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Acute Myeloid Leukemia With t(v;5q33) Is Associated With Poor Overall Survival and Often Lacks Myelodysplastic Features
SOHO Supplement 2015
Acute Myeloid Leukemia With t(v;5q33) Is Associated With Poor Overall Survival and Often Lacks Myelodysplastic Features Mariko Yabe,1 Guilin Tang,1 Guillermo Garcia-Manero,2 Sanam Loghavi,1 Xinyan Lu,1 Roberto N. Miranda,1 L. Jeffrey Medeiros,1 Hagop M. Kantarjian,2 Carlos E. Bueso-Ramos,1 Joseph D. Khoury1 Abstract Acute myeloid leukemia (AML) with specific balanced 5q33 translocations are classified as AML with myelodysplasia-related changes (AML-MRC) by WHO 2008. The clinicopathologic features of such cases are poorly understood. Our study revealed that AML with t(v; 5q33) is not usually associated with myelodysplasia but shows poorer outcome. Background: Acute myeloid leukemia (AML) with specific balanced 5q33 translocations are classified as AML with myelodysplasia-related changes regardless of their morphologic findings or antecedent hematologic disease, but the clinicopathologic features of such cases remain poorly understood. Materials and Methods: From > 2000 cases of hematological malignancies seen at our institution between 2000 and 2013, we identified 9 AML patients with 5q33 translocations with variable partner loci, t(v;5q33). Results: The study group included 8 men and 1 woman, with a median age of 64 years (range, 19-87 years). Four patients had an antecedent myeloproliferative neoplasm (MPN). Cytogenetic analysis showed t(v;5q33) as a sole chromosomal abnormality in 4 (44%) patients, t(v;5q33) and del(3)(q21;q26.2) in 1 (11%) patient, and a complex karyotype in 4 (44%) patients. Only 1 patient had morphologic features of myelodysplasia in 2 or more lineages. Follow-up was available for 7 patients and the median overall survival (OS) was 12 months. Patients with a history of MPN had a significantly shorter OS compared with those with de novo AML (11 vs. 20 months; P ¼ .0445). There was no correlation between complex karyotype and OS in this small group of AML patients (P ¼ .5904). Conclusion: The t(v;5q33) is a rare cytogenetic aberration in AML. Although associated with a poor outcome, AML with t(v;5q33) usually lacks morphologic evidence of multilineage dysplasia. Patients who have AML with t(v;5q33) after MPN have a worse OS compared with those with de novo AML. Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. S1, S85-90 ª 2015 Elsevier Inc. All rights reserved. Keywords: Acute myeloid leukemia, Balanced translocation, Chromosome 5q, Cytogenetics, Myelodysplasia-related changes
Introduction Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is defined in the World Health Organization (WHO) classification as an acute leukemia with 20% 1
Department of Hematopathology Department of Leukemia The University of Texas M.D. Anderson Cancer Center, Houston, TX 2
Submitted: Dec 7, 2014; Accepted: Feb 3, 2015; Epub: Feb 9, 2015 Address for correspondence: Joseph D. Khoury, MD, Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 Fax: 713-794-1800; e-mail contact: [email protected]
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peripheral blood (PB) or bone marrow (BM) blasts with morphological features of myelodysplasia, a history of a myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN), or MDS-related cytogenetic abnormalities, and absence of genetic abnormalities that define diseases in the WHO category of AML with recurrent genetic abnormalities.1 AML-MRC occurs mainly in elderly patients and is rare in children, and represents 24% to 35% of all cases of AML.1 As listed in the WHO classification, many chromosomal abnormalities are considered sufficient for inclusion in this category with a complex karyotype and unbalanced abnormalities, -7/del(7q) and -5/del(5q) being most common.2 Balanced chromosomal translocations are less common in the category of AML-MRC but do occur.1
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AML With t(v;5q33) Often Lacks Myelodysplastic Features Table 1 Patient Characteristics and Bone Marrow Findings of AML With Balanced 5q33 Translocations
Study ID 1 2 3 4 5 6 7 8 9
Age
Sex
Antecedent Hematological Disorder
21 87 78 19 70 64 55 56 80
M M M M M M M M F
None None None None None PV (14 years) MPN-unclassifiable (5 years) MPN-unclassifiable (2 months) ET (15 years)
BM Cellularity, %
BM Blast, %
Myelodysplasia
95 15 25 100 45 90 90 95 70
20 80 41 90 7a 29 64 36 30
Yes (E) Yes (E) No No No No No No Yes (G, E, Me)
Abbreviations: AML ¼ acute myeloid leukemia; E ¼ erythroid precursors; ET ¼ essential thrombocythemia; F ¼ female; G ¼ granulocytes; M ¼ male; Me ¼ megakaryocytes; MPN ¼ myeloproliferative neoplasm; PV ¼ polycythemia vera. a Patient with concurrent myeloid sarcoma.
Cytogenetic findings have an established role in the diagnosis and assessment of prognosis of MDS patients.3 Abnormal karyotypes show an association with the severity of cytopenia, high BM blast count, and extent of cellular dysplasias.4 In AML-MRC, some studies show that AML cases with morphologic evidence of multilineage dysplasia had no independent prognostic significance when cytogenetic findings were incorporated in the analysis. Thus, it is important to specifically designate AML-MRC cases as having morphologic evidence of dysplasia or the designation of AML-MRC based on associated cytogenetic abnormalities. According to the 2008 WHO classification, AML patients with 5q33 translocations who do not fulfill the criteria of “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRB” are categorized as AML-MRC.1 Four specific translocations are specified as being eligible for the AML-MRC category: t(5;12)(q33;p12), t(5;7)(q33;q11.2), t(5;17)(q33;p13), and t(5;10) (q33;q21). However, this subset of AML has been incompletely studied because of the limited number of patients with t(v;5q33), and a definite relationship between balanced 5q33 translocations and myelodysplasia-related changes remains unclear. Accordingly, the aim of this study was to investigate the clinicopathologic features and outcome of AML with t(v;5q33).
