Just Accepted by Leukemia & Lymphoma
Outcomes of acute myeloid leukemia with t(15;17) not associated with acute promyelocytic leukemia Amy Soni, Miroslav Djokic, Jing-Zhou Hou, Robert L. Redner, Michael Boyiadzis
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Doi: 10.3109/10428194.2015.1036262
© 2015 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Letter to the Editor Outcomes of acute myeloid leukemia with t(15;17) not associated with acute promyelocytic leukemia
Amy Soni, Miroslav Djokic, Jing-Zhou Hou, Robert L. Redner, Michael Boyiadzis
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Division of Hematology and Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Corresponding author: Michael Boyiadzis, MD, MHScm, Division of Hematology and Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Center Ave, Suite 572, Pittsburgh, PA 15232, USA. Tel: 412-648-6589. Fax: 412-648-6579. Email: [email protected]
Short title: AML with t(15;17) not associated with APL
1
Acute promyelocytic leukemia (APL) is a biologically and clinically distinct subtype of acute myeloid leukemia (AML). APL is classified as AML-M3 in the French-American-British (FAB) classification system and as acute promyelocytic leukemia with t(15;17)(q22;q21); PML-RARA in the revised World Health Organization (WHO) classification system [1]. Key morphological and clinical features distinguish APL from other forms of AML, including the presence of abnormal promyelocytes with bilobed nuclei and multiple Auer rods (“faggot cells”). Patients often present with coagulopathy, which at times leads to significant bleeding. APL with
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t(15;17)(q22;q21) is characterized by the low expression or absence of HLA-DR and CD34, bright expression of CD33, and heterogeneous expression of CD13. Many cases show expression of CD117, which may be weak [1,2]. The hallmark of APL is the reciprocal translocation of chromosomes 15 and 17 with creation of the PML-RARA fusion product [3,4]. The PML-RARA fusion protein is considered to be critical to the pathogenesis of APL and leads to a differentiation block at the promyelocytic stage of myeloid differentiation. Acute myeloid leukemias with t(15;17), in very rare cases, may have different breakpoints on chromosomes 15 and 17, which do not involve rearrangements of PML and RARA loci. These acute myeloid leukemias do not have morphological, clinical or molecular features of APL. Here, we present a case and review relevant literature of a patient newly diagnosed with AML with t(15;17) that proved to be “AML, not otherwise specified” and not APL. A 56-year-old female presented with progressive fatigue and was found to have pancytopenia with a white blood cell count of 2.2 x 109/L (segmented neutrophils 32%, lymphocytes 40%, monocytes 12%, eosinophils 2.5%, basophils 1%, blasts 10%), hemoglobin 9.8 gm/dL, and platelet count 114 x 109/L. Coagulation laboratory values were within normal limits. Bone marrow evaluation demonstrated 27% blasts which were intermediate-to-large in size with an increased nuclear/cytoplasmic ratio, prominent nucleoli and occasional cytoplasmic granules or vacuoles (Figure 1a). The flow cytometric immunophenotypic analysis demonstrated myeloblasts with the following phenotype: CD34 positive, CD117 dim positive, CD45 dim positive, CD33 positive, CD13 dim positive, HLA-DR negative. Karyotype analysis showed a translocation between the long arms of chromosomes 15 and 17: 46,XX, t(15;17)(q15;q11.2)
2
(Figure 1b). FISH study was negative for the PML-RARA gene rearrangement using a dualcolor, dual fusion translocation probe (Abbott Molecular, Des Plaines, IL) (Figure 1c). FISH analysis using a break-apart RARA probe (Abbott Molecular) was also negative for rearrangement of RARA gene. In addition, the PML-RARA fusion transcript was not detected by quantitative real-time polymerase chain reaction (PCR) using primers for both intron 3 breakpoint and exon/intron 6 breakpoint of the PML gene. Based on the morphologic, immunophenotypic and genetic testing performed, the diagnosis of t(15;17)AML not associated
