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H., Jr Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 November 2001, Vol. 98, No. 9, pp. 2651-2656 CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Prognostic significance of minimal residual disease detection and PML/RAR- isoform type: long-term follow-up in acute promyelocytic leukemia Joseph G. Jurcic, Stephen D. Nimer, David A. Scheinberg, Tony DeBlasio, Raymond P. Warrell Jr, and Wilson H. Miller Jr From the Leukemia, Hematology, and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center, and the Weill Medical College of Cornell University, New York, NY, and the Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada.     Abstract Top Abstract Introduction Patients, materials, and... Results Discussion References The t(15;17) translocation in acute promyelocytic leukemia (APL) yields a PML/RAR- fusion messenger RNA species that can be detected by reverse transcription-polymerase chain reaction (RT-PCR) amplification. Breakpoints within intron 3 of PML produce a short PML/RAR- isoform, whereas breakpoints within intron 6 result in a longer form. Using RT-PCR, serial evaluations were performed on the bone marrow of 82 patients with APL (median follow-up, > 63 months) who received retinoic acid (RA) induction followed by postremission treatment with chemotherapy, RA, and biologic agents. Sixty-four patients attained a clinical complete remission and had at least 2 RT-PCR assays performed after completing therapy. Forty of 47 patients (85%) with newly diagnosed APL who were induced using RA had residual disease detectable by RT-PCR before additional therapy. After 3 cycles of consolidation therapy, residual disease was found in only 4 of 40 evaluable patients (10%). Among newly diagnosed patients who had 2 or more negative RT-PCR assays, only 3 of 41 (7%) had a relapse, whereas all 4 patients (100%) who had 2 or more positive results had a relapse. Among 63 newly diagnosed patients, those who expressed the short isoform appeared to have shorter disease-free and overall survival durations than patients who expressed the long isoform. These data indicate that 2 or more negative RT-PCR assays on bone marrow, performed at least 1 month apart after completing therapy, are strongly associated with long-term remissions. Conversely, a confirmed positive test is highly predictive of relapse. (Blood. 2001;98:2651-2656) © 2001 by The American Society of Hematology.     Introduction Top Abstract Introduction Patients, materials, and... Results Discussion References Acute promyelocytic leukemia (APL) is characterized by a specific translocation that fuses the promyelocytic leukemia gene (PML) on chromosome 15 with a gene encoding a retinoic acid receptor (RAR-) on chromosome 17,1-4 and by responsiveness to differentiation therapy with all-trans retinoic acid (RA).5-8 Molecular detection of PML/RAR- fusion messenger RNA (mRNA) by reverse transcription and polymerase chain reaction (RT-PCR) amplification is useful in diagnosing APL, in predicting responsiveness to RA, and in detecting minimal residual disease after remission induction.9-12 Preliminary studies by us and others suggest that this assay may also be useful in predicting relapse and in identifying patients who require further antileukemic therapy.13-19 Although the breakpoint on chromosome 17 invariably disrupts the RARA gene in the second intron, rearrangement of the PML gene may occur at 2 major breakpoints. Breakpoints within PML intron 3 (bcr 3) consistently yield the short fusion mRNA transcript that joins PML exon 3 and RAR- exon 3. Breakpoints within PML intron 6 (bcr 1) consistently produce the long transcript from the joining of PML exon 6 to RAR- exon 3. Additionally, breakpoints within PML exon 6 (bcr 2) are associated with a variable length transcript in a small number of patients.10,12,20,21 The influence of breakpoint site on patient outcome remains controversial. Early reports suggested that patients who express the short isoform have an increased incidence of clinical relapse and shorter survival compared to patients with the long isoform.15,22 Others have reported no difference in disease-free survival between patients with the long or short isoforms after adjusting for the association of the short form with a higher leukocyte count at presentation.23 As a follow-up to our preliminary report,14 we have prospectively evaluated 82 patients treated with RA and chemotherapy for the presence or absence of PML/RAR- fusion mRNA over time using serial RT-PCR analyses of bone marrow. In this study, we show that elimination of the RT-PCR signal is strongly associated with long-term remission, whereas a confirmed positive assay after completion of therapy is highly predictive of relapse. In addition, we report that patients with the short isoform appear to have a shorter disease-free and overall survival compared to patients with the long isoform, independent of the initial leukocyte count.     