Materials and Methods Study Group We searched the cytogenetic archives of The University of Texas M.D. Anderson Cancer Center between 2000 and 2013 for cases with t(v;5q33). Cases with peripheral eosinophilia fulfilling the criteria of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRB were excluded. Clinical data were collected from review of the medical records, which included demographic information, clinical presentation, underlying disease, laboratory information, and clinical follow-up. The institutional review board of The University of Texas M.D. Anderson Cancer Center approved this study.
Cytogenetics
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Conventional chromosomal analysis was performed on G-banded metaphases prepared from unstimulated 24-hour and 48-hour BM
Clinical Lymphoma, Myeloma & Leukemia June 2015
aspirate cultures using standard techniques as described previously.5 Twenty metaphases were analyzed and the results were reported using the 2013 International System for Human Cytogenetics Nomenclature (2013).6
Histological Assessment Bone marrow specimens obtained at the initial diagnosis and/or at time of emergence of 5q33 translocations were evaluated. Hematoxylin and eosin-stained slides of core biopsy and clot specimens Table 2 Laboratory Features of the Study Group Value Peripheral Blood (n [ 8) WBC, 109/L Median
18.1
Range
3.1-77.7
Blast, % Median
49
Range
0-74
Hemoglobin, g/dL Median
10.4
Range
8.6-17.0
Platelets, 109/L Median
93.5
Range
27-174
LDH, IU/L Median
495
Range
339-3911
Bone Marrow (n [ 9) Cellularity, % Median
90
Range
15-100
Blast, % Median
36
Range
7-90
Abbreviations: LDH ¼ lactate dehydrogenase; WBC ¼ white blood cell count.
Mariko Yabe et al with corresponding WrighteGiemsa-stained aspirate smears and touch imprints were reviewed.
Molecular Analysis Molecular analyses were performed as part of the routine clinical work-up. A real-time reverse transcription polymerase chain reaction (PCR) was performed to detect BCR-ABL1 fusion transcripts, as described previously.7 Mutational analysis for JAK2 V617F and codons 12, 13, or 61 of KRAS and NRAS were performed using pyrosequencing,8,9 and NPM1 (exon 12), KIT (exons 8 and 17), and CEBPA were analyzed using direct Sanger sequencing.9-11 A fluorescence-based multiplex PCR was used to detect internal tandem duplication and D835 point mutation of the FLT3 gene.12,13 PCRbased DNA high-resolution melting curve analysis was used for detecting IDH1 and IDH2 gene mutations as described previously.14
Statistical Analysis Statistical analyses were performed using GraphPad Prism 6. Overall survival (OS) was calculated from the date of initial diagnosis of AML to the date of death or last follow-up. Survival was analyzed using the KaplaneMeier method and was compared using the log-rank test. A P value of < .05 was considered statistically significant.
Results Clinical and Laboratory Features The clinical features are summarized in Table 1. The study group was composed of 9 patients, including 8 men and 1 woman. The median age at the time of diagnosis of AML was 64 years (range, 19-87 years). Four patients had an antecedent MPN, which included 2 MPN-unclassifiable (cases 7, 8), 1 essential thrombocythemia (case 9), and 1 polycythemia vera (case 6). None of these 4 patients had eosinophilia during their MPN phase or subsequent AML. The complete blood cell count at time of diagnosis of AML was available for 8 patients and the results are shown in Table 2. The median leukocyte count was 18.1 109/L (range, 3.1-77.7 109/L), median blast percentage was 49% (range, 0%-74%), median hemoglobin level was 10.4 g/dL (range, 8.6-17.0 g/dL), and median platelet count was 93.5 109/L (range, 27-174 109/L). The serum lactate dehydrogenase level was available in 8 patients and the median was 495 IU/L (range, 339-3911 IU/L; reference range, 313-618 IU/L).
Morphologic Features The results of BM examination at the diagnosis of AML were available for all patients. They showed median BM cellularity of 90% (range, 15%-100%), and median BM count of 36% (range,
Figure 1 Bone Marrow of AML With t(v;5q33). (A) Core Biopsy of Case 8 Shows Hypercellular Marrow (95%) Without Obvious Dysmegakaryopoiesis (Hematoxylin and Eosin [H&E], Magnification 3400). (B) and (C) High-Magnification of Bone Marrow Smear of Case 8 Shows No Dysgranulopoiesis and Dyserythropoiesis (Wright-Giemsa, Magnification 31000). (D) Core Biopsy of Case 9 Shows Hypercellular Marrow (70%) With Hypolobated Dysplastic Megakaryocytes (H&E, Magnification 3400). (E) and (F) High-Magnification of Bone Marrow Smear of Case 9 Shows Prominent Dysgranulopoiesis and Dyserythropoiesis (Wright-Giemsa, Magnification 31000)
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AML With t(v;5q33) Often Lacks Myelodysplastic Features Table 3 Cytogenetic Findings Study ID 1 2 3 4 5
6 7
8 9
Karyotype at the Time of Diagnosis of Acute Myeloid Leukemia 46,XY,t(3;5)(q21;q33)[20] 46,Y,del(X)(q13),t(1;5)(p11;q33),-3,þ8,del(12)(p11.2), -18,þ21[17]/46,XY[3] 46,Y,t(X;5)(p22.3;q33)[14]/46,XY[6] 46,XY,del(3)(q21q26.2)[2]/46,sl,t(5;8)(q33;q13) [16]/46,sl,t(6;15)(q25;q22)[1]/46,XY[1] 46,XY,t(5;10)(q33;q21)[2]/81-85,XXYY,-1,-2,-4,add(4)(q35)x2, -5,t(5;10)(q33;q21)x2,-7,-7,-8,-9,-11,-12,-15,-16,-17,-18, -18,þ9-10mar[cp2]/46,XY[16] 46,XY,t(5;10)(q33;q21)[20] 50,XY,t(5;12)(q33;p13),-6,þ8,þ14,þ19,þ21,þ1 -2mar[19]/64,XY,-1,-2,-4,-5,t(5;12)(q33;p13),-6,-6,-7,þ8, -10, -11,þ15,þ15,-16,þ19,-20,þ21,þ2mar[1] 46, XY, t(5;12)(q33;p13)[18]/46,XY [2] 42-45,XX,t(2;5)(q21;q33),-7,-15,-16,-18,þ1-2mar [cp20]
7%-90%; Tables 1 and 2). Patient 5 was diagnosed as AML with 7% of BM blasts due to the presence of concurrent myeloid sarcoma. Only 1 (11%) patient had morphologic evidence of myelodysplasia, which fulfilled the criteria of myelodysplasia-related changed by itself (at least 50% of the cells in at least 2 lineages; case 9). Two patients (cases 1 and 2) showed mild dysplasia in the erythroid lineage. The other 6 patients did not show any features of myelodysplasia (Figure 1).
