Review Article

Advances in therapies for acute promyelocytic leukemia

Tomohiko Kamimura,1 Toshihiro Miyamoto,2,4 Mine Harada3 and Koichi Akashi2
1Department of Hematology, Harasanshin Hospital, Fukuoka; 2Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka; 3Department of Internal medicine, National Ohmuta Hospital, Fukuoka, Japan

(Received May 6, 2011 Revised July 17, 2011 Accepted July 20, 2011 Accepted manuscript online July 25, 2011 Article rst published online August 24, 2011)

Acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia (AML), results from the arrest of the maturation of hematopoietic progenitors at the promyelocyte stage. It has been shown that APL is associated with a reciprocal chromosomal translocation, involving chromosomes 15 and 17, which fuses the gene encoding the retinoic acid receptor a (RARa) and the promyelocytic leukemia (PML) gene. The resultant PMLRARa fusion protein plays a critical role in the pathogenesis of APL. Although there are many subtypes of AML, all are typically managed using a standard chemotherapy regimen of an anthracycline plus cytarabine arabinoside (CA). Despite high rates of complete remission following standard chemotherapy, most patients relapse and long-term disease-free survival is only 3040%. The introduction of drugs such as all-trans retinoic acid (ATRA) that promote progenitor differentiation by directly inhibiting the PML-RARa fusion protein has changed the treatment paradigm for APL and markedly improved patient survival. The purposes of the present review are to provide the latest results and future directions of clinical research into APL and to illustrate how new therapies, such as ATRA plus anthracycline-based induction and consolidation therapy, risk-adapted therapy, salvage therapy containing arsenic trioxide-based regimens, and hematopoietic stem cell transplantation, have improved the treatment outcomes for APL patients. (Cancer Sci 2011; 102: 1929 1937)

Clinically, APL represents a medical emergency, with a high rate of early mortality often due to hemorrhage from disseminated intravascular coagulation (DIC) or hyperbrinolysis.(11,12) Before 1992, the induction therapy for patients with APL was similar to that for all other AML and included anthracycline and cytarabine arabinoside (CA). Compared with other AML subtypes, APL cells are especially sensitive to anthracycline, possibly due to signicantly lower expression of P-glycoprotein and other resistance markers.(1315) Therefore, chemotherapy with anthracycline (daunorubicin [DNR], idarubicin [IDA], or others) and CA was the frontline treatment of APL, achieving complete remission (CR) in 7580% of patients.(16,17) Unfortunately, this standard treatment regimen was associated with a high early death rate due to the exacerbation of pre-existing DIC, necessitating intensive platelet and brinogen support. Despite high sensitivity to anthracycline, only 3545% of APL patients are cured by standard chemotherapy alone.(18,19) The introduction of all-trans retinoic acid (ATRA) in 1987 changed the treatment paradigm of APL.(20,21) High intranuclear concentrations of ATRA increase the expression of normal functioning RARa, which then outcompetes the aberrant PMLRARa, inducing remission through differentiation of neoplastic promyelocytes into mature granulocytes and the re-emergence of normal hematopoietic cells.(4,22,23) Therefore, several clinical trials have established ATRA combined with anthracyclinebased chemotherapy for induction and consolidation as standard care.(2426)
Induction Therapy
All-trans retinoic acid plus anthracycline-based induction therapy. Complete remission of APL following ATRA treat-

cute promyelocytic leukemia (APL), formerly known as AML-M3, is a biologically and clinically distinct variant of acute myelogenous leukemia (AML), characterized by the clonal expansion of hematopoietic precursors blocked at the promyelocyte stage of differentiation.(1) Acute promyelocytic leukemia is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, resulting in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor a (RARa) genes.(2) During normal hematopoiesis, retinoic acid (RA) plays a key role in myeloid progenitor differentiation through its nuclear receptors (RARs) and retinoid X receptors (RXRs).(3) The RARs are transcription factors that regulate genes involved in myeloid progenitor development and cell cycle control;(2,46) PML-RARa interferes with this process by recruiting abnormal transcrption factors and histone-modifying enzymes to these critical genes, linking the ability of the PML-RARa oncoprotein to promote self-renewal and block differentiation.(6,7) The PML-RARa protein is an aberrant RAR that contributes to leukemogenesis by dominantly antagonizing aspects of cellular differentiation regulated by the RAR RXR signaling pathway.(4,8,9) Based on these molecular ndings about leukemogenesis, APL is now classied in the World Health Organization (WHO) classication system(10) as APL with t(15;17)(q22;q12);PML-RARa.
doi: 10.1111/j.1349-7006.2011.02045.x 2011 Japanese Cancer Association

ment was rst demonstrated by the Shanghai group,(20,21) who also reported a signicant reduction in the duration of coagulopathy compared with standard chemotherapy.(27) Several studies conducted during the early 1990s found that APL patients receiving induction therapy consisting of ATRA followed by chemotherapy fared signicantly better than patients treated with chemotherapy alone.(27,28) In these studies, the rates of CR and early death were not signicantly different; however, the relapse rate was signicantly lower in the ATRA-treated group. The treatment of patients with ATRA was further rened following a randomized trial conducted by the European French BelgianSwiss APL Group (the European APL Group), showing a benet of concurrent ATRA and chemotherapy for induction compared with a sequential regimen approach.(29) In addition, ATRA therapy has signicant and potentially fatal adverse effects, known as retinoic acid syndrome, which
4To whom correspondence should be addressed. E-mail: toshmiya@intmed1.med.kyushu-u.ac.jp

