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MYELODYSPLASTIC SYNDROME

Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia

Leukemia volume 36, pages 2328–2337 (2022)Cite this article

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Abstract

Predictors, genetic characteristics, and long-term outcomes of patients with SAA who clonally evolved after immunosuppressive therapy (IST) were assessed. SAA patients were treated with IST from 1989-2020. Clonal evolution was categorized as “high-risk” (overt myeloid neoplasm [meeting WHO criteria for dysplasia, MPN or acute leukemia] or isolated chromosome-7 abnormality/complex karyotype without dysplasia or overt myeloid neoplasia) or “low-risk” (non-7 or non-complex chromosome abnormalities without morphological evidence of dysplasia or myeloid neoplasia). Univariate and multivariate analysis using Fine-Gray competing risk regression model determined predictors. Long-term outcomes included relapse, overall survival (OS) and hematopoietic stem cell transplant (HSCT). Somatic mutations in myeloid cancer genes were assessed in evolvers and in 407 patients 6 months after IST. Of 663 SAA patients, 95 developed clonal evolution. Pre-treatment age >48 years and ANC > 0.87 × 109/L were strong predictors of high-risk evolution. OS was 37% in high-risk clonal evolution by 5 years compared to 94% in low-risk. High-risk patients who underwent HSCT had improved OS. Eltrombopag did not increase high-risk evolution. Splicing factors and RUNX1 somatic variants were detected exclusively at high-risk evolution; DNMT3A, BCOR/L1 and ASXL1 were present in both. RUNX1, splicing factors and ASXL1 somatic mutations detected at 6 months after IST predicted high-risk evolution.

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Fig. 1: Age and ANC as predictors for clonal evolution.
Fig. 2: Overall survival after clonal evolution or HSCT, and cumulative incidence of clonal evolution with eltrombopag.
Fig. 3: Clonal landscape of somatic mutations at the time of clonal evolution.
Fig. 4: Cumulative Incidence of clonal evolution according to somatic mutations at 6 months after IST.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Young NS. Aplastic anemia. N Engl J Med. 2018;379:1643–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376:1540–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, et al. Eltrombopag added to immunosuppression in severe aplastic anemia. N Engl J Med. 2022;386:11–23.

    Article  CAS  PubMed  Google Scholar 

  4. Socié G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli A. Late clonal diseases of treated aplastic anemia. Semin Hematol. 2000;37:91–101.

    Article  PubMed  Google Scholar 

  5. Rosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. Jama. 2003;289:1130–5.

    Article  CAS  PubMed  Google Scholar 

  6. Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373:35–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kulasekararaj AG, Jiang J, Smith AE, Mohamedali AM, Mian S, Gandhi S, et al. Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome. Blood. 2014;124:2698–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hosokawa K, Katagiri T, Sugimori N, Ishiyama K, Sasaki Y, Seiki Y, et al. Favorable outcome of patients who have 13q deletion: a suggestion for revision of the WHO ‘MDS-U’ designation. Haematologica. 2012;97:1845–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Afable MG 2nd, Wlodarski M, Makishima H, Shaik M, Sekeres MA, Tiu RV, et al. SNP array-based karyotyping: differences and similarities between aplastic anemia and hypocellular myelodysplastic syndromes. Blood. 2011;117:6876–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shah YB, Priore SF, Li Y, Tang CN, Nicholas P, Kurre P, et al. The predictive value of PNH clones, 6p CN-LOH, and clonal TCR gene rearrangement for aplastic anemia diagnosis. Blood Adv. 2021;5:3216–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Katagiri T, Sato-Otsubo A, Kashiwase K, Morishima S, Sato Y, Mori Y, et al. Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia. Blood. 2011;118:6601–9.

    Article  CAS  PubMed  Google Scholar 

  12. Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. Blood. 2016;128:337–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Negoro E, Nagata Y, Clemente MJ, Hosono N, Shen W, Nazha A, et al. Origins of myelodysplastic syndromes after aplastic anemia. Blood. 2017;130:1953–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Patel BA, Ghannam J, Groarke EM, Goswami M, Dillon L, Gutierrez-Rodrigues F, et al. Detectable mutations precede late myeloid neoplasia in aplastic anemia. Haematologica. 2021;106:647–50.

