INTRODUCTION — Patients who are exposed to DNA-damaging agents, including cytotoxic chemotherapy and radiation therapy, are at risk for developing therapy-related myeloid neoplasms (t-MN). These conditions comprise a continuum of diseases that includes therapy-related acute myeloid leukemia (t-AML), therapy-related myelodysplastic syndrome (t-MDS), and therapy-related MDS/myeloproliferative neoplasms (t-MDS/MPN). The t-MNs are distinguished from myeloid neoplasms (MNs) that arise with no known exposure to cytotoxic agents (ie, de novo MNs), and they constitute a separate category within the World Health Organization classification of myeloid malignancies [1]. Although they share certain clinical and biological characteristics, patients with t-MNs typically have high-risk features and worse outcomes than those with the corresponding de novo AML, MDS, or MDS/MPN.
The epidemiology, causes, evaluation, and diagnosis of t-MNs are discussed here.
Management and prognosis of t-MNs and the epidemiology, causes, clinical presentation, and diagnosis of de novo AML and MDS are discussed separately. (See "Therapy-related myeloid neoplasms: Management and prognosis" and "Pathogenesis of acute myeloid leukemia" and "Induction therapy for acute myeloid leukemia in medically-fit adults" and "Acute myeloid leukemia: Management of medically-unfit adults".)
EPIDEMIOLOGY — By definition, t-MNs occur in patients who were previously treated with DNA-damaging agents, such as cytotoxic chemotherapy or radiation therapy. The incidence varies with the specific treatment exposures and the underlying disease. The interval between treatment with specific agents and development of a t-MN, called the latency period, is discussed below. (See 'Causes' below.)
Patients of any age can be affected, but the median age at diagnosis of t-MN is 61 years [2,3]. 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 a prior hematologic malignancy [4-8]. The remaining 5 to 20 percent comprise patients who were treated with cytotoxic therapy for a non-neoplastic disorder or who underwent autologous hematopoietic cell transplantation (HCT) for a non-myeloid neoplasm. t-MNs account for approximately 10 to 20 percent of all cases of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and MDS/myeloproliferative neoplasms (MDS/MPN) [5,6,8,9].
The incidence of t-MNs varies according to the underlying disease, specific agent(s), dose, and interval since treatment. A population-based study of more than 400,000 patients treated with chemotherapy in the United States from 1975 to 2008 reported that, compared to the general population, there was a 4.7-fold increased risk (95% CI 4.4-5.0) for t-AML and an excess of 3.0 cases per 10,000 person-years [10]. The highest excess annual risks for t-AML were observed after Hodgkin lymphoma (HL) and multiple myeloma (MM) and were lowest after breast cancer; this is consistent with differences in the leukemogenicity of specific agents used in these diseases. For all cancers, the risk for t-AML was particularly high in the first five years but later declined. After ≥10 years, there was no evidence of elevated t-AML risks after any non-hematologic malignancy, but a three- to sixfold increased risk persisted after HL, non-Hodgkin lymphoma (NHL), and MM.
In a single-institution study of 306 patients with t-MDS or t-AML, 77 had a prior HL, 70 had an NHL, 24 had MM or another hematologic malignant disease, 117 had various solid tumors, and 18 had nonmalignant diseases (primarily autoimmune diseases or kidney transplantation) [11]. Patients in this study had been treated with combined radiotherapy and chemotherapy (139 patients), chemotherapy alone (121 patients), or radiotherapy alone (43 patients); the majority who were treated with radiotherapy alone had received radiation to large portals encompassing active bone marrow.
Excluded from the category of t-MNs are MPNs that progress to acute leukemia, the blast crisis phase of chronic myeloid leukemia, and evolution of de novo MDS to AML (so-called "secondary" AML). 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 "Management of the hematologic complications of myelodysplastic syndromes", section on 'Transformation to AML'.)
Development of t-MNs after treatment for specific diseases is discussed separately in those topics.