Table 4 Molecular Analysis Results Gene
Tested
Positive
Negative
FLT3 NPM1 JAK2 CEBPA IDH1 IDH2 KIT ABL1 NRAS KRAS
6 1 1 1 1 1 1 4 5 5
1 1 0 0 0 0 0 0 0 0
5 0 1 1 1 1 1 4 5 5
(n ¼ 2), 12p13 (n ¼ 2), and 1 case each involved 1p11, 3q21, 8q13, and Xp22. Of note, loss of chromosome 18 was observed in 3 of 4 cases with complex karyotype. Various molecular assessments were performed, and the results are shown in Table 4. One (17%) of 6 patients assessed had an FLT3-internal tandem duplication (ITD) mutation. One patient was positive for NPM1 mutation. No mutations in JAK2 (0/1), CEBPA (0/1), IDH1 (0/1), IDH2 (0/1), KIT (0/1), ABL1 (0/4), NRAS (0/5), or KRAS (0/5) were identified among tested cases.
Treatment and Clinical Outcome Cytogenetic and Molecular Features The results of conventional cytogenetic analysis are shown in Table 3. The karyotype analysis showed t(v;5q33) as a sole abnormality in 4 (44%) patients (case 1, 3, 6, and 8), t(v;5q33) and del(3)(q21;q26.2) in 1 (11%) patient (case 4), and a complex karyotype in 4 (44%) patients (case 2, 5, 7, and 9; Figure 2). The various loci partnered with chromosome 5q33 included 10q21
The follow-up period ranged from 1 to 39 months, during which 6 patients died of disease, 2 patients were alive with disease, and 1 patient was lost to follow-up. For patients with available follow-up data, the median OS was 12 months. Antecedent MPN (n ¼ 3) was associated with a significantly shorter OS (11 vs. 20 months; P ¼ .0445). There was no correlation between complex karyotype and OS (P ¼ .5904; Figure 3).
Figure 2 Conventional Karyotype Analysis From Bone Marrow Specimen of Patients With t(v;5q33). (A) Case 1 Shows 46,XY,t(3:5)(q21;q33). (B) Case 4 Shows 46,XY,del(3)(q21q26.2),t(5;8)(q33;q13)
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Mariko Yabe et al Figure 3 Overall Survival (OS) of Patients With t(v;5q33). (A) Overall Survival for All Patients With Available Survival Data (n [ 7); Median OS is 12 Months. (B) Comparison of OS Between Patients With and Without History of Antecedent Myeloproliferative Neoplasm (MPN). The Cases With Antecedent MPN Had a Significantly Shorter Survival Than the Cases With de Novo Acute Myeloid Leukemia (AML; Median OS, 11 vs. 20 Months; P [ .0445). (C) Comparison of OS Between Patients With and Without Complex Karyotype. There Was No Correlation Between Complex Karyotype and OS in This Small Group (Median OS 11.5 vs. 20 Months; P [ .5904)
Discussion We identified a group of 9 patients with AML with t(v;5q33). Balanced cytogenetic abnormalities, including reciprocal translocations and inversions are prevalent in myeloid neoplasms such as AML or chronic myelogenous leukemia, but are uncommon in MDS, in which unbalanced chromosomal abnormalities are more prevalent.3 The median age of these 9 patients was 64 years (range, 19-87 years), and was slightly younger than previous reports of AML-MRC cases.15 BM cellularity and blast percentage were variable among these cases. In our study, this subgroup of AML patients lacked myelodysplastic features in most cases and were associated with poor OS. To encompass cases of AML with MDS-like features, including unfavorable cytogenetic abnormalities, overexpression of multidrugresistance glycoprotein, and an unfavorable response to therapy, “AML with multilineage dysplasia” was introduced initially the WHO 2001 classification.16,17 Dysplasia in at least 50% of the cells in 2 or more hematopoietic lineages was used as a surrogate marker for these MDS-related biologic features.16,17 Although the prognostic significance of AML with multilineage dysplasia has been verified in some studies,18,19 in other studies morphologic multilineage dysplasia had no independent prognostic significance when cytogenetic findings were incorporated in the analysis.20,21 To address these issues, this patient subgroup has been redesignated as AML-MRC in the WHO 2008 classification and the criteria have expanded to include a history of MDS or MDS/MPN and cytogenetic findings. Patients can be assigned to this category if they have 20% blasts in the PB or BM and: (1) evolve from previously documented MDS or MDS/MPN; (2) have specific myelodysplasiarelated cytogenetic abnormalities; or (3) exhibit dysplasia in 50% of the cells in 2 myeloid lineages.17 According to the 2008 WHO classification, specific myelodysplasia-related cytogenetic abnormalities include t(5;12)(q33;p12), t(5;7)(q33;q11.2), t(5;17)(q33;p13), and t(5;10)(q33;q21). In the WHO 2008 classification, however, no references were cited to support these conclusions. In this study, there were 2 cases of AML with t(5;10)(q33;q21), but both cases did not show morphologic evidence of myelodysplasia, nor was
there a history of MDS or MDS/MPN. In this study group, 1 case of AML with t(2;5)(q21;q33) (case 9) showed evidence of myelodysplasia, which fulfilled the criteria of myelodysplasia-related changes by itself, showing > 50% of dysplastic cells in all trilineage hematopoiesis. This case also showed a complex karyotype and thus the relationship between 5q33 translocation and myelodysplasia is difficult to establish in this case. Miesner et al analyzed 408 cases of AML following the WHO classification of 2008.22 Among these 408 cases, 175 cases were classified as AML-MRC, and among this subgroup 25 (14.3%) cases showed MDS-related cytogenetics without showing morphologic evidence of multilineage dysplasia.22 These data suggest that the MDS-related cytogenetic aberrations listed in the 2008 WHO classification are not always related to myelodysplastic features in histological assessment. Miesner and colleagues did not provide details of the cytogenetic aberrations, and it remains unclear if most cases of AML associated with t(v;5q33) lack morphologic evidence of myelodysplasia. Various molecular