Patients, materials, and methods Top Abstract Introduction Patients, materials, and... Results Discussion References Patients We analyzed the course of all newly diagnosed and relapsed patients with APL treated consecutively on protocols at Memorial Sloan-Kettering Cancer Center from June 1990 to September 1995. All patients met morphologic criteria for the diagnosis of APL (acute myelocytic leukemia [AML]-M3 or M3-variant) according to the French-American-British classification system,24 and this diagnosis was confirmed by RT-PCR analysis for PML/RAR- rearrangements.10 Treatment Most patients received all-trans RA as previously described7; 2 patients, including 1 with newly diagnosed disease, were induced with 9-cis RA.25 Only one newly diagnosed patient received all-trans RA concomitantly with chemotherapy because of leukocytosis. Newly diagnosed patients remained on retinoids for approximately 30 days after they had attained a clinical complete remission. After discontinuing RA, 3 cycles of idarubicin and cytarabine were administered to most patients as consolidation therapy, as previously described.26,27 Because of coexisting medical conditions or patient refusal, 4 newly diagnosed patients did not complete all 3 cycles of consolidation chemotherapy, and 1 patient received no consolidation therapy. Six newly diagnosed patients received postremission therapy with the recombinant humanized anti-CD33 monoclonal antibody HuM195 in addition to chemotherapy.28 Two pediatric patients received 5 or 6 cycles of chemotherapy as consolidation. Most patients who had relapsed from previous chemotherapy were maintained solely on all-trans RA unless they were candidates for bone marrow transplantation or other investigational therapy. Seven patients in second remission received postremission therapy with 131I-labeled M195,29 and one patient received unconjugated HuM195.28 One patient in early relapse underwent allogeneic bone marrow transplantation. RT-PCR analysis We analyzed serial bone marrow aspirates by RT-PCR to detect PML/RAR- rearrangements. This method, which has been previously described,10,14 has a sensitivity of approximately 1 in 104 cells. We examined samples before patients began treatment, after they achieved clinical complete remission by standard criteria,30 and periodically thereafter. Statistical analysis For inclusion in this analysis, we required patients to have achieved both a clinical complete remission and to have 2 or more RT-PCR assays performed from 1 to 3 months apart after completion of therapy. We estimated the probability of disease-free and overall survival using the Kaplan-Meier method. The log-rank test was used to compare relapse-free and overall survival durations between patient groups. The 2 test was used to compare complete remission rates between patients expressing the long or short isoforms of PML/RAR-. Multivariate analyses of disease-free and overall survival were performed using proportional hazards regression.     Results Top Abstract Introduction Patients, materials, and... Results Discussion References Patients We studied 82 patients (median age, 45 years; range, 7-80 years) whose median duration of follow-up exceeds 63 months (range, 1-119+ months). These patients received 63 courses of treatment for newly diagnosed APL and 28 courses for relapsed APL (Table 1). Patients had a mean of 4 bone marrow samples analyzed after treatment.                                View this table: [in this window] [in a new window]   Table 1. Treatment administered to patients with acute promyelocytic leukemia Molecular remission induction We monitored the effect of therapy using serial RT-PCR analyses of bone marrow throughout treatment (Figure 1). Forty-seven newly diagnosed patients who received induction therapy with RA had assays performed at the time they attained clinical complete remission. After retinoid therapy alone, only 4 patients (9%) had no evidence of residual leukemia detectable by RT-PCR. Among 35 patients who were maintained on RA for at least 30 days after achieving remission and who underwent RT-PCR evaluation before consolidation chemotherapy, 7 (20%) became negative. Molecular evidence of residual disease was eliminated in 28 of 38 