Myelodysplastic Syndrome with Excess Blasts and Fibrosis
The third case in our series on myeloid neoplasms
Sanam Loghavi, Kamran Mirza, Mikkael Sekeres | | Longer Read
68-year-old woman with progressive fatigue and exertional dyspnea.
Pertinent physical exam
Complete blood count and differential (reference range)
Serum lactate dehydrogenase
497 U/L (135–214)
Peripheral blood and bone marrow morphology
Next-generation sequencing studies showed the following mutations:
Myelodysplastic syndrome with excess blasts-2 and fibrosis.
The pathologist’s view
A variety of bone marrow (BM) disorders, both benign and malignant, may be associated with a pathologic increase in stromal fibrosis – but, within the broad spectrum of chronic myeloid neoplasms, reticulin fibrosis is most often associated with myeloproliferative neoplasms, in particular with The diagnostic approach to myeloid neoplasms begins with careful review of peripheral blood findings, including trends in the hemogram. Typically, cytopenias and morphologic dysplasia are diagnostic clues to myelodysplastic syndromes (MDS), cytoses in the absence of frank dysplasia points towards MPNs, and those with mixed features fall into the MDS/MPN overlap category. In most cases, distinction between these entities is possible with careful assessment of a good quality BM sample, including an adequately cellular aspirate smear to allow for evaluation of dysplasia in all three hematopoietic lineages and an adequate trephine biopsy to allow for assessment of megakaryocytic distribution and morphology, stromal fibrosis, and osteosclerosis. However, several situations can lead to challenges in accurate subclassification. This case is one such example.
Given the presence of splenomegaly, BM hypercellularity, megakaryocytic hyperplasia, increased reticulin fibrosis, and the presence of JAK2 V617F, a differential diagnosis of PMF is not unreasonable. However, there are several clues here that point toward a diagnosis of MDS. These include bicytopenia in the absence of cytosis, megakaryocytes without significant clustering; predominantly small, monolobated, hyperchromatic megakaryocytes (unlike PMF, which typically shows a wide range of large, atypical, hyperlobulated megakaryotyes and some smaller, hyperchromatic forms), and prominent granulocytic and erythroid dysplasia. The karyotypic abnormalities involving chromosomes 3 and 5 and the presence of a dominant clone with a TP53 mutation that has a significantly higher VAF than the JAK2 mutation also suggests a diagnosis of MDS. An alternative differential diagnosis would be acute panmyelosis with myelofibrosis; however, the chronic nature of this patient’s presentation, lack of bone pain and fever, and blast count in this case argue against this diagnosis.
MDS with excess blasts and fibrosis (MDS-EB-F) is recognized as a distinct form of MDS in the newest iteration of the WHO classification (1). The presence of significant fibrosis is an independent prognostic predictor and should be specifically noted in the pathology report. If the bone marrow aspirate smear is insufficient for a 500-cell differential count, CD34 immunohistochemistry should be considered for accurate assessment of the blast count. The prevalence of TP53 alterations is significantly higher in cases of MDS-F compared with other variants of MDS. In most cases, aberrant p53 overexpression by immunohistochemistry correlates well with TP53 mutation status and serves as a reasonable crude surrogate marker for assessment of TP53 alterations in MDS-F (2). However, more recently, the implications of TP53 allelic state have been further elucidated in MDS (3). A TP53 multi-hit state predicts an increased risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R). It is therefore critical to carefully assess the allelic state of TP53 using a wide array of ancillary techniques including mutation analysis, routine karyotype, FISH, and array-CGH for complete assessment and prognostication.
The hematologist’s view
A 68-year-old woman comes to my office with progressive fatigue and dyspnea.
But that isn’t what she tells me.
Rather, she recounts a period of months during which, having just retired from her job as an office manager, she devotes herself to the upkeep of her garden and two-acre property and finds that she has to rest more and more. She even resorts to taking an hour-long nap each afternoon before preparing dinner for her and her husband. She hands over the responsibility of doing laundry to him when it becomes a chore to slog up and down the stairs to the basement to reach the washer and dryer (she stops halfway to catch her breath). She now sleeps 11 or 12 hours each night, but wakes in the morning no more refreshed than when her head first hit the pillow.
With two cytopenias, she buys herself a bone marrow biopsy that shows multilineage dysplasia, MF2 fibrosis, blasts, karyotypic abnormalities, and molecular abnormalities. For her diagnosis of MDS, we use the IPSS-R, for which she earns a number of points: 1.5 for having a hemoglobin < 8 g/dL, 0.5 for a platelet count between 50,000 and 90,000/mL, 3 for a blast percentage >10, and 3 for poor risk cytogenetics – a total of 8 points, a risk category of “very high,” and a predicted survival of about nine months. Though the IPSS-R does not formally include molecular abnormalities, adding them to our prediction (4) makes little difference; it’s hard to make dismal even worse.
After impressing on our patient the seriousness of her diagnosis, we make two treatment recommendations: the hypomethylating agent azacitidine and hematopoietic cell transplantation.
Azacitidine is given for seven days of a 28-day cycle and can only be administered in clinic, so represents a time commitment on the part of frequently older patients. It should be given for at least four to six cycles before response can be accurately assessed. Indeed, premature dose lowering, truncated cycles, or discontinuation contributes mightily to treatment “failure.” Other hypomethylating agents are available, too, though neither decitabine nor the newly approved oral cedazuridine/decitabine have demonstrated survival advantages in clinical trials.
Hematopoietic cell transplantation is the only known cure for MDS and, for higher-risk patients, should be encouraged at diagnosis. Azacitidine is often given as a bridge to those opting for a transplant, both to cytoreduce the MDS tumor burden pre-transplant and to avoid treatment delays should transplant turn out not to be an option. Unfortunately, except at highly specialized MDS and transplant centers, this curative therapy is undertaken by a small minority of patients, whether because of comorbidities that make transplant too risky, poorly matched or unavailable donors, or – most commonly – patient preference.
Do combination chemotherapy approaches work? Yes, but often no better than azacitidine monotherapy in randomized trials. One study combined azacitidine and the drug eprenetapopt, a small molecule drug that reactivates mutant and inactivated TP53 by restoring its confirmation and function. Investigators reported an overall response rate of 87 percent, more than double what would be expected for azacitidine monotherapy (5). This combination is being studied in a randomized trial that has completed accrual.
Patients with higher-risk MDS are caught between a rock and a hard place. Should they choose treatment with hypomethylating agents, sacrificing many days each month to receive their shots? Transplantation, with its attendant complications? Both? Or neither and opt instead for palliative options? It’s our job to help guide our patients on this unwanted and often treacherous journey, and ensure their choices meet their goals for the often limited amount of time they have left.
Read on to discover our other myeloid cases...
Case 1: Clonal Cytopenia of Uncertain Significance or Myelodysplastic Syndrome?
Case 2: SF3B1-Mutant Chronic Myelomonocytic Leukemia
Case 4: Elevating the Treatment Standard in Older Patients with AML
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- RP Hasserjian et al., “Myelodysplastic Syndromes: Overview,” WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. IARC: 2017.
- S Loghavi et al., “TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis,” Br J Haematol, 171, 91 (2015). PMID: 26123119.
- E Bernard et al., “Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes,” Nat Med, 26, 1549 (2020). PMID: 32747829.
- A Nazha et al., “Incorporation of molecular data into the Revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes,” Leukemia, 30, 2214 (2016). PMID: 27311933.
- DA Sallman et al., “Phase 2 results of apr-246 and azacitidine (aza) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML),” Blood, 134, 676 (2019).