    Article  PubMed  Google Scholar 

  15. Socie G, Henry-Amar M, Bacigalupo A, Hows J, Tichelli A, Ljungman P, et al. Malignant tumors occurring after treatment of aplastic anemia. European Bone Marrow Transplantation-Severe Aplastic Anaemia Working Party. N. Engl J Med. 1993;329:1152–7.

    Article  CAS  PubMed  Google Scholar 

  16. Patel BA, Groarke EM, Lotter J, Shalhoub RN, Gutierrez-Rodrigues F, Rios OJ, et al. Long-term outcomes in severe aplastic anemia patients treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022;139:34–43.

    Article  CAS  PubMed  Google Scholar 

  17. Li Y, Li X, Ge M, Shi J, Qian L, Zheng Y, et al. Long-term follow-up of clonal evolutions in 802 aplastic anemia patients: a single-center experience. Ann Hematol. 2011;90:529–37.

    Article  PubMed  Google Scholar 

  18. Dumitriu B, Feng X, Townsley DM, Ueda Y, Yoshizato T, Calado RT, et al. Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia. Blood. 2015;125:706–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Scheinberg P, Cooper JN, Sloand EM, Wu CO, Calado RT, Young NS. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA. 2010;304:1358–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kojima S, Ohara A, Tsuchida M, Kudoh T, Hanada R, Okimoto Y, et al. Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood. 2002;100:786–90.

    Article  CAS  PubMed  Google Scholar 

  21. Socie G, Mary JY, Schrezenmeier H, Marsh J, Bacigalupo A, Locasciulli A, et al. Granulocyte-stimulating factor and severe aplastic anemia: a survey by the European Group for Blood and Marrow Transplantation (EBMT). Blood. 2007;109:2794–6.

    Article  CAS  PubMed  Google Scholar 

  22. Babushok DV, Duke JL, Xie HM, Stanley N, Atienza J, Perdigones N, et al. Somatic HLA mutations expose the role of class I–mediated autoimmunity in aplastic anemia and its clonal complications. Blood Adv. 2017;1:1900–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zaimoku Y, Patel BA, Adams SD, Shalhoub R, Groarke EM, Lee AAC, et al. HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia. Blood. 2021;138:2799–809.

    Article  CAS  PubMed  Google Scholar 

  24. Hosokawa K, Mizumaki H, Yoroidaka T, Maruyama H, Imi T, Tsuji N, et al. HLA class I allele–lacking leukocytes predict rare clonal evolution to MDS/AML in patients with acquired aplastic anemia. Blood. 2021;137:3576–80.

    Article  CAS  PubMed  Google Scholar 

  25. Maciejewski JP, Risitano A, Sloand EM, Nunez O, Young NS. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood. 2002;99:3129–35.

    Article  CAS  PubMed  Google Scholar 

  26. Ishiyama K, Karasawa M, Miyawaki S, Ueda Y, Noda M, Wakita A, et al. Aplastic anaemia with 13q–: a benign subset of bone marrow failure responsive to immunosuppressive therapy. Br J Haematol. 2002;117:747–50.

    Article  CAS  PubMed  Google Scholar 

  27. Cordoba I, Gonzalez-Porras JR, Nomdedeu B, Luno E, de Paz R, Such E, et al. Better prognosis for patients with del(7q) than for patients with monosomy 7 in myelodysplastic syndrome. Cancer. 2012;118:127–33.

    Article  CAS  PubMed  Google Scholar 

  28. Geary CG, Harrison CJ, Philpott NJ, Hows JM, Gordon-Smith EC, Marsh JCW. Abnormal cytogenetic clones in patients with aplastic anaemia: response to immunosuppressive therapy. Br J Haematol. 1999;104:271–4.

    Article  CAS  PubMed  Google Scholar 

  29. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood. 1998;92:2322–33.

    Article  CAS  PubMed  Google Scholar 

  30. Keung YK, Pettenati MJ, Cruz JM, Powell BL, Woodruff RD, Buss DH. Bone marrow cytogenetic abnormalities of aplastic anemia. Am J Hematol. 2001;66:167–71.

