Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis

INTRODUCTION — Patients who are exposed to deoxyribonucleic acid (DNA)-damaging agents, including cytotoxic chemotherapy and radiation therapy, are at risk for developing therapy-related myeloid neoplasms (t-MNs). These disorders comprise a continuum of diseases that includes acute myeloid leukemia, myelodysplastic syndromes/neoplasms (MDS), and MDS/myeloproliferative neoplasms.

Any myeloid neoplasm in a patient who previously received cytotoxic therapy for another malignancy or an autoimmune disorder is considered to have a t-MN. However, the International Classification Consensus [1] and the World Health Organization 5^th edition [2] apply different labels and diagnostic criteria for t-MNs.

Certain cytogenetic and molecular changes are common in these disorders; t-MNs frequently exhibit adverse biologic features and poor outcomes. The interval from first exposure until diagnosis of a t-MN (ie, disease latency) varies with the type of agent.

This topic discusses the epidemiology, causes, evaluation, diagnosis, and classification of t-MNs.

Management and prognosis of t-MNs are discussed separately. (See "Therapy-related myeloid neoplasms: Management and prognosis".)

DESCRIPTION — t-MNs comprise a spectrum of myeloid malignancies, including acute myeloid leukemia (AML), myelodysplastic syndromes/neoplasms (MDS), and MDS/myeloproliferative neoplasms (MPN). Compared with the corresponding de novo AML, MDS, or MDS/MPN, t-MNs more often exhibit adverse biologic features and resistance to treatment.

The names and diagnostic criteria for t-MNs differ between the two contemporary classification schemes:

●International Classification Consensus – The International Classification Consensus (ICC) describes t-MNs according to their morphologic and genetic features as either MDS, MDS/AML, AML, or MDS/MPN but adds "therapy-related" as a diagnostic qualifier [1]. t-MNs are not considered a separate category of disorders in the ICC system.

Cases of t-MNs with a mutated TP53 (which encodes p53) are included in a new ICC category called Myeloid neoplasm with mutated TP53 [1]. Cases that do not meet criteria for this category are described as either MDS, MDS/AML, AML, or MDS/MPN with "therapy-related" after the corresponding diagnosis.

Further discussion of the ICC classification system is provided separately. (See "Classification of hematopoietic neoplasms", section on 'International Consensus Classification (ICC)'.)

●World Health Organization 5^th edition – World Health Organization 5^th edition (WHO5) gives primacy to the relatedness of these disorders to prior treatment. However, within the category, it is recommended that a complete diagnosis be provided based on morphology and genetic features, and the descriptor "post cytotoxic therapy" is added to the relevant myeloid disease to distinguish them from myeloid disorders associated with germline/inherited gene variants. [2].

Cases of AML, MDS, and MDS/MPN in patients with prior exposure to cytotoxic therapy are included in a new WHO5 category, entitled Secondary myeloid neoplasms, which also includes germline/inherited disorders.

Further discussion of the WHO5 classification system is provided separately. (See "Classification of hematopoietic neoplasms", section on 'World Health Organization 5th edition (WHO5)'.)

EPIDEMIOLOGY — The incidence of t-MNs varies with the specific treatment and underlying disease. It has been estimated that t-MNs account for 10 to 20 percent of all cases of the corresponding myeloid malignancies [3-6].

●Age – Patients of any age can be affected, but the median age at diagnosis of a t-MN is 61 years [7,8]. The risk of t-MNs associated with alkylating agents and radiation therapy (RT) appears to increase with age, while the risk associated with topoisomerase II inhibitors appears to be constant across the age spectrum [9].

●Preceding condition – More than 80 percent of t-MNs are associated with treatment for a prior malignancy. It has been estimated that 70 percent of prior malignancies were a solid tumor, while 30 percent were an earlier hematologic malignancy [3-5,9,10]. The remaining 5 to 20 percent of cases arise in patients treated with cytotoxic therapy for a non-neoplastic disorder or who underwent autologous hematopoietic cell transplantation for a nonmyeloid neoplasm.

