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Therapy-Related Acute Promyelocytic Leukemia

From the Service des Maladies du Sang, Lille; Hématologie, Hôpital du Bocage, Dijon; Hématologie, CHU, Strasbourg; Hématologie, CHU, Lyon; Hématologie, Hôpital Victor Provo, Roubaix; Hématologie, CHU, Vandoeuvre; Médecine Interne, Hôpital de l’Archet, Nice; Hôpital Jean Minjoz, Besançon; Service Hématologie, CHU, Toulouse; Service Hématologie, Hôtel Dieu and Myosotis 3, Hôpital St Louis, Paris; Service Hématologie, Centre Henri Becquerel, Rouen; and Institut Paoli Calmette, Marseille, France; Hospital University La Fe, Valencia; Hospital Central Asturias, Oviedo; Hospital University, Salamanca; Hospital Ramon y Cazal, Madrid; Hospital Puerta del Mar, Cadiz; and Hospital Clinic, Barcelona, Spain.

Address reprint requests to P. Fenaux, MD, PhD, Service d’Hématologie Clinique, Hôpital Avicenne Paris 13 University, 93000 Bobigny, Paris, France; email: pierre.fenaux{at}avc.ap-hop-paris.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: To analyze patient cases of therapy-related acute promyelocytic leukemia (tAPL), occurring after chemotherapy (CT), radiotherapy (RT) or both for a prior disorder, diagnosed during the last 20 years in three European countries.

Patients and Methods: The primary disorder and its treatment, interval from primary disorder to tAPL, characteristics of tAPL, and its outcome were analyzed in 106 patients.

Results: Eighty of the 106 cases of tAPL were diagnosed during the last 10 years, indicating an increasing incidence of tAPL. Primary disorders were predominantly breast carcinoma (60 patients), non-Hodgkin’s lymphoma (15 patients), and other solid tumors (25 patients). Thirty patients had received CT alone, 27 patients had received RT alone, and 49 patients had received both. CT included at least one alkylating agent in 68 patients and at least one topoisomerase II inhibitor in 61 patients, including anthracyclines (30 patients), mitoxantrone (28 patients), and epipodophyllotoxins (19 patients). Median interval from primary disorder to tAPL diagnosis was 25 months (range, 4 to 276 months). Characteristics of tAPL were generally similar to those of de novo APL. With treatment using anthracycline-cytarabine–based CT or all-trans-retinoic acid combined with CT, actuarial survival was 59% at 8 years.

Conclusion: tAPL is not exceptional, and develops usually less than 3 years after a primary neoplasm (especially breast carcinoma) treated in particular with topoisomerase II–targeted drugs (anthracyclines or mitoxantrone and less often etoposide). Characteristics and outcome of tAPL seem similar to those of de novo APL.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
THERAPY-RELATED MYELODYSPLASTIC syndromes (tMDS) and acute myeloid leukemia (tAML) have been increasingly described during the last 30 years after neoplastic (or less often nonneoplastic) disorders treated by chemotherapy (and radiotherapy to a lesser extent).¹ Until the early 1980s, most illnesses developed 3 to 10 years after prolonged use of alkylating agents, and presented as tMDS with complete or partial deletion of chromosome 7 or 5, often with other cytogenetic abnormalities (classic tMDS-tAML).² More recently, tAML has been described after the use of topoisomerase II inhibitors (epipodophyllotoxins such as etoposide [VP16] or teniposide [VM26], and anthracycline or anthracene dione). These illnesses often developed early (12 to 36 months) after onset of chemotherapy, usually had no preleukemic phase, and showed normal karyotype or cytogenetic rearrangements specific to de novo AML.² In the latter, 11q23 rearrangements predominated, whereas t(8;21), inv(16), and t(15;17) were less often seen, and other rearrangements were rarely observed.^1,3 tMDS and tAML have also been reported after autologous stem-cell transplantation.⁴ In addition, prolonged use of hydroxyurea in myeloproliferative disorders might increase the patients’ risk of progression to AML.⁵

