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Therapy

Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation

Abstract

The purpose of this study was to assess the safety and efficacy of stem cell transplantation (SCT) mainly autologous SCT as consolidation therapy in APL patients who relapsed and achieved a second complete remission (CR2). Fifty adult patients with a first relapsed APL, of whom 39 had been previously treated with ATRA, entered a multicenter trial of oral ATRA until complete remission (CR) achievement followed by timed sequential chemotherapy (EMA combining etoposide 200 mg/m2/day for 3 days, mitoxantrone 12 mg/m2/day for 3 days, and cytarabine 500 mg/m2/day for two sequences of 3 days). ema was started either after cr achievement, or on day 1 of atra because of initial white blood cell (wbc) counts >5 × 109/l, or rapidly added to ATRA in order to prevent ATRA syndrome because WBC count increased under ATRA. Forty-five patients (90%, 95% CI 78%–97%) were in CR after induction therapy. Five patients died from infection during aplasia following EMA chemotherapy. Eleven patients who achieved CR had a familial HLA-identical donor and were allografted. The median disease-free survival (DFS) of allografted patients was 8.2 months. The 34 other CR patients were scheduled for autologous peripheral blood (PB) SCT (intent-to-treat group). Actually, autologous transplantation was only carried out in 22 patients (65%) (17 PBSCT and five autologous bone marrow transplantation (BMT)). Reasons for not autografting were early relapse (three patients), severe toxicity of EMA chemotherapy (six patients), and refusal or failure of stem cell harvest (three patients). The 3-year DFS rate of patients actually autografted was 77%. Among the 17 autografted patients still in CR2, nine patients have already reached a longer CR2 than first CR (CR1). Results of detection of PML/RARα by RT-PCR after autologous transplantation show negative findings in eight of the nine patients tested. We conclude that (1) ATRA combined to EMA chemotherapy is effective in the treatment of relapsed APL; (2) allogeneic BMT may be too toxic after salvage treatment including EMA intensive chemotherapy; (3) clinical outcome of autografted patients and preliminary molecular results regarding detection of PML/RARα after autologous PBSCT are encouraging.

Introduction

Important advances have been made over the past few years in the management of acute promyelocytic leukemia (APL). In newly diagnosed patients, combinations of the differentiating agent all-trans retinoic acid (ATRA) and conventional chemotherapy result in a better control of APL-associated coagulopathy, high remission rates, and reduction of the relapse rate by comparison to chemotherapy alone.12345 However, despite the overall good prognosis, relapses still occur in about 20 to 30% of cases. Most patients are usually reinduced into complete remission (CR) by ATRA and/or chemotherapy,67 but the best strategy regarding post-remission therapy is still not defined. Among those strategies, allogeneic bone marow transplantation (BMT) seems the most successful for reducing leukemic relapse by virtue of the high-dose chemoradiotherapy conditioning regimen and graft-versus-leukemia (GVL) effects.8 However, in addition to the requirement for HLA-identical marrow donors, transplant-related morbidity and mortality remain the major obstacles for improving clinical results of allogeneic BMT. Autologous stem cell transplantation (SCT) offers the possibility to perform the same myeloblative regimen in patients without a compatible donor and without the risks associated with graft-versus-host (GVH) disease. Because limited experience of autologous transplantation in APL is available, its place in second CR (CR2) after ATRA plus chemotherapy is unknown. The purpose of this study was to assess the safety and efficacy of autologous SCT, as consolidation therapy in relapsed APL patients who achieved a CR2 with a regimen combining ATRA and intensive timed sequential chemotherapy.