Cancer Sci | November 2011 | vol. 102 | no. 11 | 19291937

consists of elevated white blood cell (WBC) counts, fever, respiratory distress, interstitial pulmonary inltration, pleural effusion, and weight gain.(30) Among patients in remission following treatment with ATRA alone, the incidence of retinoic acid syndrome is approximately 25%,(31) whereas that in patients treated with a combination of ATRA plus chemotherapy is reduced to 5%.(24,25) Based on the results of these studies, the combination of ATRA plus chemotherapy became the standard approach for treating newly diagnosed APL. The Spanish cooperative group Program de Estudio y Trataminento de las Hemopatias Malignas (PETHEMA) took advantage of the sensitivity of leukemic promyelocytes to anthracyclines and performed Phase II studies omitting CA from the induction and consolidation therapies.(25,32) This strategy was supported by a prospective, randomized trial conducted by the Italian cooperative group Gruppo Italiano Malatte Ematologiche dellAdulto (GIMEMA) prior to the introduction of ATRA, which found no benet in combining CA with IDA in newly diagnosed APL patients.(33) It is now accepted that CR can be achieved in most APL patients without CA as part of the induction therapy, with potentially less toxicity, and ATRA plus anthracycline combination induction therapy without CA is now the standard induction treatment for APL.(34) Arsenic trixoide as an alternative approach. After excellent results with arsenic trixoide (ATO) in the treatment of APL relapse,(35,36) several studies explored the role of this agent in front-line therapy.(3741) The CR rate in these studies was similar to that obtained with the standard ATRA plus anthracyclinebased induction therapy, ranging from 86% to 95%. The use of ATO is regarded as a promising option because of its apparently most favorable safety prole compared with conventional chemotherapy, particularly with respect to myelosuppression and some uncommon late complications, as well as its proven therapeutic efcacy. However, the use of ATO would not be exempt of other real or potential disadvantages. For example, ATO is associated with prolongation of the QT interval or ventricular arrhythmias, which can be fatal. Because of the high potential for embryotoxicity, ATO cannot be recommended for use at any stage of pregnancy. Finally, long-term complications of therapy remain uncertain; in particular, there are few data regarding the incidence of secondary neoplasms in APL patients treated with ATO.(42) Currently, some ongoing large studies have been designed to compare ATRA + chemotherapy and ATO-based regimens.(43) However, until the results of these trials are available, the use of ATO for newly diagnosed APL patients as induction therapy should be restricted to patients included in clinical trials or to those in whom chemotherapy is contraindicated.
Consolidation Therapy

was given for 15 days in conjunction with chemotherapy, suggesting that ATRA contributes to the reduction in the risk of relapse.(34) Combination therapy with current ATRA and anthracycline-based chemotherapy for induction and at least two further cycles of consolidation achieves molecular remission in >90% of patients, resulting in this strategy being adopted as the standard for consolidation.(45) However, approximately 20% of patients will relapse following this treatment, indicating that there are still major obstacles to a cure for APL patients.(24,29,47) Recently, treatments have tended towards riskadapted strategies to modulate the intensity of treatment during consolidation according to the predened risk of relapse.(48) Gore et al.(49) demonstrated the efcacy of a single cycle of ATO-based consolidation therapy in newly diagnosed APL patients following ATRA-plus anthracycline-based induction therapy. They reported that the estimated disease-free survival (DFS) and overall survival (OS) rates were 90% and 88%, respectively, with a median follow-up of 2.7 years. Observations published by the North American Leukemia Intergroup suggest that the addition of ATO consolidation to standard induction and consolidation therapy signicantly improves both event-free survival (EFS) and DFS in patients with newly diagnosed APL.(50) These ndings suggest that using ATO in the primary management of APL would results in decreased exposure to other cytotoxic agents.
Maintenance Therapy

Because continuous treatment with ATRA alone will cause progressive resistance to the drug resulting in relapse usually within 36 months,(12) consolidation chemotherapy is necessary to maintain CR. Since the rst successful report of DNR monotherapy,(43) the role of CA in the treatment of APL has remained contentious. Until several years ago, no study had found any benet in the inclusion of CA compared with high-dose anthracycline monotherapy.(44) Complete molecular remission is achieved in >90% of patients receiving two or three cycles of anthracycline-based chemotherapy following induction, leading to this strategy being adopted as the standard regimen for consolidation.(25,45) The benet provided by the addition of ATRA to chemotherapy for consolidation has not yet been demonstrated in randomized studies. Nevertheless, historical comparisons of consecutive trials performed independently by the GIMEMA(46) and PETHEMA(32) groups showed a signicant improvement in outcomes when a standard dose of ATRA
1930

The European APL Group has shown benets with maintenance chemotherapy using ATRA, which was given intermediately in a randomized study (the APL93 study).(29) That study revealed a lower relapse rate with triple combination therapy with ATRA, methotrexate (MTX), and 6-mercaptopurine (6-MP), which proved particularly effective in patients with an elevated WBC count at presentation who were considered high-risk patients. In addition, long-term follow-up in that study (median follow-up 10 years) demonstrated the benet of prolonged maintenance with ATRA plus chemotherapy for high-risk patients presenting with initial WBC counts >5 109 L.(51) The inclusion of ATRA resulted in the cumulative incidence of relapse declining from 68.4% with no maintenance to 20.6% with combined ATRA and chemotherapy maintenance. In contrast, the APL97 study, conducted by the Japan Adult Leukemia Study Group (JALSG), found no benet of six courses of intensive maintenance therapy for patients in molecular remission compared with observation only after chemotherapy.(26) Similarly, a recent report from the GIMEMA group based on a very high number of patients with genetically proven APL has questioned the benet of ATRAbased maintenance therapy.(52) Therefore, it is likely that the usefulness of maintenance therapy in APL may depend on multiple variables, including the type of anthracycline (IDA versus DNR), the intensity of chemotherapy delivered during induction and consolidation, and on the relapse risk of the patient.(26,29,51,52) Despite the uncertainty of the benet provided by maintenance therapy, it is clear that many patients achieving molecular remission by the end of consolidation will ultimately relapse, especially those presenting with a high WBC (>10 109 L). Although the role of ATRA-based maintenance therapy remains contentious, none of these recent studies has included an arm without maintenance therapy, with the exception of JALSG97.(26)
Current Risk-Adapted Therapy

Despite the evidence from large multicenter trials of the benet of upfront ATRA plus anthracycline-based chemotherapy, relapse still occurs in approximately 20% of patients.(24,25,29,47,51,53) Multivariate analyses have revealed that the single most important factor for relapse is a WBC count of
doi: 10.1111/j.1349-7006.2011.02045.x 2011 Japanese Cancer Association

Kamimura et al.