CAUSES — The t-MNs comprise a continuum of diseases that includes therapy-related acute myeloid leukemia (t-AML), therapy-related myelodysplastic syndrome (t-MDS), and therapy-related MDS/myeloproliferative neoplasms (t-MDS/MPN). A wide variety of agents with different mechanisms of action are associated with development of t-MNs, and the interval between treatment and development of disease varies according to the type of therapy. Mutagenic damage by specific agents, as reflected by recurring cytogenetic abnormalities, is described below. (See 'Cytogenetic/genetic features' below.)
Specific treatments that are most often associated with t-MNs are [4]:
●Alkylating agents: Melphalan, cyclophosphamide, nitrogen mustard, chlorambucil, busulfan, carboplatin, cisplatin, dacarbazine, procarbazine, carmustine, mitomycin, thiotepa, lomustine.
●Radiation therapy (RT) is usually associated with large fields that encompass active bone marrow, alone or as combined modality treatment (ie, chemotherapy plus RT); peptide receptor radionuclide therapy.
●Topoisomerase II inhibitors: Etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, actinomycin.
●Other agents (usually in combination with other agents listed above): antimetabolites (eg, thiopurines, mycophenolate mofetil, methotrexate, fludarabine) or antitubulin agents (eg, vincristine, vinblastine, vindesine, paclitaxel, docetaxel; the role of other agents such as hydroxyurea, L-asparaginase, and radioisotopes is unclear [4]. Growth factors, such as filgrastim, may play a role in the emergence of a t-MN clone, as discussed separately. (See "Introduction to recombinant hematopoietic growth factors", section on 'Possible stimulation of malignancy'.)
The risk associated with alkylating agents and radiation appears to increase with age, while the risk associated with topoisomerase II inhibitors appears to be constant across all ages [4].
The interval between first treatment with a cytotoxic agent and identification of a t-MN varies by the cytotoxic agent [12]:
●Alkylating agents or RT – t-MNs typically present five to seven years after initial treatment with alkylating agents or RT [6,11,13-15]. Two-thirds of these patients are first recognized by evidence of myelodysplasia (usually involving trilineage dysplasia), marrow failure, and pancytopenia. Chromosomal abnormalities seen in these t-MNs often involve complex abnormalities, deletion of 5q or 17p, or monosomies (eg, -7), which are associated with unfavorable risk.
●Topoisomerase II inhibitors – t-MNs usually have a shorter latency period (eg, one to three years) after treatment with topoisomerase II inhibitors and usually present with t-AML (only rarely with t-MDS or t-MDS/MPN) [16-23]. Cytogenetic alterations typically involve abnormalities of 11q23 (eg, t(9;11)), or 21q22 abnormalities (eg, t(8;21) or t(3;21)).
●Other agents – The latency periods with other agents are not as clear. Many patients have been exposed to multiple DNA-damaging agents, making the responsible factor difficult to determine.
Because t-MNs develop in only a small percentage of patients who receive these treatments, affected individuals may have an inherited predisposition. Factors that may predispose to t-MNs include mutations in DNA damage sensing or repair genes (eg, BRCA1/2 or TP53) or polymorphisms in genes that affect drug metabolism or transport [24,25]. Exposure to cytotoxic chemotherapy may also select for progression of underlying clonal hematopoiesis with pathogenic mutations.
Other aspects of the pathogenesis of AML and MDS are discussed separately. (See "Pathogenesis of acute myeloid leukemia" and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Pathogenesis'.)
CLINICAL PRESENTATION — The clinical presentation of t-MNs is variable, but most patients present with findings that resemble those of de novo acute myeloid leukemia (AML) or a primary myelodysplastic syndrome (MDS). (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Clinical presentation' and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Clinical presentation'.)
The most common symptoms are related to pancytopenia (ie, anemia, neutropenia, and/or thrombocytopenia), such as weakness, easy fatigue, fever, and/or excessive bleeding/bruising (eg, gingival bleeding, epistaxis, menorrhagia). Some patients have minimal or no symptoms and a t-MN is diagnosed based on laboratory findings alone.