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with APL was made. The patient was treated with induction chemotherapy consisting of cytarabine (100 mg/m2 per day IV, days 1-7 days) and idarubicin (12 mg/m2 per day IV, days 1– 3). Bone marrow biopsy 14 days after initiation of therapy demonstrated persistent leukemia, and the patient was re-induced with mitoxantrone (10 mg/m2 per day IV, days 1–5) and etoposide (100 mg/m2 per day IV, days 1–5). There was still persistent disease, and, after a 3rd course of induction chemotherapy with fludarabine (30 mg/m2 per day IV, days 1-5) and cytarabine (2 gm/m2 per day IV, days 1-5), complete remission was achieved. No cytogenetic abnormalities were detected in the bone marrow after achieving complete remission. After a cycle of consolidation therapy with high dose cytarabine the patient underwent reduced intensity allogeneic hematopoietic cell transplant (HCT) from a matched sibling donor using fludarabine (40mg/m2 IV on days -6 to -3) and busulfan (130mg/m2 IV on days -6 to -3) as conditioning regimen. Fourteen months after the allogeneic HCT, the patient was found to have thrombocytopenia and a bone marrow biopsy revealed relapsed disease. The patient was subsequently treated with decitabine (20 mg/m2 per day IV, days 1-5) for 2 cycles, but did not respond and ultimately died 20 months after HCT. In the current case, blood and bone marrow specimens did not have the typical morphologic appearance of APL. Despite the presence of t(15;17) by cytogenetic analysis, FISH and RT-PCR studies for PML-RARA were negative. There was a different breakpoint on the long arm of chromosome 15, in q15 region rather than in q22 region, where the PML gene is located. The breakpoint on chromosome 17 was in q11.2 region, which is located centromerically to the RARA gene (17q21). It is interesting to note that the neurofibromatosis tumor suppressor gene
3
(NF-1) and STAT-5b transcription factor are both localized at the 17q11.2 locus. Alterations of the NF-1 gene are involved in neurofibromatosis and myeloid disorders including juvenile myelomonocytic leukemia; STAT-5b is rearranged in the der17 variant of APL. Both of these are potential candidates for involvement in the current case of acute myeloid leukemia with t(15;17). There have been a few other cases of AML with t(15;17) and a lack of evidence for APL by morphology and molecular studies [5-9] (Table 1). In addition, rare cases have been reported of AML with t(15;17) but were not classified as APL based on a lack of APL by morphology and
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clinical course despite the presence of PML-RARA fusion rearrangements by RT-PCR [10]. Similar to our case, one of the other reported cases [8] of non-APL with t(15;17) was HLA-DR negative, but none displayed the other characteristic immunophenotypic markers for APL. In contrast to APL, the outcomes of the reported cases of non-APL with t(15;17) have been poor (Table 1). Patients have typically required several cycles of induction chemotherapy. Two patients described had persistent disease/relapse during consolidation and early death [10]. Similar to the current case, HCT has been pursued in two reported cases, and both patients relapsed within 22 months of transplant[5,6]. Similarly, one patient who did not undergo HCT relapsed within a year of diagnosis [7]. One exception was a case of non-APL t(15;17) that only required one course of induction and was in remission; however, this patient was followed for only 10 months after diagnosis [8]. The introduction of all-trans retinoic acid (ATRA) into routine clinical practice changed the outcome of APL from the most fatal to the most curable subtype of AML [11,12]. Particularly in the case of low to intermediate risk APL, the combination of ATRA with arsenic trioxide (ATO) has recently been shown to have excellent outcomes, and chemotherapy can actually be avoided altogether [13,14]. Therefore, if APL is highly suspected at presentation ATRA should be commenced immediately and continued until the diagnosis is confirmed by molecular studies. In the current case, ATRA was not initiated at presentation due to the lack of morphologic and clinical characteristics of APL. Molecular studies were performed concomitant with the cytogenetic studies that revealed t(15;17) ; thus the suspicion of APL was low enough that our patient did not recived ATRA and was treated with standard induction chemotherapy. Since
4
t(15;17) AML not associated with APL is rare, if there is delay in resulting of molecular studies in patients with suspected diagnosis of AML with t (15;17) the administration of ATRA should be considered. Translocation of chromosomes 15 and 17 without other evidence of APL remains a rare entity, and it is thus difficult to draw definitive conclusions regarding prognosis and treatment options. However, available evidence from the case we present and review of previous literature suggests a poor outcome. This prognostic information may be helpful to patients and clinicians, and more
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 05/05/15 For personal use only.
aggressive treatment regimens, including allogeneic HCT, could be considered. Given that the therapeutic options between APL and non-APL acute leukemias differ significantly, this case and the similar reported cases in the literature also highlight the importance of molecular studies in the initial work-up of AML.