assessments were performed in this study group; 1 of 6 (17%) cases showed FLT3-ITD mutation and 1 case was positive for NPM1 mutation. Miesner et al studied the frequency of molecular mutations in AML subgroups, including AMLnot otherwise specified, AML-MRC with MDS-related cytogenetics and/or MDS/MPN history, and AML-MRC diagnosed solely according to morphologic criteria (AML-MLD-sole).22 The frequency of FLT3-ITD mutation and NPM1 mutation were significantly greater in the AML-MLD-sole group than in the AML-MRC with MDS-related cytogenetics or MDS/MPN history group (NPM1, 57.6% vs. 12.3%, P < .001; FLT3-ITD, 17.4% vs. 7.4%, P < .001). There was no statistical difference in the prevalence of NRAS, MLL partial tandem duplication, or CEBPA mutations in their study.22 Devillier et al analyzed the molecular aberrations of 48 cases of AML-MRC to determine whether this WHO category has specific molecular abnormalities.15 They concluded the frequency of ASXL1, DNMT3A, NPM1, and FLT3-ITD mutations were significantly greater in AML-MRC cases than in noneAML-MRC cases.15 However, Devillier and colleagues included only a complex
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AML With t(v;5q33) Often Lacks Myelodysplastic Features karyotype, -5 or del(5q), -7, 11q23 abnormalities except t(9;11), t(6;9), 3q26 abnormalities and 17p abnormalities as myelodysplasiarelated cytogenetic abnormalities. Balanced translocation involving 5q33 were not included in the study group. The median OS of our study group was 12 months. Previous studies of patients with AML with balanced 5q translocations have shown a poor prognosis with a median OS of 4.4 months in MDS patients,3 although no data for AML-MRC patients are available. History of MPN was associated with a significantly shorter OS. The patients with a history of MPN were older and had higher BM cellularity at time of diagnosis of AML and these factors might be related to a worse prognosis. There was no correlation between complex karyotype and OS in our study, but further analysis with larger numbers of patients is necessary to confirm this finding.
Conclusion In conclusion, t(v;5q33) is a rare cytogenetic aberration in AML. Although associated with a poor outcome, AML with t(v;5q33) usually lacks morphologic evidence of myelodysplasia, Patients who have AML with t(v;5q33) after MPN had a worse OS compared with those with de novo AML.
Clinical Practice Points Limited data exists to support the WHO Classification
requirement to classify acute myeloid leukemia (AML) with balanced translocations involving 5q33 as AML with myelodysplasia-related changes (AML-MRC). In this study, we demonstrate that AML with t(v;5q33), a rare cytogenetic aberration in AML, usually lack morphologic evidence of multilineage dysplasia. The median overall survival of patients with t(v;5q33) in our study group was 12 months, and those with an antecedent myeloproliferative neoplasm had a significantly shorter overall survival. In terms of impact on clinical practice, our results suggest that t(v;5q33) should be regarded as a poor-risk finding in AML but does not per se warrant designation as AML-MRC.
Disclosure The authors have stated that they have no conflicts of interest.
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2. Olney HJ, Le Beau MM. Evaluation of recurring cytogenetic abnormalities in the treatment of myelodysplastic syndromes. Leuk Res 2007; 31:427-34. 3. Haase D, Germing U, Schanz J, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 2007; 110:4385-95. 4. Giagounidis A, Haase D. Morphology, cytogenetics and classification of MDS. Best Pract Res Clin Haematol 2013; 26:337-53. 5. Khoury JD, Sen F, Abruzzo LV, Hayes K, Glassman A, Medeiros LJ. Cytogenetic findings in blastoid mantle cell lymphoma. Hum Pathol 2003; 34:1022-9. 6. Schaffer LG, McGowan-Jordan J, Schmid M. ISCN 2013: An International System for Human Cytogenetic Nomenclature (2013). Basel, Switzerland: Karger; 2013. 7. Luthra R, Sanchez-Vega B, Medeiros LJ. TaqMan RT-PCR assay coupled with capillary electrophoresis for quantification and identification of bcr-abl transcript type. Mod Pathol 2004; 17:96-103. 8. Millecker L, Lennon PA, Verstovsek S, et al. Distinct patterns of cytogenetic and clinical progression in chronic myeloproliferative neoplasms with or without JAK2 or MPL mutations. Cancer Genet Cytogenet 2010; 197:1-7. 9. Jones D, Yao H, Romans A, et al. Modeling interactions between leukemia-specific chromosomal changes, somatic mutations, and gene expression patterns during progression of core-binding factor leukemias. Genes Chromosomes Cancer 2010; 49: 182-91. 10. Liang M, Han X, Vadhan-Raj S, et al. HDM4 is overexpressed in mantle cell lymphoma and its inhibition induces p21 expression and apoptosis. Mod Pathol 2010; 23:381-91. 11. Chen W, Konoplev S, Medeiros LJ, et al. Cuplike nuclei (prominent nuclear invaginations) in acute myeloid leukemia are highly associated with FLT3 internal tandem duplication and NPM1 mutation. Cancer 2009; 115:5481-9. 12. Meshinchi S, Woods WG, Stirewalt DL, et al. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood 2001; 97:89-94. 13. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434-9. 14. Patel KP, Barkoh BA, Chen Z, et al. Diagnostic testing for IDH1 and IDH2 variants in acute myeloid leukemia; an algorithmic approach using high-resolution melting curve analysis. J Mol Diagn 2011; 13:678-86. 15. Devillier R, Gelsi-Boyer V, Brecqueville M, et al. Acute myeloid leukemia with myelodysplasia-related changes are characterized by a specific molecular pattern with high frequency of ASXL1 mutations. Am J Hematol 2012; 87:659-62. 16. Brunning RD, Matutes E, Harris NL, et al. Acute myeloid leukaemia with multilineage dysplasia. