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© 2003 American Society for Clinical Oncology Combined Treatment With Arsenic Trioxide and All-Trans-Retinoic Acid in Patients With Relapsed Acute Promyelocytic Leukemia
From the Department and Institut of Hematology, Hôpital Saint-Louis; Department of Biochemistry-Toxicology, Hôpital Fernand Widal; Department of Hematology, Hôpital Necker; Etablissement Pharmaceutique des Hôpitaux de Paris; and Délégation à la Recherche Clinique, Paris, France. Address reprint requests to Hervé Dombret, Hôpital Saint-Louis, Service Clinique des Maladies du Sang, 1 avenue Claude Vellefaux, 75010 Paris, France; email: herve.dombret{at}sls.ap-hop-paris.fr.
Purpose: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. Patients and Methods: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. Results: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. Conclusion: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.
THE t(15;17)(Q22;Q21) translocation that characterizes acute promyelocytic leukemia (APL) encodes an oncogenic chimeric promyelocytic leukemia (PML)–retinoic acid receptor alpha (RAR  ) protein involving RAR.1 The use of all-trans-retinoic acid (ATRA) as a differentiating agent has significantly improved the outcome of APL patients.2–4 European and American phase III trials have established the current standard front-line therapy, which combines ATRA with anthracycline-based chemotherapy for remission induction followed by consolidation chemotherapy and ATRA-containing maintenance.5–10 The ability to detect PML-RAR mRNA by reverse transcription polymerase chain reaction (RT-PCR) represents a useful tool to monitor the efficacy of a novel therapeutic approach. When used at the 10-4 sensitivity level, persistent positive RT-PCR after the consolidation phase strongly predicts hematologic relapse.11 In patients relapsing after ATRA-containing front-line treatment, there is still no consensus on the best approach for salvage treatment. ATRA can be administered again, usually in combination with more intensive chemotherapy.12 However, this approach is hampered by numerous acquired mechanisms of resistance to ATRA,13 especially in early relapsing patients. In addition, the safety profile of salvage chemotherapy may be considered as not acceptable in some patients, such as patients eligible for hematopoietic stem-cell transplantation (HSCT) in second complete remission (CR).
Arsenic therapy has been used for decades by Chinese investigators to treat APL patients.14,15 More recently, arsenic trioxide (As2O3 or ATO) has been shown to be an effective agent in patients with relapsed APL.16–22 In the United States study,21 ATO has been demonstrated to induce 85% hematologic and 79% molecular CR rates when used as a single agent. ATO may act on APL cells through several mechanisms, including induction of differentiation and/or apoptosis, growth inhibition, and angiogenesis inhibition.23–28 Like ATRA, ATO triggers the degradation of the PML-RAR
Study Design All patients with APL in first or subsequent relapse were eligible for the study if they were aged 12 years or more and not presenting visceral contraindication to arsenic therapy. All patients must have been previously treated with ATRA and anthracycline-based chemotherapy. The study was approved by the Ethics Committee of Hôpital Pitié-Salpêtrière (Paris, France), and all patients gave signed informed consent. Patients were randomly assigned to receive either ATO alone or ATO in combination with ATRA. ATO was manufactured by the Pharmacie Centrale des Hôpitaux de Paris (Paris, France). The formulation process was analytically (ie, research of oxidative forms) and biologically (ie, efficiency on cellular culture) validated. The stability of the ATO was re-evaluated every 6 months, and it proved to be stable for more than 4 years. ATO was administered at the dosage of 0.15 mg/kg/d by a 3-hour intravenous infusion. To prevent potential arsenic-related neurotoxicity, all patients received vitamin B1 (250 mg/d) and clobazam (10 to 30 mg/d) during treatment. For the induction cycle, ATO was administered for a maximum of 56 days, until CR achievement, severe toxicity (grade 2 to 4, depending on the organ concerned), or the arsenic serum concentration’s reaching 10-5 M or greater. After three patients had been included, the response-based stopping criteria were amended to stop ATO administration 7 days after bone marrow blast clearance. ATRA was administered at a dose of 45 mg/m2/d orally starting on day 1 of ATO administration until CR achievement. In patients presenting clinical symptoms of a treatment-induced differentiation syndrome,38–40 dexamethasone was initiated at a dose of 10 mg/12 hours for at least 3 days. In patients presenting a WBC count of more than 30 x 109/L (either at baseline or during therapy), chemotherapy consisting of 3 consecutive days of daunorubicin (60 mg/m2/d) or amsacrine (90 mg/m2/d) was initiated. Given the difficulty to demonstrate any significant improvement in outcome in the currently limited population of patients with relapsing APL, a potential surrogate marker was chosen as primary objective. It was observed in mice treated with the dual treatment that a significant reduction in the time necessary to reach CR was associated with a prolonged survival,34 and thus, the primary objective of this study was a reduction by 2 weeks of the time needed to obtain a hematologic CR. The study was initiated in September 1998 and terminated in January 2002 because the results of the first planned interim analysis (with a total of 20 patients included) showed no anticipated benefit of simultaneous ATO/ATRA administration. Secondary objectives were safety and molecular response. The results reported here are based on follow-up data as of September 5, 2002.