EVALUATION — Evaluation of a patient presenting with a presumptive diagnosis of a t-MN should be performed according to College of American Pathologists and the American Society of Hematology (CAP-ASH) guidelines [26]. Additional details of the evaluation are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)
History and physical examination — The history will reveal prior treatment with a cytotoxic agent for a solid tumor, hematologic malignancy, or nonmalignant condition. The specific agents and intervals between initial treatment and presentation should be determined.
The most common symptoms are related to pancytopenia (ie, anemia, neutropenia, and/or thrombocytopenia), including weakness, easy fatigue, findings of infections, and/or bleeding/bruising (eg, gingival bleeding, epistaxis, menorrhagia). Some patients have minimal or no symptoms. 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 and diagnosis of myelodysplastic syndromes (MDS)", section on 'Clinical presentation' and "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)
Laboratory — Laboratory studies reflect the findings of AML, MDS, or an MDS/myeloproliferative neoplasm (MDS/MPN). (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Pathologic features' and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Clinical presentation'.)
Complete blood count — The complete blood count (CBC) and differential count show 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 myeloid forms, but there may be leukopenia and/or thrombocytopenia, as described separately. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Complete blood count'.)
Blood smear — The microscopic appearance of t-MN usually resembles the corresponding AML, MDS, or MDS/MPN. In some cases there are few or no detectable abnormal forms in peripheral blood, but there is usually evidence of multilineage dysplasia with abnormalities in RBCs (eg, dyserythropoiesis) (picture 1 and picture 2) [11,27,28]. Dysplastic changes in neutrophils include nuclear hyposegmentation (eg, Pelger-Huet anomaly) (picture 3) and hypogranular cytoplasm (picture 4). There may be abnormal mononuclear cells with features intermediate between myelocytes and monocytes (picture 5), in cases of t-MDS/MPN. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Blood smear'.)
Chemistries — Patients with t-MNs can present with a range of metabolic and electrolyte abnormalities, many of which are due to a high turnover of the proliferating leukemic cells (eg, hyperuricemia; hyperphosphatemia; lactic acidosis, and disturbances of potassium or calcium), as discussed separately. (See "Overview of the complications of acute myeloid leukemia", 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".)
Bone marrow examination — Bone marrow aspiration and biopsy is a key component to the diagnosis of t-MNs and should include microscopy, histochemical studies, immunophenotyping, and cytogenetic/molecular analysis. Characterization of the bone marrow specimens is discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Bone marrow biopsy and aspirate'.)
Bone marrow cellularity is usually increased, but it may be normal or decreased and there may be reticulin fibrosis [27,29]. The normal cellular components of the marrow may be largely replaced by immature or undifferentiated cells (eg, blasts of t-AML) (picture 6), but there may be only modest infiltration by blasts (eg, in t-MDS), or monoblasts and other aberrant forms (eg, in t-MDS/MPN). Megakaryocytes are frequently dysplastic with hypolobate or non-lobated nuclei and/or widely separated lobes.
The percentage of myeloblasts in the bone marrow distinguishes t-MDS from t-AML, as described below. (See 'Diagnosis' below.)
Immunophenotype — The immunophenotype can be determined by flow cytometry from the bone marrow aspirate or from peripheral blood, if there are adequate circulating aberrant cells.
There are no specific immunophenotypical findings in t-MN, although compared with normal differentiation, myeloid antigens are often expressed aberrantly. Blasts usually express CD34 and pan-myeloid antigens (eg, CD13, CD33), but expression of maturation-associated antigens (eg, myeloperoxidase) is variable [30,31]. Flow cytometry may also indicate altered light-scattering properties of maturing neutrophils due to hypogranulation.
Flow cytometry should be performed according to the standard methods proposed by the International Flow Cytometry Working Group of the European LeukemiaNet [32,33]. There are no unique flow cytometry findings associated with a diagnosis of t-MN. However, flow cytometry is critical for identifying the blast immunophenotype and for providing supportive evidence for dysplasia.
Immunohistochemical staining of bone marrow may demonstrate abundant p53-positive cells in bone marrow, which correlates with mutation of TP53 [34,35].
