tretinoin and Isochromosomes

Acute Promyelocytic Leukemia (APL) is one of the most curable leukemia which shows great sensitivity to all-trans retinoic acid (ATRA) although a small number of the patients present poor prognosis and short survival. Isochromosome 17 in APL which usually bears an additional copy of RARA/PML fusion gene is considered to be a negative factor on its prognosis. Cryptic t(15;17) on i(17q) leads to an extra copy of PML/RARA rather than RARA/PML which may confer a worse prognosis. We describe here a rare APL case with complex chromosomal abnormality including isochromosome 17 bearing cryptic t(15;17) showing poor outcome. The patient lacks a classic t(15;17) and fluorescence in situ hybridization (FISH) presents 2 PML/RARA fusion signals on both long arms of the isochromosome. The patient also acquired a secondary mutation at relapse when the initial karyotype was already a complex karyotype involving chromosome 13, 17 and 22 at the same time. The poor response of this patient to traditional chemotherapy like ATRA and novel therapy like arsenic trioxide (ATO) suggests that early auto-hematological stem cell transplantation may be the choice of APL with isochromosome 17 especially with cryptic t(15;17) on i(17q). We are the first to show a clear history and evidence of FISH of these kind of cases. A small summary of cases with cryptic t(15;17) on isochromosome 17 is also made.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Bone Marrow Examination; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Disease Progression; Fatal Outcome; Genetic Predisposition to Disease; Humans; In Situ Hybridization, Fluorescence; Isochromosomes; Karyotype; Leukemia, Promyelocytic, Acute; Male; Molecular Diagnostic Techniques; Mutation; Oncogene Proteins, Fusion; Oxides; Phenotype; Predictive Value of Tests; Time Factors; Translocation, Genetic; Treatment Outcome; Tretinoin; Young Adult

Acute promyelocytic leukemia (APL) is a subtype of acute leukemia that is characterized by typical morphology, bleeding events and distinct chromosomal aberrations, usually the t(15;17)(q22;q21) translocation. Approximately 9% of APL patients harbor other translocations involving chromosome 17, such as the t(11;17)(q23;q21), t(5;17)(q35;q12-21), t(11;17)(q13;q21), and der(17). All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have specific targeted activities against the PML-RARA fusion protein. The combination of ATRA and ATO is reportedly superior to chemotherapy and ATRA as induction therapy for APL. The clinical significance of non-t(15:17) APL-related aberrations is controversial, with conflicting reports regarding sensitivity to modern, targeted therapy. Isochromosome 17q (iso(17q)) is rarely associated with APL and usually occurs concurrently with the t(15:17) translocation. No published data is available regarding the efficacy of ATO-based therapy for APL patients who harbor iso(17q). We report on an APL patient with iso(17q) as the sole cytogenetic aberration and a cryptic PML-RARA transcript, who was treated with ATRA and ATO after failure of chemotherapy and achieved complete remission. To our knowledge, this is the first published report of APL associated with iso(17q) as the sole cytogenetic aberration, which was successfully treated with an ATO containing regimen.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Chromosomes, Human, Pair 17; Female; Humans; Isochromosomes; Leukemia, Promyelocytic, Acute; Middle Aged; Oncogene Proteins, Fusion; Oxides; Remission Induction; Treatment Outcome; Tretinoin

We describe a patient with acute promyelocytic leukemia (APL) and the karyotype 46,XX,i(17)(q10) with PML-RARA fusion gene detected by fluorescence in situ hybridization (FISH) and nested reverse transcriptase-polymerase chain reaction (RT-PCR). FISH using dual-color translocation probes for PML (promyelocytic leukemia) and RARA (retinoic acid receptor-alpha) showed fusion signal for PML-RARA on both arms of i(17q). The patient attained complete remission (CR) with all-trans retinoic acid treatment and became PML-RARA negative. One year later, while PML-RARA negative on FISH and RT-PCR, the patient presented with thrombocytopenia. Bone marrow examination suggested an acute monoblastic leukemia (AML-M5a) including the karyotype 46,XX,t(8;16) (p11.2;p13.3),inv(11)(p15q22 approximately q23)[11]/47,idem,+i(8)(q10)[9]. She is currently in CR. The occurrence of therapy related acute leukemia after successful therapy for APL is an emerging problem.

Topics: Antineoplastic Agents; Chromosomes, Human, Pair 17; Female; Humans; In Situ Hybridization, Fluorescence; Isochromosomes; Karyotyping; Leukemia, Monocytic, Acute; Leukemia, Promyelocytic, Acute; Middle Aged; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Topics: Antineoplastic Agents; Chromosomes, Human, Pair 17; Cloning, Molecular; Humans; In Situ Hybridization, Fluorescence; Isochromosomes; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Tretinoin