Therapy-related myeloid neoplasms: Management and prognosis

INTRODUCTION — Patients who were previously treated with DNA-damaging agents such as cytotoxic chemotherapy or 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). Although t-MNs share certain clinical and biological characteristics with AML, MDS, and MDS/MPN that arise de novo (ie, with no prior exposure to DNA-damaging agents), overall, patients with t-MNs typically have worse outcomes than those with the corresponding de novo AML, primary MDS, or MDS/MPN.

Management and prognosis of t-MNs are discussed here.

The epidemiology, causes, clinical presentation, and diagnosis of t-MNs and management and prognosis of de novo AML and MDS are discussed separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis" and "Acute myeloid leukemia in adults: Overview" and "Overview of the treatment of myelodysplastic syndromes".)

EMERGENCIES

t-APL — Therapy-related acute promyelocytic leukemia (t-APL) is a distinct category of t-MN that constitutes a medical emergency. This type of leukemia is distinguished by unique clinical manifestations and complications, the characteristic t(15;17) karyotype and PML-RARA gene rearrangement, and requires urgent and specific treatment that differs from other t-MNs.

APL is more likely in patients with bleeding or bruising, when leukemic blasts have coarse or dense cytoplasmic granules, and when there are few circulating leukemic cells or a low white blood cell (WBC) count. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on 'Clinical features'.)

Management of t-APL with all-trans retinoic acid (ATRA) and arsenic trioxide is the same as that for de novo APL and is discussed separately. (See "Initial treatment of acute promyelocytic leukemia in adults".)

Other emergencies — Patients with cardiac, respiratory, or other organ system decompensation, and those with WBC count >50,000/microL, require urgent evaluation and management. Management of these complications is discussed separately. (See "Acute myeloid leukemia: Overview of complications" and "Hyperleukocytosis and leukostasis in hematologic malignancies".)

PRETREATMENT EVALUATION — Pretreatment evaluation of patients with t-MNs should assess the patient's fitness for intensive treatment (including transplantation) and assign a prognostic category based on cytogenetic and molecular features.

Clinical evaluation and diagnosis in a patient suspected of having a t-MN is discussed separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

Assess medical fitness — Medical fitness is the major determinant of therapy selection for t-MNs.

We categorize patients as medically fit for intensive treatment versus medically frail based on:

●Performance status (PS) – Eastern Cooperative Oncology Group (ECOG) scale (table 1) or Karnofsky performance status (KPS) (table 2) may be used to assess PS.

●Comorbid illness – We suggest using the modified Charlson comorbidity index (CCI) (table 3) to assess the impact of comorbid illnesses. Some experts instead apply the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) (table 4).

We categorize patients as either:

●Medically fit:

•ECOG PS (≤2) or KPS (≥50 percent)

plus

•CCI (≤2)

●Medical frailty (any of the following):

•ECOG PS (≥3)

•KPS (≤40 percent)

•CCI (≥3)

Both categories include a range of physical function and medical conditions. By definition, all patients with a t-MN had an illness that required prior treatment with a DNA-damaging agent. Medical fitness may be reduced by late effects of the prior illness or its treatment, and some patients may have persistence of the original illness. Some patients have only modest, recent, or transient impairment of functional status, while others have substantial comorbid illnesses, cognitive impairment, or other conditions that may affect their ability to tolerate treatment. Effects of the t-MN itself can impair fitness, so achieving disease control may improve fitness; conversely, effects of treatment may lead to a functional decline.

For some older patients, a comprehensive geriatric consultation may aid in assessing the individual's ability to undergo and tolerate various therapies, as described separately. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults" and "Acute myeloid leukemia: Management of medically unfit adults", section on 'Pretreatment evaluation'.)

Medical fitness should be reassessed periodically. This reassessment is especially important prior to embarking on post-remission management, as discussed below. (See 'Post-remission management' below.)

Evaluate for transplantation — We suggest evaluation for possible hematopoietic cell transplantation for all medically fit patients. (See 'Assess medical fitness' above.)

If the patient is judged to be eligible for transplantation, a search for a suitable donor should be undertaken at an early stage. (See "Donor selection for hematopoietic cell transplantation".)

Assign prognostic category — A prognostic category should be assigned based on cytogenetic and molecular features of the t-MN. Patients with t-MN are more likely to have unfavorable features than those with de novo AML. We use the European LeukemiaNet criteria (table 5) and categorize prognosis as:

•Favorable

•Intermediate

•Unfavorable

The impact of prognostic features on treatment choices and outcomes is discussed below. (See 'Choice of intensive regimen' below and 'Selection of post-remission therapy' below.)

PROGNOSTIC FACTORS — Most patients with a t-MN survive less than one year, and overall survival (OS) is generally less than 10 percent at five years [1-4]. Patients with favorable cytogenetic and/or molecular features have longer survival than others. Outcomes are also influenced by comorbid medical conditions and effects of prior disease and its therapy.

●Cytogenetic features – Cytogenetic features (table 5) are the strongest predictors for outcome with t-MNs. Adverse cytogenetic features include abnormalities of chromosomes 5 and/or 7 and complex karyotype; in general, adverse cytogenetic findings are associated with median OS <1 year [1-3,5,6]. A report of 306 patients with a t-MN reported that median OS was greatest in patients with normal karyotypes or recurring balanced rearrangements (approximately 11 months each) and was shortest in patients with abnormalities of both chromosomes 5 and 7 (approximately five months) [3]. As examples, a study of 277 patients with t-MN, in which 39 percent had adverse karyotypic features, reported median OS of 14.6 months [2]. In contrast, median OS was 6.3 months in a study in which 76 percent of the 47 patients had adverse-risk cytogenetics [7]. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis", section on 'Genetic findings'.)

