Lab Med Online.  2020 Oct;10(4):321-325. 10.47429/lmo.2020.10.4.321.

Emergence of Monosomy 7 in Philadelphia-Negative Cells during MDS Development and not CML Diagnosis Proved by Serial Droplet Digital PCR

• Park S
• Mun YC
• Seong CM
• Huh J

• KMID: 2512272
• DOI: http://doi.org/10.47429/lmo.2020.10.4.321

Abstract

Emergence of new clonal chromosomal abnormality (CCA) has been reported in Philadelphia-negative cells in patients with chronic myeloid leukemia (CML) undergoing the tyrosine kinase inhibitor (TKI) treatment. However, the time of emergence and clinical significance of CCA remains to be elucidated. In this study, we report a CML patient undergoing TKI treatment who developed myelodysplastic syndrome (MDS) after 206 months since the diagnosis of CML. Results of droplet digital PCR performed with serial bone marrow samples revealed that monosomy 7 in Philadelphia-negative cells appeared at the time of MDS development that did not exist initially at the time of CML diagnosis.

Keyword

Philadelphia-negative cell; Chronic myeloid leukemia; Monosomy 7; Droplet digital PCR; Myelodysplastic syndrome

Figure

• 

  Fig. 1 Bone marrow examination at 206 months since the diagnosis of chronic myeloid leukemia. (A and B) Bone marrow aspirate smears stained with the Wright-Giemsa stain show erythroid dysplasia of nuclear budding and megaloblastoid change, (1,000×). (C) Bone marrow biopsy sections stained with hematoxylin and eosin show hypocellularity (100×) and (D and E) clustered, multinucleated or hypolobated megakaryocytes (1,000×).

Reference

1. Ni H, Sun X, Xu Y, Lyle D, Peterson P, Zhao X, et al. 2019; Clinical implications of clonal chromosomal abnormalities in Philadelphia negative cells in CML patients after treated with tyrosine kinase inhibitors. Cancer Genet. 238:44–9. DOI: 10.1016/j.cancergen.2019.07.008. PMID: 31425925.

2. Issa GC, Kantarjian HM, Gonzalez GN, Borthakur G, Tang G, Wierda W, et al. 2017; Clonal chromosomal abnormalities appearing in Philadelphia chromosome-negative metaphases during CML treatment. Blood. 130:2084–91. DOI: 10.1182/blood-2017-07-792143. PMID: 28835440. PMCID: PMC5680612.

3. Lin Y, Bruyère H, Horsman DE, Pantzar T, Barnett MJ, Hogge DE, et al. 2006; Philadelphia-negative clonal hematopoiesis following imatinib therapy in patients with chronic myeloid leukemia: a report of nine cases and analysis of predictive factors. Cancer Genet Cytogenet. 170:16–23. DOI: 10.1016/j.cancergencyto.2006.04.012. PMID: 16965950.

4. Bumm T, Müller C, Al-Ali HK, Krohn K, Shepherd P, Schmidt E, et al. 2003; Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood. 101:1941–9. DOI: 10.1182/blood-2002-07-2053. PMID: 12411298.

5. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. 2013; European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 122:872–84. DOI: 10.1182/blood-2013-05-501569. PMID: 23803709. PMCID: PMC4915804.

6. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Last accessed on Mar 2020.

7. Radich JP, Deininger M, Abboud CN, Altman JK, Berman E, Bhatia R, et al. 2018; Chronic Myeloid Leukemia, Version 1. 2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 16:1108–35. DOI: 10.6004/jnccn.2018.0071. PMID: 30181422.

8. Zaccaria A, Testoni N, Valenti AM, Luatti S, Tonelli M, Marzocchi G, et al. 2010; Chromosome abnormalities additional to the Philadelphia chromosome at the diagnosis of chronic myelogenous leukemia: pathogenetic and prognostic implications. Cancer Genet Cytogenet. 199:76–80. DOI: 10.1016/j.cancergencyto.2010.02.003. PMID: 20471509.

