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Case Study: TP53-Mutated Myelodysplastic Syndrome

  • Advances in Hematologic Malignancies Issue 9, Fall 2018

    David P. Steensma, MD FACP

    A 70-year-old woman was referred to us by her primary care doctor for pancytopenia. Twenty-two years earlier, she had undergone adjuvant chemotherapy and radiation therapy for locally-advanced breast cancer. There had been no evidence of recurrence of the breast cancer in the intervening years.

    Her marrow biopsy was hypercellular for age and demonstrated multilineage dysplasia, with 4% myeloid blasts, consistent with a diagnosis of myelodysplastic syndrome with multilineage dysplasia (MDS-MLD). The karyotype showed trisomy 8 and monosomy 7 in 15/20 metaphases, and a "Rapid Hematology Panel" next-generation sequencing assay revealed mutations in U2AF1 (an mRNA splicing factor) and DNMT3A (DNA methyltransferase), which are acquired (somatic) mutations commonly associated with MDS. Unfortunately, a TP53 R175H mutation was also noted, in 31% of sequencing reads.

    In MDS, TP53 mutations are frequently associated with a complex or monosomal karyotype, reflecting the importance of intact TP53 protein function for genome stability. Such mutations confer the highest risk for disease progression and death among known MDS-associated mutations. A recent analysis of the International Working Group for Prognosis in MDS (IWG-PM) indicates that TP53 mutations and deletions account for most of the adverse outcomes associated with a complex karyotype. In patients with MDS or acute myeloid leukemia (AML), TP53 mutations are most commonly seen in patients who have previously undergone chemotherapy or radiotherapy treatment for another neoplasm (i.e., those who have therapy-related MDS/AML), but can be seen in de novo cases as well.

    TP53 mutations also strongly influence treatment outcomes. Loss of TP53 function confers resistance to conventional cytotoxic drugs such as alkylating agents, and patients with AML who have TP53 mutations rarely achieve durable remission after induction chemotherapy. Patients with TP53 mutations who receive DNA hypomethylating agents often respond favorably to treatment, especially with 10-day decitabine (Welch J et al, New Engl J Med 2016), but response duration is short: a median of about 8 months. Among patients who go to allogeneic hematopoietic cell transplantation for MDS, TP53 mutant patients do the worst, with long-term disease-free survivals below 20% (Lindsley RC et al, New Engl J Med 2017) compared to >40% for TP53 wild-type cases. TP53 loss, which commonly results from loss of chromosome 17 (del17p), may have different implications compared to TP53 point mutations.

    The patient described here elected to defer transplant evaluation and was enrolled in a Phase 1B/2 clinical trial of azacitidine combined with APR-246, a novel drug that promotes refolding of TP53 and restoration of TP53 function, which may sensitize clonal cells to chemotherapy. This clinical trial (Dana-Farber #17-378) is currently open at 3 sites, including Dana-Farber Cancer Institute. Eligible patients receive APR-246 for the first 4 days of each 28-day cycle, and then on day 4 they begin standard 7-day azacitidine. The most common adverse events of APR-246 described to date include reversible neuropathy and nausea. Initial promising results from this clinical trial were presented by Dr. David Sallman from the H. Lee Moffitt Cancer Center at the European Hematology Association (Figures 1 and 2). This study is now in phase 2 and due to the high rate of response among the initial cohorts, further studies in MDS are planned.

     

  • MDS case study - figure 1

    Figure 1: Response of patients in Phase I portion of APR-246 + azacitidine study in TP53 mutant MDS.
    From Sallman D, Sweet K, DeZern A, Steensma D et al, European Hematology Association 23rd Annual Meeting, June 2018, Stockholm, Sweden. Subsequently, all 3 patients at dose level 3 (DL3), including the patient described in this vignette, also achieved CR or marrow CR. CR = complete response, mCR = marrow CR (<5% blasts), HI = hematological improvement, NR = no response, NE = not evaluable, DL = dose level.

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  • MDS case study - figure 2

    Figure 2: Serial p53 immunohistochemistry (IHC) in a patient treated with APR-246 + azacytidine, demonstrating reduction of the neoplastic clone (200x).
    Of note, bright, diffuse immunoexpression of P53 protein correlates with TP53 gene mutation, since aberrant TP53 has prolonged turnover. (A) Pre-treatment bone marrow (BM) biopsy with 90% cellularity and 4-5% blasts (Haematoxylin & Eosin); (B) p53 IHC showing elevated p53; (C) BM biopsy from same patient following 3 cycles of therapy showing normocellularity without increase in blasts (H&E); (D) significantly decreased p53 compared to pre-treatment marrow. From Sallman D, Sweet K, DeZern A, Steensma D et al, European Hematology Association 23rd Annual Meeting, June 2018, Stockholm, Sweden.