Cytogenetic/genetic features — All patients with a suspected t-MN should undergo metaphase cytogenetic analysis of the bone marrow aspirate specimen. Most cases of t-MN have an abnormal karyotype and cytogenetic findings are an important prognostic feature that are used to stratify treatment, as discussed separately. (See "Therapy-related myeloid neoplasms: Management and prognosis".)
More than 90 percent of cases of t-MN demonstrate a clonal chromosomal abnormality and two-thirds have unbalanced chromosomal aberrations. Cytogenetic studies frequently reveal deletion or partial deletion of chromosome 5 and/or 7 or a complex karyotype [7,11,15,36-39]. Approximately 80 percent of cases with del(5q) also have abnormalities of 17p (usually indicative of loss of TP53, discussed below); loss of 5q is often associated with at least one of the following: 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 are similar to those in de novo AML but differ in frequency. In an illustrative report, patients with t-MN were less likely to have normal cytogenetics (approximately 10 versus 40 percent, respectively) and more likely to have an unfavorable cytogenetic profile (approximately 46 versus 20 percent) when compared with patients with de novo AML [40].
Different cytotoxic exposures may cause mutagenic damage that is reflected by recurring cytogenetic abnormalities. One study compared the outcomes of 181 patients who developed t-MN after chemotherapy (with or without radiation therapy [RT]) with 47 patients who developed t-MN after RT alone and 222 patients who presented with de novo MDS or AML [41]. The proportion of patients with normal karyotypes was 14, 43, and 45 percent in patients with t-MN after RT, de novo MDS, and de novo AML, respectively. Deletions or loss of chromosome 5 and/or 7 were observed in 63, 26, and 23 percent, respectively.
Mutations of TP53 are present in up to half of cases of t-MN and mutations of PPM1D, a gene that encodes a regulator of p53, are also more common in t-MN than in primary AML [34,35,42]. The incidence of TP53 mutations in t-MNs is higher than the rate in de novo MDS or AML, and this correlates with a poor prognosis. Other commonly mutated genes include TET2, PTPN11, IDH1/2, NRAS, and FLT3 [37,43-45]. NPM1 mutations are uncommon in t-MN.
Additional details of cytogenetic and molecular abnormalities in AML, MDS, and MDS/MPN are presented separately. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Molecular features' and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Bone marrow examination' and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Bone marrow biopsy and aspirate'.)
DIAGNOSIS — A t-MN should be suspected in a patient with prior exposure to cytotoxic agents who presents with clinical findings or laboratory abnormalities related to leukocytosis or pancytopenia, circulating blasts or other immature myeloid cells, or evidence of aberrant hematopoietic differentiation, as discussed above. (See 'Clinical presentation' above.)
Diagnosis of a t-MN is based on clinical and laboratory findings in peripheral blood and/or bone marrow of a patient with prior exposure to cytotoxic agents. The t-MNs comprise a continuum of diseases. The specific entities of therapy-related acute myeloid leukemia (t-AML), therapy-related myelodysplastic syndromes (t-MDS), and therapy-related MDS/myeloproliferative neoplasm (t-MDS/MPN) are distinguished by morphologic, immunophenotypic, and cytogenetic findings that reflect the dysplasia, aberrant differentiation, and immature blood cells (eg, myeloblasts) of the corresponding de novo myeloid neoplasms [4,46]. Criteria for the diagnosis of the corresponding de novo myeloid neoplasms are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia" and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)" and "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Diagnosis'.)
t-AML — The diagnosis of t-AML requires all of the following [4]:
●History of prior treatment with DNA damaging agents (cytotoxic chemotherapy or radiation therapy)
●Documentation of >20 percent bone marrow infiltration with blasts
●Either or both of the following:
•Evidence that the leukemic cells are of myeloid origin (eg, Auer rods, cytochemical positivity for myeloperoxidase, or presence of sufficient myeloid/monocytic markers by immunophenotyping)
or
•Diagnostic cytogenetic/molecular findings (regardless of the blast count):
-t(8;21)(q22;q22); RUNX1-RUNX1T1 (previously AML1-ETO)
-inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
-t(15;17)(q22;q21.1); PML-RARA (in therapy-related acute promyelocytic leukemia) (see "Therapy-related myeloid neoplasms: Management and prognosis", section on 't-APL')
When these recurrent balanced rearrangements are seen in patients with prior exposure to DNA damaging agents, the leukemia should be considered therapy-related.