9. Krysiak K, Christopher MJ, Skidmore ZL, Demeter RT, Magrini V, Kunisaki J, et al. 2016; A genomic analysis of Philadelphia chromosome-negative AML arising in patients with CML. Blood Cancer J. 6:e413. DOI: 10.1038/bcj.2016.18. PMID: 27058228. PMCID: PMC4855253.

10. Giustacchini A, Thongjuea S, Barkas N, Woll PS, Povinelli BJ, Booth CAG, et al. 2017; Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat Med. 23:692–702. DOI: 10.1038/nm.4336. PMID: 28504724.

11. Abyzov A, Mariani J, Palejev D, Zhang Y, Haney MS, Tomasini L, et al. 2012; Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature. 492:438–42. DOI: 10.1038/nature11629. PMID: 23160490. PMCID: PMC3532053.

12. Paul TR, Uppin SG, Uppin MS, Jacob RT, Rao DR, Rajappa SJ. 2010; Evaluation of cytopenias occurring in imatinib treated chronic myeloid leukemia (CML) patients. Indian J Hematol Blood Transfus. 26:56–61. DOI: 10.1007/s12288-010-0030-6. PMID: 21629637. PMCID: PMC3002067.

13. Quintás-Cardama A, De Souza Santos FP, Kantarjian H, O'Brien S, Faderl S, Awais A, et al. 2009; Dynamics and management of cytopenias associated with dasatinib therapy in patients with chronic myeloid leukemia in chronic phase after imatinib failure. Cancer. 115:3935–43. DOI: 10.1002/cncr.24432. PMID: 19517473. PMCID: PMC4386888.

14. LeMarbre G, Schinstock C, Hoyer R, Krook J, Tefferi A. 2007; Late onset aplastic anemia during treatment of chronic myeloid leukemia with imatinib mesylate. Leuk Res. 31:414–5. DOI: 10.1016/j.leukres.2006.08.011. PMID: 17010430. PMCID: PMC4342850.

15. Ramdial JL, Aguirre LE, Ali RA, Swords R, Goodman M. 2019; Aplasia in chronic phase CML post-TKI therapy: A management dilemma. Case Rep Hematol. 2019:4861673. DOI: 10.1155/2019/4861673. PMID: 31662918. PMCID: PMC6778880.

16. Jawad MD, Go RS, Ketterling RP, Begna KH, Reichard KK, Shi M. 2016; Transient monosomy 7 in a chronic myelogenous leukemia patient during nilotinib therapy: a case report. Clin Case Rep. 4:282–6. DOI: 10.1002/ccr3.506. PMID: 27014453. PMCID: PMC4771850.

17. Larsson N, Billström R, Lilljebjörn H, Lassen C, Richter J, Ekblom M, etal . 2010; Genetic analysis of dasatinib-treated chronic myeloid leukemia rapidly developing into acute myeloid leukemia with monosomy 7 in Philadelphia-negative cells. Cancer Genet Cytogenet. 199:89–95. DOI: 10.1016/j.cancergencyto.2010.02.005. PMID: 20471511.

18. Navarro JT, Feliu E, Grau J, Espinet B, Colomer D, Ribera JM, et al. 2007; Monosomy 7 with severe myelodysplasia developing during imatinib treatment of Philadelphia-positive chronic myeloid leukemia: two cases with a different outcome. Am J Hematol. 82:849–51. DOI: 10.1002/ajh.20859. PMID: 17563075.

19. Bidet A, Dulucq S, Smol T, Marceau-Renaut A, Morisset S, Coiteux V, et al. 2019; Poor prognosis of chromosome 7 clonal aberrations in Philadelphia-negative metaphases and relevance of potential underlying myelodysplastic features in chronic myeloid leukemia. Haematologica. 104:1150–5. DOI: 10.3324/haematol.2018.208801. PMID: 30573507. PMCID: PMC6545846.