Patients and methods

Patients

Patients with APL in first relapse with age below 65 years, a World Health Organization (WHO) performance status less than 3, and no major organ failure were eligible for entry into the trial. Fifty patients were enrolled between December 1994 and June 1998 at 22 participating centers. Median age was 47 years (range: 20–65 years) at the time of relapse. The median first CR duration was 17 months (range: 6–286 months). All patients fulfilled morphological criteria for APL (M3 or M3v) at the time of relapse.9 Diagnosis was confirmed by the presence of t(15;17) translocation and/or PML/RARα gene rearrangement.10 Four patients were not included in specific APL protocols at the time of initial diagnosis and received a combination of an anthracycline for 3 days and cytarabine for 7 days. In all other cases, the front-line treatment was administered according to three different specific protocols (APL91 (four patients), APL93 (35 patients), CHA-Promyelo (seven patients)) adopted at the time of diagnosis.51112 Thirty-nine of those patients received ATRA therapy. Briefly, in the European APL91 trial, patients were randomly allocated to the chemotherapy group or the ATRA plus chemotherapy group where chemotherapy was started after CR achievement with ATRA. Chemotherapy included two identical courses of chemotherapy combining daunorubicin for 3 days and cytarabine for 7 days, followed by a third course combining daunorubicin for 3 days and cytarabine for 4 days.5 In the APL93 trial, patients with WBC counts <5 × 109/l were randomized between ATRA followed by chemotherapy as in APL91, or ATRA with chemotherapy started on day 3. Patients with WBC counts >5 × 109/l received ATRA and chemotherapy from day 1. Patients achieving CR received the two consolidation courses as in the APL91 trial and were then randomized for maintenance between no treatment, ATRA alone, continuous 6-mercaptopurine (6-MP) plus methotrexate, or both.11 CHA-Promyelo trial included progressive administration of cytarabine, given by continuous intravenous infusion for 10 days, daunorubicin administered progressively for 6 days, and lomustine (CCNU) for 2 days. Three weeks after CR achievement, patients entered a 3-year maintenance regimen combining: (1) periodic reinductions consisting of cytarabine, daunorubicin, and CCNU each 3 months, followed by 1 month rest; (2) weekly combinations of 6-thioguanine and cytarabine for 2 months.12

Treatment design for relapsed patients

Reinduction therapy:

ATRA was administered at regular doses (45 mg/m2/day) until CR achievement. Once CR was achieved, patients received an intensive timed sequential chemotherapy (EMA) as previously described.13 Briefly, EMA schedule included two 3-day sequences of chemotherapy separated by a 4-day chemotherapy-free interval. The first sequence combined mitoxantrone, 12 mg/m2/day as a 30-min intravenous infusion from day 1 to day 3, and cytarabine, 500 mg/m2/day as a continuous infusion over the same period. The second sequence, administered after a 4-day chemotherapy-free interval, consisted of etoposide, 200 mg/m2/day as a continuous intravenous infusion from day 8 to day 10, and cytarabine, 500 mg/m2/day as a continuous intravenous infusion on the same days. Patients with WBC counts greater than 5 × 109/l at presentation received ATRA plus EMA chemotherapy from day 1. EMA chemotherapy was added to ATRA if the WBC count was increased to greater than 6 × 109/l, 10 × 109/l, or 15 × 109/l by day 5, 10, and 15 of ATRA treatment, respectively, because, from our experience, patients were at risk of ATRA syndrome above those thresholds.3 Patients developing clinical signs of ATRA syndrome received chemotherapy and intravenous dexamethasone. All patients had a central venous catheter placed for chemotherapy, fluids, and blood products administration. Patients were monitored either in conventional reverse isolation rooms or in sterile laminar air-flow rooms. All patients received prophylactic red blood cells and platelet transfusions. Broad spectrum empirical antibiotherapy was initiated in case of fever higher than 38°C whenever the neutrophil counts were less than 0.5 × 109/l. Patients with documented fungal infection or persistent fever after 72 to 96 h of antibiotic therapy received intravenous amphotericin B.