A population-based study of more than 400,000 patients treated with chemotherapy in the United States (1975 to 2008) reported that, compared with the general population, there was a 4.7-fold increased risk (95% CI 4.4-5.0) for therapy-related acute myeloid leukemia (AML) [11]. The highest excess annual risks were observed after treatment for Hodgkin lymphoma (HL) and multiple myeloma (MM), while the lowest were after breast cancer.

●Disease latency – Disease latency refers to the interval from first exposure to the cytotoxic agent until the diagnosis of t-MNs. Disease latency varies with the implicated agent(s).

In one study, the incidence for therapy-related AML was highest in the first five years after treatment, but the risk subsequently declined [11]. After ≥10 years, there was no increased risk after treatment for a nonhematologic malignancy, but a three- to sixfold increased risk persisted for patients with a prior HL, non-Hodgkin lymphoma (NHL), or MM.

In a single-institution study of 306 patients with a t-MN, 77 had a prior HL, 70 had an NHL, 24 had MM or another hematologic malignancy, 117 had various solid tumors, and 18 had nonmalignant diseases (primarily autoimmune diseases or kidney transplantation) [12]. Patients in this study had been treated with combined RT plus chemotherapy (139 patients), chemotherapy alone (121 patients), or RT alone (43 patients). Most patients treated with RT alone received radiation to large portals encompassing active bone marrow. Median latency for the entire population was 62 months, but it was longer in patients with nonmalignant primary diagnoses and in younger patients.

Development of t-MNs after treatment for specific diseases is discussed in those topics.

CAUSES — By definition, t-MNs occur in patients who were previously treated with DNA-damaging agents, such as cytotoxic chemotherapy or radiation therapy (RT). Designation as a t-MN does not prove causality in an individual case.

t-MNs may be a direct consequence of mutational events induced by cytotoxic therapy and/or by selection and expansion of treatment-resistant clones [13-15]. Various DNA-damaging treatments and underlying diseases are associated with the development of t-MNs, but certain individuals also have an inherited predisposition or other contributing factors.

Causal agents — Several categories of cytotoxic therapy have been most frequently associated with t-MNs. Disease latency varies with the type of therapy.

●Alkylating agents – Alkylating agents that have been associated with t-MNs include melphalan, cyclophosphamide, nitrogen mustard, chlorambucil, busulfan, carboplatin, cisplatin, dacarbazine, procarbazine, carmustine, mitomycin, thiotepa, and lomustine.

t-MNs typically present five to seven years after initial treatment with alkylating agents or RT [4,12,16-18]. Two-thirds of cases are first recognized by evidence of myelodysplasia (usually trilineage dysplasia), marrow failure, and pancytopenia. The most common chromosomal findings involve complex abnormalities, deletion of 5q or 17p, and monosomies (eg, -7).

●Topoisomerase II inhibitors – Implicated agents include etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, and actinomycin. The malignancies usually present as acute myeloid leukemia (AML) and only rarely as other myeloid neoplasms.

The latency with topoisomerase II inhibitors is generally one to three years after treatment, which is shorter than after alkylating agent therapy; antecedent myelodysplastic syndromes/neoplasms (MDS) is rare [19-23]. Topoisomerase II inhibitors are associated with breakage at topoisomerase II sites leading to abnormal recombination and balanced translocations; examples include KMT2A at chromosome 11q23.3, RUNX1 at 21q22.1, or RARA at 17q21.2.

●PARP inhibitors – PARP (poly [ADP-ribose] polymerase) inhibitors have been associated with an increased risk for t-MNs [24]. A meta-analysis that included 18 randomized placebo-controlled trials reported that PARP inhibitors increased the odds ratio 2.63-fold (CI 1.13–6.14) for MDS and AML; median latency from initial treatment to diagnosis was 18 months [25].

●Radiation therapy – t-MNs usually arise after RT that involves large fields that encompass active bone marrow. RT alone, RT plus chemotherapy (combined modality treatment), and radionuclide-linked agents have been associated with t-MNs. The latency period after RT is typically five to seven years [16-18].