Table 1. Euro APL group (APL 2000)(54) High risk (WBC >10 109 L) Low WBC counts (<10 109 L) High WBC counts (10 109 L) High risk (WBC >10 109 L) ATRA (45 mg m2) until CR DNR (60 mg m2; Days 1, 2, 3) CA (200 mg m2; Days 1, 2, 3, 4, 5, 6, 7) ATRA (45 mg m2) until CR DNR (60 mg m2; Days 1, 2, 3) CA (200 mg m2; Days 1, 2, 3, 4, 5, 6, 7) Intrethecal CHT 1 DNR (60 mg m2; Days 1, 2, 3) CA (200 mg m2; Days 1, 2, 3, 4, 5, 6, 7) Intrethecal CHT 2 IDA (5 mg m2; Days 1, 2, 3, 4) ATRA (45 mg m2 for 15 days) CA (1 g m2; Days 1, 2, 3, 4) IDA (5 mg m2; Days 1, 2, 3, 4) ATRA (45 mg m2 for 15 days) Mit (10 mg m2; Days 1, 2, 3, 4, 5) ATRA (45 mg m2 for 15 days) Etop (100 mg m2; Days 1, 2, 3, 4, 5) Mit (10 mg m2; Days 1, 2, 3, 4, 5) ATRA (45 mg m2 for 15 days) ATRA (45 mg m2) until CR IDA (12 mg m2; Days 2, 4, 6, 8) Low risk (WBC 10 109 L; PLT >40 109 L) Intermediate risk (WBC 10 109 L; PLT 40 109 L) Low risk (WBC 10 109 L; PLT >40 109 L) GIMEMA (AIDA 2000)(46)

Risk-adapted therapy for patients with acute promyelocytic leukemia PETHEMA (LPA 2005)(56) Intermediate risk (WBC 10 109 L; PLT 40 109 L) ATRA (45 mg m2 per day) until CR IDA (12 mg m2; Days 2, 4, 6, 8) High risk (WBC >10 109 L)

PETHEMA (LPA 99)(32)

Low risk (WBC 10 109 L; PLT >40 109 L)

Intermediate risk (WBC 10 109 L; PLT 40 109 L)

Induction therapy

ATRA (45 mg m2) until CR IDA (12 mg m2; Days 2, 4, 6, 8)

Consolidation 1st IDA (5 mg m2; Days 1, 2, 3, 4) IDA (5 mg m2; Days 1, 2, 3, 4) ATRA (45 mg m2 for 15 days) DNR (60 mg m2; Days 1, 2, 3) CA (200 mg m2; Days 1, 2, 3, 4, 5, 6, 7)

IDA (5 mg m2; Days 1, 2, 3, 4)

IDA (7 mg m2; Days 1, 2, 3, 4) ATRA (45 mg m2 for 15 days)

Cancer Sci | November 2011 | vol. 102 | no. 11 | 1931 2011 Japanese Cancer Association

2nd DNR (45 mg m2; Days 1, 2, 3) CA (2 g m2 every 12 h; Days 1, 2, 3, 4, 5, 6, 7) Intrethecal CHT 2

Mit (10 mg m2; Days 1, 2, 3, 4, 5)

Mit (10 mg m2; Days 1, 2, 3, 4, 5) ATRA (45 mg m2 for 15 days)

DNR (45 mg m2; Days 1, 2, 3) CA (1 g m2 every 12 h; Days 1, 2, 3, 4, 5, 6, 7)

Mit (10 mg m2; Days 1, 2, 3) ATRA (45 mg m2 for 15 days)

IDA (7 mg m2; Days 1, 2, 3, 4) ATRA (45 mg m2 for 15 days) CA (1 g m2; Days 1, 2, 3, 4) Mit (10 mg m2; Days 1, 2, 3, 4, 5) ATRA (45 mg m2 for 15 days)

1932

Table 1. Euro APL group (APL 2000)(54) GIMEMA (AIDA 2000)(46)

(continued) PETHEMA (LPA 2005)(56)

PETHEMA (LPA 99)(32)

Low risk (WBC 10 109 L; PLT >40 109 L) Intermediate risk (WBC 10 109 L; PLT 40 109 L) High risk (WBC >10 109 L) Low WBC counts (<10 109 L) High WBC counts (10 109 L) High risk (WBC >10 109 L) IDA (12 mg m2; Day 1) ATRA (45 mg m2 for 15 days) IDA (12 mg m2; Day 1) CA (150 mg m2 every 8 h; Days 1, 2, 3, 4, 5) 6-TG (70 mg m2 every 8 h; Days 1, 2, 3, 4, 5) ATRA (45 mg m2 for 15 days) CHT + ATRA 89% 6-year OS 83% 6-year OS Low risk (WBC 10 109 L; PLT >40 109 L) IDA (12 mg m2; Day 1) ATRA (45 mg m2 for 15 days)

Intermediate risk (WBC 10 109 L; PLT 40 109 L)

Low risk (WBC 10 109 L; PLT >40 109 L) IDA (12 mg m2; Day 1) ATRA (45 mg m2 for 15 days)

Intermediate risk (WBC 10 109 L; PLT 40 109 L) IDA (12 mg m2; Days 1, 2) ATRA (45 mg m2 for 15 days)