patients (74%) who were evaluated after one cycle of consolidation with idarubicin and cytarabine. After the second and third cycles of chemotherapy, RT-PCR-detectable disease was eliminated in 33 of 39 patients (85%) and 36 of 40 patients (90%) who were evaluated, respectively. None of the patients who achieved molecular complete remissions converted to RT-PCR positivity while still receiving consolidation therapy. View larger version (17K): [in this window] [in a new window]   Figure 1. Molecular remission after RA and chemotherapy. Molecular remission rates are shown for patients with newly diagnosed APL after treatment with all-trans RA at the time of documented clinical complete remission and after 30 days of maintenance with RA followed by postremission therapy with 1, 2, or 3 cycles of idarubicin and cytarabine. Within this limited patient sample, the time at which patients achieved molecular remission during their treatment course did not appear to affect long-term disease-free survival. Among the 7 patients who were RT-PCR negative after induction with RA alone, 1 (14%) relapsed. Of the 21 patients who achieved molecular remission after one cycle of consolidation therapy, 4 (19%) had relapses. In contrast, none of the 8 patients who achieved molecular remission after second or third cycles of chemotherapy had a relapse. Prognostic significance of the RT-PCR assay Forty-five patients with newly diagnosed APL achieved a clinical complete remission and had 2 or more RT-PCR assays performed between 1 and 3 months apart following the completion of therapy. All 4 patients (100%) who had at least 2 positive RT-PCR determinations had relapse (Table 2). The median disease-free survival was 9 months (range, 5-23 months) from the time of documented clinical complete remission (Figure 2). The prognostic value of the test decreased if only a single assay was performed. Among the 10 patients who had at least one positive assay following therapy, 7 patients (70%) had relapse.                                View this table: [in this window] [in a new window]   Table 2. Prognostic significance of RT-PCR View larger version (15K): [in this window] [in a new window]   Figure 2. Prognostic significance of RT-PCR in APL. This Kaplan-Meier plot shows the probability of disease-free survival for newly diagnosed patients with at least 2 negative RT-PCR assays or fewer than 2 negative assays after completion of therapy. Tick marks indicate the time of last follow-up. The probability of remaining leukemia-free after 5 years for patients with at least 2 negative assays was 92%. All patients with a confirmed positive test relapsed after a median of 9 months (P < .0001). Conversely, among the 41 patients with newly diagnosed APL who had 2 or more negative RT-PCR assays performed following therapy, only 3 patients (7%) relapsed (Table 2). The median remission duration for this group exceeds 75 months (range, 11-117+ months; P < .0001; Figure 2). Again, the prognostic value of the assay decreased if a single test was performed. Six of 40 patients (15%) with only one negative assay relapsed. Among patients with at least 3 negative assays following treatment, however, only 1 of 34 patients (3%) had a relapse, similar to the outcomes of patients with at least 2 negative determinations. Analogous results were found for patients in second or greater remission. All 18 patients (100%) with at least 2 positive RT-PCR determinations performed after the completion of therapy relapsed after a median of 6 months (range, 2-39 months). Of the 7 patients beyond first remission with 2 or more negative assays, 1 patient (14%) relapsed after 14 months. If only one RT-PCR assay was performed, the prognostic significance of the test decreased. For the 13 patients with at least one negative assay, 7 patients (53%) relapsed. Nevertheless, among the 6 patients with at least 3 negative assays, only 1 patient (17%) relapsed. This was comparable to the outcomes of patients with only 2 negative determinations. Time from molecular relapse detection to overt clinical relapse Seven patients (4 newly diagnosed, 3 relapsed) who attained a molecular remission established by at least 2 negative RT-PCR bone marrow determinations performed at least 1 month apart later relapsed (Figure 3). Four of these patients had positive RT-PCR assays 1, 4, 8, and 9 months before the time of clinical relapse, consistent with our previously reported results.15 Despite serial monitoring with RT-PCR every 3 to 6 months in 2 of the remaining 3 patients, the assay failed to predict clinical relapse in these individuals who were found to be RT-PCR positive only at the time of overt clinical relapse. View larger version (25K): [in this window] [in a new window]   Figure 3. Time from molecular relapse detection to clinical relapse. Longitudinal RT-PCR results from bone marrow aspirates of 7 patients who attained a molecular remission but later relapsed are shown. Each circle represents an assay performed at the indicated time after achieving clinical complete remission. Only samples with adequate RNA quality for amplification of control RNA are included.  