●Other agents – Antimetabolites (eg, thiopurines, mycophenolate mofetil, fludarabine) and antitubulin agents (eg, vincristine, vinblastine, vindesine, paclitaxel, docetaxel) have been implicated, often when they were administered with one or more of the agents listed above. Methotrexate was excluded as a causal agent in the World Health Organization 5th edition [2], but its possible role remains uncertain.

Latency periods with these other agents are less certain because many patients had exposure to multiple and/or sequential DNA-damaging agents.

The role of agents such as hydroxyurea, L-asparaginase, and radioisotopes is less certain. Growth factors, such as filgrastim, may facilitate emergence of a t-MN clone, as discussed separately. (See "Introduction to recombinant hematopoietic growth factors", section on 'Possible stimulation of malignancy'.)

Mechanisms — In many cases, t-MNs are thought to be the direct consequence of mutational events induced by cytotoxic therapy. In general, t-MNs are associated with adverse genetic lesions, and more than 90 percent show an abnormal karyotype.

Because t-MNs develop in only a small percentage of patients treated with these agents, the underlying pathophysiology is not well defined. The following mechanisms are thought to contribute to the pathophysiology of t-MNs:

●Inherited predisposition – Some affected individuals may have an inherited predisposition, such as a pathogenic variant in a DNA damage-sensing or repair gene (eg, BRCA1/2 or TP53) or polymorphisms in genes that affect drug metabolism or transport [26-28].

●Selection for progression of aberrant clones – Cytotoxic agents can select for clones of cells that are relatively resistant to treatment. Such clones may reflect clonal hematopoiesis of indeterminate potential (CHIP) or a pre-existing population of chemotherapy-resistant cells.

•CHIP refers to a clone of cells with a somatic mutation of a myeloid neoplasm driver gene with ≥2 percent allele frequency in a patient lacking a myeloid neoplasm or unexplained cytopenia. CHIP can be a precursor to a t-MN, and it may also occur as a consequence of cytotoxic therapy [29]. CHIP is discussed in greater detail separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

•Expansion of a pre-existing chemotherapy-resistant myeloid clone may contribute to t-MN development [30]. As examples, hematopoietic stem or progenitor cells that carry mutated TP53 or PPM1D may undergo positive selection by cytotoxic therapy. Mutations found at diagnosis of a t-MN have been identified at low frequency in blood or bone marrow specimens from many years earlier [31].

CLINICAL PRESENTATION — The clinical presentation of a t-MN varies, but most patients present with findings that resemble those of de novo acute myeloid leukemia or primary myelodysplastic syndromes/neoplasms. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Clinical presentation' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Clinical presentation'.)

EVALUATION — A patient with a suspected t-MN should undergo clinical evaluation, laboratory studies, and bone marrow examination.

Evaluation for a t-MN should be performed in accordance with College of American Pathologists and the American Society of Hematology (CAP-ASH) guidelines [32] and European LeukemiaNet [33,34]. Additional details of the evaluation are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

It is important to evaluate the patient for a germline or inherited predisposition, especially in cases with mutated PPM1D, DNA-damage response genes, or other uncommon genetic findings. Germline conditions are especially likely in cases where the variant allele frequency (VAF) is approximately 50 percent or the VAF does not change at the time of remission.

Clinical

●History reveals prior treatment with a cytotoxic agent for another malignancy or nonmalignant condition. The specific agents and period of exposure should be determined.

The most common symptoms are related to pancytopenia, such as weakness, easy fatigue, fever, and/or excessive bleeding/bruising (eg, gingival bleeding, epistaxis, menorrhagia). Some patients have few or no symptoms; in such cases the diagnosis is based on laboratory findings alone.

●Physical examination may reveal pallor, petechiae, or ecchymoses, but there may be no abnormal findings. Occasionally, a patient may present with splenomegaly or a myeloid sarcoma (chloroma).

The clinical presentations of de novo AML and MDS are described separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Clinical presentation' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Clinical presentation'.)

Laboratory — Laboratory studies reflect findings associated with acute myeloid leukemia (AML), myelodysplastic syndromes/neoplasms (MDS), or an MDS/myeloproliferative neoplasm (MPN).

