How would you reduce the transfusion burden in a patient with CCUS?

David Steensma, MD
Edward P. Evans Chair in MDS Research and Institute Physician at the Dana-Farber Cancer Institute; Associate Professor of Medicine at Harvard Medical School; Editor-in-chief of ASH Clinical News

This month, David Steensma, MD, discusses transfusion burden in a patient with clonal cytopenias of undetermined significance.

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I am caring for a 67-year-old man who underwent a liver transplant four months ago. He had transfusion requirements of unclear etiology for one year prior to transplant, which have now increased. A bone marrow (BM) biopsy was done prior to the transplant, but it was non-diagnostic. The absolute neutrophil count since transplant has been variable, ranging from 700 to 6,000/mm3. The BM biopsy was hypercellular (70%) with myeloid left shift, but no dysplasia. Flow was unrevealing; there was no clonal lymphocyte population. Cytogenetics were normal. A next-generation sequencing panel showed the following mutations: TET2 (15-35%), ASXL1 (40-50%), and ZRSR2 (80-85%). So, technically he has clonal cytopenias of undetermined significance (CCUS). His erythropoietin level is 680 U/L. What therapeutic options are available to reduce his transfusion requirement?


Cytopenias evolving in a patient who has undergone a solid organ transplant have a broad differential diagnosis.1 An opportunistic infection, adverse medication effect, immune-mediated BM suppression, passenger lymphocyte syndrome, graft-versus-host disease (due to proliferation of allograft-associated lymphocytes), post-transplant lymphoproliferative disorder, and hemophagocytic lymphohistiocytosis are all potential causes. Among older patients, a coincidental clonal myeloid neoplasm also is a possibility. The latter is a particular concern in this case because of the unexplained transfusion requirement prior to transplant, despite the normal BM morphology.

The sequencing results are helpful in this case because they provide convincing evidence that the patient has clonal hematopoiesis. We must then ask if those clonal mutations are causing the cytopenias. Detection of a mutation does not automatically mean the mutation is directly resulting in the cytopenias. We need to keep in mind that about 10 percent of healthy people in this age cohort have single clonal mutations at a low variant allele frequency (VAF; e.g., DNMT3A, TET2, or ASXL1 mutation at <20% VAF), which is termed clonal hematopoiesis of indeterminate potential (CHIP), and they have normal blood counts.2-5 CHIP could be coincidentally present with another unrelated cause of cytopenias. However, the presence of multiple mutations is more characteristic of myelodysplastic syndromes (MDS).6,7 Patients who have CCUS, especially with multiple mutations, including spliceosome mutations like ZRSR2 in this case, have a natural history similar to lower-risk MDS and a much higher risk of developing a hematologic neoplasm.8 Based on the VAFs, most cells in this patient’s BM are clonal. (ZRSR2 VAFs tend to be high in males since ZRSR2 is an X-linked gene.) So, while it is possible that there is more than one contributing factor to the cytopenias, the sequencing results suggest that a substantial component of this patient’s BM failure is related to the clonal disorder.

Given his increasing transfusion needs, treatment is indicated. He is unlikely to respond to an erythropoiesis-stimulating agent (ESA) given the high EPO level. Using the Nordic model, patients with a serum EPO >500 U/L who require transfusions have a <10 percent chance of responding to an ESA.9 One could consider a DNA hypomethylating agent (HMA), but the optimal HMA dose and schedule in this case is unknown, especially for patients who lack higher-risk features such as excess blasts or a complex karyotype. An ongoing multicenter trial is exploring short-schedule 3-day decitabine versus 3- or 5- day azacitidine dosing in International Prognostic Scoring System lower-risk patients.10 One also could consider lenalidomide, despite the absence of del5q.11,12 If drug therapy fails and the disease progresses, allogeneic hematopoietic cell transplantation (alloHCT) is a last resort, and it represents the only potentially curative approach to a clonal process. Although certainly feasible, allo-HCT can be challenging in someone who has previously had a solid organ transplant. Finally, iron chelation therapy could be considered if it does not interact with his other medications. The risk-benefit balance of chelation in acquired BM failure syndromes is still controversial, but given the repeated transfusions would be worth discussing with the patient.

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  1. Smith EP. Hematologic disorders after solid organ transplantation. Hematology Am Soc Hematol Educ Program 2010;2010:281-6.
  2. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9-16.
  3. Genovese G, Kähler AK, Rose SA, et al. Clonal hematopoiesis and cancer risk in blood derived DNA sequence. N Engl J Med. 2014;371:2477-87.
  4. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488-98.
  5. Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472-8.
  6. Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536-47.
  7. Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122:3616-27.
  8. Malcovati L, Galli A, Travaglino E, et al. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood. 2017;129:3371-8.
  9. Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003;120:1037-46.
  10. Jabbour E, Short NJ, Montalban-Bravo G, et al. A randomized phase II study of low-dose decitabine versus low-dose azacitidine in lower risk MDS and MDS/MPN. Blood. 2017;130:1514-22.
  11. Santini V, Almeida A, Giagounidis A, et al. Randomized phase III study of lenalidomide versus placebo in RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes and ineligible for or refractory to erythropoiesis-stimulating agents. J Clin Oncol. 2016;34:2988-96.
  12. Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111:86-93.


For many years I have been caring for a now 35-year-old woman with hemoglobin (Hb) H disease. Her long-term numbers are average (Hb about 7.5 g/dL, reticulocytes about 7%, bilirubin about 2.5 mg/dL). She does not need transfusions but accumulates iron and needs long-term deferasirox to prevent her ferritin from rising above 1,000 μg/mL (was 1,700 in past). Would a splenectomy be a good option to improve her Hb, reduce iron overload, and improve quality of life?

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