Response Criteria
Postremission Therapy
Pharmacokinetic (PK) Studies Residual serum arsenic concentrations were determined just before the injection, namely 21 hours after the end of the previous injection. Arsenic concentrations were evaluated at baseline, day 5, and day 13, and then once a week until the end of each cycle. In addition, a 24-hour PK study was performed in three patients (patients 1101, 1103, and 1105) at day 1, day 5, and day 28 of the induction cycle. Serum peak concentrations were measured 3 hours after the onset of ATO infusion (ie, at the end of ATO infusion), and the peak magnitude was calculated as the difference between peak and residual concentrations. Total arsenic was determined in serum by electrothermal atomic absorption spectrometry on a 5100 spectrometer with Zeeman effect background correction system (Perkin Elmer, Les Ulis, France). An arsenic electrodeless lamp operating at 300 mA and a furnace with an integrated platform were used. Samples were diluted in a 1:1 ratio with a solution containing nickel and palladium as matrix modifiers. Calibration was performed on an arsenic-free plasma, and peak area was used for calculations. The detection limit was 0.010 µmol/L, and reproducibility was 4% at 0.3 µmol/L.
Safety Evaluation
Statistical Methods
Patient Characteristics
Response to Induction Therapy The hematologic CR rate was 80% (16 out of 20 patients; eight patients in each treatment group; Table 3  ). Two patients from the ATO group died early during the induction cycle. Patient 1109, who had a previous history of CNS hemorrhage, died at day 14 because of a septic shock with seizures. Patient 1113 died at day 16 because of an ATO-induced differentiation syndrome with hyperleukocytosis, which did not respond to dexamethasone and amsacrine administration. Two patients from the ATO/ATRA group were alive with resistant APL after the induction cycle. In the 16 patients who reached CR, the median time necessary to reach marrow blast clearance was 28 days (range, 28 to 42 days), and the median duration of the ATO ± ATRA treatment was 35 days (range, 32 to 56 days). The median time necessary to reach hematologic CR was 42 days in both treatment groups (P = .58, by the Mann-Whitney test). The Kaplan-Meier cumulative percentage of CR was similar in both treatment groups (P = .74, by the log-rank test). There was no evidence for earlier morphologic changes induced in APL cells by the combined treatment compared with ATO alone (Fig 1). In addition, no difference was observed in the correction of the coagulopathy in the three ATO/ATRA patients (patients 1104, 1112, and 1116) compared with the four ATO patients (patients 1102, 1109, 1119, and 3120) with baseline low fibrinogen levels (not shown). Finally, three out of 16 CR patients reached a molecular remission after the first cycle (patients 1111 and 3120 from the ATO group and patient 1112 from the ATO/ATRA group). These three patients had received additional amsacrine for hyperleukocytosis occurring during treatment. Patients 1103 and 1107 (who were not exposed to ATRA for 11 and 22 months, respectively, at the time of ATO/ATRA treatment initiation) did not seem to have a better response than the remaining 14 CR patients.
Postremission Therapy Ten CR patients received consolidation with either one (n = 1) or two (n = 9) additional ATO ± ATRA cycles (Table 1  ). No hematologic relapse occurred in these patients during the consolidation period. As indicated in Table 4, all of these patients had positive RT-PCR after the first consolidation cycle (including patients 1111 and 1112 who were RT-PCR–negative after an induction cycle that included amsacrine); whereas two of the eight patients tested after the second consolidation cycle were RT-PCR–negative. Patient 1111, who was RT-PCR–positive after two consolidation cycles, became RT-PCR–negative during ATO-containing maintenance therapy.
Overall, eight CR patients received autologous (n = 1) or allogeneic HSCT (n = 7, including two pheno-identical and one nonmyeloablative allogeneic HSCT; Table 1 ). Two patients underwent transplantation immediately after CR achievement with ATO/ATRA. One patient underwent transplantation after one consolidation cycle with ATO/ATRA. The remaining five patients underwent transplantation after two consolidation cycles with ATO ± ATRA. No patient received maintenance therapy after HSCT. At the time of analysis, all eight patients were still alive in CR with the exception of patient 1112, who died from early relapse after a nonmyeloablative HSCT procedure, and patient 1115, who relapsed 16 months after autologous HSCT.