Postinduction therapy:

All patients achieving CR were scheduled to receive SCT as consolidation therapy. Patients aged less than 55 who had an HLA-identical sibling donor received an allogeneic BMT based on institutional policy to allograft all eligible APL patients in second CR. All other patients in CR2 were scheduled to receive an autologous PBSCT as consolidation therapy. Stem cells were mobilized in stable phase after EMA chemotherapy. Harvest was performed after checking the absence of blast cells in bone marrow by morphological and karyotypic examinations. Recombinant granulocyte colony-stimulating factor (G-CSF) (Amgen, Thousand Oaks, CA, USA) was given as the priming agent at a dose of 5 to 10 μg/kg/day by subcutaneous administration for 5 to 8 days, and cytapheresis were performed daily on the fifth day until a minimum of 2 × 106 CD34+ cells/kg were obtained. Each cytapheresis product was processed, frozen, thawed, and washed according to standard techniques. Recommended myeloablative conditioning regimen was similar for allogeneic BMT and autologous PBSCT, and consisted of cyclophosphamide (60 mg/kg/day for 2 days) followed by fractionated total body irradiation (TBI) (12 Gy). Blood counts were monitored daily. Irradiated leukocyte-depleted blood products were exclusively used for blood component substitution throughout the post-transplant course.

Evaluation of therapy

Complete remission was defined according to the Cancer and Leukemia Group B (CALGB) criteria as less than 5% blasts or promyelocytes in bone marrow aspirates with evidence of maturation of cell lines and restoration of peripheral blood counts.14 Treatment failures were classified, according to Preisler,15 as nonresponse (NR), including all patients with proven blastic regrowth after chemotherapy even if they died before blood count recovery, and other failures (OF) corresponding to patients who died while nonblastic from presumably chemotherapy-related toxicity. Severity of treatment-related toxicity was graded according to the WHO criteria.16 Prospective reverse-transcription polymerase chain reaction (RT-PCR) studies of the PML/RARα fusion gene were only performed in 13 autografted patients. Six of those patients had a bcr1-breakpoint, two had a bcr2-breakpoint and five had a bcr3-breakpoint. BM samples for RT-PCR analysis were collected in all 13 cases at the time of hematologic first relapse, in eight cases before harvesting or autologous transplantation, in six cases on harvest samples, and in nine cases during the follow-up post-transplant. RT-PCR of PML/RARα was performed using previously published techniques.10 Amplification of such a leukemia-specific marker by RT-PCR can identify one leukemic cell among 105 normal cells. Harvested cells were reinfused without taking into account RT-PCR results.

Statistical analysis

All patients were registered at the time of first relapse. Time to recovery from cytopenia was defined as the number of days from the start of chemotherapy until the first day that granulocytes and platelets were >0.5 × 109/l and >50 × 109/l, respectively, for 2 consecutive days. Engraftment was defined as the number of days from transplant until the first day that granulocytes and platelets were >0.5 × 109/l and >50 × 109/l, respectively, for 2 consecutive days. Survival duration was measured from the time of registration to the time of death or last follow-up. Disease-free survival (DFS) was calculated in patients who achieved a second CR from the time of second CR to the time of relapse, death from any cause, or last follow-up. The 95% confidence intervals (CIs) on proportions of CR, NR and OF patients were calculated using a binomial formula. Survival and DFS curves were estimated by the Kaplan–Meier method.17 Prognostic factors for DFS and overall survival were studied using Cox's proportional hazard model.18 The log-rank test was used to assess the significance of differences in survival or DFS between groups.19 Only probability values less than 0.05 were considered statistically significant. The median follow-up duration was 33.6 months. The final analysis was performed as of June 1999. Analysis was done first for the whole population, and subsequently only for patients previously treated by ATRA in first-line therapy. Statistical calculations were performed using the BMDP statistical package (BMDP Statistical Software, Los Angeles, CA, USA).