Acute promyelocytic leukemia (APL) is a specific subtype of AML characterized by the morphology of blasts (hypergranular cells with many Auer rods),^6,7 t(15;17) translocation leading at the molecular level to promyelocytic leukemia–retinoic acid receptor alpha (PML-RAR) rearrangement,⁸ major coagulopathy,⁹ and specific differentiation of blast cells by all-trans-retinoic acid (ATRA).^10–12 APL generally occurs de novo, without known cause. Occurrences of tAPL after chemotherapy for a neoplastic (or less often a nonneoplastic disorder) have been increasingly described, however.^13–36 Recently, an international workshop on therapy-related MDS and AML reported 41 patients with tAPL.³⁷

We report on 106 patients with tAPL observed in three European countries during the last 20 years, and analyze their characteristics (previous tumor, previous drugs, hematologic features) and outcome.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
In this retrospective analysis, information on patients with APL occurring after chemotherapy and/or radiotherapy for a previous neoplasm or nonmalignant disorder, and diagnosed between 1982 and 2001, were collected in French, Spanish, and Belgian centers belonging to our European APL group (excluding the French centers that accrued tAPL patients in the International Workshop on tMDS and AML).³⁷ To obtain patient information, questionnaires were sent to all participating centers. Patients with APL that occurred after a neoplasm treated by surgery or hormonal therapy alone were excluded. Likewise, we excluded patients with APL that occurred during the evolution of myeloproliferative disorder (MPD) or myelodysplastic syndrome (MDS), even if they had been treated with chemotherapy, because natural progression of MDS or MPD to APL has been reported in rare instances.³⁸

For patient inclusion, diagnosis of APL had to be confirmed by the presence of t(15;17) translocation or of PML-RAR rearrangement by molecular biology. In some patients without cytogenetic and molecular biology material available for analysis, diagnosis of APL was confirmed by review of the initial marrow slides by two independent morphologists. For each patient, review of primary diagnosis and type and amount of chemotherapy and radiotherapy received for the first disease was made. Before 1990, treatment of APL combined an anthracycline and cytarabine (Ara-C) with cumulative doses of daunorubicin during induction ranged from 160 to 360 mg/m², followed by anthracycline–Ara-C consolidation therapy, without maintenance, according to ongoing multicenter trials. After 1990, patients generally received ATRA combined with or followed by anthracycline (with or without Ara-C) chemotherapy, generally for three courses; many patients were included in APL 90, 91, 93, and 2000 French trials,^39–41 and LAP 96 and 99 Spanish trials.^42,43 Patients included in APL 90 and 91 trials received no maintenance. In the APL 93 trial, patients were randomly assigned to receive no maintenance, maintenance with chemotherapy (mercaptopurine and methotrexate), intermittent ATRA, or both, whereas in APL 2000, leucemia aguda promielocitica (LAP) 96, and LAP 99, both chemotherapy and ATRA were administered to all patients. Other patients were treated according to those multicenter trials but without inclusion.

Survival was measured from diagnosis of APL using the Kaplan and Meier method. Twenty of the 106 patients with tAPL reported here were included in previous studies; that is, patients 1 to 10, 15 to 18, 61 to 63, and 80 to 82 (Table 1).^24,44

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

Initial Neoplasm or Nonneoplastic Disorder and Its Treatment
tAPL occurred after a primary neoplasm in 104 patients and after a nonneoplastic disorder in two patients (multiple sclerosis and chronic polyradiculoneuritis, respectively; Table 2). The primary neoplasm was breast carcinoma in 60 patients (57%), non-Hodgkin’s lymphoma (NHL) in 15 patients (14%), other solid tumors in 25 patients (24%), and other hematologic malignancies in four patients (4%). NHL was the variable histologic type. For the category of other solid tumors, 15 tumor types were represented, including prostate carcinoma in five patients and colonic carcinoma in five patients (Table 2).

