Originally published as JCO Early Release 10.1200/JCO.2005.03.127 on November 8 2004

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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

From the European Acute Promyelocytic Leukemia Group. See Appendix for the complete list of participants and locations

Address reprint requests to P. Fenaux, MD, PhD, Service d’Hématologie Clinique, Hôpital Avicenne, Université Paris XIII, 125 rue de Stalingrad, 93009 Bobigny, France; e-mail: pierre.fenaux{at}avc.ap-hop-paris.fr

	ABSTRACT

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PURPOSE: To retrospectively determine the outcome of acute promyelocytic leukemia (APL) patients who underwent autologous or allogeneic stem-cell transplantation (SCT) during second complete remission.

PATIENTS AND METHODS: Of 122 relapsing patients included in two successive multicenter APL trials who achieved hematological second complete remission (generally after a salvage regimen of all-trans-retinoic acid [ATRA] combined with chemotherapy), 73 (60%) received allogeneic (n = 23) or autologous (n = 50) SCT.

RESULTS: Seven-year relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in the autologous SCT group were 79.4%, 60.6%, and 59.8%, respectively, with a transplant-related mortality (TRM) of 6%. Of the 28 and two patients autografted with negative and positive, respectively, reverse transcriptase-polymerase chain reaction before auto SCT, three (11%) and one relapsed, respectively. In the allogeneic SCT group, 7-year RFS, EFS, and OS were 92.3%, 52.2%, and 51.8%, respectively, with 39% TRM. OS was significantly better in the autologous SCT group than in the allogeneic SCT group (P = .04), whereas RFS and EFS did not differ significantly (P = .19 and P = .11, respectively). In patients not receiving transplantation, 7-year RFS, EFS, and OS were 38%, 30.4%, and 39.5%, respectively.

CONCLUSION: These retrospective data suggest that autologous SCT is very effective in APL relapsing after treatment with ATRA if performed in molecular remission. Allogeneic SCT yields few relapses, but it is associated with high TRM when performed after salvage with very intensive chemotherapy. Salvage with arsenic trioxyde, which has lower toxicity, should further improve the outcome of relapsing APL, especially before allogeneic SCT.

	INTRODUCTION

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Even with the introduction of all-trans-retinoic acid (ATRA) in the first-line treatment of acute promyelocytic leukemia (APL) and of maintenance treatment, relapses still occur in 15% to 25% of cases.^1-7 Most relapsing patients can achieve a second complete remission (CR2) with ATRA, chemotherapy (CT), both treatments, or arsenic trioxyde (ATO).^8-14 However, the most effective postremission therapy in those patients is not defined.^15,16 Allogeneic (allo) stem-cell transplantation (SCT) in CR 2 is considered to be the most effective option for reducing the relapse rate in acute myeloid leukemia (AML) in general, but it requires a human leukocyte antigen–identical donor, and induces relatively high transplant-related mortality (TRM) rates.¹⁷ Its results have been evaluated in APL patients allografted in CR2, but before the ATRA era.¹⁸ Autologous (auto) SCT is less toxic but is generally associated with higher relapse rates in AML¹⁹ in general. However, a preliminary report suggested that few relapses occurred in APL patients autografted in molecular remission.²⁰

We retrospectively analyzed the outcome of 73 APL patients, initially treated with ATRA and CT, who relapsed and received auto or allo SCT after achievement of CR2.

	PATIENTS AND METHODS

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Patients younger than 66 years included in two multicenter clinical trials combining ATRA and CT in the treatment of newly diagnosed APL (APL 91 and 93 trials) who, after a first relapse, were salvaged and received allo SCT or auto SCT in CR2, were analyzed.

APL 91 and 93 Trials
Between March 1991 and October 1998, patients with newly diagnosed APL had been included in APL 91 and 93 trials. In the APL 91 trial,² patients were randomly assigned to induction treatment between CT with daunorubicin (DNR) + cytarabine (AraC) alone and ATRA (45 mg/m²/d orally until complete remission [CR]), followed by the same CT (ATRACT group), but only the latter were eligible for the present study. In the APL 93 trial,³ patients 65 years or younger with WBC count less than 5,000/µL were randomly assigned between ATRACT (as in the APL 91 trial) and ATRA + CT (with CT started on day 3 of ATRA treatment). Patients 65 years or younger with WBC more than 5,000/mm³ were not randomized and received ATRA + CT begun on day 1 of ATRA treatment. Patients who achieved CR received two DNR-AraC consolidation courses without maintenance treatment (APL 91 trial), or the same two consolidation courses followed by random assignment for maintenance, testing both intermittent ATRA and continuous CT with 6 mercaptopurine and methotrexate, scheduled for 2 years.