High risk (WBC >10 109 L)

3rd

IDA (12 mg m2; Day 1)

IDA (12 mg m2; Day 1) ATRA (45 mg m2 for 15 days) CA (150 mg m2 every 8 h; Days 1, 2, 3, 4, 5)

Maintenance Outcome 68% 4-year OS

89% 4-year OS

CHT + ATRA 88% 4-year OS

CHT + ATRA 96% 5-year OS 93% 5-year OS (very high WBC counts [50 109 L]: 89% 5-year OS)

96% 4-year OS

CHT + ATRA 91% 4-year OS

79% 4-year OS

Intrathecal CHT, intrathecal injection of MTX (15 mg), CA (50 mg), and crticosteroid. CHT + ATRA, mercaptopurine (50 mg m2 per day, p.o.), MTX (15 mg m2 per week, p.o.), and ATRA (45 mg m2 per day) for 15 days every 3 months for 2 years. CHT + ATRA, mercaptopurine (90 mg m2 per day, p.o.), MTX (15 mg m2 per week, p.o.), and ATRA (45 mg m2 per day) for 15 days every 3 months for 2 years. 6-TG, 6-thioguanine; ATRA, all-trans retinoic acid; CA, cytarabine arabinoside; CHT, chemotherapy; CR, complete remission; DNR, daunorubicin; Etop, etoposide; IDA, idarubicin; Mit, mitoxantrone; MTX, methotrexate; OS, overall survival; WBC, white blood cell count.

doi: 10.1111/j.1349-7006.2011.02045.x 2011 Japanese Cancer Association

10 109 L or higher at presentation.(25,32,47,48) Therefore, many investigators have tried to classify individual patient risk and modulate the intensity of induction or consolidation therapy accordingly (Table 1).(32,54) A joint analysis by the PETHEMA and the European APL Groups comparing the outcomes of PETHEMA LPA99 and European APL 2000 trials demonstrated that the addition of high-dose of CA during consolidation is of benet to high-risk patients.(55) Subsequently, through the combined analysis of the APL93 and APL2000 trials, the European APL Group also conrmed a marked improvement in the prognosis of APL patients with high WBC counts treated with escalating doses of CA: in patients with WBC counts between 10 and 50 109 L, the remission rate increased from 89% to 93% and the 5-year cumulative incidence of relapse decreased from 40% to 9.5%; in patients with very high WBC counts (50 109 L), the remission rate increased from 82% to 91% and the 5-year cumulative incidence of relapse decreased from 59% to 24%.(54) These results demonstrated that upfront ATRA combined with intensied consolidation with high-dose CA has potential benets for high-risk APL patients. Recently, the GIMEMA (AIDA 2000)(46) and the PETHEMA (LPA 2005)(56) groups demonstrated that the administration of high-dose CA (1 g m2) for 4 days during consolidation improves the outcome of patients at high risk. In the AIDA 2000 trial, the 6-year OS was 89% in patients with low- and intermediate-risk disease compared with 83% in patients with high-risk disease.(46) Similarly, in the LPA2005 study, the 4-year OS was 96% in low-risk patients, 91% in intermediate-risk patients, and 79% in high-risk patients.(56) These two studies have revealed improved outcome compared with each of their previous risk-adapted protocols using increased anthracycline doses, instead of CA, in high-risk APL patients. There is great expectation that minimal residual disease (MRD) monitoring will enable precise identication of patients who will relapse.(57,58) Lee et al.(59) reported that MRD by realtime quantitative polymerase chain reaction (RQ-PCR) analysis after upfront ATRA and anthracycline-based induction chemotherapy was detectable in half of the patients, but was undetectable in the remaining half. All patients negative for RQPCR after induction had a favorable clinical course thereafter, without relapse. In contrast, after the rst consolidation, MRD was still detectable exclusively in approximately 30% of patients positive for RQ-PCR after induction, who were highly susceptible to subsequent hematologic relapses despite

additional consolidation.(59) Recently, Grimwade et al.(60) demonstrated that MRD monitoring by RQ-PCR successfully identied the majority of APL patients subject to relapse and provided the most powerful predictor of relapse-free survival (RFS), and was far superior to presenting WBC counts. In that study, early treatment intervention with ATO prevented progression to overt relapse in most patients and the RFS rate at 1 year from molecular relapse was 73%. The results of these studies suggest that careful follow-up with serial quantication of MRD by RQ-PCR would be needed to assess the value of an individualized, response-oriented treatment strategy in the treatment of APL patients.
Salvage Therapy for Relapsed and Refractory APL Patients

The standard salvage therapy for patients with relapsed or refractory APL used to consist of the readministration of ATRA and chemotherapy for induction, generally containing a high dose of CA, followed by additional chemotherapy and or hematopoietic stem cell transplantation (HSCT).(61) However, the identication of ATO as an effective salvage therapy has changed the approach signicantly. After the initial report of the use of ATO from the Shanghai group,(62) several groups conrmed the high efcacy of ATO for patients with APL who relapsed after ATRA-containing regimens. Recent studies have shown that one to three treatment cycles with ATO achieve a second molecular remission in nearly 80% of relapsed or refractory patients, with overall 2-year survival rates of 5060% after repeated cycles of ATO combined with chemotherapy (Table 2).(6368) Given the high efcacy of ATO in this patient group, ATO is now regarded as the best treatment option in these settings;(36,69) however, the best consolidation strategy following the ATO-induced second molecular remission remains unknown.
Hematopoietic Stem Cell Transplantation

The risk-adapted protocols described above clearly illustrate the benets, in terms of both efcacy and safety, of matching the intensity of post-remission treatment to the risk group.(32,46,54) To maximize treatment intensity for very high-risk patients, chemotherapy can be combined with some form of HSCT. Autologous HSCT, such as autologous peripheral stem cell transplantation (auto-PBSCT), would be the ideal therapy

