proved EFS and improved toxicity profile in the ATRA/ATOarm. These findings were non-significant but the numbersanalyzed were small [57]. Given the low toxicity ofATRA/ATO, this regimen may be especially appropriate forthe elderly population but further studies are required.

Considerations in Relapsed APL

With current treatment regimens, approximately 10 % of APLpatients will relapse [46]. Most studies use ATO alone or incombination with other agents in the relapsed setting [22, 23,58–62]. Soignet reported results of 40 patients with relapsedAPL. Patients received ATO for induction followed by consol-idation and maintenance with ATO. Eighty-five percent of pa-tients achieved CR; at 18 months follow-up, the OS was 66 %and relapse free survival was 56 % [58]. Shigeno used singleagent ATO for induction and consolidation for 34 patients withrelapsed APL; they reported a 2-year OS of 56 % [61]. One

Curr Hematol Malig Rep

small trial by French investigators randomized relapsed patientsto ATRA/ATO or ATO alone [60]. Outcomes were similarbetween groups leading its authors to conclude that there wasno benefit to adding ATRA to ATO. Current guidelines suggestATO+/−ATRA for treatment of relapsed disease; however, nowthat ATRA/ATO is recommended first line, it is unclear how thiswill affect management of relapsed disease [30]. A retrospectivereport was recently published of 25 patients with relapsed APLwho had been exposed to upfront ATRA/ATO in addition tocytotoxic agents. Patients received a variety of re-inductionregimens at relapse including ATRA/ATO or chemotherapyregimens. The authors reported a 40 % CR rate in the patientsreceiving ATRA/ATO; however, complete molecular remissionwas low and relapse remained high [63]. For patients withrelapsed APL after prior ATRA/ATO exposure, a trial of re-induction with ATRA/ATO is appropriate if sufficient time haspassed from last ATO exposure (6–12 months). Alternatively,standard ATRA/chemotherapy regimens can be utilized. OnceCR is obtained, we would recommend following guidelines forconsolidation with an autologous or allogeneic stem cell trans-plant (SCT) depending on molecular status.

After attaining a second remission, CSF evaluation andintrathecal chemotherapy is recommended given the risk ofCNS involvement in relapsed APL. Autologous SCT is alsorecommended as post-remission therapy in patients in completemolecular remission (CMR). In a retrospective study of 37patients with relapsed APL, patients received induction andconsolidation with ATO alone or ATO in combination withother agents. Thirty-three patients (89 %) achieved a secondremission and of these, 14 received an autologous SCT and 19received monthly ATO +/− ATRA for six months. At a median32-month follow-up, EFS was 83 % in the transplant armcompared to 34.4 % in ATO +/− ATRA arm [64]. AutologousSCT has been compared to allogeneic SCT in the relapsedsetting as well. In a retrospective study by French investigators,122 patients with relapsed APL in second remission receivedautologous SCT or allogeneic SCT. Seven-year RFS and OSwere 79.4% and 59.8% in the autologous SCT group comparedto 92.3 % RFS and 51.8 %OS in the allogeneic SCT group. OSwas significantly lower in the allogeneic SCT group secondaryto increased treatment related toxicity [65]. Investigators fromMD Anderson retrospectively reviewed outcomes in 40 re-lapsed APL patients undergoing autologous SCT, allogeneicSCT or chemotherapy alone. They found no difference in EFSor OS between groups but the numbers were small, and therewas a trend toward improved outcomes in the autologous SCTgroup [66]. Therefore, autologous SCT in second CMR isrecommended in patients able to receive the high dose chemo-therapy required for conditioning. Allogeneic SCT should bereserved for patients that do not achieve CMR. In this group, thegraft vs. leukemia effect leads to a decreased rate of relapse. Ifpatients are not transplant eligible, consolidation with ATO orenrollment on a clinical trial is recommended [30].

New Drugs and Formulations

Oral Arsenic

ATO has only been available in IV forms until recently. Thereis considerable interest in developing an oral formulation ofATO. This would have particular relevance in the long con-solidation phase in which patients must come to the officedaily for IV ATO. A recent phase III randomized trial com-pared IVATO to a new oral formulation of ATO and demon-strated non-inferiority of oral ATO to IVATO, showing com-parable rates of CR, OS and adverse events [67••]. This oralform of ATO is not currently available in the United States, butthere is interest among investigators throughout NorthAmerica, Europe, and Australia in developing an oral formu-lation of ATO.