Radiotherapy alone included external radiotherapy in 24 patients and iodine-131 in three patients; the latter had thyroid carcinoma. Chemotherapy (Table 3) included at least one alkylating agent in 68 patients, mainly cyclophosphamide (administered in 53 patients) or ifosfamide (administered in nine patients). Those two agents had always been administered as monthly or bimonthly bolus injection and not as continuous treatment. At least one topoisomerase II inhibitor had been used in 61 patients, including anthracyclines (doxorubicin, epirubicin, or daunorubicin) in 30 patients, an anthracene dione (mitoxantrone) in 28 patients, and epipodophyllotoxin (VP16 and/or VM26) in 19 patients. Notably, VP16 or VM26 had been used without an anthracycline or anthracene dione in only three patients, whereas an anthracycline or anthracenedione had been used without VP16 or VP26 in 42 patients. Three patients (patients 73, 78, and 85) had received intensive chemotherapy followed by autologous stem-cell transplantation (ASCT).

Interval From Treatment of Primary Disease to Diagnosis of tAPL
The interval from treatment of primary disease to diagnosis of tAPL ranged from 4 to 276 months (median, 25 months). The interval was less than 12 months in three patients (4, 8, and 9 months, respectively), and greater than 36 months in 29 patients. Median interval to tAPL was 24 months after breast carcinoma (range, 9 to 276 months), 29 months after NHL (range, 15 to 89 months), and 24 months after other diseases (range, 4 to 93 months). Regarding drugs received, median interval from onset of chemotherapy for the primary disorder and tAPL was 22 months after mitoxantrone, 25 months after anthracyclines, and 30 months after other drugs.

Clinical and Hematologic Characteristics of tAPL
Diagnosis of APL was retrospectively confirmed by the presence of t(15;17) translocation in 83 patients and the presence of PML-RAR rearrangement in 11 patients. In the remaining 12 patients, diagnosis was confirmed by independent review of the initial marrow slides by two investigators. Morphologically, 86 patients had typical hypergranular APL (M₃), and nine patients had the microgranular variant APL (M_3v), and no information on morphological subtype of M₃ was available for 11 patients.

Cytogenetically, of 89 patients, 83 patients had t(15;17) translocation and six patients had apparently normal karyotype. The six patients without detectable t(15;17) had PML-RAR rearrangement. Sixty-two patients [75% of the patients with t(15;17)] had isolated t(15;17) translocation and 21 patients [25% of the patients with t(15;17)] had additional chromosomal rearrangements. Additional rearrangements included complete or partial deletion of chromosomes 5 or 7 in eight patients, trisomy8 in four patients, chromosome 17 rearrangement in six patients, and involvement of chromosome 6 in three patients (Table 1).

PML-RAR rearrangement was found in the 36 patients studied. However, the breakpoint was precisely analyzed in only 20 patients, showing bcr1, bcr2, or bcr3 breakpoint in 10, three, and seven patients, respectively.

Outcome of tAPL
Six patients rapidly died, before any specific treatment was started, and treatment modalities and outcome were unknown in one patient. Sixteen patients received induction treatment with anthracycline-based chemotherapy before the ATRA era: 14 patients (87%) achieved complete remission (CR) and two patients had early death. Eighty-three patients received induction treatment with ATRA followed or not by chemotherapy: 66 patients (80%) achieved CR and 17 patients had early death. Ten of the complete remitters subsequently relapsed (five patients relapsed after chemotherapy alone and five patients relapsed after ATRA followed by chemotherapy), seven patients died from their primary tumor, one patient died from sepsis, one patient died from cardiac failure, and 61 patients remained in first CR after 2 to 120 months. Actuarial survival was 59% at 8 years.

Outcome of tAPL on the basis of treatment administered for the primary tumor was also analyzed: actuarial survival at 8 years was 68%, 59%, and 52%, respectively, in patients who had received chemotherapy alone, radiotherapy alone, or both from their primary tumor (differences not significant) and 46%, 66%, and 59%, respectively, in patients who had previously received alkylating agents, topoisomerase II inhibitors, and both (differences not significant).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
A growing number of patients with tAPL have been reported in the last few years: 77 patient cases were described in the literature, to our knowledge, before the end of 2001 (if patients 1 to 10, 15 to 18, 61 to 63, and 80 to 82 of the present series, who were already described in the literature, are not taken into account).^13–36 In addition, a recent workshop on tMDS and tAML reported 41 patients with tAPL.³⁷ Because we are not certain if some of the 41 patient cases presented by this international workshop had not been previously described in the literature, data relating to the 77 previously described patients and the 41 patients reported by this workshop are presented separately in Tables 2 and 3.

