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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2001-12-0174. This Article Abstract Full Text (PDF) All Versions of this Article: 2001-12-0174v1 99/11/4222    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Estey, E. H. Articles by Kantarjian, H. M. Search for Related Content PubMed PubMed Citation Articles by Estey, E. H. Articles by Kantarjian, H. M. Related Collections Immunobiology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 June 2002, Vol. 99, No. 11, pp. 4222-4224 BRIEF REPORT Experience with gemtuzumab ozogamycin ("mylotarg") and all-trans retinoic acid in untreated acute promyelocytic leukemia Elihu H. Estey, Francis J. Giles, Miloslav Beran, Susan O'Brien, Sherry A. Pierce, Stefan H. Faderl, Jorge E. Cortes, and Hagop M. Kantarjian From the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.     Abstract Top Abstract Introduction Study design Results and discussion References We administered gemtuzumab ozogamycin ("mylotarg"; 9 mg/m2 day 1 or 5) and all-trans retinoic acid (ATRA) to 19 patients with untreated acute promyelocytic leukemia (APL). There were 3 patients who also received idarubicin because of a white blood cell (WBC) count of more than 30 000/µL. In complete remission (CR), patients were to receive 8 courses of mylotarg (9 mg/m2 every 4 to 5 weeks) and ATRA; idarubicin was added only for persistent or recurrent polymerase chain reaction (PCR) positivity. The CR rate was 16/19 (84%). All 12 patients tested to date were PCR-negative 2 to 4 months from CR date; none of the 7 patients evaluated subsequently have reverted to PCR positivity (median follow-up in CR was 5 months, up to 14 months). Mylotarg was well tolerated. A median of 5 post-CR courses have been given to date with 3 patients having currently received 8 post-CR courses, and 4 patients receiving 7 post-CR courses. Mylotarg appears active in APL, and repeated administration is feasible. (Blood. 2002;99:4222-4224) © 2002 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References CD33 expression is essentially universal in acute promyelocytic leukemia (APL), and the APL cell's surface typically contains large amounts of the antigen. The anti-CD33 antibody (HuM195), although unattached to a cytotoxic agent, produced polymerase chain reaction (PCR) "negativity" in 11 out of 22 patients with APL who remained PCR "positive" in hematologic complete remission (CR).1 Gemtuzumab ozogamicin ("mylotarg") combines an anti-CD33 antibody (hP 67.6) with calicheamicin, a cytotoxic agent that, given its similarities with anthracyclines,2 might be expected to be particularly active in APL. These observations led to the trial described below.     Study design Top Abstract Introduction Study design Results and discussion References After formal institutional review board approval, 19 patients, in each of whom the morphologic impression of APL was confirmed molecularly, were treated. Their median age was 50 years; all were ambulatory with a serum bilirubin less than 2.0 mg/mL. There were 18 patients with the characteristic t(15;17). The median initial white blood cell (WBC) count was 3700/µL (up to 101 000/µL) and the median initial platelet count 29 000/µL. There were 8 patients who were "high-risk," 5 who were "low-risk," and 6 who were "intermediate risk."3 Patients received all-trans retinoic acid (ATRA) (45 mg/m2 daily) until CR, after which the same dose was administered using a 2-weeks-on, 2-weeks-off schedule. Mylotarg, 9 mg/m2, was given on day 5 (day 1 if the presenting WBC count was > 10 000/µL). There were 3 patients with initial WBC counts of more than 30 000/µL who also received idarubicin (12 mg/m2 daily, days 1-3). In CR, patients were to receive 9 mg/m2 mylotarg once every 4 to 5 weeks provided platelet and neutrophil counts were more than 100 000/µL and more than 1000/µL, respectively. If counts had not recovered, the next course was to be delayed and the dose reduced; dose reduction was also permitted for extramedullary toxicity. Therapy was to be discontinued after administration of 8 postremission doses of mylotarg (ie, 9 total doses). PCR testing at a level of 104 was conducted every 2 to 4 months in CR. If the test was "positive," 3 cycles of idarubicin (12 mg/m2 daily, days 1 and 2) were to be given, mylotarg discontinued, and ATRA continued. Approval for the trial was provided by the M. D. Anderson institutional review board and informed consent was provided according to the Declaration of Helsinki.     Results and discussion Top Abstract Introduction Study design Results and discussion References The CR rate was 16 out of 19 (84%; 95% confidence interval [CI], 60%-97%) and was 14 out of 16 (88%; 95% CI, 62%-98%) in patients given mylotarg and ATRA without idarubicin. These rates were essentially identical to those we previously observed with single-agent liposomal ATRA,4 or oral ATRA and idarubicin,5 as were the rates in high-risk patients (5/8 +/ idarubicin, 3/5 no idarubicin). The median time to hematologic CR (as usually defined) was 27 days, considering all patients or only those given ATRA and mylotarg without idarubicin. The 3 patients who did not achieve CR died (2 of hemorrhage, 1 of multiorgan failure) before antileukemic response was known. There were 2 episodes of possible ATRA syndrome; both resolved with conventional management. Veno-occlusive disease of the liver was not seen, although 7 patients developed asymptomatic self-limited increases in serum glutamic-pyruvic transaminase (SGPT) (up to 192 mg/mL) within one week of starting therapy. There were 2 additional patients (each also given idarubicin) who had asymptomatic self-limited rises in bilirubin (up to 4.1 mg/mL) within 13 days after beginning treatment. Of the 4 patients in whom sufficient time has passed, 3 have received all 8 planned post-CR courses.The fourth patient did not receive the eighth course (because of a self-limited, asymptomatic rise in bilirubin to 2.1 mg/mL on the preceding course). This patient and one with a