Results

Patients characteristics

Fifty patients with APL in first relapse prospectively entered the study. All patients entered were eligible and subsequently analyzed. Main clinical and hematological characteristics of the 50 patients are presented in Table 1. Thirty-nine patients (78%) have been previously treated with ATRA in first-line therapy. Seventeen of them received ATRA before chemotherapy and 22 received ATRA plus chemotherapy. Fourteen of those 39 patients underwent maintenance therapy either with ATRA alone (seven patients), or with chemotherapy alone (6-mercaptopurine and methotrexate) (two patients), or with a combination of ATRA and chemotherapy (five patients).11

Table 1  Main clinical and biological characteristics of the 50 patients at time of first relapse

Induction therapy

All patients received ATRA therapy. Median duration of ATRA administration was 34 days (range, 2–95 days). One patient did not receive EMA chemotherapy because of severe infectious complications. All other patients received the full dose of all three chemotherapeutic agents in the EMA course. Chemotherapy was effectively started after CR2 achievement in only 21 patients. The median duration of ATRA administration was 53 days (range, 28–95 days). In 13 cases, EMA chemotherapy was started on day 1 of ATRA therapy, and in 15 cases chemotherapy was rapidly added to ATRA in order to prevent leukostasis. In that last group, the median duration of ATRA therapy alone before starting chemotherapy was 6 days (range, 1–16 days). All patients receiving ATRA alone (one patient) or followed by EMA chemotherapy (21 patients) achieved CR after ATRA. However, three of the 21 patients receiving the chemotherapy died from toxicity. All patients, for whom EMA was started on day 1 of ATRA, achieved CR. In the group of patients in which EMA was rapidly started after ATRA, 13 achieved CR and two died from toxicity following chemotherapy. Overall, 90% of APL patients were in CR2 after induction therapy (ATRA ± EMA) (95% CI 78%–97%). Ten percent died from toxicity (95% CI 3%–21%). There were no cases of resistant disease (Table 2). During induction therapy, seven patients (14%) developed retinoic acid syndrome: two of whom were receiving ATRA plus chemotherapy, and five receiving initially ATRA alone. Outcome was favorable in all cases. Hematological toxicity of EMA therapy included cytopenias with granulocyte count below 0.5 × 109/l for a median of 33 days (range, 17–50 days) and with platelets below 50 × 109/l for a median time of 38 days (range, 14–89 days). Twenty-seven patients (54%) developed severe infection graded according to WHO system (grade 3 or more), of whom 14 had documented bacteremia and 14 had documented pneumonia.

Table 2  Efficacy of reinduction therapy after first relapse regarding prior ATRA administration in first-line therapy

Post-remission therapy

Median DFS of the entire cohort was 20 months. However, all patients did not receive the same post-remission treatment (Table 3). Eleven patients, aged less than 55 years, with an HLA-familial donor received allogeneic BMT. The median DFS of those patients was only 8.2 months (Figure 1). Eight of them died while in CR either from severe infection or from graft-versus-host (GVH) disease, one relapsed 18 months after allogeneic BMT, and two patients remained in CR2. In the 34 other patients who achieved CR2 and were theoretically scheduled for autologous transplantation (intent-to-treat group), PBSC harvest was performed in only 27 cases. Reasons for not harvesting PBSC were early relapse (one patient), technical problems during PBSC harvest (one patient), refusal of PBSC harvest (one patient), direct harvest from BM (one patient), and severe toxicity of EMA (three patients). A median of three cytaphereses was realized (range, 1–4). PBSC harvests contained a median number of 18.8 × 104 CFU-GM/kg (range, 0–294) and of 4.87 × 106 CD34+ cells/kg (range, 0–7.1). Six of the 27 harvested patients were not autografted due to early relapse (two patients), severe toxicity of EMA (three patients), or failure of cytapheresis (one patient).

Table 3  Post-remission therapy regarding reinduction schedule after first relapse and prior ATRA administration in first-line therapy
Figure 1
figure1

 Kaplan–Meier plots of DFS (autologous vs allogeneic transplant).