Salvage Treatment in First Relapse
Five hundred sixty-four patients younger than 66 years were included in APL 91 (ATRACT group) and APL 93 trials, and 525 (93%) achieved CR; 140 (27%) relapsed. Because relapses occurred between 1992 and 2001, a period during which standard of care and recommendations for the treatment of relapsing APL evolved, salvage treatments were not homogeneous. Of the 140 relapsing patients, six received no systemic salvage treatment due to early death (n = 4), loss to follow-up (n = 1), or due to the fact that relapse only involved an extramedullary site (skin; n = 1). One hundred thirty-four patients received salvage treatment with ATO alone (n = 4), ATRA alone (n = 8), CT alone (n = 24), and ATRA combined with CT (n = 98; Table 1).

After CR2 achievement, recommended postremission therapy was allo SCT in patients 50 years or younger with a familial donor. In patients without a familial donor, allo SCT with an unrelated donor was generally not recommended. In addition, during the period of study, nonmyeloablative allo SCT was not recommended in older patients with a familial donor. In patients without a familial donor younger than 60 years (to 65 years), auto SCT was strongly recommended. In other patients considered unfit for auto SCT, additional anthracycline-AraC followed by maintenance with intermittent ATRA and low-dose 6 mercaptopurine and methotrexate was suggested, especially in patients who had not received maintenance before relapse.

Seventy-three (60%) of the relapsing patients received allo or auto SCT after CR2 achievement. No patient 50 years or younger with a familial donor was autografted, and no nonmyeloablative allo SCT was performed. We made five allo SCTs using an unrelated donor, two of them in children, and two in patients who remained positive for reverse transcriptase-polymerase chain reaction (RT-PCR) after consolidation treatment.

The remaining 49 patients were not allografted or autografted in CR2. One received syngeneic SCT, and 48 received various consolidation and/or maintenance regimens with CT and/or ATRA. Reasons for not performing autologous SCT in patients who could not be allografted included age older than 60 years and relatively poor general condition (n = 10), early relapse (n = 10), severe toxicity of the salvage CT regimen (n = 7), stem-cell collection failure (n = 2), patient refusal (n = 2), death in CR2 (n = 2), and medical decision (n = 15).

SCT
Stem-cell collection was made in CR2 from bone marrow in the first patients, and then from granulocyte colony-stimulating factor–mobilized blood stem cells (in steady-state, or after EMA or other regimens) after assessing complete remission with morphological and karyotypic examination. A minimum of 2 x 10⁶ CD34⁺ cells/kg were required. For allo SCT, the stem-cell source was bone marrow in 17 cases and granulocyte colony-stimulating factor–mobilized blood stem cells in three cases; the donor was unrelated in five cases (Table 2). The conditioning regimen was cyclophosphamide and fractionated total-body irradiation in 45 patients (including 28 autografted patients and 17 allografted patients), busulfan, and cyclophosphamide in 23 patients (including 17 autografted patients and six allografted patients), or other regimens in the remaining patients (Table 2). Four of the autografted patients received maintenance treatment (intermittent ATRA and continuous low-dose CT) after the procedure.

Statistical Methods
Relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) were estimated by the Kaplan-Meier method.^23,24 For quantitative variables, data are given as medians (with the 25th to 75th percentiles [Q1-Q3] in parentheses), while for qualitative variables, data were given as number of patients (percentages).

Analyses were performed on the SAS version 8.2 (SAS Inc, Cary, NC) and Splus 2000 (MathSoft, Seattle, WA) software packages. All statistical tests were two-sided, with P values .05 denoting statistical significance.