Table 2. Reference

Arsenic trixoide therapy for relapsed refractory acute promyelocytic leukemia n 15 12 47 40 20 28 34 Median age (years) 40 34 38 NA 46 52 47 First-line therapy ATRA + CHT or CHT ATRA + CHT ATRA + CHT ATRA or 9-cis RA + CHT ATRA + CHT NA CHT ATRA CR (%) 93 91.7 85.1 85 80 86 91 Molecular CR (%) NA 66.7 NA 77.5 NA NA 72 NA Five to six cycles of ATO ATO or CHT or ATO + CHT ATO or CHT or auto allo-HSCT One to two cycles of ATO ATRA auto allo-HSCT ATO + CHT auto allo-HSCT ATO or CHT or auto allo-HSCT Postremission therapy Outcome 85% 76% 63% 49% 50% 41% 66% 56% 59% 59% 73% 84% 56% 17% 1-year OS 1-year DFS 2-year OS 2-year DFS 2-year OS 2-year DFS 1.5-year OS 1.5-year RFS 2-year OS 2-year RFS 2-year OS 2-year DFS 2-year OS 2-year EFS

Shen et al.(62) Soignet et al.(64) Niu et al.(63) Soignet et al.(65) Raffoux et al.(66) Thomas et al.(67) Shigeno et al.(70)

Note, in these cases OS and DFS refer to joint analysis.(79) 9-cis RA, 9-cis retinoic acid; allo-HSCT, allogeneic hematopoietic stem cell transplantation; ATRA, all-trans retinoic acid; auto-HSCT, autologous hematopoietic stem cell transplantation; DFS, disease-free survival; DFS, disease-free survival; EFS, event-free survival; NA, not available; OS, overall survaval; RFS, relapse-free survival.

Kamimura et al.

Cancer Sci | November 2011 | vol. 102 | no. 11 | 1933 2011 Japanese Cancer Association

because this would maximize the antileukemic effects while keeping transplant-related mortality (TRM) to a minimum. The Fukuoka BMT group has used upfront auto-PBSCT in 20 APL patients in CR and after consolidation, including ve high-risk patients.(70) Pretransplant conditioning consisted of the BEA regimen: busulfan 1 mg kg every 6 h, p.o., on Days -8 to -5, etoposide 20 mg kg, i.v., on Days -4 and -3, and CA 3 g m2, i.v., every 12 h on Days -3 and -2. Granulocyte colony-stimulating factor (G-CSF) was also included (G-CSF combined BEA regimen), given i.v., as follows: 5 lg kg on Days -14 to -8, 10 lg kg on Days -7 and -6, and 20 lg kg on Days -5 and -4 in combination with continuous infusion of CA 100 mg m2 on Days -12 to -6.(71,72) Rapid engraftment was obtained in all patients with no TRM. Remarkably, leukemia-free survival (LFS) in the absence of maintenance therapy was 100% at 10 years (Table 3). All peripheral blood stem cells (PBSC) that were infused were negative for MRD in both low- and high-risk patients who were examined. Thus, high-dose chemotherapy followed by auto-PBSCT as well as deep remission status, reecting negative MRD in PBSC, would have beneted our patients, because several reports indicate that molecular remission would be an important prognostic factor for patients undergoing autotransplantation during the second molecular remission. In contrast, according to a multicenter retrospective survey from the European Cooperative Group for Blood and Marrow Transplantation (EBMT), autologous HSCT (autoHSCT) does not lead to any improvement in 5-year LFS (70% in 149 patients in rst remission) compared with ATRA-combining risk-adapted chemotherapy.(55) Therefore, auto-HSCT is

not routinely recommended for APL patients in rst remission,(34,73) although these treatments have yet to be compared directly in a randomized trial.(7478) Regarding successive consolidation, there is some evidence that treatment intensication with HSCT may improve the outcomes for patients in second remission following ATO therapy.(79) The consolidation strategy after ATO-induced second remission generally consists of HSCT, with the choice of transplant modality based mainly on PCR status. Although allogeneic HSCT (allo-HSCT) offers the greatest antileukemic activity due to its graft-versus-leukemia effect, it is only recommended for patients who have not achieved second molecular remission because of the risk of TRM.(68) Autologous HSCT has a lower risk of TRM than allo-HSCT and is a reasonable option for consolidation in relapsed APL patients (Table 3).(34,68,73,74) The EBMT surveyed the outcome of APL patients in second remission who underwent auto-HSCT between 1993 and 2003 and found a 5-year LFS of 51%.(74) De Botton et al.(80) also documented the benet of auto-HSCT in 50 APL patients who relapsed after an ATRA-containing treatment in 2004: the RFS at 7 years was 79.4%, with a TRM of only 6% after auto-HSCT. In that study, two of 30 PBSC samples were positive for MRD by PCR; one of these patients relapsed following autograft compared with three of the 28 PCR-negative patients (11%) who relapsed.(80) Of the patients autografted with PCR-negative PBSC, the RFS at 7 years increased to 87.3%, indicating that auto-HSCT would be effective for the treatment of relapsed APL if performed during the second molecular remission, consistent with previous studies(57,81,82) (Table 3).

Table 3.