PK Studies
Patient Outcome Overall survival was similar in both treatment groups (Fig 3A ). With a median actuarial follow-up of 21 months, the estimated 2-year overall survival was 59% (95% confidence interval, 35% to 77%). Of the 16 CR patients, five relapsed and five died (including four deaths from relapse and APL progression and one death in CR from a sepsis occurring after consolidation chemotherapy). Among the nine patients with available follow-up data and still alive in CR, six patients received allogeneic HSCT and are all still RT-PCR–negative with a median follow-up of 18 months (range, 10 to 26 months) after HSCT (patients 1103, 1105, 1107, 1110, 1114, and 1118); two patients converted to RT-PCR–negative after receiving additional chemotherapy (patients 1106 and 3120); and the remaining patient was the patient who converted to RT-PCR–negative during ATO-containing maintenance therapy (patient 1111). DFS was similar in both patient groups (Fig 3B). At 2 years, the estimated DFS was 59% (95% confidence interval, 29% to 80%).
Adverse Events The most common adverse events possibly or probably related to the treatment are listed in Table 5 . There was no difference in the incidence of these events between both treatment groups, with the possible exception of headaches, which were more frequently observed in the ATO/ATRA group. QT prolongation was transient and moderate. Elevation in serum transaminases was transient and did not exceed grade 2, except in patient 1113 who died from a differentiation syndrome. Peripheral neuropathy was rare, mild, and transient. The most severe adverse event was the APL-related differentiation syndrome, with fever, gain in weight, edema, hypotension, and dyspnea, associated or not with induced hyperleukocytosis. Seven patients developed this syndrome (three from the ATO group and four from the ATO/ATRA group); in six of the patients, the syndrome was associated with hyperleukocytosis more than 30 x 109/L requiring additional chemotherapy according to the protocol (Table 2). Major pulmonary symptoms leading to respiratory failure were observed in three patients (patients 1111, 1112, and 1113) and were responsible for one death (patient 1113). Differentiation syndrome occurrence was markedly related to high baseline WBC counts compared with no differentiation syndrome occurrence (median WBC, 9.6 x 109/L v 2.2 x 109/L, respectively; P = .004, by the Mann-Whitney test). With the exception of patient 1109 who died from a septic shock, there were no severe or life-threatening infectious events. However, five patients without previous history of herpes zoster (patients 1104, 1106, 1115, 1118, and 3120) developed a herpes zoster infection, either during the induction cycle (patients 1104, 1106, and 3120) or during the first consolidation cycle (patients 1115 and 1118), without relationship to dexamethasone administration.
Results of the present study confirm that ATO is safe and effective to induce CR in patients with relapsing APL. The 80% CR rate is in accordance with previously reported CR rates.16–22 The safety profile of ATO compares favorably with intensive chemotherapy. In vivo, several observations argued for a differentiating rather than a pro-apoptotic effect of ATO. Morphologic APL cell changes, time necessary to reach blast clearance and remission criteria, and incidence of a differentiation syndrome were as previously reported with ATRA when used as a single agent.45,46 In addition, PK results showed that residual serum arsenic levels did not exceed the 10-6 M level in most patients. As long as serum concentration may be considered as representative of bone marrow concentration, which has been not evaluated yet, concentrations attainable in vivo (10-7 to 10-6 M) are not high enough to induce pro-apoptotic effects in vitro.23 Thus, it is likely that ATO-induced degradation of the PML-RAR fusion protein, already achieved at 10-7 M, represents the major mechanism in vivo. The quality of CR obtained after ATO salvage treatment remains an open question. This is important because of the postremission treatment that may be proposed to these patients. For instance, the result of autologous HSCT in second CR is likely to depend on the minimal residual disease level. Even if the Italian group has reported that RT-PCR negativity at the 10-4 level seems to be associated with a good posttransplant outcome,47 the minimal level required in patients with APL in second CR still has to be determined. In the United States study, using a 10-4 sensitivity level, the molecular response rate was 48% after one ATO cycle.21 In both the Kwong et al22 study and present study using a higher sensitivity level (10-5 to 10-6), the molecular response rate was 0%, at least in patients who did not receive simultaneous chemotherapy. In this respect, the United States study results