	RESULTS

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Auto SCT
In the 50 patients autografted in CR2, median first CR (CR1) duration had been 23.4 months (Q1-Q3: 13.9 to 39.7; Table 1). Median time from CR2 achievement to auto SCT was 112 days (Q1-Q3: 82 to 137; Table 2). Three (6%) of the 50 patients died from TRM (severe sepsis in two cases and veno-occlusive disease in one case; all three patients had received EMA as salvage therapy). Nine patients relapsed after 3 to 18 months, two developed MDS, seven and 62 months after CR2 achievement, and one died from lung cancer 49 months after auto SCT. The remaining 35 patients were still in CR2, with CR2 duration greater than CR1 duration in 25 of them (71%), all with negative RT-PCR. Seven-year RFS, EFS, and OS were 79.4%, 60.6%, and 59.8%, respectively (Fig 1). RT-PCR before auto SCT, available in 30 cases, was positive in two cases and negative in 28 cases (including 12 cases for which RT-PCR was also performed in the harvested cells). Of the 28, two, and 20 patients autografted with negative RT-PCR, positive RT-PCR, and without PCR assessment before auto SCT, three (11%), one, and six (30%) relapsed, respectively. Patients in molecular remission at the time of stem-cell harvest had a 7-year RFS, EFS, and OS of 87.3%, 76.5%, and 75.3%, as compared with 69.8%, 49.2%, and 51.1% in patients who lacked molecular assessment at the time of stem-cell harvest (P = .11, P = .07, and P = .20, respectively).

View larger version (17K): [in this window] [in a new window]   Fig 1. Outcome of the 122 APL patients in second hematological complete remission according to postremission therapy. (A) Relapse-free survival; (B) event-free survival; (C) overall survival.

Allogeneic SCT
In the 23 patients allografted in CR2, median CR1 duration had been 14.6 months (Q1-Q3: 11.5 to 23.9; Table 1). Median time from CR2 achievement to allo SCT was 80.5 days (Q1-Q3: 55 to 125; Table 2). Nine (39%) of the 23 patients allografted in CR2 died from TRM (graft-versus-host disease in four patients, infection and multiorgan failure in five patients), one died from post-transplantation non-Hodgkin’s lymphoma, and one relapsed after 17 months. CR1 duration and interval from CR2 achievement to allo SCT had no influence on the occurrence of TRM. Twelve (52%) patients remained in CR2, with CR2 greater than CR1 in nine patient (75%)s, and with negative PCR. Seven-year RFS, EFS, and OS were 92.3%, 52.2%, and 51.8%, respectively (Fig 1). RT-PCR before allogeneic SCT, available in nine cases, was positive in six cases and negative in three cases. Of the six patients with positive RT-PCR before the allograft, three died (two from TRM and one from relapse), and three were in CR2 with negative RT-PCR. All three patients with negative RT-PCR before allo SCT remained in CR2 with negative RT-PCR. There was a trend for a higher incidence of TRM in patients salvaged with EMA: seven (64%) of the 11 patients who received the EMA regimen before allo SCT had TRM, versus three (23%) of the 12 patients successfully treated with other regimens (three of them with high-dose AraC; P = .10). Three of the five patients allografted with an unrelated donor died, and two remained in CR2.

Other Consolidation Treatments
In the 49 patients in CR2 who received no auto or allo SCT as postremission therapy, median CR1 duration had been 14.5 months (Q1-Q3: 10.1 to 23.9). They received, in CR2, consolidation treatment with various CT regimens followed or not by maintenance treatment with intermittent ATRA and/or continuous low-dose CT. Five died in CR2; 26 (53%) had a second relapse after 2 to 22 months; and 19 (39%) remained in CR2 after 7 to 97 months, with CR2 greater than CR1 in 17 of them. Of the 26 patients who had a second relapse, five obtained further CR, of whom two received autologous SCT in CR3 (one is still in CR3, to date), and three received unrelated donor allo SCT in CR3 (one is still in CR3). Seven-year RFS, EFS, and OS were 38%, 30.4%, and 39.5%, respectively (Fig 1). Excluding the nine patients who relapsed within 3 months of CR2 achievement, 7-year RFS, EFS, and OS were 42.7%, 37.4%, and 46%, respectively.

Comparisons Between the Different Consolidation Groups
Seven-year RFS and EFS did not significantly differ in autografted patients and allografted patients (P = .19 and P = .11, respectively), but OS was significantly better in autografted patients (P = .04). Seven-year RFS, EFS, and OS were significantly better in autografted patients than in patients not receiving transplantation (P = .002, P = .0005, and P = .001, respectively), and the differences remained significant after exclusion of patients not receiving transplantation who relapsed within 3 months after CR2 achievement. Seven-year EFS and OS were similar in allografted patients and patients not receiving transplantation (P = .17, P = .41, respectively), but RFS was significantly better in allografted patients (P = .0018), even after excluding the nine patients who relapsed within 3 months of CR2 achievement.