Autotransplantation for acute promyelocytic leukemia Median age (years) 30 38 Disease status at transplantation CR1: 129 CR2: 58 CR2: 15 Source of autotransplantation BM BM Pretransplant BM PCR NA Negative 8 Positive 7 NA Negative 2 Negative 8 Negative 12 Posirtive 3

Reference Mandelli et al.(75) Meloni et al.(81)

n 187 15

Graft PCR NA NA

Outcome CR1: 42% 7-year LFS CR2: 22% 4-year LFS Median duration of CR PCR positive: 5 months PCR negative: 28.5 months 70% 3-year LFS 83% 3-year OS Median survival: 41 months Median duration of CR: 11 months Median survival CR1: 55 months CR2: 16 months 77% 3-year DFS Median duration of CR: 36 months 79% 7-year RFS 61% 7-year EFS CR1: 70% 5-year LFS CR2: 51% 5-year LFS 83% 5-year EFS CR1: 100% 11-year LFS CR2: 100% 3-year LFS

Ferrant et al.(76) Roman et al.(78) Lo Coco et al.(57) Ottaviani et al.(77)

36 10 8 16

NA 47 40 30

CR1: 36 CR1: 8 CR2: 1 PR: 1 CR2: 8 CR1: 13 PR: 1 CR2: 1 CR3: 1 CR2: 22 CR2: 6 CR2: 50 CR1: CR2: CR2: CR3: CR1: CR2: 149 195 12 2 20 6

BM BM 4 BM BM

NA NA NA NA

Thomas et al.(67) Ferrara et al.(82) de Botton et al.(80) Sanz et al.(74) Thirugnanam et al.(83) Kamimura et al.(70)

22 6 50 344 14 26

NA 38 45 50 (CR1) 38 (CR2) 33 45

BM 5 PB 17 BM or PB BM 43 PB 7 CR1: BM 92, PB 57 CR2: BM 91, PB 104 PB PB

Negative 2 Positive 4 Negative 6 Negative 20 Positive 2 NA NA CR1: Negative 15

Negative 9 Positive 1 Negative 6 Negative 28 Positive 2 NA Negative 14 CR2: Nevative 6

Polymerase chain reaction (PCR) positive: pretransplant BM PCR positive. Polymerase chain reaction negative: pretransplant BM PCR negative. BM, bone marrow; CR, complete remission; CR1, rst complete remission; CR2, second complete remission; DFS, disease free survival; EFS, event free survival; LFS, leukemia-free survival; NA, not available; OS, Overall survival; PBSC, peripheral blood stem cell; PR, partial response; TRM, treatment-related mortality.

1934

doi: 10.1111/j.1349-7006.2011.02045.x 2011 Japanese Cancer Association

Thomas et al.(67) used ATO as reinduction therapy for 28 relapsed APL patients. Nine of 24 patients achieving molecular remission underwent auto-HSCT, all of whom achieved second remission with 2-year LFS and OS rates of 100%. In our study,(70) six low-risk patients relapsed after cessation of maintenance therapy, three of whom were treated with chemotherapy as reinduction for relapsed APL prior to the use of ATO, whereas the remainder underwent ATO-containing chemotherapy. All six patients achieved second molecular remission after a single course of reinduction chemotherapy and PBSC were harvested at this time. Six patients received auto-HSCT during their second remission and remained in CR without maintenance for a median of 41 months (range 2187 months). Furthermore, Thirugnanam et al.(83) have recently shown that, for patients in second remission following ATO-based regimens, consolidation with auto-HSCT is associated with a signicantly superior clinical outcome compared with ATO-based maintenance: 5-year EFS was 83.3% in patients receiving auto-HSCT compared with 34.4% in those who did not. Because ATO therapy achieves molecular remission in nearly 80% of relapsed patients when given for at least two cycles,(68) auto-HSCT may be adopted as standard therapy for this patient group (Table 3).
Conclusions

which has reduced both the incidence of early death and relapse. Large multicenter studies have shown that treatment regimens combining upfront ATRA and anthracycline-based chemotherapy without CA for induction and consolidation, as well as ATRA-based maintenance therapy, are sufcient for the majority of low-risk patients. In addition, escalating doses of CA during consolidation therapy benet high-risk patients. There is a trend towards designing risk-adapted treatment strategies, which modulate treatment intensity during consolidation according to the risk of relapse, as indicated by the WBC count at presentation. These strategies are proving to be very effective in improving survival even in high-risk groups, where survival rates of 85% are possible. Because of these successes, HSCT is not routinely recommended for APL patients in rst molecular remission. In contrast, auto-HSCT can be considered as consolidation therapy for relapsed and refractory patients following ATRA-containing regimens, provided that the patient achieves a second molecular remission and the harvested PBSC or bone marrow cells are PCR negative. Autologous HSCT may play a more prominent role in the treatment of relapsed and refractory APL patients in the future, based on the high incidence of second remissions following ATO treatment.
Disclosure Statement
The authors declare no potential conict of interest.

The outcomes of APL have improved over the past 20 years due to the incorporation of ATRA into chemotherapy regimens,

References
1 Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classication of the acute leukaemias. FrenchAmericanBritish (FAB) co-operative group. Br J Haematol 1976; 33: 4518. 2 Chen Z, Tong JH, Dong S, Zhu J, Wang ZY, Chen SJ. Retinoic acid regulatory pathways, chromosomal translocations, and acute promyelocytic leukemia. Genes Chromosom Cancer 1996; 15: 14756. 3 Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J 1996; 10: 94054. 4 Warrell RP Jr, de The H, Wang ZY, Degos L. Acute promyelocytic leukemia. N Engl J Med 1993; 329: 17789. 5 Grignani F, Fagioli M, Alcalay M et al. Acute promyelocytic leukemia: from genetics to treatment. Blood 1994; 83: 1025. 6 Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93: 3167215. 7 Licht JD. Acute promyelocytic leukemia: weapons of mass differentiation. N Engl J Med 2009; 360: 92830. 8 Chang KS, Trujillo JM, Ogura T et al. Rearrangement of the retinoic acid receptor gene in acute promyelocytic leukemia. Leukemia 1991; 5: 2004. 9 Miller WH Jr, Kakizuka A, Frankel SR et al. Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor alpha claries diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci USA 1992; 89: 26948. 10 Vardiman JW, Thiele J, Arber DA et al. The 2008 revision of the World Health Organization (WHO) classication of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 93751. 11 Bernard J, Mathe G, Boulay J, Ceoard B, Chome J. [Acute promyelocytic leukemia: a study made on 20 cases]. Schweiz Med Wochenschr 1959; 89: 6048 (in French). 12 Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008; 111: 250515. 13 Paietta E, Andersen J, Racevskis J et al. Signicantly lower P-glycoprotein expression in acute promyelocytic leukemia than in other types of acute myeloid leukemia: immunological, molecular and functional analyses. Leukemia 1994; 8: 96873. 14 Michieli M, Damiani D, Ermacora A et al. P-glycoprotein (PGP), lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP) expression in acute promyelocytic leukaemia. Br J Haematol 2000; 108: 7039. 15 Takeshita A, Shinjo K, Naito K et al. Role of P-glycoprotein in all-trans retinoic acid (ATRA) resistance in acute promyelocytic leukaemia cells: analysis of intracellular concentration of ATRA. Br J Haematol 2000; 108: 902.

