Here’s how readers responded to a You Make the Call question about reducing the transfusion burden in a patient with clonal cytopenias of undetermined significance.
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With these gene mutations, there is a strong probability of progression to a myeloid malignancy but, depending on the age of the patient, it may never become defined. Use of erythropoietin (EPO) or other growth factors in patients who are transfusion dependent usually is not successful and I would only try this if other factors make it worthwhile. Best to look out for other causes of anemia, including anemia of chronic disease. We sometimes see an underlying lymphoid disorder, so should be vigilant about this possibility.
Russel Kaufman, MD
Duke University School of Medicine
Mixalis Mixail, MD
Nicosia General Hospital
I think it’s important to improve iron status and consider erythropoietin.
Alicia Vilaseca, MD
San Camilo Clinic
Buenos Aires, Argentina
What’s the indication of liver transplant? How high is his serum ferritin level? I would rather initiate deferasirox 20 mg per kg body weight per day, escalating the dose gradually to 40 mg. Studies show that reducing iron may help in reducing transfusion requirements in MDS.
Ahmed Hamandi, MD
Al Kafeel Specialty Hospital
Since his erythropoietin levels are more than 300 U/L, it is unlikely that he will respond to erythropoietin replacement. However, a trial of epoetin alfa is worthwhile. I would also consider decreasing his immunomodulators like tacrolimus and or cyclosporine, which could contribute to the anemia. Lastly, I would consider starting red cell-enhancing drugs or enrolling him in a clinical trial with these agents.
V.C. Harish, MD
UNC Regional Physicians
High Point, NC
This clinical dilemma refers mainly to a paper by Luca Malcovati, MD, and colleagues, published last year in the Blood journal (Malcovati L. et al., Blood 2017; 129 (25): 3371-8). The TET2 and ASXL1 mutations might represent a “background” clone (age-related clonal hematopoiesis [ARCH] or clonal hematopoiesis of indeterminate potential [CHIP]). Mutations in TET2, DNMT3A, or ASXL1 have a lower positive predictive value (for diagnosing a myeloid neoplasm in patients with clonal cytopenia) when they occur as single lesions. Their positive predictive value is significantly higher when they are accompanied by additional genetic lesions, such as ZRSR2.
Therefore, the presence of ZRSR2 mutation might imply that this ARCH clone has already transformed to a more myelodysplastic syndromes (MDS)-like, less benign, condition. This is also supported by observations described by Brian Kwok, MD, and colleagues that showed that patients harboring a mutation in this gene were more likely to have MDS or CCUS with some dysplasia rather than CCUS without dysplasia (Kwok B et al., Blood 2015; 126 (21): 2355).
The ZRSR2 gene is located on the X chromosome, which explains its high allele frequency (85%). ZRSR2 is a gene that encodes for a member of the spliceosome complex. It was found to be mutated in 2.2 percent (Lindsley CR et al N Engl J Med 2017; 376:536) to 5 percent (as summarized by Bejar R et al Blood 2014; 124 (18):2793) of patients with MDS. It is one of the recurrently mutated genes in the subgroup of acute myeloid leukemia with mutated chromatin, RNA splicing genes, or both (Papaemmanuil E, et al. N Engl J Med. 2016;374:2209).
Patients with MDS with the mutated gene were found to have significantly lower relapse rates, but higher rates of non-relapse mortality, following allogeneic hematopoietic cell transplantation (alloHCT) even in multivariable analyses (Lindsley CR, et al. N Engl J Med. 2017; 376:536).
In CCUS, detecting a mutant ZRSR2 has a high positive predictive value for diagnosing a myeloid neoplasm regardless of whether this mutation is detected as an isolated lesion or in combination patterns. Moreover, patients with spliceosome gene mutations or mutations in TET2, ASXL1, or DNMT3A combined with additional mutations were shown to have a five-year cumulative probability of developing a myeloid neoplasm of 95 percent (Malcovati L, et al. Blood. 2017;129:3371.).
In my opinion, one should keep this patient under close follow up, support him with blood transfusions and iron chelation and look for a donor for alloHCT. Recruiting this patient to a clinical trial that targets this clone is another alternative, if available. However, one must always keep in mind that this patient’s entire hematopoietic system might be produced by this clone. Eliminating it might lead to aplasia.
Amos Tuval, MD
Meir Medical Center
Kfar Saba, Israel
The multiple mutations of CHIP-associated genes suggest that the patient has a high risk for developing MDS in the future, but at this point he has only CCUS, which is a term, not a diagnosis. EPO would be an option in MDS, but not in this patient without a proven hematologic disease and with such a high EPO-level. It’s not certain at all that CCUS is responsible for the cytopenias. Other causes should be excluded, especially in this patient who underwent a liver transplantation. We don’t know what the primary liver disease was, whether the patient has splenomegaly, etc. An anemia cannot be treated without knowing its cause.