5
References 1. Swerdlow SH, Cancer IAfRo, Organization WH. WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer; 2008. 2.
Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood 2008;111:3941-3967.
3.
de The H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 05/05/15 For personal use only.
transcribed locus. Nature 1990;347:558-561. 4.
Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999;93:3167-3215.
5.
Cotter M, Enright H. A novel t(15;17) translocation in acute myeloid leukaemia not associated with PML/RARalpha rearrangement. Clin Lab Haematol 2003;25:255-257.
6.
Di Bona E, Montaldi A, Guercini N, et al. . A (15;17) translocation not associated with acute promyelocytic leukaemia. Br J Haematol 1996;95:706-709.
7.
Kwan Ma ES, Au W, Kong Wan TS, Lam Kwong Y, Chan LC. Translocation (15;17)(q22;q21) not associated with acute promyelocytic leukemia and negative for PML/RARa rearrangement. Haematologica 2000;85:768-769.
8.
Li S, Zhang L, Kern WF, et al. . Identification of t(15;17) and a segmental duplication of chromosome 11q23 in a patient with acute myeloblastic leukemia M2. Cancer Genet Cytogenet 2002;138:149-152.
9.
Varella-Garcia M, Brizard F, Roche J, Flandrin G, Drabkin H, Brizard A. Aml1/ETO and Pml/RARA rearrangements in a case of AML-M2 acute myeloblastic leukemia with t(15;17). Leuk Lymphoma 1999;33:403-406.
10.
Allford S, Grimwade D, Langabeer S, et al. . Identification of the t(15;17) in AML FAB types other than M3: evaluation of the role of molecular screening for the PML/RARalpha rearrangement in newly diagnosed AML. The Medical Research Council (MRC) Adult Leukaemia Working Party. Br J Haematol 1999;105:198-207.
6
11.
Tallman MS, Andersen JW, Schiffer CA, et al. . All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997;337:1021-1028.
12.
Sanz MA, Montesinos P, Rayon C, et al. . Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010;115:5137-5146.
13.
Hu J, Liu YF, Wu CF, et al. . Long-term efficacy and safety of all-trans retinoic
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 05/05/15 For personal use only.
acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 2009;106:3342-3347. 14.
Lo-Coco F, Avvisati G, Vignetti M, et al. . Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-121.
7
Table 1 legend:
Table 1. Clinical features of AML patients with t(15;17) not associated with APL
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Age Gender Flow (years) cytometry/ Immunephenotype
Chromosome analysis/ FISH
Molecular testing
Time of t (15;17) discovery
Treatment
Outcome
Reference
35
F
HLA-DR+, CD34+, CD33+, CD13+
t(15;17)(q24. 3;q21.1) by chromosome analysis, negative by FISH
PMLRARA (-) by PCR and Southern blot
Diagnosis
3 cycles of induction chemotherapy, no CR achieved short course ATRA, allogeneic HCT
Relapse 97 days after allo-HCT, death from AML 16 months after diagnosis
[6]
39
F
Not available
t(15;17)(q22; q12) and t(8;21) by chromosome analysis and FISH
Not available
Diagnosis
Not available
Not available
[9]
36
M
Not available
t(15;17) by chromosome analysis
Several PMLmonths RARA (+) after by PCR classified as diagnosis (patient AML of treated as FAB type NHL M2 based initially, on morphology BM biopsy showing t(15;17) after induction chemother apy for AML
2 cycles of induction chemotherapy, no CR achieved
Persistent disease, death
[10]
15
F
HLA-DR+, CD33+, CD13+
t(15;17) by chromosome analysis
PMLRARA (+) by PCR classified as AML of
1 cycle of Relapse 2 induction months after chemotherapy last CR achieved , consolidation followed by 3 (re-induced
8
Diagnosis
[10]
cycles of with FLAG consolidation plus ATRA), chemotherapy death 11 days later