Twenty-two patients were actually autografted. Their median age was 48 (range, 23–65 years). Seventeen of them received autologous PBSCT, one of whom was performed after CD34+ cell selection, and five received autologous BMT (one of whom was directly harvested from BM), three of whom were performed from BM purged with mafosfamide.20 Nine of the patients neither allografted nor autografted received maintenance chemotherapy by either mini-EMA regimen13 (mitoxantrone 12 mg/m2 and etoposide 200 mg/m2 on day 1 and cytarabine 80 mg/m2/day from days 1 to 5) (one patient), or a combination of 6-mercaptopurine and methotrexate with (four patients) or without ATRA (four patients).11 Three patients did not receive any consolidation therapy: one patient relapsed before harvesting, one patient relapsed after harvesting but before autologous PBSC transplant, one patient did not receive any post-induction therapy because of persistent severe toxicity after EMA chemotherapy. The 3-year DFS rate of the intent-to-treat group was 63% (Figure 2). The 3-year DFS rate of patients who received only maintenance therapy was 51%.

Figure 2
figure2

 Kaplan–Meier plots of DFS (intent-to-treat) group.

When considering only the 39 patients previously treated by ATRA in first-line therapy, the 3-year DFS rate after CR2 was 54%. The median DFS of the seven patients receiving allogeneic BMT was only 7.1 months. PBSC harvest was performed in 23 cases. Nineteen patients were actually autografted (Table 3). The 3-year DFS rate of the intent-to-treat group was 66%.

Efficacy of autologous transplantation as post-remission therapy

Cryopreserved cells containing a median number of 41.5 × 104 CFU-GM/kg (range, 2–294) and 5.02 × 106 CD34+ cells/kg (range, 2.1–7.1) were reinfused at transplantation. Different conditioning regimens were used before autologous SCT including cyclophosphamide plus TBI (16 patients), busulfan plus melphalan (three patients), and busulfan combined with cyclophosphamide (three patients). Engraftment was obtained after a median of 13 days for granulocytes (range, 8–19 days) and a median of 18 days for platelets (range, 13–210+ days) after autologous PBSCT, and after a median of 48 days for granulocytes (range, 14–68 days) and a median of 31 days for platelets (range, 16–47 days) after autologous BMT. Transplant-related mortality was observed in two cases: one patient died from cardiomyopathy related to cyclophosphamide and one patient from veno-occlusive disease. The 3-year DFS rate of patients actually autografted was 77% (Figure 1). Only three of the 22 patients who received autologous transplantation (two PBSCT and one purged BMT) have relapsed (5.2 months, 6.2 months, and 11 months after transplantation). Among the 17 autografted patients still in CR2, nine patients have already reached a CR2 longer than CR1 at a median follow-up of 23.5+ months (range, 8.8+–43.3+ months). Six autografted patients were analyzed for residual disease on harvest samples and nine autografted patients were analyzed for residual disease after autologous transplantation (Figure 3). After transplantation, eight of the nine patients tested by RT-PCR are currently in ongoing molecular remission at a median time of 10 months from autologous transplantation (range, 4–28 months) (Figure 3). The only patient with positive PCR after transplantation relapsed and died a few months later. All patients tested immediately after EMA chemotherapy were PCR negative. RT-PCR analyses harvested PBSC was negative in all harvests in two cases, and negative in at least one harvest in the four other cases (Figure 3).

Figure 3
figure3

 Monitoring of minimal residual disease by RT-PCR of PML/RARα.

