5-13 Variations in the reported incidence of RA-induced CR in APL patients (72% to 100%) have been related to early disease complications, to RA toxicity, or to other extenuating circumstances (such as inadequate diagnostic criteria). © 1998 by The American Society of Hematology.ĪLL- TRANS RETINOIC ACID (RA), which functions by inducing terminal granulocytic differentiation of acute promyelocytic leukemia (APL) cells, 1-4 is a highly effective agent for inducing complete hematologic and clinical remission (CR) in APL patients. We conclude that APL cellular resistance occurs with high incidence after relapse from RA + DA therapy administered in a nonconcurrent manner and that mutations in the RAR region of the PML-RAR gene are present in and likely mechanistically involved in RA resistance in a subset of these cases. Minor additional PML-RAR isoforms encoding truncated PML proteins were detected in 2 cases. No mutations were detected in the corresponding sequences of the normal RAR or PML (partial) alleles. All pretreatment analyses were normal except for a C to T base change in the 3′-untranslated (UT) region of 1 patient that was also present after relapse from DA therapy. Relative to normal RAR1, the mutations were Leu290Val, Arg394Trp, and Met413Thr. All 3 mutations were located in the ligand binding domain (LBD) of the RAR region of PML-RAR. ![]() From analysis of sequences encoding the principal functional domains of the PML and RAR portions of PML-RAR, we found missense mutations in relapse specimens from 3 of 12 RA-treated patients and 0 of 8 DA-treated patients. Of 10 RA-treated patients evaluable for a change in APL cell sensitivity to RA-induced differentiation in vitro, 8 showed diminished sensitivity at relapse, whereas, of 6 evaluable patients treated with DA alone, only 1 had marginally reduced sensitivity. We studied matched pretreatment and relapse specimens from 12 patients who received variable amounts of RA, primarily in nonconcurrent combination with daunorubicin and cytarabine (DA) on Eastern Cooperative Oncology Group (ECOG) protocol E2491, and from 8 patients who received DA only on protocol E2491. This study evaluated whether relapse of acute promyelocytic leukemia (APL) patients from clinical remissions achieved and/or maintained with all- trans retinoic acid (RA) in combination with intensive chemotherapy is associated with leukemic cellular resistance to RA and with alterations in the PML-RAR fusion gene.
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