FAB type M1 based on morphology
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44
M
HLA-DR+, CD34+, CD33+, CD13+, CD7+, and surface CD22+
t(15;17)(q22; q21) by chromosome analysis
PMLRARA (-)
Diagnosis
ATRA x 2 Relapse weeks after one (discontinued year, death after molecula results), induction chemotherapy achieved CR, cycles of consolidation chemotherapy
[7]
[8]
32
M
HLA-DR-, CD45+, CD34+, CD33+, CD13+
t(15;17)(q22; q21) and duplication 11q23 by chromosome analysis and FISH
Not available
Diagnosis
1 cycle of In remission induction 10 months chemotherapy after diagnosis CR achieved (time case report published)
27
F
HLA-DR+, CD117+, CD34+, CD7+
t(15;17)(q15; q11) by chromosome analysis , negative by FISH
Not available
Diagnosis
3 cycles of induction chemotherapy to achieve CR, then autologous HCT
Remission 22 months after transplant
[5]
56
F
HLA-DR-, CD117+, CD34+, CD 33+, CD13+
t(15;17)(q15; q11.2) by chromosome analysis, negative by FISH
PMLRARA (-) by PCR
Diagnosis
3 cycles of induction chemothera py to achieve CR, followed by allogeneic HCT
Relapse 14 months after transplant.
Current case
9
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FISH: fluorescence in situ hybridization; PCR: polymerase chain reaction; Allo-HCT: allogeneic hematopoietic cell transplant
10
Figure 1 legend: Figure 1. (a). A bone marrow touch imprint shows intermediate sized blasts with high nuclear/cytoplasmic ratio, slightly irregular nuclear contour, prominent nucleoli and agranular cytoplasm (modified Wright-Giemsa stain, 500X magnification) (b). Cytogenetic findings at the diagnosis of AML. Karyotype of the abnormal clone with reciprocal translocation t(15;17)(q15;q11.2). Arrows point to derivative chromosome 15 and derivative chromosome 17 (c). FISH analysis shows a normal pattern with PML/RARA dual fusion, dual color probe (2 red
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signals, 2 green signals). Fusion signal(s) is not present.
11
Outcomes of acute myeloid leukemia with t(15;17) not associated with acute promyelocytic leukemia Amy Soni, Miroslav Djokic, Jing-Zhou Hou, Robert L. Redner, Michael Boyiadzis
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Doi: 10.3109/10428194.2015.1036262
© 2015 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Letter to the Editor Outcomes of acute myeloid leukemia with t(15;17) not associated with acute promyelocytic leukemia
Amy Soni, Miroslav Djokic, Jing-Zhou Hou, Robert L. Redner, Michael Boyiadzis
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 05/05/15 For personal use only.
Division of Hematology and Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Corresponding author: Michael Boyiadzis, MD, MHScm, Division of Hematology and Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Center Ave, Suite 572, Pittsburgh, PA 15232, USA. Tel: 412-648-6589. Fax: 412-648-6579. Email: [email protected]
Short title: AML with t(15;17) not associated with APL
1
Acute promyelocytic leukemia (APL) is a biologically and clinically distinct subtype of acute myeloid leukemia (AML). APL is classified as AML-M3 in the French-American-British (FAB) classification system and as acute promyelocytic leukemia with t(15;17)(q22;q21); PML-RARA in the revised World Health Organization (WHO) classification system [1]. Key morphological and clinical features distinguish APL from other forms of AML, including the presence of abnormal promyelocytes with bilobed nuclei and multiple Auer rods (“faggot cells”). Patients often present with coagulopathy, which at times leads to significant bleeding. APL with
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 05/05/15 For personal use only.