When considering only the 19 autografted patients previously treated by ATRA in first-line therapy, the 3-year DFS rate after CR2 was 79%. Cryopreserved PBSC containing a median number of 70.22 × 104 CFU-GM/kg (range, 2–294) and of 5.02 × 106 CD34+ cells/kg (range, 2.1–7.1) were reinfused at autologous PBSCT (14 patients). Cryopreserved BM cells containing a median number of 16.81 × 104 CFU-GM/kg (range, 11.8–24.02) and of 5.52 × 106 CD34+ cells/kg (range, 2.15–6) were reinfused at autologous BMT (five patients). Only two patients have relapsed. Among the 17 patients still in CR2, seven patients have already reached a CR2 longer than CR1.

Discussion

Several reports have shown that APL patients initially treated with chemotherapy alone who relapse can, in a large proportion, be durably salvaged by ATRA combined with chemotherapy, and possibly intensification with allogeneic or autologous SCT. However, the outcome of patients relapsing after a first-line treatment that included ATRA is not known. Likewise, a retrospective survey21 indicated that about 45% of M3 patients reaching transplant, whether allogeneic or autologous BMT, in second CR were likely to be cured. However, those results were obtained before the ATRA era. The main objective of our study was to evaluate the safety and efficacy of stem cell transplantation as consolidation therapy in relapsed APL patients who had initially received ATRA (allogeneic BMT or autologous SCT depending on the presence or not of an identical sibling donor).

This intensive consolidation treatment was administered after an induction therapy combining ATRA, known as the treatment of choice in APL,34 with a timed sequential chemotherapy that has previously shown to be a very effective regimen in refractory and relapsed AML patients.13 Previous retrospective studies have shown that ATRA could induce a high CR rate in first relapse APL even in case of preliminary treatment with ATRA provided relapse occurred at least 5 to 6 months after discontinuation of the drug.67 This was confirmed in the current trial in which all patients treated initially by ATRA alone achieved a second CR. The occurrence of relapses with resistant clones was not observed among this subgroup of patients derived from the French APL trials. Of note is that, in our experience of APL patients treated with ATRA combined with chemotherapy as first-line therapy, relapse rarely occurs less than 6 months after CR achievement. ATRA had therefore been generally discontinued at least 6 months before relapse. EMA chemotherapy could be administered in all but one patient. Toxicity of EMA chemotherapy explained to a large extent why only 73% of the patients achieving a CR received the assigned intensive treatment and only 63% of patients having cytapheresis underwent autologous stem cell transplant. Indeed, the rate of severe toxicity (most particularly infectious complications) after EMA chemotherapy was relatively high. Toxicity of WHO grade more than 2 following EMA therapy was observed in 23% of cases and did not compare favorably to the 8% previously reported by Stein et al22 with high-dose cytarabine in AML from all subtypes. Failure of harvesting could be exceptionally related to prior treatment by ATRA and early intensification chemotherapy. On the other hand, early intensification chemotherapy by EMA prior to cell harvesting may play an important role in reducing the tumor burden before PBSC collection (‘in vivo purging’). This is suggested by RT-PCR analysis which frequently remains positive after ATRA alone and induction standard chemotherapy, probably due to a combination of residual disease and maturing myeloid cells that still express PML/RARα mRNA, whilst the majority of patients tests PCR negative following completion of consolidation chemotherapy.23 All patients but one tested after timed sequential chemotherapy were, in our study, PCR negative for PML/RARα in their pre-transplant marrow.

In the current study, median DFS was not reached for patients who actually underwent PBSCT or ABMT and 3-year survival was at 77%. Those results were much better than those reported by the European survey of bone marrow transplantation in APL regarding patients treated before the ATRA era,21 and tend to compare favorably with those of more recent studies using less intensive regimens.2425 Another interesting point was the comparison between lengths of first and second CR duration in autografted patients. This confirm that it might be appropriate to adopt more aggressive protocols in relapsing patients despite the easy CR2 achievement with the combination of ATRA and chemotherapy. In contrast with a previous study, we did not find any difference in terms of CR achievement as well as of CR2 duration between patients previously treated with ATRA and those who did not.26 Some centers have proposed to harvest and to cryopreserve bone marrow or peripheral stem cell in first CR after completion of 3 months of maintenance ATRA therapy with the aim to use those cryopreserved cells after CR2 achievement.27 In spite of difficulties, in terms of realization and cost, required by these techniques, our results showing achievement of CR2 longer than CR1 suggest the use of very intensive chemotherapy in first-line therapy to obtain ‘in vivo purging’ before harvesting and consequently an unnecessary high-risk of treatment-related toxicity in a patient population known for its overall good prognosis.