	DISCUSSION

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Before the ATRA era, in APL transplanted in CR2, leukemia-free survival, and TRM were reported to be 31% and 23% for auto SCT and 22% and 40% for allo SCT, respectively.¹⁸ Since the advent of ATRA combined with CT as front-line treatment, one report²⁰ of 15 autografts performed in CR2 found that six of eight patients with negative RT-PCR in the bone marrow before auto SCT had prolonged CR. By contrast, all seven patients with positive bone marrow RT-PCR relapsed, stressing the prognostic importance of RT-PCR in this situation.

Results of the present study should be interpreted with caution because of their retrospective nature. However, we found that auto SCT in CR2 gave favorable results, with low TRM and prolonged CR2 in almost 60% of the patients. Most patients were successfully treated with intensive CT regimens, generally in combination with ATRA, that were very efficient in obtaining rapid and significant reduction of the leukemic burden and probably contributed to the overall good outcome of autografted patients. However, the EMA regimen, a very myelosuppressive regimen with intermediate dose AraC, mitoxantrone, and VP16, which has proven very effective in relapsing AML in general,²¹ gave less favorable results than other CT regimens (with or without high-dose AraC). This seemed to result both from higher TRM and higher incidence of relapse with the EMA regimen. Overall favorable results of auto SCT were also probably explained by the fact that in most of the cases tested by RT-PCR, stem cells were collected after PCR negativity was obtained. This point was indirectly confirmed by the trend for lower RFS and EFS observed in patients in whom PCR analysis was not performed at the time of stem-cell collection. The busulfan-cyclophosphamide conditioning regimen was at least as effective as the cyclophosphamide–total-body irradiation conditioning regimen, suggesting that total-body irradiation might be avoided in case of auto SCT in APL.

The outcome of allografted patients was less favorable, owing mainly to high incidence of TRM. TRM was especially important after the EMA salvage regimen, and less important with other CT regimens that containing or not containing high-dose AraC. This suggests that very intensive CT regimens before allo SCT may be deleterious in relapsing APL. On the other hand, only one of the six PCR-positive patients before allo SCT relapsed. This confirmed the effectiveness of allo SCT in APL in CR2, and was in agreement with the results of a recent series in which among six patients with positive RT-PCR before allo SCT, only two relapsed.²⁵

Results of auto SCT, therefore, seemed superior to those of allogeneic SCT, with significantly better survival after auto SCT. However, comparisons were difficult to interpret once again because this was a retrospective study; because most failures after allo SCT were due to an unexpectedly high TRM (mainly after the EMA regimen); and because allografted patients had more high-risk features than autografted patients (mean higher WBC counts, shorter CR1 duration, greater incidence of PCR positivity after consolidation treatment). Still, our study seems to confirm that auto SCT, when stem cells are collected in molecular remission, is associated with few relapses. On the other hand, in patients remaining PCR positive after salvage therapy, allo SCT also yields few relapses. Our study also suggests that very myelosuppressive CT regimens like the EMA regimen before allo SCT (and to lesser extent before auto SCT), may lead to important TRM.

Although postinduction treatment in CR2 was not randomized in this series, the relapse rate seemed higher in patients who were neither allografted nor autografted in CR2. In this last group however, 39% remained in CR2—an interesting finding, as those patients had generally received ATRA and CT both at diagnosis and in relapse (ATO was administered in relapse in only two of those patients).

Our results suggest that APL patients who achieve CR2 should be allografted or autografted whenever possible. It is difficult from our study to determine whether APL patients with a human leukocyte antigen–identical donor should be allo or autografted. Indeed, the high mortality of allo SCT that we observed, which is not representative of the current general experience with this procedure, made any comparison difficult. However, our findings show that auto SCT is very effective in APL patients in CR2 who achieve PCR negativity. On the other hand, patients who remain PCR positive after salvage treatment may have few relapses with allo SCT.