t(15;17)(q22;q21) is characterized by the low expression or absence of HLA-DR and CD34, bright expression of CD33, and heterogeneous expression of CD13. Many cases show expression of CD117, which may be weak [1,2]. The hallmark of APL is the reciprocal translocation of chromosomes 15 and 17 with creation of the PML-RARA fusion product [3,4]. The PML-RARA fusion protein is considered to be critical to the pathogenesis of APL and leads to a differentiation block at the promyelocytic stage of myeloid differentiation. Acute myeloid leukemias with t(15;17), in very rare cases, may have different breakpoints on chromosomes 15 and 17, which do not involve rearrangements of PML and RARA loci. These acute myeloid leukemias do not have morphological, clinical or molecular features of APL. Here, we present a case and review relevant literature of a patient newly diagnosed with AML with t(15;17) that proved to be “AML, not otherwise specified” and not APL. A 56-year-old female presented with progressive fatigue and was found to have pancytopenia with a white blood cell count of 2.2 x 109/L (segmented neutrophils 32%, lymphocytes 40%, monocytes 12%, eosinophils 2.5%, basophils 1%, blasts 10%), hemoglobin 9.8 gm/dL, and platelet count 114 x 109/L. Coagulation laboratory values were within normal limits. Bone marrow evaluation demonstrated 27% blasts which were intermediate-to-large in size with an increased nuclear/cytoplasmic ratio, prominent nucleoli and occasional cytoplasmic granules or vacuoles (Figure 1a). The flow cytometric immunophenotypic analysis demonstrated myeloblasts with the following phenotype: CD34 positive, CD117 dim positive, CD45 dim positive, CD33 positive, CD13 dim positive, HLA-DR negative. Karyotype analysis showed a translocation between the long arms of chromosomes 15 and 17: 46,XX, t(15;17)(q15;q11.2)
2
(Figure 1b). FISH study was negative for the PML-RARA gene rearrangement using a dualcolor, dual fusion translocation probe (Abbott Molecular, Des Plaines, IL) (Figure 1c). FISH analysis using a break-apart RARA probe (Abbott Molecular) was also negative for rearrangement of RARA gene. In addition, the PML-RARA fusion transcript was not detected by quantitative real-time polymerase chain reaction (PCR) using primers for both intron 3 breakpoint and exon/intron 6 breakpoint of the PML gene. Based on the morphologic, immunophenotypic and genetic testing performed, the diagnosis of t(15;17)AML not associated
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with APL was made. The patient was treated with induction chemotherapy consisting of cytarabine (100 mg/m2 per day IV, days 1-7 days) and idarubicin (12 mg/m2 per day IV, days 1– 3). Bone marrow biopsy 14 days after initiation of therapy demonstrated persistent leukemia, and the patient was re-induced with mitoxantrone (10 mg/m2 per day IV, days 1–5) and etoposide (100 mg/m2 per day IV, days 1–5). There was still persistent disease, and, after a 3rd course of induction chemotherapy with fludarabine (30 mg/m2 per day IV, days 1-5) and cytarabine (2 gm/m2 per day IV, days 1-5), complete remission was achieved. No cytogenetic abnormalities were detected in the bone marrow after achieving complete remission. After a cycle of consolidation therapy with high dose cytarabine the patient underwent reduced intensity allogeneic hematopoietic cell transplant (HCT) from a matched sibling donor using fludarabine (40mg/m2 IV on days -6 to -3) and busulfan (130mg/m2 IV on days -6 to -3) as conditioning regimen. Fourteen months after the allogeneic HCT, the patient was found to have thrombocytopenia and a bone marrow biopsy revealed relapsed disease. The patient was subsequently treated with decitabine (20 mg/m2 per day IV, days 1-5) for 2 cycles, but did not respond and ultimately died 20 months after HCT. In the current case, blood and bone marrow specimens did not have the typical morphologic appearance of APL. Despite the presence of t(15;17) by cytogenetic analysis, FISH and RT-PCR studies for PML-RARA were negative. There was a different breakpoint on the long arm of chromosome 15, in q15 region rather than in q22 region, where the PML gene is located. The breakpoint on chromosome 17 was in q11.2 region, which is located centromerically to the RARA gene (17q21). It is interesting to note that the neurofibromatosis tumor suppressor gene
3
(NF-1) and STAT-5b transcription factor are both localized at the 17q11.2 locus. Alterations of the NF-1 gene are involved in neurofibromatosis and myeloid disorders including juvenile myelomonocytic leukemia; STAT-5b is rearranged in the der17 variant of APL. Both of these are potential candidates for involvement in the current case of acute myeloid leukemia with t(15;17). There have been a few other cases of AML with t(15;17) and a lack of evidence for APL by morphology and molecular studies [5-9] (Table 1). In addition, rare cases have been reported of AML with t(15;17) but were not classified as APL based on a lack of APL by morphology and
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 05/05/15 For personal use only.