The following laboratory studies should be performed:

●Hematology

•Complete blood count with differential leukocyte count

The complete blood count (CBC) and differential count typically reveal one or more cytopenias. Anemia is almost always present, and red blood cells (RBCs) are usually normochromic/normocytic or macrocytic (increased mean cell volume [MCV]) with poikilocytosis (elevated red cell distribution width [RDW]).

Some patients have leukocytosis related to circulating blasts or other immature or dysplastic myeloid forms, while others may have leukopenia and/or thrombocytopenia.

•Blood smear – Microscopy resembles the corresponding AML, MDS, or MDS/MPN.

Myeloid blasts, with or without Auer rods (picture 1), may be apparent in peripheral blood. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Peripheral blood'.)

There may be dysplasia with RBC abnormalities (eg, dyserythropoiesis) (picture 2 and picture 3) [12,35,36], but some cases manifest few or no detectable abnormal forms in peripheral blood. There may be dysplasia in the neutrophil lineage, such as nuclear hyposegmentation (eg, Pelger-Huet anomaly) (picture 4) and/or hypogranular cytoplasm (picture 5). (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Blood smear'.)

In cases of MDS/MPN, there may be abnormal mononuclear cells with features intermediate between myelocytes and monocytes (picture 6). (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

●Chemistries – Serum chemistries should include electrolytes, glucose, kidney function, and liver function tests.

Patients can present with a range of metabolic and electrolyte abnormalities, some of which are due to a high turnover of proliferating leukemic cells (eg, hyperuricemia; hyperphosphatemia; lactic acidosis, elevated lactate dehydrogenase, and disturbances of potassium or calcium), as discussed separately. (See "Acute myeloid leukemia: Overview of complications", section on 'Metabolic abnormalities'.)

Tumor lysis syndrome is a medical emergency that should be suspected in patients with hyperphosphatemia, hypocalcemia, hyperuricemia, and/or hyperkalemia. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Characteristic laboratory findings associated with MDS, AML, and MDS/MPN are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Pathologic features' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Clinical presentation' and "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

Bone marrow examination — Bone marrow aspiration and biopsy are required to diagnose a t-MN.

Studies should include microscopy, histochemical studies, immunophenotyping, and cytogenetic/molecular analysis, as discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Bone marrow biopsy and aspirate'.)

Morphology — Bone marrow cellularity is usually increased, but it may be normal or decreased, and there may be reticulin fibrosis [35,37]. The normal cellular components of the marrow may be mostly replaced by immature or undifferentiated blasts (picture 1), but there may be only modest infiltration by blasts or other abnormal forms. Megakaryocytes are frequently dysplastic and exhibit hypolobated or nonlobated nuclei and/or widely separated lobes.

Diagnosis and classification of t-MNs require determination of the percentage of myeloblasts in the bone marrow and blood, as described below. (See 'Diagnosis and classification' below.)

Immunophenotype — Flow cytometry is used to characterize the immunophenotype of a bone marrow specimen; immunophenotype can be determined using peripheral blood if there are adequate circulating aberrant cells.

●Immunophenotype – There are no unique or specific immunophenotypical findings associated with t-MNs, but flow cytometry is essential for identifying the blast immunophenotype and providing supportive evidence for dysplasia. Flow cytometry should be performed according to the standard methods proposed by the International Flow Cytometry Working Group of the European LeukemiaNet [38,39].

Myeloid antigens are often expressed aberrantly. Blasts usually express CD34 and pan-myeloid antigens (eg, CD13, CD33), but the expression of maturation-associated antigens (eg, myeloperoxidase) is variable [40,41]. Flow cytometry may also indicate hypogranularity of maturing neutrophils.

●Immunohistochemistry – Staining of bone marrow may demonstrate abundant p53-positive cells in bone marrow, which correlates with mutation of TP53 [42,43].

Genetic findings — Metaphase cytogenetic analysis of the bone marrow aspirate specimen must be performed. Most cases of t-MN have an abnormal karyotype, and cytogenetic findings may influence treatment, as discussed separately. (See "Therapy-related myeloid neoplasms: Management and prognosis".)

