Autologous and Allogeneic Stem-Cell Transplantation As Salvage Treatment of Acute Promyelocytic Leukemia Initially Treated With All-Trans-Re
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《临床肿瘤学》
the European Acute Promyelocytic Leukemia Group. See Appendix for the complete list of participants and locations
ABSTRACT
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
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
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 (ATRA->CT 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 ATRA->CT (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 (ATRA->CT 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).
Salvage CT regimens varied during the period of inclusion and in different centers, as no recommendations were made for a specific CT regimen, except for the period from 1995 to 1999, when recommended salvage CT in our APL study group was a timed sequential regimen (EMA; mitoxantrone 12 mg/m2/d 30-minute intravenous [IV] infusion from day 1 to day 3, and AraC 500 mg/m2/d continuous infusion from day 1 to day 3, followed by etoposide 200 mg/m2/d continuous IV infusion from day 8 to day 10, and AraC, 500 mg/m2/d continuous IV infusion from day 8 to day 10 as previously published21). Seventy-one patients received the EMA regimen, and 51 patients received other anthracycline-AraC regimens with conventional (n = 32) or high-dose AraC (ie, > 1 g/m2/d; n = 18) that were generally less myelosuppressive than the EMA regimen. Excluding the patients lost to follow-up, 122 (88%) of the 139 relapsing patients achieved hematological CR2 (detailed salvage treatments are summarized in 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.
RT-PCR
Molecular assessment was not performed before SCT in all patients in this retrospective study in which some patients relapsed as early as 1992. RT-PCR analysis was made before auto or allo SCT in 39 (53%) of the patients receiving transplantation, including 30 of the 50 autografted patients (with simultaneous assessment of the stem-cell harvest in 12 of the 30 cases) and nine of the 23 allografted patients. RT-PCR analysis was performed on bone marrow cells using a previously described22 nested RT-PCR technique for PML-RAR amplification, whose sensitivity ranges from 10–5 to 10–6.
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
Of the 35 patients who received EMA as salvage therapy and were autografted, three died from transplant-related complications, and nine (26%) relapsed as compared with none, and none of the 15 patients who received other CT salvage regimens (including eight patients who received high-dose AraC-based salvage CT). There was a trend for poorer EFS in patients treated with the EMA regimen (P = .06). Of the 28 patients who received cyclophosphamide–total-body irradiation as a conditioning regimen, seven (25%) relapsed, compared with two (12%) of the 17 patients who received busulfan and cyclophosphamide (P = .45).
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
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, ATO11-14 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
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. Conde (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
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 (Comite du Nord).
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
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
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
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 (ATRA->CT 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 ATRA->CT (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 (ATRA->CT 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).
Salvage CT regimens varied during the period of inclusion and in different centers, as no recommendations were made for a specific CT regimen, except for the period from 1995 to 1999, when recommended salvage CT in our APL study group was a timed sequential regimen (EMA; mitoxantrone 12 mg/m2/d 30-minute intravenous [IV] infusion from day 1 to day 3, and AraC 500 mg/m2/d continuous infusion from day 1 to day 3, followed by etoposide 200 mg/m2/d continuous IV infusion from day 8 to day 10, and AraC, 500 mg/m2/d continuous IV infusion from day 8 to day 10 as previously published21). Seventy-one patients received the EMA regimen, and 51 patients received other anthracycline-AraC regimens with conventional (n = 32) or high-dose AraC (ie, > 1 g/m2/d; n = 18) that were generally less myelosuppressive than the EMA regimen. Excluding the patients lost to follow-up, 122 (88%) of the 139 relapsing patients achieved hematological CR2 (detailed salvage treatments are summarized in 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.
RT-PCR
Molecular assessment was not performed before SCT in all patients in this retrospective study in which some patients relapsed as early as 1992. RT-PCR analysis was made before auto or allo SCT in 39 (53%) of the patients receiving transplantation, including 30 of the 50 autografted patients (with simultaneous assessment of the stem-cell harvest in 12 of the 30 cases) and nine of the 23 allografted patients. RT-PCR analysis was performed on bone marrow cells using a previously described22 nested RT-PCR technique for PML-RAR amplification, whose sensitivity ranges from 10–5 to 10–6.
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
Of the 35 patients who received EMA as salvage therapy and were autografted, three died from transplant-related complications, and nine (26%) relapsed as compared with none, and none of the 15 patients who received other CT salvage regimens (including eight patients who received high-dose AraC-based salvage CT). There was a trend for poorer EFS in patients treated with the EMA regimen (P = .06). Of the 28 patients who received cyclophosphamide–total-body irradiation as a conditioning regimen, seven (25%) relapsed, compared with two (12%) of the 17 patients who received busulfan and cyclophosphamide (P = .45).
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
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, ATO11-14 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
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. Conde (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
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 (Comite du Nord).
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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