HAEM4Backup:Therapy-Related Myeloid Neoplasms

Primary Author(s)*

Shawn A. Silver, DO, Shashi Shetty, Ph.D.

Cancer Category/Type

Therapy related myeloid neoplasms

Cancer Sub-Classification / Subtype

Therapy related cases of:

- Acute myeloid leukemia (tAML)

- Myelodysplastic syndrome (tMDS)

- Myelodysplastic/myeloproliferative neoplasm (tMDS/MPN)

Definition / Description of Disease

-Therapy related disease that occurs as a complication of cytotoxic chemotherapy and/or radiation therapy administered for a prior neoplastic or non-neoplastic disorder.

-Excluded from this category are progression of MPN and primary MDS or MDS/MPN to AML as progression to AML is part of the natural history of the primary disease and is nearly impossible to distinguish.

Synonyms / Terminology

-Therapy related acute myeloid leukemia

-Alkylating agent related

-Epipodophyllotoxin related

-Therapy related acute myeloid leukemia, NOS

Epidemiology / Prevalence

-Therapy related myeloid neoplasms (tMN) account for 10-20% of all cases of AML, MDS, and MDS/MPN. The incidence of tMN amongst treated patients depends on the underlying disease and the treatment strategy (see table below).

-Data suggest that about 70% of patients have been treated previously for a solid tumor and 30% have been treated for a hematological neoplasm. Breast cancer and non-Hodgkin lymphoma account for the largest number of cases, respectively.

-Between 5-20% of cases occur following therapy for a non-neoplastic disorder.

-All age groups affected, but risk rises with age.

Clinical Features

Two subsets of tMNs are generally recognized clinically:

More common, occurs 5-10 years after exposure to alkylating agents and/or ionizing radiation. Often present with an MDS with bone marrow failure and one or more cytopenias. Rare subset may present with tMDS/MPN or tAML.

1. Commonly associated with unbalanced loss of gtenetic material, often involving chromosomes 5 and/or 7, as well as complex karyotypes and mutations or loss of TP53.
2. Accounts for 20-30% of cases and has a shorter latent period of about 1-5 years. Usually follows treatment with DNA topoisomerase II. Most cases present with overt AML and often associated with a balanced chromosomal translocation.

Sites of Involvement

Bone marrow and blood. Initial presentation as extramedullary myeloid sarcoma has been reported.

Morphologic Features

-Most patients present with MDS or acute leukemia associated with multi-lineage dysplasia.

-Peripheral blood shows one or more cytopenias.

-Anemia is almost always present and RBC morphology is usually macrocytic and poikilocytic.

-neutrophils show abnormal nuclear segmentation and hypogranulation.

-basophilia is often present.

-Bone marrow may be hypo/hyper/or normocellular. Reticulin fibrosis is common.

-Dysgranulopoiesis and dyserythropoiesis is common.

-Dysplastic megakaryocytes with non lobated or hypolobated neuclie or widely separated lobes are common.

Immunophenotype

-Immunophenotypic findings reflect the heterogeneity of the underlying morphology.

-Blasts are generally CD34+ and express pan-myeloid antigens: CD13, CD 33, and MPO (MPO may be downregulated).

Additional Description:

-p53 positive cells in bone marrow biopsies have been demonstrated to correlate well with TP53 mutations and with a poor prognosis.

Chromosomal Rearrangements (Gene Fusions)

NA

Characteristic Chromosomal Aberrations / Patterns

-Leukemic cells of >90% of patients with tMN show an abnormal karyotype.

A) Approximately 70% of patients harbor unbalanced chromosomal aberrations, most commonly:

Loss of chromosome 7 or del(7q)

Partial loss of 5q or t(5q)

Loss of 5q is associated with:

del(13q)

del(20q)

del(11q)

del(3p)

Loss of 17p or chromosome 17

Loss of chromosome 18 or 21

Gain of chromosome 8

*Up to 80% of patients with del(5q) have mutations or deletion of TP53 as a result of abnormalities of 17p.

These changes are associated with: long latent period, preceding myelodysplastic phase or tAML with dysplastic features, and alkylating agent and/or radiation therapy.

B) 20-30% of patients have balance translocations that involve rearrangements of 11q23.3, including:

           t(9;11)(p21.3;q23.3)

           t(11;19)(q23.3;p13.1)

           21q22.1

           t(8;21)(q22;22.1)

           t(3;21)(q26.2q22.1)

           t(15;17)(q24.1;q21.1)

           inv(16)(p13.1q22)

These translocations are associated with: short latent period, present as tAML without a preceding myelodysplastic phase, prior topoisomerase II inhibitor therapy or radiation alone.