clinical course despite the presence of PML-RARA fusion rearrangements by RT-PCR [10]. Similar to our case, one of the other reported cases [8] of non-APL with t(15;17) was HLA-DR negative, but none displayed the other characteristic immunophenotypic markers for APL. In contrast to APL, the outcomes of the reported cases of non-APL with t(15;17) have been poor (Table 1). Patients have typically required several cycles of induction chemotherapy. Two patients described had persistent disease/relapse during consolidation and early death [10]. Similar to the current case, HCT has been pursued in two reported cases, and both patients relapsed within 22 months of transplant[5,6]. Similarly, one patient who did not undergo HCT relapsed within a year of diagnosis [7]. One exception was a case of non-APL t(15;17) that only required one course of induction and was in remission; however, this patient was followed for only 10 months after diagnosis [8]. The introduction of all-trans retinoic acid (ATRA) into routine clinical practice changed the outcome of APL from the most fatal to the most curable subtype of AML [11,12]. Particularly in the case of low to intermediate risk APL, the combination of ATRA with arsenic trioxide (ATO) has recently been shown to have excellent outcomes, and chemotherapy can actually be avoided altogether [13,14]. Therefore, if APL is highly suspected at presentation ATRA should be commenced immediately and continued until the diagnosis is confirmed by molecular studies. In the current case, ATRA was not initiated at presentation due to the lack of morphologic and clinical characteristics of APL. Molecular studies were performed concomitant with the cytogenetic studies that revealed t(15;17) ; thus the suspicion of APL was low enough that our patient did not recived ATRA and was treated with standard induction chemotherapy. Since
4
t(15;17) AML not associated with APL is rare, if there is delay in resulting of molecular studies in patients with suspected diagnosis of AML with t (15;17) the administration of ATRA should be considered. Translocation of chromosomes 15 and 17 without other evidence of APL remains a rare entity, and it is thus difficult to draw definitive conclusions regarding prognosis and treatment options. However, available evidence from the case we present and review of previous literature suggests a poor outcome. This prognostic information may be helpful to patients and clinicians, and more
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 05/05/15 For personal use only.
aggressive treatment regimens, including allogeneic HCT, could be considered. Given that the therapeutic options between APL and non-APL acute leukemias differ significantly, this case and the similar reported cases in the literature also highlight the importance of molecular studies in the initial work-up of AML.
5
References 1. Swerdlow SH, Cancer IAfRo, Organization WH. WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer; 2008. 2.
Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood 2008;111:3941-3967.
3.
de The H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 05/05/15 For personal use only.
transcribed locus. Nature 1990;347:558-561. 4.
Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999;93:3167-3215.
5.
Cotter M, Enright H. A novel t(15;17) translocation in acute myeloid leukaemia not associated with PML/RARalpha rearrangement. Clin Lab Haematol 2003;25:255-257.
6.
Di Bona E, Montaldi A, Guercini N, et al. . A (15;17) translocation not associated with acute promyelocytic leukaemia. Br J Haematol 1996;95:706-709.
7.
Kwan Ma ES, Au W, Kong Wan TS, Lam Kwong Y, Chan LC. Translocation (15;17)(q22;q21) not associated with acute promyelocytic leukemia and negative for PML/RARa rearrangement. Haematologica 2000;85:768-769.
8.
Li S, Zhang L, Kern WF, et al. . Identification of t(15;17) and a segmental duplication of chromosome 11q23 in a patient with acute myeloblastic leukemia M2. Cancer Genet Cytogenet 2002;138:149-152.
9.
Varella-Garcia M, Brizard F, Roche J, Flandrin G, Drabkin H, Brizard A. Aml1/ETO and Pml/RARA rearrangements in a case of AML-M2 acute myeloblastic leukemia with t(15;17). Leuk Lymphoma 1999;33:403-406.
10.
Allford S, Grimwade D, Langabeer S, et al. . Identification of the t(15;17) in AML FAB types other than M3: evaluation of the role of molecular screening for the PML/RARalpha rearrangement in newly diagnosed AML. The Medical Research Council (MRC) Adult Leukaemia Working Party. Br J Haematol 1999;105:198-207.