●Cytogenetic abnormalities – More than 90 percent of cases of t-MN exhibit a clonal chromosomal abnormality [44]. Approximately two-thirds have unbalanced chromosomal aberrations, most often involving partial loss of 5q, loss of chromosome 7, or del(7q) [10,12,18,45-48]. Approximately 80 percent of cases with del(5q) also have abnormalities of 17p (usually indicative of loss of TP53). Loss of 5q may also be associated with del(13q), del(20q), del(11q), del(3p), monosomy 17 or del(17p), del(18), del(21), or gain of chromosome 8.

Cytogenetic abnormalities in t-MNs may resemble those in de novo AML, but they differ in frequency. In one study, compared with patients with de novo AML, patients with a t-MN were less likely to have normal cytogenetics (10 versus 40 percent, respectively) and were more likely to have an unfavorable cytogenetic profile (46 versus 20 percent) [49].

Cytogenetic abnormalities differ in t-MNs that arise after radiation therapy (RT) alone compared with t-MNs after chemotherapy exposure. One study compared t-MNs that arose after RT alone (47 patients) or after cytotoxic chemotherapy (with or without RT; 181 patients) with 222 patients who had de novo MDS or AML [50]. Patients with a t-MN after chemotherapy exposure had more high-risk karyotypic features and inferior survival compared with t-MNs after RT alone or de novo MDS or AML; there was no significant difference in survival or frequency of high-risk karyotypes between the RT and de novo groups.

In a single-center study of 109 patients who developed a t-MN after receiving only RT, the most common cytogenetic abnormality was a clonal abnormality in chromosome 5 and/or 7 (45 percent of patients); other findings included a recurring translocation (14 percent), other clonal abnormalities (17 percent), and a normal karyotype (24 percent) [51].

●Mutations – Mutations in TP53 or PPM1D (a gene that encodes a regulator of p53) are more common in t-MNs than in de novo MDS or AML; these abnormalities are associated with inferior prognosis [30,42,43,46,51,52]. Mutations of SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 are more also more frequent in t-MNs compared with de novo disorders [45].

Additional details of cytogenetic and molecular abnormalities in AML, MDS, and MDS/MPN are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Bone marrow biopsy and aspirate' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Bone marrow examination' and "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Molecular features'.)

DIAGNOSIS AND CLASSIFICATION — A t-MN should be suspected in patients with prior exposure to cytotoxic agents or radiation therapy (RT) for another condition who present with findings related to leukocytosis or cytopenias, circulating blasts, or other abnormal myeloid cells, as discussed above. (See 'Clinical presentation' above.)

Diagnosis — Diagnosis of t-MNs is based on documentation of acute myeloid leukemia (AML), myelodysplastic syndromes/neoplasms (MDS), or MDS/myeloproliferative neoplasm (MPN) in a patient treated with chemotherapy or RT for another malignancy or another disease (eg, an autoimmune disorder).

It should be recognized that although there are biologic, treatment, and prognostic differences between t-MNs and the corresponding myeloid malignancies, the primary diagnostic distinction is epidemiologic (ie, a history of exposure to a cytotoxic agent). Distinguishing a t-MN from a de novo myeloid malignancy is discussed below. (See 'de novo myeloid neoplasms' below.)

Excluded from a diagnosis of a t-MN are MPNs that progress to acute leukemia, blast phase of chronic myeloid leukemia, and evolution of de novo MDS to AML (so-called "secondary" AML) in the absence of cytotoxic therapy. In these settings, disease progression is considered part of the natural history of the primary disease. (See "Overview of the treatment of chronic myeloid leukemia", section on 'Pretreatment evaluation' and "Overview of the myeloproliferative neoplasms", section on 'Malignancies and disease transformation' and "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Transformation to acute myeloid leukemia'.)

Diagnostic criteria for the corresponding de novo MNs are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia" and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)" and "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Diagnosis'.)