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumors Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues. Lyon: IARC; 2001:88-9. 17. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114:937-51. 18. Arber DA, Stein AS, Carter NH, Ikle D, Forman SJ, Slovak ML. Prognostic impact of acute myeloid leukemia classification. Importance of detection of recurring cytogenetic abnormalities and multilineage dysplasia on survival. Am J Clin Pathol 2003; 119:672-80. 19. Weinberg OK, Seetharam M, Ren L, et al. Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system. Blood 2009; 113:1906-8. 20. Wandt H, Schakel U, Kroschinsky F, et al. MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients. Blood 2008; 111:1855-61. 21. Haferlach T, Schoch C, Loffler H, et al. Morphologic dysplasia in de novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: results of a multiparameter analysis from the German AML Cooperative Group studies. J Clin Pathol 2003; 21:256-65. 22. Miesner M, Haferlach C, Bacher U, et al. Multilineage dysplasia (MLD) in acute myeloid leukemia (AML) correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: a comparison of 408 cases classified as “AML not otherwise specified” (AML-NOS) or “AML with myelodysplasia-related changes” (AML-MRC). Blood 2010; 116:2742-51.
Acute Myeloid Leukemia With t(v;5q33) Is Associated With Poor Overall Survival and Often Lacks Myelodysplastic Features Mariko Yabe,1 Guilin Tang,1 Guillermo Garcia-Manero,2 Sanam Loghavi,1 Xinyan Lu,1 Roberto N. Miranda,1 L. Jeffrey Medeiros,1 Hagop M. Kantarjian,2 Carlos E. Bueso-Ramos,1 Joseph D. Khoury1 Abstract Acute myeloid leukemia (AML) with specific balanced 5q33 translocations are classified as AML with myelodysplasia-related changes (AML-MRC) by WHO 2008. The clinicopathologic features of such cases are poorly understood. Our study revealed that AML with t(v; 5q33) is not usually associated with myelodysplasia but shows poorer outcome. Background: Acute myeloid leukemia (AML) with specific balanced 5q33 translocations are classified as AML with myelodysplasia-related changes regardless of their morphologic findings or antecedent hematologic disease, but the clinicopathologic features of such cases remain poorly understood. Materials and Methods: From > 2000 cases of hematological malignancies seen at our institution between 2000 and 2013, we identified 9 AML patients with 5q33 translocations with variable partner loci, t(v;5q33). Results: The study group included 8 men and 1 woman, with a median age of 64 years (range, 19-87 years). Four patients had an antecedent myeloproliferative neoplasm (MPN). Cytogenetic analysis showed t(v;5q33) as a sole chromosomal abnormality in 4 (44%) patients, t(v;5q33) and del(3)(q21;q26.2) in 1 (11%) patient, and a complex karyotype in 4 (44%) patients. Only 1 patient had morphologic features of myelodysplasia in 2 or more lineages. Follow-up was available for 7 patients and the median overall survival (OS) was 12 months. Patients with a history of MPN had a significantly shorter OS compared with those with de novo AML (11 vs. 20 months; P ¼ .0445). There was no correlation between complex karyotype and OS in this small group of AML patients (P ¼ .5904). Conclusion: The t(v;5q33) is a rare cytogenetic aberration in AML. Although associated with a poor outcome, AML with t(v;5q33) usually lacks morphologic evidence of multilineage dysplasia. Patients who have AML with t(v;5q33) after MPN have a worse OS compared with those with de novo AML. Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. S1, S85-90 ª 2015 Elsevier Inc. All rights reserved. Keywords: Acute myeloid leukemia, Balanced translocation, Chromosome 5q, Cytogenetics, Myelodysplasia-related changes
Introduction Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is defined in the World Health Organization (WHO) classification as an acute leukemia with 20% 1
Department of Hematopathology Department of Leukemia The University of Texas M.D. Anderson Cancer Center, Houston, TX 2
Submitted: Dec 7, 2014; Accepted: Feb 3, 2015; Epub: Feb 9, 2015 Address for correspondence: Joseph D. Khoury, MD, Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 Fax: 713-794-1800; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.02.007
peripheral blood (PB) or bone marrow (BM) blasts with morphological features of myelodysplasia, a history of a myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN), or MDS-related cytogenetic abnormalities, and absence of genetic abnormalities that define diseases in the WHO category of AML with recurrent genetic abnormalities.1 AML-MRC occurs mainly in elderly patients and is rare in children, and represents 24% to 35% of all cases of AML.1 As listed in the WHO classification, many chromosomal abnormalities are considered sufficient for inclusion in this category with a complex karyotype and unbalanced abnormalities, -7/del(7q) and -5/del(5q) being most common.2 Balanced chromosomal translocations are less common in the category of AML-MRC but do occur.1
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AML With t(v;5q33) Often Lacks Myelodysplastic Features Table 1 Patient Characteristics and Bone Marrow Findings of AML With Balanced 5q33 Translocations
Study ID 1 2 3 4 5 6 7 8 9
Age
Sex
Antecedent Hematological Disorder
21 87 78 19 70 64 55 56 80
M M M M M M M M F
None None None None None PV (14 years) MPN-unclassifiable (5 years) MPN-unclassifiable (2 months) ET (15 years)
BM Cellularity, %
BM Blast, %
Myelodysplasia
95 15 25 100 45 90 90 95 70
20 80 41 90 7a 29 64 36 30
Yes (E) Yes (E) No No No No No No Yes (G, E, Me)
Abbreviations: AML ¼ acute myeloid leukemia; E ¼ erythroid precursors; ET ¼ essential thrombocythemia; F ¼ female; G ¼ granulocytes; M ¼ male; Me ¼ megakaryocytes; MPN ¼ myeloproliferative neoplasm; PV ¼ polycythemia vera. a Patient with concurrent myeloid sarcoma.