6
11.
Tallman MS, Andersen JW, Schiffer CA, et al. . All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997;337:1021-1028.
12.
Sanz MA, Montesinos P, Rayon C, et al. . Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010;115:5137-5146.
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Hu J, Liu YF, Wu CF, et al. . Long-term efficacy and safety of all-trans retinoic
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acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 2009;106:3342-3347. 14.
Lo-Coco F, Avvisati G, Vignetti M, et al. . Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-121.
7
Table 1 legend:
Table 1. Clinical features of AML patients with t(15;17) not associated with APL
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Age Gender Flow (years) cytometry/ Immunephenotype
Chromosome analysis/ FISH
Molecular testing
Time of t (15;17) discovery
Treatment
Outcome
Reference
35
F
HLA-DR+, CD34+, CD33+, CD13+
t(15;17)(q24. 3;q21.1) by chromosome analysis, negative by FISH
PMLRARA (-) by PCR and Southern blot
Diagnosis
3 cycles of induction chemotherapy, no CR achieved short course ATRA, allogeneic HCT
Relapse 97 days after allo-HCT, death from AML 16 months after diagnosis
[6]
39
F
Not available
t(15;17)(q22; q12) and t(8;21) by chromosome analysis and FISH
Not available
Diagnosis
Not available
Not available
[9]
36
M
Not available
t(15;17) by chromosome analysis
Several PMLmonths RARA (+) after by PCR classified as diagnosis (patient AML of treated as FAB type NHL M2 based initially, on morphology BM biopsy showing t(15;17) after induction chemother apy for AML
2 cycles of induction chemotherapy, no CR achieved
Persistent disease, death
[10]
15
F
HLA-DR+, CD33+, CD13+
t(15;17) by chromosome analysis
PMLRARA (+) by PCR classified as AML of
1 cycle of Relapse 2 induction months after chemotherapy last CR achieved , consolidation followed by 3 (re-induced
8
Diagnosis
[10]
cycles of with FLAG consolidation plus ATRA), chemotherapy death 11 days later
FAB type M1 based on morphology
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44
M
HLA-DR+, CD34+, CD33+, CD13+, CD7+, and surface CD22+
t(15;17)(q22; q21) by chromosome analysis
PMLRARA (-)
Diagnosis
ATRA x 2 Relapse weeks after one (discontinued year, death after molecula results), induction chemotherapy achieved CR, cycles of consolidation chemotherapy
[7]
[8]
32
M
HLA-DR-, CD45+, CD34+, CD33+, CD13+
t(15;17)(q22; q21) and duplication 11q23 by chromosome analysis and FISH
Not available
Diagnosis
1 cycle of In remission induction 10 months chemotherapy after diagnosis CR achieved (time case report published)
27
F
HLA-DR+, CD117+, CD34+, CD7+
t(15;17)(q15; q11) by chromosome analysis , negative by FISH
Not available
Diagnosis
3 cycles of induction chemotherapy to achieve CR, then autologous HCT
Remission 22 months after transplant
[5]
56
F
HLA-DR-, CD117+, CD34+, CD 33+, CD13+
t(15;17)(q15; q11.2) by chromosome analysis, negative by FISH
PMLRARA (-) by PCR
Diagnosis
3 cycles of induction chemothera py to achieve CR, followed by allogeneic HCT
Relapse 14 months after transplant.
Current case
9
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FISH: fluorescence in situ hybridization; PCR: polymerase chain reaction; Allo-HCT: allogeneic hematopoietic cell transplant
10
Figure 1 legend: Figure 1. (a). A bone marrow touch imprint shows intermediate sized blasts with high nuclear/cytoplasmic ratio, slightly irregular nuclear contour, prominent nucleoli and agranular cytoplasm (modified Wright-Giemsa stain, 500X magnification) (b). Cytogenetic findings at the diagnosis of AML. Karyotype of the abnormal clone with reciprocal translocation t(15;17)(q15;q11.2). Arrows point to derivative chromosome 15 and derivative chromosome 17 (c). FISH analysis shows a normal pattern with PML/RARA dual fusion, dual color probe (2 red
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signals, 2 green signals). Fusion signal(s) is not present.
11