A small percentage of tMN patients have a reported normal karyotype.

Genomic Gain/Loss/LOH

NA

Gene Mutations (SNV/INDEL)

NA

Other Mutations

NA

Epigenomics (Methylation)

Unknown

Genes and Main Pathways Involved

Thought to be the consequence of mutation events in hematopoietic stem cells induced by cytotoxic therapy or selection of a myeloid clone with a mutator phenotype. Only a small proportion of patients treated with identical protocols develop tMN, suggesting that some individuals may have predisopistion due to mutations in DNA damage sensing or prepair genes, or polymorphisms in genes that affect drug metabolism, transport, or repair.

Diagnostic Testing Methods

Diagnosis is typically made by in the same fashion as the de novo counterparts with the added history of prior cytotoxic chemotherapy and/or radiation.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Prognosis is generally poor, common reported 5 year survival rates are <10%.

Cases with abnormalities in chromosome 5 and/or 7, TP53 mutations, and a complex karyotype have a particularly poor outcome with mean survival time of <1 year.

Cases with balanced chromosomal translocations generally have a better prognosis, however, such cases (except those with t(15;17), inv(16), or t(16;16)) have a shorter median survival time than their de novo counterparts.

Patients with therapy related APL with PML-RARA should be managed with the same urgency as de novo APL.

Familial Forms

Unknown

Other Information

Agents implicated in therapy related myeloid neoplasms:

Alkylating Agents: Melphalan, cyclophosphamide, nitrogen mustard, chlorambucil, busulfan, carboplatin, cisplatin, dacarbazine, procarbazine, carmustine, mitomycin C, thiotepa, Iomustine.

Ionizing Radiation Therapy: Large fields containing active bone marrow.

Topoisomerase II Inhibitors: Etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, actinomycin.

Others: Thiopurines, mycophenolate mofetil, fludarabine, vincristine, vinblastine, vindesine, paclitaxel, docetaxel.

-Use of adjuvant hematopoietic growth factors will typically increase the risk of developing tMN.

Links

NA

References

1. Campo E, Harris NL, Pileri SA et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Who Classification of Tum; 2017.
2. Churpek JE, Larson RA. The evolving challenge of therapy-related myeloid neoplasms. Best Pract Res Clin Haematol. 2013;26(4):309-17.
3. Granfeldt Østgård LS, Medeiros BC, Sengeløv H, et al. Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study. J Clin Oncol. 2015;33(31):3641-9.
4. Fianchi L, Pagano L, Piciocchi A, et al. Characteristics and outcome of therapy-related myeloid neoplasms: Report from the Italian network on secondary leukemias. Am J Hematol. 2015;90(5):E80-5.
5. Smith SM, Le beau MM, Huo D, et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood. 2003;102(1):43-52.
6. Guillem VM, Collado M, Terol MJ, et al. Role of MTHFR (677, 1298) haplotype in the risk of developing secondary leukemia after treatment of breast cancer and hematological malignancies. Leukemia. 2007;21(7):1413-22.
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8. Kayser S, Döhner K, Krauter J, et al. The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood. 2011;117(7):2137-45.
9. Arber DA, Slovak ML, Popplewell L, et al. Therapy-related acute myeloid leukemia/myelodysplasia with balanced 21q22 translocations. Am J Clin Pathol. 2002;117(2):306-13.
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12. Bloomfield CD, Archer KJ, Mrózek K, et al. 11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002;33(4):362-78.
13. Qian Z, Fernald AA, Godley LA, Larson RA, Le beau MM. Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia. Proc Natl Acad Sci USA. 2002;99(23):14925-30.
14. Fianchi L, Pagano L, Piciocchi A, et al. Characteristics and outcome of therapy-related myeloid neoplasms: Report from the Italian network on secondary leukemias. Am J Hematol. 2015;90(5):E80-5.
15. Cleven AH, Nardi V, Ok CY, et al. High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome. Mod Pathol. 2015;28(4):552-63.
16. Bhatia S. Therapy-related myelodysplasia and acute myeloid leukemia. Semin Oncol. 2013;40(6):666-75.
17. Larson RA. Cytogenetics, not just previous therapy, determines the course of therapy-related myeloid neoplasms. J Clin Oncol. 2012;30(19):2300-2.
18. Larson RA. Therapy-related myeloid neoplasms. Haematologica. 2009;94(4):454-9.

Notes

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