It may be particularly challenging to diagnose t-AML after prior treatment for a de novo myeloid neoplasm, as discussed below. (See 'de novo MNs' below.)
t-MDS — The diagnosis of t-MDS requires all of the following [4]:
●History of prior treatment with cytotoxic chemotherapy or radiation therapy.
●Morphologic evidence of significant dysplasia (ie, ≥10 percent of erythroid precursors, granulocytes, or megakaryocytes) on the peripheral blood smear or bone marrow examination, in the absence of other causes of dysplasia (table 1). In the absence of morphologic evidence of dysplasia, a presumptive diagnosis of MDS can be made in patients with otherwise unexplained refractory cytopenias together with certain genetic abnormalities, which are described separately. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Cytogenetic and molecular features'.)
●Blast count in bone marrow is ≤20 percent (except in cases associated with t(8;21), inv(16), or t(15;17)), as described above).
t-MDS/MPN — The diagnosis of t-MDS/MPN requires all of the following [4]:
●History of prior treatment with cytotoxic agents
●Persistent (≥3 months) peripheral blood monocytosis; absolute monocyte count >1000/microL and >10 percent of the entire white blood cell differential
●Not meeting World Health Organization criteria for BCR-ABL1-positive chronic myeloid leukemia, primary myelofibrosis, polycythemia vera, or essential thrombocytosis [4]
●<20 percent myeloblasts + monoblasts + promonocytes in peripheral blood and bone marrow
●Dysplastic changes in one or more myeloid lineages. If myelodysplastic changes are absent or minimal, the diagnosis of chronic myelomonocytic can be made if the above three criteria are met and:
•An acquired clonal cytogenetic (or mutational) abnormality is present in bone marrow cells or
•Persistent monocytosis for ≥3 months and all other causes of monocytosis have been excluded
By definition, cases do not exhibit rearrangements of the genes encoding the platelet derived growth factor receptor (PDGFRA or PDGFRB), FGFR1, or PCM1-JAK2. Further details of the diagnosis of t-MDS/MPN are presented separately. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of t-MNs includes the corresponding de novo myeloid neoplasms (MNs), other hematologic malignancies, and disorders associated with pancytopenia.
de novo MNs — Most clinical and laboratory findings of t-MNs and de novo MNs are similar and may be indistinguishable. The distinction between de novo MNs and t-MNs is based on a history of prior exposure to one or more cytotoxic agents.
Distinguishing a relapse of de novo acute myeloid leukemia (AML) from t-AML that arose from treatment of the prior de novo AML can be challenging [47-49]. By comparing the karyotype, mutation profile, and immunophenotype at relapse from those at the time of the initial diagnosis, it is sometimes possible to make this distinction. As an example, the 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.
Details of the clinical manifestations and diagnosis of AML, myelodysplastic syndrome, and myelodysplastic syndrome/myeloproliferative neoplasm are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia" and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)" and "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Diagnosis'.)
Other causes of pancytopenia — Various conditions, including aplastic anemia, myelofibrosis, nutritional deficiencies, heavy metal toxicity such as arsenic, medications, and other disorders can cause pancytopenia. Some of these may 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".)
Chronic myeloid leukemia — Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm associated with the Philadelphia chromosome and the BCR-ABL1 oncogene. CML can present with circulating blasts, anemia or other cytopenias, and symptoms such as weight loss, fever, or bleeding/bruising that may resemble clinical findings in t-MNs. The diagnosis of CML is based on a karyotype that reveals the characteristic t(9;22) reciprocal translocation or detection of the BCR-ABL1 oncogene. The increased percentage of blasts in accelerated phase (AP) or blast crisis (BC) of CML may be difficult to distinguish from t-AML, but AP/BC CML are not considered types of t-MN. However, there are rare cases of myeloid neoplasms with t(9;22) arising in patients with exposure to prior cytotoxic therapy.