denotes a positive assay;  denotes a negative assay. Periods of consolidation therapy with chemotherapy or humanized anti-CD33 monoclonal antibody HuM195 are shown by the shaded bars. Arrows indicate the time of clinical relapse. Prognostic significance of PML/RAR- isoform type To determine the influence of PML/RAR- breakpoint patterns on disease-free and overall survival, we included only the 63 patients who were treated for newly diagnosed disease. There was no significant difference in the incidence of clinical complete remission in the patients who expressed the short (81%; n = 21) or long (90%; n = 42) isoform of PML/RAR- (P = .28). Nevertheless, the breakpoint location appeared to influence both disease-free and overall survival. Among the 55 patients who attained remission, the estimated probability of remaining disease-free after 5 years was 86% for the patients expressing the long isoform and 65% for those expressing the short isoform; this difference was borderline significant at P = .06 (Figure 4A). For all 63 patients, the probability of 5-year survival was 86% for patients with the long transcript and 67% for patients with the short transcript (Figure 4B; P = .08). We found a strong trend toward improved disease-free survival (P = .08) and overall survival (P = .31) for patients with an initial leukocyte count of fewer than 5000 cells/µL in this series, but not a highly significant association as others have reported.8,23,31,32 A multivariate proportional hazards model showed that the leukocyte count at presentation (P = .007) affected disease-free survival to a greater extent than PML/RAR- isoform type (P = .08; Table 3), as previously reported by Gallagher and coworkers.23 In a similar analysis, however, the breakpoint location (P = .08), but not the leukocyte count (P = .93), tended to influence overall survival (Table 3). View larger version (22K): [in this window] [in a new window]   Figure 4. Survival by PML/RAR- isoform type. Probabilities of disease-free survival for newly diagnosed patients achieving clinical complete remission (A) and overall survival (B) in patients who expressed either the short or long transcript of PML/RAR- are shown. Tick marks indicate the time of last follow-up. Patients with the short transcript had an inferior remission duration (P = .06) and overall survival (P = .08) compared with patients expressing the long isoform.                                View this table: [in this window] [in a new window]   Table 3. Prognostic factors in multivariate proportional hazards model     Discussion Top Abstract Introduction Patients, materials, and... Results Discussion References Reverse transcription PCR for the detection of mRNA product of the PML/RAR- fusion gene is a useful diagnostic and prognostic tool for patients with APL because the elimination of residual disease detectable by the currently used methods of RT-PCR is necessary for patients to achieve long-term remission. In this study, all patients who had 2 positive tests after treatment relapsed. Although the prognostic significance of a single negative assay is uncertain, newly diagnosed patients with at least 2 negative assays after the completion of therapy had only a 7% risk of relapse. Reduction of minimal residual disease below the level of detection by RT-PCR without complete eradication of the APL clonogenic cells may explain clinical relapse in this group of patients. Diverio and colleagues reported that among 142 patients with newly diagnosed APL who tested negative in 2 or more assays after consolidation therapy, only 8 (6%) relapsed.33 These data, along with previously reported studies,13-19,31 support the use of additional therapy for all patients with a confirmed positive RT-PCR assay after treatment. Despite achieving clinical complete remission, most patients treated solely with RA for induction had persistent evidence of leukemia detectable by RT-PCR before consolidation therapy in this study. After 3 courses of consolidation chemotherapy, 90% of patients were RT-PCR negative. No differences in