Classification — The names and classification of t-MNs differ between contemporary classification schemes for hematologic malignancies:

●International Classification Consensus – International Classification Consensus (ICC) of myeloid neoplasms and acute leukemia

●World Health Organization 5th edition – The World Health Organization 5th edition (WHO5) classification of hematolymphoid tumors: myeloid and histiocytic/dendritic neoplasms

Similarities and differences between the ICC and WHO5 systems are discussed separately. (See "Classification of hematopoietic neoplasms".)

International Classification Consensus — The ICC designates t-MNs according to morphologic and genetic features as either MDS, MDS/AML, AML, or MDS/MPN, with the addition of "therapy-related" as a diagnostic qualifier [1].

Many t-MNs have mutated TP53. Cases that meet criteria for multihit (ie, bi-allelic) TP53 mutations are included in the new ICC disease category, Myeloid neoplasm with mutated TP53 [1]. Classification and categorization of cases that meet the criteria for Myeloid neoplasms with mutated TP53 are described separately. (See "Classification of hematopoietic neoplasms", section on 'Myeloid neoplasms with mutated TP53'.)

Cases that do not meet multi-hit TP53 mutation criteria are described as either MDS, MDS/AML, AML, or MDS/MPN with "therapy-related" after the corresponding diagnosis.

World Health Organization 5th edition — WHO5 gives primacy to the relatedness of these diseases to prior treatment rather than to the morphologic and genetic features [2]. As a result, cases of AML, MDS, and MDS/MPN in patients who were exposed to cytotoxic therapy are included in a new category, Myeloid neoplasms post-cytotoxic therapy (MN-pCT), which is a subset of Secondary myeloid neoplasms.

Designation as a MN-pCT is based on the medical history rather than the specific diagnosis. Cases must fulfill criteria for the specific myeloid neoplasm plus a documented history of chemotherapy or large-field RT for another condition. Cases are labeled with the most specific subtype of myeloid neoplasm, according to morphologic and genetic features, with "post-cytotoxic therapy" appended. Prior treatment with methotrexate is not considered a qualifying exposure by WHO5.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of t-MNs includes the corresponding de novo myeloid neoplasms, other hematologic malignancies, and conditions associated with cytopenias.

de novo myeloid neoplasms — Clinical features and laboratory findings of t-MNs and de novo myeloid neoplasms are similar and may be indistinguishable. t-MNs are distinguished from de novo myeloid neoplasms by a history of prior exposure to a cytotoxic agent for an unrelated disorder (eg, another malignancy or other condition).

Distinguishing a relapse of de novo acute myeloid leukemia (AML) from therapy-related AML that arose from treatment of the prior de novo AML can be challenging [53-55]. The distinction can be made in some cases by comparing the karyotype, mutation profile, and immunophenotype at relapse with those at the time of the initial diagnosis; emergence of a distinctly different karyotype or molecular profile suggests, but does not prove, a therapy-related origin rather than relapse/recurrence of the original leukemic clone.

Chronic myeloid leukemia (CML) is associated with BCR::ABL1 (the Philadelphia chromosome; t(9;22)), and CML in accelerated phase or blast crisis may present with circulating blasts, cytopenias, and symptoms that resemble a t-MN. Although t(9;22) can occasionally be found in a patient with prior cytotoxic therapy exposure, the presence of BCR::ABL1 excludes the diagnosis of a t-MN. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

Details of the clinical manifestations and diagnosis of AML, myelodysplastic syndrome (MDS), and MDS/myeloproliferative neoplasm are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia" and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)" and "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Diagnosis'.)

Other hematologic malignancies — Other hematologic malignancies, such as systemic mastocytosis (SM) can resemble a t-MN with circulating blasts, cytopenias, or symptoms related to pancytopenia. Therapy-related cases of acute lymphoblastic leukemia (ALL) have also been observed.

SM can be distinguished by the presence of aberrant mast cells in blood, bone marrow, skin, or other organs and is typically accompanied by manifestations of mast cell activation (eg, flushing, urticaria, diarrhea, abdominal cramping, wheezing, syncope). Clinical manifestations and diagnosis of SM are discussed separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Additional evaluation and bone marrow biopsy'.)