Details of the clinical presentation and diagnosis of CML are presented separately. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)
Other hematologic malignancies — Other hematologic malignancies, including systemic mastocytosis (SM) may present with circulating blasts, cytopenias, and symptoms related to pancytopenia that resemble t-MNs. Therapy-related cases of acute lymphoblastic leukemia (ALL) have also been observed.
In the case of ALL or other lymphoid malignancies, circulating blasts will exhibit lymphoid, rather than myeloid, morphologic, histochemical, or immunophenotypic features. Details of the diagnosis of these conditions are presented separately.
SM can be distinguished based on 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 presented separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Additional evaluation and bone marrow biopsy'.)
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".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Patients who are exposed to DNA-damaging agents, including cytotoxic chemotherapy and radiation therapy, are at risk of developing therapy-related myeloid neoplasms (t-MN). These conditions comprise a continuum of diseases that includes therapy-related acute myeloid leukemia (t-AML), therapy-related myelodysplastic syndrome (t-MDS), and therapy-related MDS/myeloproliferative neoplasms (t-MDS/MPN).
●By definition, t-MNs develop in patients who were previously treated with cytotoxic agents or have received radiation therapy. The incidence of t-MNs among people who were treated with a cytotoxic agent is small and varies with the specific treatment and underlying disease. Most cases of t-MN arise after treatment for a malignancy, but a small percentage were treated for a non-neoplastic disorder. (See 'Epidemiology' above.)
●A wide variety of agents with different mechanisms of action are associated with development of t-MNs, and the interval between treatment and development of disease (the latency period) varies according to the type of therapy. Specific agents include alkylating agents, radiation therapy, topoisomerase II inhibitors, and other miscellaneous agents, as described above. (See 'Causes' above.)
●The clinical presentation of t-MNs is variable, but most patients have symptoms that are related to pancytopenia (eg, weakness, easy fatigue, infections, bleeding/bruising). Some patients have minimal or no symptoms and a t-MN is diagnosed based on laboratory findings alone. (See 'Clinical presentation' above.)
●A t-MN should be suspected in a patient with prior exposure to cytotoxic agents who presents with clinical findings or laboratory abnormalities related to leukocytosis or pancytopenia, circulating blasts or other immature myeloid cells, or evidence of aberrant hematopoietic differentiation. The diagnosis of t-MN is based on clinical and laboratory findings in peripheral blood and/or bone marrow. (See 'Evaluation' above and 'Diagnosis' above.)
●The t-MNs comprise a continuum of diseases and the specific entities are distinguished by morphologic, immunophenotypic, and cytogenetic/genetic findings. In addition to prior exposure to a mutagenic agent, the specific entities are diagnosed as follows:
•t-AML: Documentation of >20 percent bone marrow infiltration with blast forms and evidence that the leukemic cells are of myeloid origin (by morphology, cytochemistry, and/or immunophenotype) or diagnostic cytogenetic/molecular findings, as described above. (See 't-AML' above.)
•t-MDS: Blast count in bone marrow is ≤20 percent (except in cases associated with t(8;21) or inv(16), as described above) and morphologic evidence of significant dysplasia or certain genetic abnormalities, as described above. (See 't-MDS' above.)
•t-MDS/MPN: Persistent peripheral blood monocytosis, <20 percent myeloblasts + monoblasts + promonocytes in peripheral blood and bone marrow, dysplastic changes in one or more myeloid lineages, and exclusion of other conditions based on molecular studies, as described above. (See 't-MDS/MPN' above.)
●The differential diagnosis of t-MNs includes the corresponding de novo myeloid neoplasms (ie, AML, MDS, MDS/MPN), other hematologic malignancies, and other disorders associated with pancytopenia. (See 'Differential diagnosis' above.)