presenting leukocyte count, isoform type, or additional cytogenetic abnormalities were identified between the small group of patients who never achieved molecular remission and the patients who became RT-PCR negative. Using RA and chemotherapy together, Mandelli and colleagues reported that 60% of patients with newly diagnosed APL were RT-PCR negative after induction and that 98% of patients tested negative after 3 cycles of consolidation therapy.34 These data suggest that by carefully monitoring residual disease during treatment, the requirement for postremission chemotherapy may be reduced or eventually eliminated in APL, particularly as newer agents, such as arsenic trioxide,35 liposomal all-trans RA,36 and antibody-based therapies,28 are integrated into treatment strategies. Unlike the Medical Research Council,31 we found that within this small series, patients who attained molecular remission earlier in their course of treatment did not have a reduced risk of relapse. Among the 28 patients who were RT-PCR negative after RA alone or RA induction and one cycle of consolidation chemotherapy, 5 (18%) relapsed, whereas none of the 8 patients who achieved molecular remission after a second or third course of consolidation therapy relapsed. In patients who attained molecular remission determined by 2 or more negative RT-PCR assays but who later relapsed, the time from molecular to clinical relapse varied from 1 to 9 months. Diverio and colleagues found that among 20 similar patients, the median time from a positive RT-PCR determination to overt relapse was 3 months (range, 1-14 months).33 Based on these data, we recommend RT-PCR evaluations of bone marrow every 3 months during the initial 2 years after remission is achieved, when the risk of relapse is greatest. Additional studies will be needed to assess the impact of molecular monitoring in patients receiving maintenance therapy with RA alone or in combination with chemotherapy.18,37 At present, however, we recommend serial RT-PCR testing every 3 months even in patients receiving maintenance therapy. The role of RT-PCR for the detection of minimal residual disease has been investigated in other types of leukemia. The prognostic significance of RT-PCR for bcr/abl in chronic myelogenous leukemia (CML) depends on the clinical setting in which it is used. Early after allogeneic bone marrow transplantation, a significant proportion of patients may continue to express the bcr/abl fusion transcript.38-40 Spontaneous conversion to RT-PCR negativity for bcr/abl transcripts could occur either as long-lived nonclonogenic cells (such as B lymphocytes, which may carry the bcr/abl transcript) die after transplantation, or as a T-cell-mediated graft-versus-leukemia effect eliminates residual host leukemia.38 Conversely, the persistence of bcr/abl mRNA, particularly in the setting of mixed donor/host T-cell chimerism,41 has correlated with a high incidence of relapse. Another study has indicated that RT-PCR positivity in patients with CML receiving interferon is not necessarily associated with immediate disease recurrence.42 The prognostic value of RT-PCR for AML1/ETO in t(8;21) AML is less clear. Several groups have detected this rearrangement in long-term survivors, possibly because this genetic alteration is only one of several required for leukemogenesis.43-45 More recently, however, Morschhauser and colleagues reported that negative RT-PCR results strongly correlated with long-term remissions in patients with t(8;21) AML when a standardized one-step RT-PCR technique was used to analyze bone marrow samples.46 Because the sensitivity of bcr/abl testing by RT-PCR (ie, 1 cell in 106)47 considerably exceeds that achieved by most groups for PML/RAR- testing, the incidence of false-negative results may be higher for APL, particularly for patients in second or greater remission. Frequent bone marrow evaluations may increase the predictive value of this assay. Preliminary data also suggest that quantitative real-time RT-PCR techniques may provide important prognostic information for patients with APL.48 Nevertheless, the assay used in this study10 and similar assays9,11,12 provide a level of sensitivity that is clinically useful for assessing response to therapy and for predicting relapse. Previously, we22 and others15 reported that the location of the PML/RAR- breakpoint affects prognosis in APL (Table 4). In the present study, patients with the short isoform appeared to have a shorter remission duration and overall survival compared to patients with the long isoform. With a median follow-up of 5 years, 86% of the patients