Cytogenetic findings have an established role in the diagnosis and assessment of prognosis of MDS patients.3 Abnormal karyotypes show an association with the severity of cytopenia, high BM blast count, and extent of cellular dysplasias.4 In AML-MRC, some studies show that AML cases with morphologic evidence of multilineage dysplasia had no independent prognostic significance when cytogenetic findings were incorporated in the analysis. Thus, it is important to specifically designate AML-MRC cases as having morphologic evidence of dysplasia or the designation of AML-MRC based on associated cytogenetic abnormalities. According to the 2008 WHO classification, AML patients with 5q33 translocations who do not fulfill the criteria of “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRB” are categorized as AML-MRC.1 Four specific translocations are specified as being eligible for the AML-MRC category: t(5;12)(q33;p12), t(5;7)(q33;q11.2), t(5;17)(q33;p13), and t(5;10) (q33;q21). However, this subset of AML has been incompletely studied because of the limited number of patients with t(v;5q33), and a definite relationship between balanced 5q33 translocations and myelodysplasia-related changes remains unclear. Accordingly, the aim of this study was to investigate the clinicopathologic features and outcome of AML with t(v;5q33).
Materials and Methods Study Group We searched the cytogenetic archives of The University of Texas M.D. Anderson Cancer Center between 2000 and 2013 for cases with t(v;5q33). Cases with peripheral eosinophilia fulfilling the criteria of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRB were excluded. Clinical data were collected from review of the medical records, which included demographic information, clinical presentation, underlying disease, laboratory information, and clinical follow-up. The institutional review board of The University of Texas M.D. Anderson Cancer Center approved this study.
Cytogenetics
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Conventional chromosomal analysis was performed on G-banded metaphases prepared from unstimulated 24-hour and 48-hour BM
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aspirate cultures using standard techniques as described previously.5 Twenty metaphases were analyzed and the results were reported using the 2013 International System for Human Cytogenetics Nomenclature (2013).6
Histological Assessment Bone marrow specimens obtained at the initial diagnosis and/or at time of emergence of 5q33 translocations were evaluated. Hematoxylin and eosin-stained slides of core biopsy and clot specimens Table 2 Laboratory Features of the Study Group Value Peripheral Blood (n [ 8) WBC, 109/L Median
18.1
Range
3.1-77.7
Blast, % Median
49
Range
0-74
Hemoglobin, g/dL Median
10.4
Range
8.6-17.0
Platelets, 109/L Median
93.5
Range
27-174
LDH, IU/L Median
495
Range
339-3911
Bone Marrow (n [ 9) Cellularity, % Median
90
Range
15-100
Blast, % Median
36
Range
7-90
Abbreviations: LDH ¼ lactate dehydrogenase; WBC ¼ white blood cell count.
Mariko Yabe et al with corresponding WrighteGiemsa-stained aspirate smears and touch imprints were reviewed.
Molecular Analysis Molecular analyses were performed as part of the routine clinical work-up. A real-time reverse transcription polymerase chain reaction (PCR) was performed to detect BCR-ABL1 fusion transcripts, as described previously.7 Mutational analysis for JAK2 V617F and codons 12, 13, or 61 of KRAS and NRAS were performed using pyrosequencing,8,9 and NPM1 (exon 12), KIT (exons 8 and 17), and CEBPA were analyzed using direct Sanger sequencing.9-11 A fluorescence-based multiplex PCR was used to detect internal tandem duplication and D835 point mutation of the FLT3 gene.12,13 PCRbased DNA high-resolution melting curve analysis was used for detecting IDH1 and IDH2 gene mutations as described previously.14
Statistical Analysis Statistical analyses were performed using GraphPad Prism 6. Overall survival (OS) was calculated from the date of initial diagnosis of AML to the date of death or last follow-up. Survival was analyzed using the KaplaneMeier method and was compared using the log-rank test. A P value of < .05 was considered statistically significant.
Results Clinical and Laboratory Features The clinical features are summarized in Table 1. The study group was composed of 9 patients, including 8 men and 1 woman. The median age at the time of diagnosis of AML was 64 years (range, 19-87 years). Four patients had an antecedent MPN, which included 2 MPN-unclassifiable (cases 7, 8), 1 essential thrombocythemia (case 9), and 1 polycythemia vera (case 6). None of these 4 patients had eosinophilia during their MPN phase or subsequent AML. The complete blood cell count at time of diagnosis of AML was available for 8 patients and the results are shown in Table 2. The median leukocyte count was 18.1 109/L (range, 3.1-77.7 109/L), median blast percentage was 49% (range, 0%-74%), median hemoglobin level was 10.4 g/dL (range, 8.6-17.0 g/dL), and median platelet count was 93.5 109/L (range, 27-174 109/L). The serum lactate dehydrogenase level was available in 8 patients and the median was 495 IU/L (range, 339-3911 IU/L; reference range, 313-618 IU/L).