seem to indicate that repeated cycles of ATO may be beneficial because the molecular response rate reached 86% after the second ATO cycle.21 This is not so clear in the present study. Even if three patients converted to RT-PCR–negative after the third ATO ± ATRA cycle or during ATO maintenance, two patients who resulted as RT-PCR–negative after the first ATO (+ dexamethasone/amsacrine) ± ATRA cycle converted to RT-PCR–positive after one ATO ± ATRA consolidation cycle. This might represent a variability in RT-PCR technique in patients with persistent 10-6 to 10-5 minimal residual leukemia. This comparative study failed to demonstrate any synergistic effect of the ATO/ATRA combination in vivo. Time necessary to reach blast clearance, correction of APL-related coagulopathy, CR rate, time necessary to reach CR, molecular response, and outcome of CR patients were similar in both treatment groups. One might argue that most patients selected to enter the study were probably clinically resistant to ATRA because median time from the last ATRA exposure was only 5 months. Unfortunately, in vitro sensitivity to ATRA was not evaluated at baseline in these patients. However, the two patients who were not exposed to ATRA for 11 and 22 months before inclusion did not present a better response to the dual treatment. However, the population of patients included in the present study is probably representative of the current population of patients with relapsing APL. Thus, it is tempting to conclude that ATO/ATRA therapy is not superior to ATO therapy alone in this patient population. Different results might, nevertheless, be observed in patients with newly diagnosed APL. If concomitant administration of ATRA does not improve the rapidity and quality of response to ATO, other agents may play a role in this setting. Subsequent chemotherapy with idarubicin has been reported as being effective in reaching RT-PCR negativity in patients with persistent minimal residual disease after one ATO cycle.22 In the present study, simultaneous administration of chemotherapy given for treatment-induced hyperleukocytosis also seems able to improve the response to ATO ± ATRA. The effect of arsenic on PML and other proteins targeting to nuclear bodies may provide a biologic rationale for increased susceptibility to chemotherapy-induced cell death.48 However, we have recently reported that concomitant administration of theophylline, a cyclic adenosine monophosphate (cAMP) signaling activator, enhances ATO-induced APL cell differentiation and accelerates restoration of normal hematopoiesis in vivo.49 Therefore, combined administrations of ATO plus chemotherapy and ATO plus theophylline may be evaluated to improve the response to ATO.
The following persons participated in the APL As98 study either directly or by referring patients to the study centers: T. Bibi Triki, J.C. Brouet, B. Cassinat, S. Chevret, C. Chomienne, M.T. Daniel, L. Degos, H. de Thé, A. Devergie, A. Do, H. Dombret, H. Espérou, J.P. Fermand, E. Gluckman, G. Lebbé, O. Maarek, M. Malphettes, X. Mariette, J.M. Micléa, D. Réa, P. Ribaud, P. Rousselot, B. Royer, F. Sigaux, G. Socié, M.L. Scrobohaci, and A.L. Taksin (Hôpital Saint Louis, Paris); A. Buzyn, E. Delabesse, R. Delarue, O. Hermine, E. MacIntyre, F. Lefrère, F. Valensi, and B. Varet (Hôpital Necker, Paris); J. Poupon (Hôpital Fernand Widal, Paris); S. Choquet, N. Dhedin, V. Leblond, M. Renaud, L. Sutton, and J.P. Vernant (Hôpital Pitié Salpétrière, Paris); D. Blaise, R. Bouabdallah, C. Faucher, J.A. Gastaut, D. Maraninchi, A.M. Stoppa, and N. Vey (Institut Paoli Calmettes, Marseille); C. Cordonnier, M. Kuentz, and C. Pautas, (Hôpital Henri Mondor, Créteil); D. Fière, M. Michallet, and X. Thomas (Hôpital Ed. Herriot, Lyon); M. Attal, X. Carles, A. Huynh, G. Laurent, J. Pris, C. Recher, and F. Rigal-Huguet (Hôpital Purpan, Toulouse); A. Delmer, O. Legrand, J.P. Marie, B. Rio, and A. Vekhoff (Hotel Dieu, Paris); C. Gardin, J.J. Kiladjian, and J. Brière (Hôpital Beaujon, Clichy); V. Ribrag and J.H. Bourhis (Institut Gustave Roussy, Villejuif); B. Corront and C. Martin (Centre Hospitalier, Annecy); D. Bordessoule, A. Jaccard, L. Remenieras, and P. Turlure (Hôpital Dupuytren, Limoges); M. Boasson, M. Gardembas, N. Ifrah, and M. Hunault (Centre Hospitalier Universitaire, Angers); J.M. Boulet and S. Letortorec (Hôpital La Source, Orléans); A. Tibi (Pharmacie Centrale des Hôpitaux de Paris, Paris); and P. Chaumet-Riffaud, P. Cimerman, and S. Solbes-Latourette (Délégation Regionale á la Recherche Clinique, Paris, France).
We thank Wim van Putten for providing a Stata package with facilities for Kaplan-Meier survival curves.
Supported by grant no. P970708 and AOM 97088 from Le Programme Hospitalier de Recherche Clinique, Ministère de l’Emploi et de la Solidarité, France.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