In papers published 10 or more years ago, the incidence of patients with therapy-related APL ranged from 1.7% to 5.8%.^24,45–48 In this series of tAPL patients, 26 patients were diagnosed between 1982 and 1991 and 80 patients were diagnosed between 1992 and 2001. Because the overall incidence of APL does not seem to increase, those results are compatible with either an increase in patients with tAPL or with better recognition of the disease. Indeed, some years ago, some of the occurrences of APL that developed after chemotherapy or radiotherapy for a previous neoplasm may have not been considered therapy related because they did not fit with classic features of tAML (precession by a preleukemic phase, exhibiting rearrangements of chromosome 5, 7, or both; or exhibiting tAML with 11q23 rearrangements). Conversely, at the University Hospital of Lille, France, after careful review of previous chemotherapy and radiotherapy in APL patients diagnosed between 1984 and 2000, we found a proportion of tAPL of 5% from 1984 to 1993 and of 22% from 1994 to 2000.⁴⁹ Likewise, only one in 60 patient cases with APL reported in a first series by the M.D. Anderson Cancer Center (Houston, TX) group⁴⁵ was related to therapy, compared with 14 of 113 patient cases in a subsequent series.³² These findings indicate a true increase in patients with tAPL.

In this series of 106 tAPL patients, breast carcinoma was by far the most frequent previous tumor (57%), followed by lymphoma (18%, with a large predominance of NHL compared with Hodgkin’s disease [HD]), whereas other tumor types were found with lower incidence. This distribution was different from that observed in previously published literature, in which breast carcinoma accounted for only 17% of prior tumors, lymphoma accounted for 23% (with a predominance for HD compared with NHL), and nonneoplastic disorders (Langerhans cell histiocytosis [LCH] and psoriasis) accounted for 16% of the patients (Table 2). Explanations for those differences could include the fact that our patients were generally more recently diagnosed than previously described tAPL patients and that reports came from different countries or cooperative groups. Recent years have been characterized by modifications in the treatment strategies of several neoplasms, with a larger number of breast carcinoma patients being treated with anthracycline (or anthracene dione)-based chemotherapy; fewer HD patients receiving mechlorethamine, vincristine, procarbazine, and prednisone (MOPP); and larger numbers of NHL patients receiving high-dose anthracycline-based regimens (especially in France, with a reinforced cyclophosphamide, doxorubicin, vincristine, and prednisone regimen).⁵⁰ Conversely, in some clinical trials, widespread use is made of VP16 in LCH, whereas other trials rarely use VP16. As listed in Table 2, distribution of previous tumors in the 41 patients reported by the International Workshop was rather similar to the distribution in the patients we observed.³⁷

In the 77 patients with tAPL described in the literature, previous chemotherapy with doxorubicin, cyclophosphamide (generally in combination), and VP16 (generally as single-agent chemotherapy) predominated (Table 3). Results were somewhat different in our series, with intercalating agents (anthracyclines and mitoxantrone) clearly being used more often than VP16, generally in combination with cyclophosphamide. Furthermore, in our patients, VP16 had been used without an anthracycline or mitoxantrone in only three patients, whereas an anthracycline or mitoxantrone had been used without VP16 or VM26 in 45 patients. Likewise, in the 41 tAPL patients reported by the International Workshop, previous administration of anthracyclines and mitoxantrone (n = 18) predominated over that of VP16 (n = 5).³⁷