The best choice for autologous transplantation is still controversial. Rapid hematopoietic reconstitution is observed with auto-transplantation using G-CSF-mobilized PBSC.28 PBSC transplantation is linked to faster neutrophil and platelet recovery than BM transplantation. A slow hematologic recovery would be an even more critical issue if, as suggested by the results of the European survey,29 purged marrow was to be preferred over PBSC. The contribution of residual malignant cells contaminating the autologous graft with the occurrence of post-transplant relapse is still unclear. The place of molecular monitoring in the prediction of outcome following transplantation procedures performed in CR2 is still discussed and has been recently reviewed by Grimwade.30 In our six patients tested on harvested samples, two showed no contamination by PML/RARα rearrangement, while in the other cases at least one sample was contaminated. Among those last patients, one died from conditioning regimen toxicity, but two of the three others obtained a second CR duration longer that the first one (patients 3 and 4). As in a previous report,31 prolonged clinical and molecular remission experienced post-transplant suggests that autologous PBSC infusion is still worthy of consideration for patients with APL in spite of the detection of PML/RARα-positive cells in the PBSC collections. However, determination of the right time for harvesting is certainly an important point as suggested in other hematological diseases.32 The fact that 80% of APL blasts are negative for CD34 antigen33 suggests a possible role for autologous transplantation using circulating progenitors collected after CD34+ selection.

Contrasting with the encouraging data regarding autologous SCT, the results of allogeneic BMT in relapsing APL patients achieving CR2 were very disappointing. Although our series of allografted patients was too small to give definitive conclusions, our results tend to demonstrate that this type of post-remission treatment is too toxic after salvage therapy including ATRA and EMA intensive chemotherapy. The use of a very intensive chemotherapy before transplantation could be responsible for the higher mortality rate observed after allogeneic BMT.34 Furthermore, administration of intensive chemotherapy could adversely influence prognosis by increasing the time from diagnosis of relapse to transplant.35

The use of RT-PCR as a means of detecting minimal residual disease theoretically allows a real-time determination of the effects of treatment administered. RT-PCR of the PML/RARα fusion gene has proved extremely useful for sensitive detection of minimal residual disease363738 and may predict relapse in APL patients in hematologic CR.242539 As a consequence, several investigators have adopted the term of molecular remission as a more advanced therapeutic goal in this disease.4041 In our study, preliminary results regarding detection of PML/RARα by a RT-PCR assay after autologous PBSCt are encouraging and tend to confirm that autologous transplantation in APL achieving a second CR is likely to result in prolonged clinical and molecular remissions.

Although the best strategy for salvage therapy in APL has not been defined, autologous BMT or autologous PBSCT in an ATRA-induced second CR, using PCR-negative stem cells, may be the safest, most widely applicable, and most effective approach. A recent study suggests that early administration of salvage therapy at the time of molecular relapse is advantageous in APL.41 Additional options for salvage therapy including arsenic trioxide, known as more potent than ATRA for inducing molecular remission,40 could also probably be useful here,42 as well as the use of ATRA therapy post-transplant39 and new modalities of autologous SCT.

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Acknowledgements

This work was supported by PHRC 1995 (CHU Lille).

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Correspondence to X Thomas.

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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. Leukemia 14, 1006–1013 (2000). https://doi.org/10.1038/sj.leu.2401800

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Keywords

  • relapse
  • acute leukemia
  • acute promyelocytic leukemia
  • stem cell transplantation

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