In the case of ALL or other lymphoid malignancies, circulating blasts exhibit lymphoid morphologic, histochemical, or immunophenotypic features rather than myeloid features. Diagnosis of ALL is discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)

Other causes of pancytopenia — Aplastic anemia, myelofibrosis, nutritional deficiencies, medications, arsenic toxicity, and other disorders can cause pancytopenia. Some of these conditions can be associated with aberrant circulating cells that resemble myeloblasts. The distinction between t-MNs and other causes of pancytopenia is made by history, physical examination, laboratory studies, and bone marrow examination, as described separately. (See "Approach to the adult with pancytopenia".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute myeloid leukemia" and "Society guideline links: Myelodysplastic syndromes".)

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SUMMARY

●Description – Therapy-related myeloid neoplasms (t-MNs) refer to cases of acute myeloid leukemia (AML), myelodysplastic syndromes/neoplasms (MDS), or MDS/myeloproliferative neoplasms (MPN) that arise in patients who received cytotoxic chemotherapy or radiation therapy (RT) for another condition (eg, another malignancy or autoimmune disorder).

●Epidemiology – t-MNs account for up to 20 percent of myeloid malignancies. They can present at any age, but the median age is the 60s. Most cases arise after treatment for a prior malignancy, but some cases present after treatment for a non-neoplastic disorder or after autologous hematopoietic cell transplantation for a nonmyeloid neoplasm. (See 'Epidemiology' above.)

●Causes – The most commonly implicated cytotoxic agents are alkylating agents, topoisomerase II inhibitors, PARP (poly [ADP-ribose] polymerase) inhibitors, and/or RT. The interval between treatment and disease development varies with the type of treatment. (See 'Causes' above.)

Because t-MNs arise in only a small percentage of patients who receive these agents, there may be predisposing conditions (eg, inherited variants in DNA damage-sensing or repair genes or metabolic pathways). In addition to direct DNA damage, cytotoxic treatment may select for outgrowth of pre-existent chemotherapy-resistant clones from multi-hit mutational events in hematopoietic stem cells.

●Presentation – The clinical presentation is variable, but most patients present with findings that resemble those of the corresponding de novo myeloid neoplasms. (See 'Clinical presentation' above.)

●Evaluation – Clinical evaluation reveals exposure to cytotoxic therapy for an unrelated condition and findings associated with a myeloid neoplasm. (See 'Evaluation' above.)

Laboratory studies and evaluation of bone marrow and blood are like those for the corresponding myeloid neoplasms.

●Diagnosis – A t-MN should be suspected in a patient with prior cytotoxic chemotherapy or RT for another condition who has clinical or laboratory findings suggestive of a myeloid malignancy. (See 'Diagnosis' above.)

Diagnosis of a t-MN is based on pathologic findings of AML, MDS, or MDS/MPN in a patient with prior treatment with chemotherapy or RT for another condition.

●Classification – Classification criteria and labels differ between contemporary classification systems (see 'Classification' above):

•International Classification Consensus – The International Classification Consensus classifies cases according to the disease category (ie, MDS, MDS/AML, AML, or MDS/MPN) with "therapy-related" added after the diagnosis. (See 'International Classification Consensus' above.)

Many cases of t-MN meet criteria for Myeloid neoplasm with mutated TP53. Other cases are described as either MDS, MDS/AML, AML, or MDS/MPN with "therapy-related" after the corresponding diagnosis.

•World Health Organization 5th edition – The World Health Organization classification 5^th edition gives primacy to the relatedness of these diseases to prior treatment rather than to the morphologic and genetic features. Cases of AML, MDS, and MDS/MPN in patients previously treated with cytotoxic therapy for an unrelated disorder are included in the category of Myeloid neoplasms post-cytotoxic therapy (MN-pCT). (See 'World Health Organization 5th edition' above.)

●Differential diagnosis – t-MNs must be distinguished from the corresponding de novo myeloid neoplasms (ie, AML, MDS, MDS/MPN), other hematologic malignancies (eg, systemic mastocytosis), and other causes of cytopenias. (See 'Differential diagnosis' above.)