Morphologic Features The results of BM examination at the diagnosis of AML were available for all patients. They showed median BM cellularity of 90% (range, 15%-100%), and median BM count of 36% (range,
Figure 1 Bone Marrow of AML With t(v;5q33). (A) Core Biopsy of Case 8 Shows Hypercellular Marrow (95%) Without Obvious Dysmegakaryopoiesis (Hematoxylin and Eosin [H&E], Magnification 3400). (B) and (C) High-Magnification of Bone Marrow Smear of Case 8 Shows No Dysgranulopoiesis and Dyserythropoiesis (Wright-Giemsa, Magnification 31000). (D) Core Biopsy of Case 9 Shows Hypercellular Marrow (70%) With Hypolobated Dysplastic Megakaryocytes (H&E, Magnification 3400). (E) and (F) High-Magnification of Bone Marrow Smear of Case 9 Shows Prominent Dysgranulopoiesis and Dyserythropoiesis (Wright-Giemsa, Magnification 31000)
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AML With t(v;5q33) Often Lacks Myelodysplastic Features Table 3 Cytogenetic Findings Study ID 1 2 3 4 5
6 7
8 9
Karyotype at the Time of Diagnosis of Acute Myeloid Leukemia 46,XY,t(3;5)(q21;q33)[20] 46,Y,del(X)(q13),t(1;5)(p11;q33),-3,þ8,del(12)(p11.2), -18,þ21[17]/46,XY[3] 46,Y,t(X;5)(p22.3;q33)[14]/46,XY[6] 46,XY,del(3)(q21q26.2)[2]/46,sl,t(5;8)(q33;q13) [16]/46,sl,t(6;15)(q25;q22)[1]/46,XY[1] 46,XY,t(5;10)(q33;q21)[2]/81-85,XXYY,-1,-2,-4,add(4)(q35)x2, -5,t(5;10)(q33;q21)x2,-7,-7,-8,-9,-11,-12,-15,-16,-17,-18, -18,þ9-10mar[cp2]/46,XY[16] 46,XY,t(5;10)(q33;q21)[20] 50,XY,t(5;12)(q33;p13),-6,þ8,þ14,þ19,þ21,þ1 -2mar[19]/64,XY,-1,-2,-4,-5,t(5;12)(q33;p13),-6,-6,-7,þ8, -10, -11,þ15,þ15,-16,þ19,-20,þ21,þ2mar[1] 46, XY, t(5;12)(q33;p13)[18]/46,XY [2] 42-45,XX,t(2;5)(q21;q33),-7,-15,-16,-18,þ1-2mar [cp20]
7%-90%; Tables 1 and 2). Patient 5 was diagnosed as AML with 7% of BM blasts due to the presence of concurrent myeloid sarcoma. Only 1 (11%) patient had morphologic evidence of myelodysplasia, which fulfilled the criteria of myelodysplasia-related changed by itself (at least 50% of the cells in at least 2 lineages; case 9). Two patients (cases 1 and 2) showed mild dysplasia in the erythroid lineage. The other 6 patients did not show any features of myelodysplasia (Figure 1).
Table 4 Molecular Analysis Results Gene
Tested
Positive
Negative
FLT3 NPM1 JAK2 CEBPA IDH1 IDH2 KIT ABL1 NRAS KRAS
6 1 1 1 1 1 1 4 5 5
1 1 0 0 0 0 0 0 0 0
5 0 1 1 1 1 1 4 5 5
(n ¼ 2), 12p13 (n ¼ 2), and 1 case each involved 1p11, 3q21, 8q13, and Xp22. Of note, loss of chromosome 18 was observed in 3 of 4 cases with complex karyotype. Various molecular assessments were performed, and the results are shown in Table 4. One (17%) of 6 patients assessed had an FLT3-internal tandem duplication (ITD) mutation. One patient was positive for NPM1 mutation. No mutations in JAK2 (0/1), CEBPA (0/1), IDH1 (0/1), IDH2 (0/1), KIT (0/1), ABL1 (0/4), NRAS (0/5), or KRAS (0/5) were identified among tested cases.
Treatment and Clinical Outcome Cytogenetic and Molecular Features The results of conventional cytogenetic analysis are shown in Table 3. The karyotype analysis showed t(v;5q33) as a sole abnormality in 4 (44%) patients (case 1, 3, 6, and 8), t(v;5q33) and del(3)(q21;q26.2) in 1 (11%) patient (case 4), and a complex karyotype in 4 (44%) patients (case 2, 5, 7, and 9; Figure 2). The various loci partnered with chromosome 5q33 included 10q21
The follow-up period ranged from 1 to 39 months, during which 6 patients died of disease, 2 patients were alive with disease, and 1 patient was lost to follow-up. For patients with available follow-up data, the median OS was 12 months. Antecedent MPN (n ¼ 3) was associated with a significantly shorter OS (11 vs. 20 months; P ¼ .0445). There was no correlation between complex karyotype and OS (P ¼ .5904; Figure 3).
