ARTICLE IN PRESS
Cancer Genetics ■■ (2015) ■■–■■
SHORT COMMUNICATION
Acute promyelocytic leukemia with isochromosome 17q and cryptic PML-RARA successfully treated with all-trans retinoic acid and arsenic trioxide Daniel Shepshelovich a,b,*, Nino Oniashvili c, Doris Parnes d, Alina Klein a, Eli Muchtar b,e, Josepha Yeshaya c, Adina Aviram d, Esther Rabizadeh d,f, Pia Raanani b,e a
Medicine A, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; b Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; c Cytogenetic Laboratory, Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; d Hematological Laboratories, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; e Institute of Hematology, Davidoff Center, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; f Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel 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). Alltrans 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) APLrelated 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. Keywords APL, isochromosome 17q, ATRA, ATO © 2015 Elsevier Inc. All rights reserved.
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). APL has particular morphologic features and is characterized by the t(15; 17)(q22;q21) translocation in a majority of cases. The two genes fused are PML, which is located on chromosome 15q, and the retinoic acid receptor alpha (RARA) gene on chromosome 17q. PML−RARA encodes for a fusion protein that inhibits differentiation and promotes survival of myeloid precursor cells (1). With contemporary targeted therapy, APL has become a highly
Received June 7, 2015; received in revised form August 11, 2015; accepted August 12, 2015. * Corresponding author. E-mail address: [email protected] 2210-7762/$ - see front matter © 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cancergen.2015.08.001
curable disease with complete remission rates of over 95% and cure rates of over 80% (2–6). Not all APL patients have the t(15;17) translocation. Approximately 9% of APL patients harbor other aberrations involving chromosome 17, such as the t(11;17)(q23;q21), t(5;17)(q35;q12-21), t(11;17)(q13;q21), or der(17) (7). Most of these aberrations are still associated with formation of the fusion gene, which is created by insertion events or more complex rearrangements (7). The clinical significance of such “atypical” APL-related aberrations is controversial (8–11). Isochromosome of the long arm of chromosome 17 (iso(17q)) is a rare cause of APL. In a recent review of the literature, Manola et al. demonstrated that iso(17q) is twice as frequent in males than in females, is associated with a low initial white blood cell count, and, opposite to the common
ARTICLE IN PRESS 2 notion, does not confer an adverse prognosis in APL patients who are treated with ATRA and chemotherapy (12). In all 53 cases of iso(17q) reviewed by Manola et al., iso(17q) was present in addition to the t(15;17). Herein, we report the first case of APL harboring iso(17q) as the sole chromosomal rearrangement that was successfully treated with ATO and ATRA.
Materials and methods Case report A 53-year-old, previously healthy patient was diagnosed in another country with AML FAB M4 and a karyotype of 46XX, iso(17)(q11). She was treated according to the “3 + 7” protocol with daunorubicin at a dose of 60 mg/m2 for 3 days and continuous cytarabine at a dose of 100 mg/m2 for 7 days. Bone marrow (BM) examination performed 1 month later was compatible with refractory disease. The patient was referred to our hospital. The CBC showed pancytopenia with 10,000/uL platelets, 460/uL leukocytes, and hemoglobin of 9.3g/dL. Coagulation test results were within normal limits. Aspiration BM morphology performed 2 months after induction therapy was compatible with full-blown APL, with 80% of the cells being promyelocytes. The karyotype was 46XX, iso(17q)(q10). Reverse transcriptase (RT)-PCR was positive for the PML−RARA transcript. Therefore, the patient was diagnosed with APL and was treated with ATRA at a dose of 45 mg/m2/day. Ten days later, ATO at a dose of 0.15 mg/kg/day was added to the regimen, as previously described (13). Thrombocytopenia and leukopenia resolved on days 16 and 40, respectively. BM aspiration done on day 37 showed
Cancer Genetics ■■ (2015) ■■–■■
SHORT COMMUNICATION
Acute promyelocytic leukemia with isochromosome 17q and cryptic PML-RARA successfully treated with all-trans retinoic acid and arsenic trioxide Daniel Shepshelovich a,b,*, Nino Oniashvili c, Doris Parnes d, Alina Klein a, Eli Muchtar b,e, Josepha Yeshaya c, Adina Aviram d, Esther Rabizadeh d,f, Pia Raanani b,e a
Medicine A, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; b Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; c Cytogenetic Laboratory, Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; d Hematological Laboratories, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; e Institute of Hematology, Davidoff Center, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; f Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel 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). Alltrans 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) APLrelated 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. Keywords APL, isochromosome 17q, ATRA, ATO © 2015 Elsevier Inc. All rights reserved.
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). APL has particular morphologic features and is characterized by the t(15; 17)(q22;q21) translocation in a majority of cases. The two genes fused are PML, which is located on chromosome 15q, and the retinoic acid receptor alpha (RARA) gene on chromosome 17q. PML−RARA encodes for a fusion protein that inhibits differentiation and promotes survival of myeloid precursor cells (1). With contemporary targeted therapy, APL has become a highly
Received June 7, 2015; received in revised form August 11, 2015; accepted August 12, 2015. * Corresponding author. E-mail address: [email protected] 2210-7762/$ - see front matter © 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cancergen.2015.08.001
curable disease with complete remission rates of over 95% and cure rates of over 80% (2–6). Not all APL patients have the t(15;17) translocation. Approximately 9% of APL patients harbor other aberrations involving chromosome 17, such as the t(11;17)(q23;q21), t(5;17)(q35;q12-21), t(11;17)(q13;q21), or der(17) (7). Most of these aberrations are still associated with formation of the fusion gene, which is created by insertion events or more complex rearrangements (7). The clinical significance of such “atypical” APL-related aberrations is controversial (8–11). Isochromosome of the long arm of chromosome 17 (iso(17q)) is a rare cause of APL. In a recent review of the literature, Manola et al. demonstrated that iso(17q) is twice as frequent in males than in females, is associated with a low initial white blood cell count, and, opposite to the common
ARTICLE IN PRESS 2 notion, does not confer an adverse prognosis in APL patients who are treated with ATRA and chemotherapy (12). In all 53 cases of iso(17q) reviewed by Manola et al., iso(17q) was present in addition to the t(15;17). Herein, we report the first case of APL harboring iso(17q) as the sole chromosomal rearrangement that was successfully treated with ATO and ATRA.
Materials and methods Case report A 53-year-old, previously healthy patient was diagnosed in another country with AML FAB M4 and a karyotype of 46XX, iso(17)(q11). She was treated according to the “3 + 7” protocol with daunorubicin at a dose of 60 mg/m2 for 3 days and continuous cytarabine at a dose of 100 mg/m2 for 7 days. Bone marrow (BM) examination performed 1 month later was compatible with refractory disease. The patient was referred to our hospital. The CBC showed pancytopenia with 10,000/uL platelets, 460/uL leukocytes, and hemoglobin of 9.3g/dL. Coagulation test results were within normal limits. Aspiration BM morphology performed 2 months after induction therapy was compatible with full-blown APL, with 80% of the cells being promyelocytes. The karyotype was 46XX, iso(17q)(q10). Reverse transcriptase (RT)-PCR was positive for the PML−RARA transcript. Therefore, the patient was diagnosed with APL and was treated with ATRA at a dose of 45 mg/m2/day. Ten days later, ATO at a dose of 0.15 mg/kg/day was added to the regimen, as previously described (13). Thrombocytopenia and leukopenia resolved on days 16 and 40, respectively. BM aspiration done on day 37 showed