16 Cunningham I, Gee TS, Reich LM, Kempin SJ, Naval AN, Clarkson BD. Acute promyelocytic leukemia: treatment results during a decade at Memorial Hospital. Blood 1989; 73: 111622. 17 Sanz MA, Jarque I, Martin G et al. Acute promyelocytic leukemia. Therapy results and prognostic factors. Cancer 1988; 61: 713. 18 Fenaux P, Wang ZZ, Degos L. Treatment of acute promyelocytic leukemia by retinoids. Curr Top Microbiol Immunol 2007; 313: 10128. 19 Ribeiro RC, Rego E. Management of APL in developing countries: epidemiology, challenges and opportunities for international collaboration. Hematology Am Soc Hematol Educ Program. Washington DC: American Society of Hematology (ASH), 2006; 1628. 20 Huang ME, Ye YC, Chen SR et al. All-trans retinoic acid with or without low dose cytosine arabinoside in acute promyelocytic leukemia. Report of 6 cases. Chin Med J 1987; 100: 94953. 21 Huang ME, Ye YC, Chen SR et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 56772. 22 Chomienne C, Ballerini P, Balitrand N et al. All-trans retinoic acid in acute promyelocytic leukemias. II. In vitro studies: structurefunction relationship. Blood 1990; 76: 171017. 23 Lo Coco F, Avvisati G, Diverio D et al. Molecular evaluation of response to all-trans-retinoic acid therapy in patients with acute promyelocytic leukemia. Blood 1991; 77: 16579. 24 Mandelli F, Diverio D, Avvisati G et al. Molecular remission in PML RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dellAdulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 1997; 90: 101421. 25 Sanz MA, Martin G, Rayon C et al. A modied AIDA protocol with anthracycline-based consolidation results in high antileukemic efcacy and reduced toxicity in newly diagnosed PML RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood 1999; 94: 301521. 26 Asou N, Kishimoto Y, Kiyoi H et al. A randomized study with or without intensied maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARalpha transcript after consolidation therapy: the Japan Adult Leukemia Study Group (JALSG) APL97 study. Blood 2007; 110: 5966. 27 Tallman MS, Andersen JW, Schiffer CA et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997; 337: 10218. 28 Fenaux P, Le Deley MC, Castaigne S et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 1993; 82: 32419. 29 Fenaux P, Chastang C, Chevret S et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999; 94: 1192200.

Kamimura et al.

Cancer Sci | November 2011 | vol. 102 | no. 11 | 1935 2011 Japanese Cancer Association

30 Larson RS, Tallman MS. Retinoic acid syndrome: manifestations, pathogenesis, and treatment. Best Pract Res Clin Haematol 2003; 16: 45361. 31 Vahdat L, Maslak P, Miller WH Jr et al. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood 1994; 84: 38439. 32 Sanz MA, Martin G, Gonzalez M et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004; 103: 123743. 33 Avvisati G, Petti MC, Lo-Coco F et al. Induction therapy with idarubicin alone signicantly inuences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: nal results of the GIMEMA randomized study LAP 0389 with 7 years of minimal followup. Blood 2002; 100: 31416. 34 Sanz MA, Grimwade D, Tallman MS et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009; 113: 187591. 35 Douer D, Tallman MS. Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J Clin Oncol 2005; 23: 2396410. 36 Shigeno K, Naito K, Sahara N et al. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol 2005; 82: 2249. 37 Ghavamzadeh A, Alimoghaddam K, Ghaffari SH et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and or chemotherapy. Ann Oncol 2006; 17: 1314. 38 Shen ZX, Shi ZZ, Fang J et al. All-trans retinoic acid As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 2004; 101: 532835. 39 Mathews V, George B, Chendamarai E et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol 2010; 28: 386671. 40 Estey E, Garcia-Manero G, Ferrajoli A et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006; 107: 346973. 41 Ravandi F, Estey E, Jones D et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009; 27: 50410. 42 Au WY, Kumana CR, Lam CW et al. Solid tumors subsequent to arsenic trioxide treatment for acute promyelocytic leukemia. Leuk Res 2007; 31: 1058. 43 Sanz MA, Lo-Coco F. Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol 2011; 29: 495503. 44 Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Gemon MF. Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood 1973; 41: 48996. 45 Sanz MA, Tallman MS, Lo-Coco F. Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood 2005; 105: 301925. 46 Lo-Coco F, Avvisati G, Vignetti M et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 2010; 116: 31719. 47 Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood 1999; 93: 413143. 48 Sanz MA, Lo Coco F, Martin G et al. Denition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000; 96: 124753. 49 Gore SD, Gojo I, Sekeres MA et al. Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia. J Clin Oncol 2010; 28: 104753. 50 Powell BL, Moser B, Stock W et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010; 116: 37517. 51 Ades L, Guerci A, Raffoux E et al. Very long-term outcome of acute promyelocytic leukemia after treatment wtih all trans retinoic acid and chemotherapy: the European APL Group experience. Blood 2009; 115: 16906. 52 Avvisati G, Lo-Coco F, Paoloni FP et al. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 2011; 117: 471625. 53 Tallman MS, Andersen JW, Schiffer CA et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100: 4298302.