with the long isoform remain in first remission, compared with only 65% of those with the short isoform in the present study (P = .06). Although 86% of patients with the long isoform remain alive, only 67% of those with the short isoform are alive (P = .08). Unlike Gallagher and colleagues,23 we could not attribute these apparent differences solely to the higher initial leukocyte counts in patients expressing the short isoform. Presenting white blood cell counts, however, have been reported to significantly influence disease-free survival in several studies.23,31,32 Ultimately, longer follow-up and greater patient numbers will be needed to clarify the influence of the breakpoint location on patient outcomes.                                View this table: [in this window] [in a new window]   Table 4. Prognostic significance of PML/RAR- isoform type Differences in the biologic activities of the long and short isoforms may also offer some insight into clinical outcomes. When the long and short isoforms were constitutively expressed in a human erythroleukemia cell line, the long isoform, but not the short, inhibited growth of these cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF).49 In the absence of GM-CSF, the short isoform partially protected against apoptosis, whereas the long isoform accelerated cell death. Moreover, inhibition of cell growth by all-trans RA was greater in cells expressing the long isoform than the short.49 These data suggest that APL cells expressing the short isoform may be more resistant to differentiation therapy with RA, to cytotoxic chemotherapy, or to intrinsic biologic or immunologic control of the residual clone than cells with the long isoform. Similar in vitro studies examining the impact of isoform type on the activity of arsenic trioxide are needed. Prospective trials examining the use of newer agents, such as arsenic trioxide35 or antibody-based therapies,28 should be investigated in high-risk patients who express the short isoform or have elevated initial leukocyte counts. Additionally, correlation of clinical outcomes and PML/RAR- isoform types will be needed in patients receiving arsenic trioxide.     Acknowledgments We wish to thank Dr Kristi Levine for her laboratory assistance and Drs Ellin Berman, Peter Maslak, Mark Weiss, and Mark Heaney for their clinical assistance.     Footnotes Submitted September 14, 2000; accepted June 28, 2001. Supported in part by grants from the Orphan Products Division, Food and Drug Administration (FD-R-000764 and FD-R-000925); the National Cancer Institute (CA 33049); the National Institutes of Health (CA 05826); the American Cancer Society (EDT-47); and the Lymphoma Foundation. J.G.J. is the recipient of a Clinical Oncology Career Development Award from the American Cancer Society. W.H.M. is the recipient of a scholarship of the Medical Research Council of Canada. D.A.S. is a Translational Investigator of the Leukemia Society of America and the recipient of a Doris Duke Distinguished Clinical Scientist Award. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Joseph G. Jurcic, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: jurcicj{at}mskcc.org.     References Top Abstract Introduction Patients, materials, and... Results Discussion References 1. de Thé H, Chomienne C, Lanotte M, Degos L, Déjean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor  gene to a novel transcribed locus. Nature. 1990;347:558-561[CrossRef][Medline] [Order article via Infotrieve]. 2. Miller WH Jr, Warrell RP Jr, Frankel SR, et al. Novel retinoic acid receptor- transcripts in acute promyelocytic leukemia responsive to all-trans retinoic acid. J Natl Cancer Inst. 1990;32:1932-1933. 3. Kakizuka A, Miller WH Jr, Umesono K, et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR- with a novel putative transcription factor, PML. Cell. 1991;66:663-674[CrossRef][Medline] [Order article via Infotrieve]. 4. de Thé H, Lavau C, Marcio A, Chomienne C, Degos L, Déjean A. The PML-RAR- fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991;66:675-684[CrossRef][Medline] [Order article via Infotrieve]. 5. Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72:567-572[Abstract/Free Full Text]. 6. Castaigne S, Chomienne C, Daniel MT, Berger R, Fenaux P, Degos L. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia; I: clinical results. Blood. 1990;76:1704-1709[Abstract/Free Full Text]. 7. Warrell RP Jr, Frankel SR, Miller WH Jr, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991;324:1385-1393[Abstract]. 8. Tallman MS, Anderson JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337:1021-1028[Abstract/Free Full Text]. 