negative PCR but a platelet count of 50 000/µL 9 weeks after post-CR course 4 have been the only patients in whom a post-CR course has been omitted. The number of post-CR courses given to date is as follows: 8 courses (3 patients), 7 courses (4 patients), 5 courses (1 patient), 4 courses (1 patient), 3 courses (3 patients), 2 courses (2 patients), 1 course (2 patients) (Table 1). A median of one week (range, 0-5 weeks) has elapsed between CR date and administration of the first postremission course, and a median of 5 weeks (range, 4-8 weeks) between subsequent courses. The interval between courses has not increased as therapy progresses. Reductions from the planned dose of 9 mg/m2 have been carried out in 5 patients because of infection (3 patients), a lower extremity thrombus (1 patient), and infusion-related complications (1 patient). All 16 patients who entered CR remain alive in hematologic CR, although the median follow-up in CR is only 5 months (up to 14 months).                                View this table: [in this window] [in a new window]   Table 1. Postremission data Of the 16 patients, 14 have become PCR-negative, including 6 who became negative after induction, and 2, 4, and 2 who became negative after 1, 2, and 3 post-CR courses, respectively. Given these data, there may be no need to give 8 post-CR courses of mylotarg. The 2 patients who remain PCR-positive have been in CR only 1 to 2 months and have not yet had follow-up PCRs. Of the 11 patients tested at time of CR, 6 were PCR-negative (5/10; 95% CI, 19%-82% among patients not given idarubicin) (Table 2). At 1 to 4 months from CR all 12 patients tested to date were PCR-negative (10/10; 95% CI, 69%-100% considering only patients not given idarubicin during induction). Of the 7 patients who had subsequent PCR testing, 5 were PCR-negative, with the most recent tests performed 5, 11, 12, 12, and 13 months, respectively, from CR date. In 2 patients, positive PCRs were detected 5 months from CR date but were likely falsely positive (Table 2). Thus the rates of PCR negativity are as follows: at 1 to 4 months, 12/12; at 5 to 8 months, 7/7; and at 9 to 12 months, 4/4. Corresponding rates in patients given only ATRA and mylotarg during induction are 10/10, 6/6, and 3/3. Thus, no patients have yet received idarubicin in CR. Assuming a true 21% rate of PCR negativity with single-agent ATRA ("monotherapy") at 1 to 4 months as reported by Jurcic et al,1 the probability of our data if mylotarg did not add to the effectiveness of ATRA is (.21)10 = 0.0000002. Assuming even a true 50% rate of PCR negativity, the probabilities of our data are 0.001, 0.016, and 0.125 at 1 to 4, 5 to 8, and 9 to 12 months, respectively. Thus we believe that our data reflect the addition of mylotarg to ATRA. While the above analysis cannot substitute for a control population given ATRA monotherapy and followed with our assay, such a population would be difficult to obtain given that Chinese data suggested a median CR duration of only 5 months in patients given ATRA monotherapy,6 which is identical to what would result in the unlikely event that each of our 14 patients given only mylotarg and ATRA were to relapse within the next month. Indeed, the rates of PCR negativity that we observed are similar to those reported with ATRA and idarubicin in GIMEMA and American trials,7,8 recognizing that we had many fewer patients and that their prognoses were possibly different from patients in these other trials. A randomized trial might address the comparative benefits of ATRA and idarubicin or ATRA and mylotarg in untreated patients at relatively high risk of relapse if given ATRA and idarubicin.3                                View this table: [in this window] [in a new window]   Table 2. PCR data     Acknowledgments The authors thank Angela Culler for her expert secretarial assistance.     Footnotes Submitted December 5, 2001; accepted January 17, 2002. Prepublished online as Blood First Edition Paper, April 30, 2002; DOI 10.1182/blood-2001-12-0174. 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: Elihu H. Estey, Department of Leukemia, Box 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: ehestey{at}mdanderson.org.     References Top Abstract Introduction Study design Results and discussion References 1. Jurcic JG, DeBlasio T, Dumont L, Yao T-J, 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]. 2. Appelbaum FR. Antibody-targeted therapy for myeloid leukemia. Semin Hematol. 1999;36:2-8[Medline] [Order article via Infotrieve]. 3. Sanz MA, LoCoco F, Martin 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]. 4. 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]. 5. Estey E, Thall PF, Pierce S, Kantarjian H, Keating M. Treatment of newly-diagnosed acute promyelocytic leukemia without cytosine arabinoside. J Clin Oncol. 1997;15:483-490[Abstract/Free Full Text]. 6. Fenaux P, Castaigne S, Chomienne C, Dombret H, Degos L. All-trans retinoic acid for patients with acute promyelocytic leukemia. Leukemia. 1992;6(suppl 1):64-66[Medline] [Order article via Infotrieve]. 7. 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]. 8. Jurcic JG, Nimer SD, Scheinberg DA, DeBlasio T, Warrell RP, Miller WH. Prognostic significance of minimal residual disease detection and PML/RAR  isoform type: long-term follow-up in acute promyelocytic leukemia. Blood. 2001;98:2651-2656[Abstract/Free Full Text]. © 2002 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: C. Kelaidi, S. Chevret, S. De Botton, E. Raffoux, A. Guerci, X. Thomas, A. Pigneux, T. Lamy, F. Rigal-Huguet, S. Meyer-Monard, et al. 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[Abstract] [Full Text] This Article Abstract Full Text (PDF) All Versions of this Article: 2001-12-0174v1 99/11/4222    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Estey, E. H. Articles by Kantarjian, H. M. Search for Related Content PubMed PubMed Citation Articles by Estey, E. H. Articles by Kantarjian, H. M. Related Collections Immunobiology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020