Figure 2 Conventional Karyotype Analysis From Bone Marrow Specimen of Patients With t(v;5q33). (A) Case 1 Shows 46,XY,t(3:5)(q21;q33). (B) Case 4 Shows 46,XY,del(3)(q21q26.2),t(5;8)(q33;q13)
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Mariko Yabe et al Figure 3 Overall Survival (OS) of Patients With t(v;5q33). (A) Overall Survival for All Patients With Available Survival Data (n [ 7); Median OS is 12 Months. (B) Comparison of OS Between Patients With and Without History of Antecedent Myeloproliferative Neoplasm (MPN). The Cases With Antecedent MPN Had a Significantly Shorter Survival Than the Cases With de Novo Acute Myeloid Leukemia (AML; Median OS, 11 vs. 20 Months; P [ .0445). (C) Comparison of OS Between Patients With and Without Complex Karyotype. There Was No Correlation Between Complex Karyotype and OS in This Small Group (Median OS 11.5 vs. 20 Months; P [ .5904)
Discussion We identified a group of 9 patients with AML with t(v;5q33). Balanced cytogenetic abnormalities, including reciprocal translocations and inversions are prevalent in myeloid neoplasms such as AML or chronic myelogenous leukemia, but are uncommon in MDS, in which unbalanced chromosomal abnormalities are more prevalent.3 The median age of these 9 patients was 64 years (range, 19-87 years), and was slightly younger than previous reports of AML-MRC cases.15 BM cellularity and blast percentage were variable among these cases. In our study, this subgroup of AML patients lacked myelodysplastic features in most cases and were associated with poor OS. To encompass cases of AML with MDS-like features, including unfavorable cytogenetic abnormalities, overexpression of multidrugresistance glycoprotein, and an unfavorable response to therapy, “AML with multilineage dysplasia” was introduced initially the WHO 2001 classification.16,17 Dysplasia in at least 50% of the cells in 2 or more hematopoietic lineages was used as a surrogate marker for these MDS-related biologic features.16,17 Although the prognostic significance of AML with multilineage dysplasia has been verified in some studies,18,19 in other studies morphologic multilineage dysplasia had no independent prognostic significance when cytogenetic findings were incorporated in the analysis.20,21 To address these issues, this patient subgroup has been redesignated as AML-MRC in the WHO 2008 classification and the criteria have expanded to include a history of MDS or MDS/MPN and cytogenetic findings. Patients can be assigned to this category if they have 20% blasts in the PB or BM and: (1) evolve from previously documented MDS or MDS/MPN; (2) have specific myelodysplasiarelated cytogenetic abnormalities; or (3) exhibit dysplasia in 50% of the cells in 2 myeloid lineages.17 According to the 2008 WHO classification, specific myelodysplasia-related cytogenetic abnormalities include t(5;12)(q33;p12), t(5;7)(q33;q11.2), t(5;17)(q33;p13), and t(5;10)(q33;q21). In the WHO 2008 classification, however, no references were cited to support these conclusions. In this study, there were 2 cases of AML with t(5;10)(q33;q21), but both cases did not show morphologic evidence of myelodysplasia, nor was
there a history of MDS or MDS/MPN. In this study group, 1 case of AML with t(2;5)(q21;q33) (case 9) showed evidence of myelodysplasia, which fulfilled the criteria of myelodysplasia-related changes by itself, showing > 50% of dysplastic cells in all trilineage hematopoiesis. This case also showed a complex karyotype and thus the relationship between 5q33 translocation and myelodysplasia is difficult to establish in this case. Miesner et al analyzed 408 cases of AML following the WHO classification of 2008.22 Among these 408 cases, 175 cases were classified as AML-MRC, and among this subgroup 25 (14.3%) cases showed MDS-related cytogenetics without showing morphologic evidence of multilineage dysplasia.22 These data suggest that the MDS-related cytogenetic aberrations listed in the 2008 WHO classification are not always related to myelodysplastic features in histological assessment. Miesner and colleagues did not provide details of the cytogenetic aberrations, and it remains unclear if most cases of AML associated with t(v;5q33) lack morphologic evidence of myelodysplasia. Various molecular assessments were performed in this study group; 1 of 6 (17%) cases showed FLT3-ITD mutation and 1 case was positive for NPM1 mutation. Miesner et al studied the frequency of molecular mutations in AML subgroups, including AMLnot otherwise specified, AML-MRC with MDS-related cytogenetics and/or MDS/MPN history, and AML-MRC diagnosed solely according to morphologic criteria (AML-MLD-sole).22 The frequency of FLT3-ITD mutation and NPM1 mutation were significantly greater in the AML-MLD-sole group than in the AML-MRC with MDS-related cytogenetics or MDS/MPN history group (NPM1, 57.6% vs. 12.3%, P < .001; FLT3-ITD, 17.4% vs. 7.4%, P < .001). There was no statistical difference in the prevalence of NRAS, MLL partial tandem duplication, or CEBPA mutations in their study.22 Devillier et al analyzed the molecular aberrations of 48 cases of AML-MRC to determine whether this WHO category has specific molecular abnormalities.15 They concluded the frequency of ASXL1, DNMT3A, NPM1, and FLT3-ITD mutations were significantly greater in AML-MRC cases than in noneAML-MRC cases.15 However, Devillier and colleagues included only a complex
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AML With t(v;5q33) Often Lacks Myelodysplastic Features karyotype, -5 or del(5q), -7, 11q23 abnormalities except t(9;11), t(6;9), 3q26 abnormalities and 17p abnormalities as myelodysplasiarelated cytogenetic abnormalities. Balanced translocation involving 5q33 were not included in the study group. The median OS of our study group was 12 months. Previous studies of patients with AML with balanced 5q translocations have shown a poor prognosis with a median OS of 4.4 months in MDS patients,3 although no data for AML-MRC patients are available. History of MPN was associated with a significantly shorter OS. The patients with a history of MPN were older and had higher BM cellularity at time of diagnosis of AML and these factors might be related to a worse prognosis. There was no correlation between complex karyotype and OS in our study, but further analysis with larger numbers of patients is necessary to confirm this finding.
Conclusion In conclusion, t(v;5q33) is a rare cytogenetic aberration in AML. Although associated with a poor outcome, AML with t(v;5q33) usually lacks morphologic evidence of myelodysplasia, Patients who have AML with t(v;5q33) after MPN had a worse OS compared with those with de novo AML.
Clinical Practice Points Limited data exists to support the WHO Classification
requirement to classify acute myeloid leukemia (AML) with balanced translocations involving 5q33 as AML with myelodysplasia-related changes (AML-MRC). In this study, we demonstrate that AML with t(v;5q33), a rare cytogenetic aberration in AML, usually lack morphologic evidence of multilineage dysplasia. The median overall survival of patients with t(v;5q33) in our study group was 12 months, and those with an antecedent myeloproliferative neoplasm had a significantly shorter overall survival. In terms of impact on clinical practice, our results suggest that t(v;5q33) should be regarded as a poor-risk finding in AML but does not per se warrant designation as AML-MRC.
Disclosure The authors have stated that they have no conflicts of interest.
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