    Article  CAS  PubMed  Google Scholar 

  31. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.

    Article  Google Scholar 

  32. Scrucca L, Santucci A, Aversa F. Regression modeling of competing risk using R: an in depth guide for clinicians. Bone Marrow Transplant. 2010;45:1388–95.

    Article  CAS  PubMed  Google Scholar 

  33. Calhoun P, Su X, Nunn M, Fan J. Constructing multivariate survival trees. MST Package R 2018. 2018;83:21.

    Google Scholar 

  34. Terry Therneau PMG. Modeling Survival Data: Extending the Cox Model: Springer, New York, NY; 2000.

  35. Pagliuca S, Gurnari C, Awada H, Kishtagari A, Kongkiatkamon S, Terkawi L, et al. The similarity of class II HLA genotypes defines patterns of autoreactivity in idiopathic bone marrow failure disorders. Blood. 2021;138:2781–98.

    Article  CAS  PubMed  Google Scholar 

  36. Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl J Med. 2014;371:2477–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Cazzola M. Myelodysplastic syndromes. N. Engl J Med. 2020;383:1358–74.

    Article  CAS  PubMed  Google Scholar 

  38. Watson CJ, Papula AL, Poon GYP, Wong WH, Young AL, Druley TE, et al. The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science. 2020;367:1449–54.

    Article  CAS  PubMed  Google Scholar 

  39. Bono E, McLornan D, Travaglino E, Gandhi S, Gallì A, Khan AA, et al. Clinical, histopathological and molecular characterization of hypoplastic myelodysplastic syndrome. Leukemia. 2019;33:2495–505.

    Article  CAS  PubMed  Google Scholar 

  40. Winkler T, Fan X, Cooper J, Desmond R, Young DJ, Townsley DM, et al. Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag. Blood. 2019;133:2575–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kennedy JA, Ebert BL. Clinical implications of genetic mutations in myelodysplastic syndrome. J Clin Oncol. 2017;35:968–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–7.

    Article  CAS  PubMed  Google Scholar 

  43. Quentin S, Cuccuini W, Ceccaldi R, Nibourel O, Pondarre C, Pagès MP, et al. Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions. Blood. 2011;117:e161–70.

    Article  CAS  PubMed  Google Scholar 

  44. Sood R, Kamikubo Y, Liu P. Role of RUNX1 in hematological malignancies. Blood. 2017;129:2070–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Funding for this study was provided by the intramural research program of the National Heart, Lung, and Blood Institute. NSY and CED receive research funding from Novartis via a CRADA. This study was presented as an oral abstract at the American Society of Hematology annual meeting 2021. Graphic artist credit to Alan Hoofring, NIH Medical Arts Department.

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Author notes

  1. These authors contributed equally: Emma M. Groarke, Bhavisha A. Patel.

Authors and Affiliations

  1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Emma M. Groarke, Bhavisha A. Patel, Fernanda Gutierrez-Rodrigues, Parth Desai, Harshraj Leuva, Yoshitaka Zaimoku, Casey Paton, Nina Spitofsky, Jennifer Lotter, Olga Rios & Neal S. Young

  2. Office of Biostatistics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Ruba Shalhoub & Colin O. Wu

  3. Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Richard W. Childs

  4. Translational Stem Cell Biology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    David J. Young & Cynthia E. Dunbar

  5. Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA

    Alina Dulau-Florea & Katherine R. Calvo

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Contributions

EMG designed and performed research, analyzed data, provided clinical care, and wrote the paper. BAP and NSY designed and performed research, analyzed data, provided clinical care, and edited the paper. RS and COW analyzed data. FGR performed sequencing and analyzed data. PD, HL, CP, NS, YZ analyzed data. KRC, AD-F reviewed marrows and analyzed data. JL and OR provided clinical care. RWC, CED, DJY provided clinical care and performed research.

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Correspondence to Emma M. Groarke.

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NSY and CED receive funding from a Collaborative Research and Development Agreements between NIH and Novartis. No other authors have relevant conflicts of interest.

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Groarke, E.M., Patel, B.A., Shalhoub, R. et al. Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia. Leukemia 36, 2328–2337 (2022). https://doi.org/10.1038/s41375-022-01636-8

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