9. Biondi A, Rambaldi A, Alcalay M, et al. RAR- rearrangements as a genetic marker for diagnosis and monitoring in acute promyelocytic leukemia. Blood. 1991;77:1418-1422[Abstract/Free Full Text]. 10. Miller WH Jr, Kakizuka A, Frankel SR, et al. Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor- clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 1992;89:2694-2698[Abstract/Free Full Text]. 11. Castaigne S, Balitrand N, de Thé H, Déjean A, Degos L, Chomienne C. A PML/retinoic acid receptor- fusion transcript is constantly detected by RNA-based polymerase chain reaction in acute promyelocytic leukemia. Blood. 1992;79:3110-3115[Abstract/Free Full Text]. 12. Borrow J, Goddard AD, Gibbons B, et al. Diagnosis of acute promyelocytic leukaemia by RT-PCR: detection of PML-RARA and RAR-PML fusion transcripts. Br J Haematol. 1992;82:529-540[Medline] [Order article via Infotrieve]. 13. LoCoco F, Diverio D, Pandolfi PP, et al. Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukemia. Lancet. 1992;340:1437-1438[CrossRef][Medline] [Order article via Infotrieve]. 14. Miller WH Jr, Levine K, DeBlasio A, Frankel SR, Dmitrovsky E, Warrell RP Jr. Detection of minimal residual disease in acute promyelocytic leukemia by a reverse transcription polymerase chain reaction assay for the PML/RAR- fusion mRNA. Blood. 1993;82:1689-1694[Abstract/Free Full Text]. 15. Huang W, Sun G-L, Li Z-S, et al. Acute promyelocytic leukemia: clinical relevance of two major PML-RAR isoforms and detection of minimal residual disease by retrotranscriptase/polymerase chain reaction to predict relapse. Blood. 1993;82:1264-1269[Abstract/Free Full Text]. 16. Diverio D, Pandofi PP, Biondi A, et al. Absence of reverse transcription-polymerase chain reaction detectable residual disease in patients with acute promyelocytic leukemia in long-term remission. Blood. 1993;82:3556-3559[Abstract/Free Full Text]. 17. Ikeda K, Sasaki K, Tasaka T, et al. Reverse transcription-polymerase chain reaction for PML-RAR fusion transcripts in acute promyelocytic leukemia and its application to minimal residual leukemia detection. Leukemia. 1993;7:544-548[Medline] [Order article via Infotrieve]. 18. Fukutani H, Naoe T, Ohno R, et al. Prognostic significance of the RT-PCR assay of PML-RARA transcripts in acute promyelocytic leukemia. Leukemia. 1995;9:588-593[Medline] [Order article via Infotrieve]. 19. Takatsuki H, Umemura T, Sadamura S, et al. Detection of minimal residual disease by reverse transcriptase polymerase chain reaction for the PML/RAR fusion mRNA: a study in patients with acute promyelocytic leukemia following peripheral stem cell transplantation. Leukemia. 1995;9:889-892[Medline] [Order article via Infotrieve]. 20. Pandolfi PP, Alcalay M, Fagioli M, et al. Genomic variability and alternative splicing generate multiple PML/RAR transcripts that encode aberrant PML proteins and PML/RAR isoforms in acute promyelocytic leukemia. EMBO J. 1992;11:1397-1407[Medline] [Order article via Infotrieve]. 21. Biondi A, Rambaldi A, Pandofi PP, et al. Molecular monitoring of myl/RAR- fusion gene in acute promyelocytic leukemia by polymerase chain reaction. Blood. 1992;80:492-497[Abstract/Free Full Text]. 22. Vahdat L, Maslak P, Miller WH Jr, et al. Early mortality and retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PML/RAR- isoform, and CD13 expression in patients treated with all-trans retinoid acid. Blood. 1994;84:3843-3849[Abstract/Free Full Text]. 23. Gallagher R, Willman CL, Slack JL, et al. Association of PML/RAR fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: an intergroup molecular study. Blood. 1997;90:1656-1663[Abstract/Free Full Text]. 24. Bennett JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British Cooperative Group. Ann Intern Med. 1985;103:460-462. 25. Miller WH Jr, Jakubowski A, Tong WP, et al. 9-cis retinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia. Blood. 1995;85:3021-3027[Abstract/Free Full Text]. 26. Frankel SR, Eardley A, Heller G, et al. All-trans-retinoic acid for acute promyelocytic leukemia: results of the New York study. Ann Intern Med. 1994;120:278-286[Abstract/Free Full Text]. 27. Warrell RP Jr, Maslak P, Eardley A, Heller G, Miller WH Jr, Frankel SR. Treatment of acute promyelocytic leukemia with all-trans retinoic acid: an update of the New York experience. Leukemia. 1994;8:929-933[Medline] [Order article via Infotrieve]. 28. Jurcic JG, DeBlasio T, Dumont L, Yao TJ, Scheinberg DA. Molecular remission induction with retinoic acid and anti-CD33 monoclonal antibody HuM195 in acute promyelocytic leukemia. Clin Cancer Res. 2000;6:372-380[Abstract/Free Full Text]. 