The advent of ATO for the treatment of APL relapses should probably modify treatment recommendations. Indeed, ATO^11-14 seems to induce CR2 rates at least as good as the combination of ATRA and CT (and possibly higher rates of molecular remission¹¹), but with much less toxicity, and, especially, no myelosuppression. ATO alone or with moderate consolidation CT probably cannot cure most relapsing patients however,^12,13 and consolidation with allo or auto SCT is still recommended after ATO treatment. But there is hope that those procedures, when performed after ATO, will carry less TRM than after intensive consolidation CT. Nonmyeloablative allo SCT may also reduce early TRM after allo SCT, but there is no large published experience on the use of this approach in APL to our knowledge.

	Appendix

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Dr P. Fenaux and Dr L. Degos served as cochairmen, and Dr C. Chastang and S. Chevret-Chastang (Department of Biostatistics, Hopital St Louis, Paris), as biostatiscians. The following clinical departments participated in APL93 trial:

French APL Group: S. Castaigne, H. Dombret (Paris), R. Zittoun (Paris), E. Archimbaud (Lyon), P. Travade (Clermont Ferrand), C. Gardin (Clichy), A. Guerci (Nancy), S. de Botton (Lille), A.M. Stoppa (Marseille), F. Dreyfus (Paris), F. Stamatoulas (Rouen), F. Rigal-Huguet (Toulouse), H. Guy (Dijon), J.J. Sotto (Grenoble), F. Maloisel (Strasbourg), J. Reiffers (Pessac), A. Gardembas (Angers), D. Bordessoule (Limoges), N. Fegueux (Montpellier), A. Veil (Paris), T. Lamy (Rennes), M. Hayat (Villejuif), E. Deconinck (Besancon), E. Guyotat (St Etienne), M. Martin (Annecy), E. Cony-Makhoul (Bordeaux), J.P. Abgrall (Brest), O. Reman (Caen), B. Desablens (Amiens), J.L. Harousseau (Nantes), Y. Bastion (Lyon), J.P. Pollet (Valenciennes), J. Pulik (Argenteuil), M. Lepeu (Avignon), M. Renoux (Bayonne), P. Morel (Lens), P. Henon (Mulhouse), N. Gratecos (Nice), P. Colombat (Tours), D. Machover (Villejuif), A. Dor (Antibes), P. Casassus (Bobigny), J. Donadio (Castelnou), B. Salles (Chalon), B. Legros (Clermont Ferrand), P. Audhuy (Colmar), A. Dutel (Compiègne), N. Philippe (Lyon), B. Benothman (Meaux), C. Christian (Metz), C. Margueritte (Montpellier), F. Witz (Nancy), A. Pesce (Nice), A. Baruchel (Paris), L. Sutton (Paris), C. Quetin (Pointe à Pitre), B. Pignon (Reims), E. Vilmer (Paris), E. Bourquard (St Brieuc), J.P. Marolleau (Paris), P. Robert (Toulouse), B. Despax (Toulouse), G. Nedellec, P. Auzanneau (Paris), M. Janvier (St Cloud).

Spanish AML Group: O. Rayon (Oviedo), M. Sanz (Valencia), J. San Miguel (Salamanca), J. Montagud (Valencia), E. Condé (Santander), P. Javier de la Serna (Madrid), G. Martin (Valencia), M. Perez Encinas (Santiago), J.P. Torres Carrete (Juan Canalejo), J. Zuazu (Barcelone), J. Odriozola (Madrid), E. Gomez-Sanz (Madrid), L. Palomera (Zaragoza), L. Villegas (Almeria), A. Deben (Juan Canalejo), P. Besalduch (Palma de Mallorca).

Cooperative AML Study Group, Germany: H. Link (Hannover), A. Ganser (Frankfurt), E. Wandt (Nurnberg), A. Breitenbach (Stuttgart), B. Brennscheidt (Freiburg), D. Herrmann (Ulm), H. Soucek (Dresden), H. Strobel (Erlangen).

Swiss Group for Clinical Cancer Research AML group: K. Geiser (Berne), M. Fey (Berne), T. Egger (Berne), E. Jacky.

Belgian Group: J.L. Michaux (Bruxelles), A. Bosly (Yvoir), E. Meeus (Anvers), A. Boulet (Mons).

Dutch group: P. Daenen (Groningen), P. Muus (Nijmegen).

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by the Programme Hospitalier de Recherche Clinique (CHU Lille), the Association de Recherche Contre le Cancer, and the Ligue Nationale Contre le Cancer (Comité du Nord).