In breast carcinomas, a large majority of tAPL in this study occurred in patients who had received an anthracycline (epirubicin or doxorubicin) or mitoxantrone, cyclophosphamide, and fluorouracil, with or without radiotherapy. Three studies^44,51–53 recently have shown that chemotherapy with an anthracycline (and more importantly, with mitoxantrone) increased the risk of tAML after breast carcinoma. Among those tAML patients, the incidence of tAPL was unexpectedly high, especially after mitoxantrone. Mitoxantrone has also been used in two patients with tAPL that occurred during the course of multiple sclerosis, including one patient in our series and one described in the literature.³³ Therefore, the large proportion of breast carcinomas as primary cancer in our series could reflect the widespread use of anthracyclines and, more importantly, mitoxantrone-based chemotherapy in this cancer in France, Belgium, and Spain during the last 10 years. On the other hand, 15 of the patients in this study were diagnosed with tAPL after breast carcinoma treated with radiotherapy alone. Because large series of breast carcinomas have shown that radiotherapy alone increased the risk of acute leukemia by a factor of only about 2,⁵⁴ and because several patients with APL have been reported after breast carcinoma treated by surgery alone,²⁵ a certain predisposition to APL may exist in patients with breast carcinoma, which is obviously increased by treatment with anthracyclines, mitoxantrone, and radiotherapy.

Another difference between our findings and previously published data was the low incidence of prior HD we observed (2%), compared with 12 of 77 (16%) in published reports. There was also a predominance of prior NHL as compared with HD in the International Workshop series³⁷ (Table 2). Reduction in the incidence of tMDS and tAML after HD has been observed during the last 10 years, to a large extent because of decreased use of the MOPP protocol; however, MOPP was mainly associated with classic tMDS and AML, which developed after a relatively prolonged interval with chromosome 5, 7, or both rearrangements.¹ Notably, five of the reported patients and one of two patients with tAPL after HD had received MOPP, with or without radiotherapy, with short latency ( 30 months) in four patients. Four other patients described in the literature had received radiotherapy alone and latency was 14 to 16 months in three of them.

The most striking difference between our report and the previously described 77 patients with tAPL was the absence of patients with tAPL after LCH in our series, whereas they accounted for 12 of 77 patients previously described in the literature. Those 12 patients were children who all had received VP16 for their disease. Cumulative doses of VP16, known to have occurred in nine of the patients, exceeded 4,500 mg/m² in all patients. In addition to those 12 patients, only one child with tAPL has been reported to our knowledge (our patient 82) after radiotherapy for a brain tumor. APL is a rare disease in children,⁵⁵ and the relatively large number of patients with APL occurring after their LCH was treated by VP16 is, therefore, striking. Haupt et al,³⁵ who reviewed the literature reports of 24 patients with AML occurring during the course of LCH, found that nine patients had APL, whereas eight of 16 AML patients reported in a registry of cancers after LCH had APL.⁵⁶ Furthermore, no tAML was observed in a French series of 348 LCH patients treated with a cumulative VP16 dose of less than 2,000 mg/m²,⁵⁷ whereas five patients with tAPL were reported in an Italian series of 241 LCH patients treated with a median cumulative VP16 dose of 5,000 mg/m².^35,58 Those findings indicate a close correlation between treatment of LCH with VP16 at high cumulative doses and development of APL in children. No occurrence of tAPL was reported after LCH by the International Workshop on tMDS and tAML.³⁷ Finally, of note is the relatively large number of patients with APL reported after bimolane and razoxane treatment of psoriasis; these patients were exclusively from China.^56,59 Both drugs are topoisomerase II inhibitors that have been associated with the development of tAML, including a large proportion of tAPL.

Median interval from treatment of primary disease to diagnosis of tAPL was 25 months, comparable to the 25 months observed in the 77 patients with tAPL described in the literature and 29 months in the 41 patients described at the International Workshop.³⁷ This confirmed the short latency of tAPL, as for other types of tAML with karyotype specific of de novo AML.^2,3

No preleukemic phase was reported in our series of 106 patients. Hematologic findings did not differ from those observed in de novo APL, as previously reported for other tAML with specific karyotype.^2,3 Cytogenetically, however, although the incidence of secondary rearrangements was similar to that observed in de novo APL (24% v 26%),⁶⁰ the type of second rearrangements was somewhat different: 85% of the patients with tAPL with additional rearrangement had involvement of chromosomes 5, 7, or 17, as compared with 12% of our de novo patients.⁶⁰ In contrast, an association with trisomy 8 was seen in 45% of our de novo APL patients versus 19% of tAPL patients. Rearrangements of chromosomes 5, 7, and 17 are typical of tMDS and tAML, and this indicates possible different pathways of leukemogenesis between tAPL and de novo APL. Conversely, 17% of the 41 tAPL patients reported by the International Workshop had additional rearrangements, including five patients with trisomy 8 and three patients with rearrangements involving chromosomes 5 or 7.³⁷

