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Association of PML-RAR Fusion mRNA Type With Pretreatment Hematologic Characteristics But Not Treatment Outcome in Acute Promyelocytic Leukemia: An Intergroup Molecular Study
Robert E. Gallagher,
Cheryl L. Willman,
James L. Slack,
Janet W. Andersen,
Yun-Ping Li,
David Viswanatha,
Clara D. Bloomfield,
Frederick R. Appelbaum,
Charles A. Schiffer,
Martin S. Tallman, and
Peter H. Wiernik
From the Departments of Oncology and Medicine, Montefiore Medical Center and Albert Einstein Cancer Center, Bronx, NY; the Departments of Pathology and Cell Biology, University of New Mexico Cancer Center, Albuquerque, NM; the Division of Hematology/Oncology, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY; the Division of Biostatistics, Dana-Farber Cancer Institute, Boston, MA; the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD; and the Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, Chicago, IL.
In each case of acute promyelocytic leukemia (APL) one of three PML-RAR mRNA types is produced, depending on the break/fusion site in the PML gene that is linked to a common RAR gene segment: a short (S)-form type, PML exon 3 RAR exon 3; a long (L)-form type, PML exon 6 RAR exon 3; or a variable (V)-form type, variably deleted PML exon 6 RAR exon 3. We evaluated whether PML-RAR mRNA type is associated with distinct pretreatment clinical characteristics and therapeutic outcome in previously untreated adult APL patients registered to protocol INT 0129 by the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Cancer and Leukemia Group B. Of 279 clinically eligible cases, 230 were molecularly evaluable, and of these, 111 were randomized to receive remission induction therapy with all-trans retinoic acid (ATRA) and 119 with conventional chemotherapy. Nine cases not excluded by central pathology review were PML-RAR negative, and notably, none of five of these cases treated with ATRA achieved complete remission (CR). Among 221 PML-RAR-positive cases, there were 82 S-form cases (37%), 121 L-form cases (55%), and 18 V-form cases (8%). Before any antileukemic therapy, the S-form type, compared with the L-form type, was associated with higher values for the white blood cell (WBC) count (median 2,500/µL v 1,600/µL; P = .009), the percentage of blood blasts plus promyelocytes (median 29% v 8.5%; P = .03), and the absolute blood blasts plus promyelocytes (884/µL v 126/µL; P = .019). Also, an increased percentage of S-form versus L-form cases had the M3 variant phenotype, 24% v 12% (P = .036). There were no differences between S-form and L-form cases in either CR rate (79% v 69%; P = .14) or disease free survival distribution (multivariate analysis adjusting for the association of S-form type and higher WBC count; P = .40). We conclude that the S-form type is associated with previously-identified adverse risk WBC parameters but that the identification of the S-form or L-form type of PML-RAR mRNA, per se, does not predict clinical outcome or add to the value of an increased WBC count as a negative prognostic indicator in APL patients.
Blood, Vol. 90 No. 4 (August 15), 1997:
pp. 1656-1663
© 1997 by The American Society of Hematology.
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