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors’ Disclosures of... REFERENCES

 
1. Tallman MS, Nabhan C, Feusner JH, et al: Acute promyelocytic leukemia: Evolving therapeutic strategies. Blood 99:759-767, 2002[Abstract/Free Full Text]

2. Fenaux P, Chevret S, Guerci A, et al: Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia: European APL group. Leukemia 14:1371-1377, 2000[CrossRef][Medline]

3. Fenaux P, Chastang C, Chevret S, et al: A randomized comparison of all trans-retinoic 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 94:1192-1200, 1999[Abstract/Free Full Text]

4. 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 dell’Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 90:1014-1102, 1997[Abstract/Free Full Text]

5. Burnett AK, Grimwade D, Solomon E, et al: Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemiatreated with all-trans retinoic acid: Result of the Randomized MRC Trial. Blood 93:4131-4143, 1999[Abstract/Free Full Text]

6. 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 100:4298-4302, 2002[Abstract/Free Full Text]

7. Sanz MA, Martin G, Rayon C, et al: A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RAR-alpha-positive acute promyelocytic leukemia. Blood 94:3015-3021, 1999[Abstract/Free Full Text]

8. Thomas X, Anglaret B, Thiebaut A, et al: Improvement of prognosis in refractory and relapsed acute promyelocytic leukemia over recent years: The role of all-trans retinoic acid therapy. Ann Hematol 75:195-200, 1997[CrossRef][Medline]

9. Cortes JE, Kantarjian H, O’Brien S, et al: All-trans retinoic acid followed by chemotherapy for salvage of refractory or relapsed acute promyelocytic leukemia. Cancer 73:2946-2952, 1994[CrossRef][Medline]

10. Castaigne S, Chomienne C, Daniel MT, et al: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia, I: Clinical results. Blood 76:1704-1709, 1990[Abstract/Free Full Text]

11. Shen Z, Chen G, Ni J, et al: Use of arsenic trioxide in the treatment of APL, clinical efficacy and pharmacokinetics in relapsed patients. Blood 89:3354-3360, 1997[Abstract/Free Full Text]

12. Soignet SL, Frankel SR, Douer D, et al: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19:3852-3860, 2001[Abstract/Free Full Text]

13. Raffoux E, P. 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 21:2326-2334, 2003[Abstract/Free Full Text]

14. Douer D, Hu W, Giralt S, et al: Arsenic trioxide (trisenox) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation. Oncologist 8:132-140, 2003[Abstract/Free Full Text]

15. Nabhan C, Mehta J, Tallman MS: The role of bone marrow transplantation in acute promyelocytic leukemia. Bone Marrow Transplant 28:219-226, 2001[CrossRef][Medline]

16. 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 6:1006-1013, 2000

17. Appelbaum FR, Rowe JM, Radich J, et al: Acute myeloid leukemia. Hematology 62-86, 2001

18. 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 14:293-298, 1994[Medline]

19. Gorin NC: Autologous stem cell transplantation in acute myelocytic leukemia. Blood 92:1073-1090, 1998[Free Full Text]

20. 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 90:1321-1325, 1997[Abstract/Free Full Text]

21. Archimbaud E, Leblond V, Michallet M, et al: Intensive sequential chemotherapy with mitoxantrone and continuous infusion etoposide and cytarabine for previously treated acute myelogenous leukemia. Blood 77:1894-1900, 1991[Abstract/Free Full Text]

22. Eclache V, Benzacken B, Le Roux G, et al: PML/RAR alpha rearrangement in acute promyelocytic leukaemia with t(1;17) elucidated using fluorescence in situ hybridization. Br J Haematol 98:440-443, 1997[CrossRef][Medline]

23. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-472, 1958[CrossRef]

24. Peto R, Peto J: Asymptotically efficient rank invariant test procedures (with discussion). J R Stat Soc A 135:185-194, 1972

25. Lo-Coco F, Romano A, Mengarelli A, et al: Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: Results in patients treated in second molecular remission or with molecularly persistent disease. Leukemia 17:1930-1933, 2003[CrossRef][Medline]

Submitted March 18, 2004; accepted September 23, 2004.

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				M. A. Sanz Treatment of Acute Promyelocytic Leukemia Hematology, January 1, 2006; 2006(1): 147 - 155. [Abstract] [Full Text] [PDF]

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