All of the patients analyzed in this study showed PML-RAR rearrangement, but the precise breakpoint on the PML gene was known in only 20 patients. Interestingly, the incidence of bcr2 (15%) and bcr3 (35%) breakpoints was higher than generally observed in AML,⁸ but the sample size was too small for any conclusions to be made. In the rare tAPL patients in whom the precise breakpoints on chromosomes 15 and 17 were studied at the DNA level, some differences were observed with de novo APL, possibly also indicating somewhat different pathogenetic mechanisms.⁶¹

Previous reports have indicated that tAML with karyotype specific of de novo AML had an outcome similar to de novo AML with the same karyotype.²² This has already been shown to be true on a smaller series of tAPL patients.^25,32 This study confirms that finding because 87% and 80% of the patients treated with chemotherapy alone (before the ATRA era) and ATRA followed by chemotherapy, respectively, achieved CR, and only 10 patients relapsed. Possibly of note, however, is that with ATRA, the CR rate was somewhat lower than in most series of de novo APL, in which it was generally in the range of 90%.⁴¹ This was apparently because of a higher incidence of early death during treatment (17 patients), to which the six deaths that occurred before onset of any treatment have to be added.

In conclusion, our findings in a large multicenter series confirm that tAPL generally develops shortly (< 3 years) after treatment of a primary neoplasm with topoisomerase II–targeted drugs (anthracyclines or mitoxantrone, and less often VP16). They also indicate an increasing incidence of tAPL over recent years, possibly because of increased use of topoisomerase II–targeted drugs. The high incidence of tAPL after breast carcinoma (our series) and LCH (in the literature) indicates a possible predisposition to APL in patients with these cancers, which is greatly increased by the use of anthracyclines or mitoxantrone, and VP16, respectively.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following centers and investigators participated in this study. France: M. Beaumont, P. Fenaux, Service des maladies du Sang, Centre Hospitalier Universiteire (CHU), N. Cambier, Médecine Interne, Hôpital Saint Vincent, Lille; P.M. Carli, Hématologie, Hôpital du Bocage, Dijon; F. Maloisel, Hématologie, CHU, Strasbourg; X. Thomas, Hématologie, CHU, Lyon; L. Detourmignies, I. Plantier, Hématologie, Hôpital Victor Provo, Roubaix; A. Guerci, Hématologie, CHU, Vandoeuvre; N. Gratecos, Médecine Interne, Hôpital de l’Archet, Nice; J.Y. Cahn, Hôpital Jean Minjoz, Besançon; F. Huguet, Service Hématologie, CHU, Toulouse; A. Vekhof, Service Hématologie, Hôtel Dieu; H. Dombret, Myosotis 3, Hôpital Saint Louis; F. Lefrère, Service Hématologie, Hôpital Necker, Paris; A. Stamatoulas, Service Hématologie, Centre Henri Becquerel, Rouen; T. Lamy, Service Hématologie, Hôpital de Pontchaillou; M. Gardembas, Service Hématologie, Hôpital de Pontchaillou, Rennes; M. Gardembas, Service Hématologie, CHU, Angers; A. Sadoun, Service Hématologie, CHU, Poitiers; M. Janvier, Centre René Huguenin, Saint Cloud; and A.M. Stoppa, Institut Paoli Calmette, Marseille. Spain: M. Sanz, Hospital University La Fe, Valencia; C. Rayon, Hospital Central Asturias, Oviedo; J. San Miguel, Hospital University, Salamanca; J. Odriozola, Hospital Ramon y Cazal, Madrid; F. Capote, Hospital Puerta del Mar, Cadiz; and J. Esteve, Hospital Clinic, Barcelona. Belgium: A. Ferrant, Service Hématologie, Clinique University, St Luc, Bruxelles.

	REFERENCES

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Submitted September 13, 2002; accepted January 28, 2003.

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