Liposomal ATRA

Lipo-ATRA, a liposomal form of ATRA, was initially studiedwith the intent of trying to eliminate chemotherapy in APLtreatment. In a study with healthy volunteers, plasma levels oflipo-ATRAwere 15-fold elevated compared to oral ATRA andthe half-life was also prolonged [68]. Initiated in 1997 prior tothe advent of ATO, a prospective trial was performed usinglipo-ATRA alone in 34 patients with untreated APL andresults were compared to historical controls who had receivedthe AIDA regimen. The CR rate in the standard risk group was92 %, similar to CR rates achieved in historical controls;however, in the high-risk group, the CR rate was only 38 %,significantly lower than matched historical controls [69]. At13-year follow up, the authors reported an OS of 65 % and nosecondary malignancies noted [70]. Lipo-ATRA is not rou-tinely used or readily available but could be considered insituations where oral ATRA is not feasible.

Tamibarotene

Tamibarotene is a synthetic retinoid, developed and approvedin Japan for treatment of relapsed/refractory APL prior towidespread use of ATO in the relapsed setting. ATRA resis-tance is uncommon but when it does occur, is postulated to besecondary to RAR-α mutations, increased levels of cellularretinoic acid binding protein (CRABP), accelerated elimina-tion of ATRA and other genetic mutations [71, 72].Tamibarotene exhibits more potent differentiation ability com-pared to ATRA and is also more specific in its binding.Tamibaratone only binds to RAR-α and RAR-β whileATRA also binds to RAR-γ (present on dermal epithelium).This difference in binding suggests that tamibarotene may beassociated with fewer rashes and other skin toxicities thanATRA. Additionally, tamibarotene, unlike ATRA, does nothave a high binding affinity to CRABP, suggesting it may be

Curr Hematol Malig Rep

more active in an ATRA-resistant setting [73]. One smallJapanese study was performed in which 24 evaluable patientswith relapsed APL following ATRA exposure receivedtamibarotene. Fifty-eight percent of patients achieved a CR.The most significant serious side effect was hyperlipidemiabut overall, treatment was well tolerated [74]. Data with thisdrug is limited in the US and Europe, used in the relapsed/refractory setting [75, 76]. A phase II clinical trial (STAR-1),evaluating tamibarotene in the relapsed setting following priorATRA and ATO therapy, was initiated with results currentlypending.

Conclusions

Treatment for APL is one of the major success stories inoncology. APL was once the most deadly form of AML andis now the most treatable. Cure rates have improved signifi-cantly after ATRAwas added to chemotherapy, and withthe advent of ATO in combination with ATRA, it isnow possible to cure many patients without chemother-apy. Given that APL more commonly occurs in youngerpatients, decreasing secondary malignancies by avoid-ance of chemotherapy is of paramount importance.Furthermore, utilization of ATO/ATRA decreases treat-ment related toxicity and may be particularly beneficialfor older adults. EDR continues to be a pressing prob-lem, even at experienced centers, and maintaining ahigh suspicion of APL, employing aggressive bloodproduct support, and initiating ATRA early should beutilized to minimize early deaths. Further study is re-quired to determine therapeutic options for recurrentdisease after initial ATRA/ATO based therapy. Newdrug combinations and novel drug formulations continueto be developed with the goal of optimizing APL ther-apy, minimizing toxicities and making therapy moreconvenient for patients.

Acknowledgment The project described was supported by AwardNumber P30 CA060553 from the National Cancer Institute. The contentis solely the responsibility of the authors and does not necessarily repre-sent the official views of the National Cancer Institute or the NationalInstitutes of Health.

Compliance with Ethics Guidelines

Conflict of Interest Dr. Elizabeth H. Cull declares no potential con-flicts of interest relevant to this article.

Dr. Jessica K. Altman is a consultant for Teva Pharmaceuticals,Astellas Pharmaceuticals, BMS, Novartis, and Ariad. Dr. Altman issupported, in part, by a Cancer Center supplement grant.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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