54 Kelaidi C, Chevret S, De Botton S et al. Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience. J Clin Oncol 2009; 27: 266876. 55 Ades L, Sanz MA, Chevret S et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of FrenchBelgianSwiss and PETHEMA results. Blood 2008; 111: 107884. 56 Sanz MA, Montesinos P, Rayon C et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010; 115: 513746. 57 Lo Coco F, Diverio D, Avvisati G et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood 1999; 94: 22259. 58 Esteve J, Escoda L, Martin G et al. Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benet of an early intervention. Leukemia 2007; 21: 44652. 59 Lee S, Kim YJ, Eom KS et al. The signicance of minimal residual disease kinetics in adults with newly diagnosed PML-RARalpha-positive acute promyelocytic leukemia: results of a prospective trial. Haematologica 2006; 91: 6714. 60 Grimwade D, Jovanovic JV, Hills RK et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol 2009; 27: 36508. 61 Thomas X, Dombret H, Cordonnier C et al. Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. APL Study Group. Acute promyelocytic leukemia. Leukemia 2000; 14: 100613. 62 Shen ZX, Chen GQ, Ni JH et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efcacy and pharmacokinetics in relapsed patients. Blood 1997; 89: 335460. 63 Niu C, Yan H, Yu T et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999; 94: 331524. 64 Soignet SL, Maslak P, Wang ZG et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998; 339: 13418. 65 Soignet SL, Frankel SR, Douer D et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19: 385260. 66 Raffoux E, Rousselot P, Poupon J et al. Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 2003; 21: 232634. 67 Thomas X, Pigneux A, Raffoux E et al. Arsenic trioxide(As2O3) therapy for relapsed acute promyelocytic leukemia(APL): comparison with historic control combining all-trans retinoic acid(ATRA) plus intensive chemotherapy (Abstract). Blood 2005; 106: 263a. 68 Tallman MS. Treatment of relapsed or refractory acute promyelocytic leukemia. Best Pract Res Clin Haematol 2007; 20: 5765. 69 Chen Z, Zhao WL, Shen ZX et al. Arsenic trioxide and acute promyelocytic leukemia: clinical and biological. Curr Top Microbiol Immunol 2007; 313: 12944. 70 Kamimura T, Miyamoto T, Nagafuji K et al. Role of autotransplantation in the treatment of acute promyelocytic leukemia patients in remission: Fukuoka BMT Group observations and a literature review. Bone Marrow Transplant 2010; 46: 8206. 71 Gondo H, Harada M, Miyamoto T et al. Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia. Bone Marrow Transplant 1997; 20: 8216. 72 Harada M, Akashi K, Hayashi S et al. Granulocyte colony-stimulating factorcombined marrow-ablative chemotherapy and autologous blood cell transplantation for the treatment of patients with acute myelogenous leukemia in rst remission. The Fukouka Bone Marrow Transplant Group. Int J Hematol 1997; 66: 297301. 73 Kharfan-Dabaja MA, Abou Mourad YR, Fernandez HF, Pasquini MC, Santos ES. Hematopoietic cell transplantation in acute promyelocytic leukemia: a comprehensive review. Biol Blood Marrow Transplant 2007; 13: 9971004. 74 Sanz MA, Labopin M, Gorin NC et al. Hematopoietic stem cell transplantation for adults with acute promyelocytic leukemia in the ATRA era: a survey of the European Cooperative Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2007; 39: 4619. 75 Mandelli F, Labopin M, Granena A et al. European survey of bone marrow transplantation in acute promyelocytic leukemia (M3). Working Party on Acute Leukemia of the European Cooperative Group for Bone Marrow Transplantation (EMBT). Bone Marrow Transplant 1994; 14: 2938. 76 Ferrant A, Labopin M, Frassoni F et al. Karyotype in acute myeloblastic leukemia: prognostic signicance for bone marrow transplantation in rst remission: a European Group for Blood and Marrow Transplantation study. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Blood 1997; 90: 29318.

1936

doi: 10.1111/j.1349-7006.2011.02045.x 2011 Japanese Cancer Association

77 Ottaviani E, Martinelli G, Testoni N, Visani G, Tani M, Tura S. Role of autologous bone marrow transplantation as consolidation therapy in acute promyelocytic leukemia patients in complete remission. Haematologica 1998; 83: 10515. 78 Roman J, Martin C, Torres A et al. Absence of detectable PML-RAR alpha fusion transcripts in long-term remission patients after BMT for acute promyelocytic leukemia. Bone Marrow Transplant 1997; 19: 67983. 79 Douer D, Hu W, Giralt S, Lill M, DiPersio J. Arsenic trioxide (trisenox) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation. Oncologist 2003; 8: 13240. 80 de Botton S, Fawaz A, Chevret S et al. Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 2005; 23: 1206.

81 Meloni G, Diverio D, Vignetti M et al. Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML RAR alpha fusion gene. Blood 1997; 90: 13215. 82 Ferrara F, Palmieri S, Annunziata M, Pocali B, Viola A, Pane F. Prolonged molecular remission after autologous stem cell transplantation in relapsed acute promyelocytic leukemia. Haematologica 2004; 89: 6212. 83 Thirugnanam R, George B, Chendamarai E et al. Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 2009; 15: 147984.

Kamimura et al.

Cancer Sci | November 2011 | vol. 102 | no. 11 | 1937 2011 Japanese Cancer Association