29. Jurcic JG, Caron PC, Miller WH Jr, et al. Sequential targeted therapy for relapsed acute promyelocytic leukemia with all-trans retinoic acid and anti-CD33 monoclonal antibody M195. Leukemia. 1995;9:244-248[Medline] [Order article via Infotrieve]. 30. Cheson BD, Cassileth PA, Head DR, et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol. 1990;8:813-819[Abstract]. 31. Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH, and the MRC Adult Leukaemia Working Party. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood. 1999;93:4131-4143[Abstract/Free Full Text]. 32. Sanz MA, LoCoco F, Martín G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000;96:1247-1253[Abstract/Free Full Text]. 33. Diverio D, Rossi V, Avvisati G, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RAR fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. Blood. 1998;92:784-789[Abstract/Free Full Text]. 34. Mandelli F, Diverio D, Avvisati G, et al. Molecular remission in PML/RAR-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997;90:1014-1021[Abstract/Free Full Text]. 35. Soignet SL, Maslak P, Wang Z-G, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:1341-1348[Abstract/Free Full Text]. 36. Estey E, Giles F, Kantarjian H, et al. Molecular remissions induced by liposomal-encapsulated all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia. Blood. 1999;94:2230-2235[Abstract/Free Full Text]. 37. Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all-trans retinoic acid (ATRA) following chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. Blood. 1999;94:1192-1200[Abstract/Free Full Text]. 38. Hughes TP, Morgan GJ, Martiat P, Goldman JM. Detection of residual leukemia after bone marrow transplant for chronic myeloid leukemia: role of polymerase chain reaction in predicting relapse. Blood. 1991;77:874-878[Abstract/Free Full Text]. 39. Pignon JM, Henni T, Amselem S, et al. Frequent detection of minimal residual disease by use of the polymerase chain reaction in long-term survivors after bone marrow transplantation for chronic myeloid leukemia. Leukemia. 1990;4:83-86[Medline] [Order article via Infotrieve]. 40. Delfau M-H, Kerckaert J-P, d'Hooghe MC, et al. Detection of minimal residual disease in chronic myeloid leukemia patients after bone marrow transplantation by polymerase chain reaction. Leukemia. 1989;4:1-5. 41. Mackinnon S, Barnett L, Heller G, O'Reilly RJ. Minimal residual disease is more common in patients who have mixed T-cell chimerism after bone marrow transplantation for chronic myelogenous leukemia. Blood. 1994;83:3409-3416[Abstract/Free Full Text]. 42. Lee M-S, Kantarjian H, Talpaz M, et al. Detection of minimal residual disease by polymerase chain reaction in Philadelphia chromosome-positive chronic myelogenous leukemia following interferon therapy. Blood. 1992;79:1920-1923[Abstract/Free Full Text]. 43. Nucifora G, Larson RA, Rowley JD. Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission. Blood. 1993;82:712-715[Abstract/Free Full Text]. 44. Miyamoto T, Nagafuji K, Akashi K, et al. Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with (8;21) acute myelogenous leukemia. Blood. 1996;87:4789-4796[Abstract/Free Full Text]. 45. Jurlander J, Caliguiri MA, Ruutu T, et al. Persistence of the AML1/ETO fusion transcript in patients treated with allogeneic bone marrow transplantation for t(8;21) leukemia. Blood. 1996;88:2183-2191[Abstract/Free Full Text]. 46. Morschhauser F, Cayuela JM, Martini S, et al. Evaluation of minimal residual disease using reverse transcription polymerase chain reaction in t(8;21) acute myeloid leukemia: a multicenter study of 51 patients. J Clin Oncol. 2000;18:788-794[Abstract/Free Full Text]. 47. Roth MS, Antin JH, Bingham EL, Ginsburg D. Detection of Philadelphia chromosome-positive cells by the polymerase chain reaction following bone marrow transplant for chronic myelogenous leukemia. Blood. 1989;74:882-885[Abstract/Free Full Text]. 48. Willman CL, Yeap B, Bi W, et al. Predictive value of automated, quantitative real-time RT-PCR performed at the end of consolidation of acute promyelocytic leukemia (APL): a SWOG, CALGB, and ECOG intergroup study (INT-0129). Proc Am Soc Clin Oncol. 2000;19:5a. 49. Slack JL, Yu M. Constitutive expression of promyelocytic leukemia-associated oncogene PML-RAR in TF1 cells: isoform-specific and retinoic acid-dependent effects on growth, bcl-2 expression, and apoptosis. Blood. 1998;91:3347-3356[Abstract/Free Full Text]. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z.-Y. Wang and Z. 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