●Molecular features – Mutations of TP53 have been reported in one-quarter to one-half of cases of t-MN and are associated with inferior survival. A study of 217 patients with therapy-related acute myeloid leukemia (t-AML) reported TP53 mutations in 23 percent, and other studies reported similar rates [8-10]. In one study of 95 patients, multivariate analysis demonstrated that mutant TP53 was an independent prognostic marker for inferior OS [6]. There is a paucity of data regarding the prognostic significance for t-MN of mutations that are routinely evaluated for risk stratification with de novo AML (ie, FLT3-ITD, CEBPA, NPM1), other mutations associated with de novo AML (eg, TET2, PTPN11, IDH1/2, N-RAS), or genes that are commonly mutated in de novo myelodysplastic syndrome (eg, SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2) [6,11,12].

●Other factors:

•Disease classification – Outcomes are not known to differ based on whether a patient is classified as having therapy-related myelodysplastic syndrome (t-MDS) versus t-AML, because t-MNs comprise a continuum of diseases. A study of 155 patients with t-MNs reported that survival rates were not associated with the specific morphologic category of t-MN; instead, outcomes were affected on cytogenetic abnormalities [13]. The diagnostic distinction between t-MDS and t-AML is described separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis", section on 'Diagnosis and classification'.)

•Prior therapy – When compared with patients who had previously received chemotherapy, patients with a t-MN after radiation therapy had a higher frequency of favorable cytogenetic abnormalities (65 versus 12 percent), and this was reflected by better survival rates [14].

•Prior malignancy – The status of the prior malignancy contributes to outcomes in this population. As an example, analysis of a cohort of 411 patients with t-MDS that excluded deaths not related to t-MN reported that median t-MDS-specific survival was 17 months, while median OS was 10.3 months; the difference appears to reflect deaths associated with the primary malignancies [15].

GOALS OF CARE — For most patients with a t-MN, achievement of remission is an appropriate goal, as patients who achieve remission typically have prolongation of survival, including the possibility of long-term disease control, and improved quality of life (QOL). Medical fitness and personal values and fears should be considered in establishing the goals of care, but we do not view age per se as a primary determinant of goals.

Goals of care should be determined by shared decision-making by clinicians and the patient, with input from loved ones. The goals of care will influence management, including the "aggressiveness" of treatment. Goals should be evaluated at the time of diagnosis and periodically reassessed through the course of the disease. The discussion should acknowledge the generally adverse prognosis and recognize that a t-MN will be a life-ending disease for most patients, while emphasizing the potential short- and long-term benefits of treatment.

We suggest:

●For most medically fit patients, the goal is to achieve long-term survival, while alleviating symptoms and improving QOL. (See 'Medically fit' below.)

●For medically frail patients, the goals are to prolong life, alleviate symptoms, and/or improve QOL. For some patients with extreme debility, advanced age, or severe comorbid conditions, treatment aimed at modifying the disease course may be inadvisable, and supportive care alone (eg, blood transfusions, antibiotics) or other means of providing symptom relief are offered. (See 'Medically frail' below.)

Mutual understanding between the patient, family members, and practitioners facilitates goal-setting and decisions regarding health care proxies, do-not-resuscitate directives, and end-of-life decisions. It should be recognized that many patients with hematologic malignancies overestimate their long-term prognosis and chance for cure, and don't recall being offered more than one approach to treatment [16,17].

Assessment of medical fitness is discussed above. (See 'Assess medical fitness' above.)

MANAGEMENT APPROACH — Selection of a treatment approach is based on medical fitness for intensive treatment, cytogenetic and molecular features of the t-MN, prior therapy, and the patient's goals and preferences.

Assessment of medical fitness and assignment of prognostic category are described above. (See 'Assess medical fitness' above and 'Assign prognostic category' above.)

Medically fit — For medically fit patients, we suggest stratifying treatment on the basis of prognostic category (table 5) (see 'Assign prognostic category' above):

●Favorable or intermediate prognosis – For medically fit patients with favorable or intermediate prognostic features (table 5), we suggest intensive remission induction therapy rather than lower intensity treatment approaches (eg, targeted therapy, hypomethylating agent). Compared with lower intensity approaches, intensive remission induction therapy offers the most favorable balance of efficacy and toxicity in this setting. Selection of an intensive treatment regimen is discussed below. (See 'Choice of intensive regimen' below.)

●Adverse prognosis – For medically fit patients with adverse prognostic features (table 5), we strongly encourage participation in a clinical trial. Outside of a clinical trial, there is no consensus regarding a preferred approach, and we consider intensive regimens, targeted treatments, or hypomethylating agents to be acceptable options.

Selection of therapy for a patient with an adverse-prognosis t-MN must be individualized and should reflect the individual's personal values, goals, and concerns. As an example, an especially vigorous or younger (eg, <40 years) patient may favor intensive remission induction therapy, followed by transplantation. Other patients may opt for lower intensity approaches or supportive care alone, due to effects of prior disease and treatment, comorbid illness, age, or personal values. Various treatment options are discussed below. (See 'Medical therapy' below.)

Importantly, we do not select therapy for medically fit patients based on:

●Age – Age alone should not be a primary determination of treatment selection, although age may affect certain aspects of treatment. (See '7+3 anthracycline plus cytarabine' below.)

●Disease classification – Classification of the t-MN as therapy-related acute myeloid leukemia (t-AML), therapy-related myelodysplastic syndrome (t-MDS), or therapy-related MDS/myeloproliferative neoplasm (t-MDS/MPN) should not determine treatment choice. The sole exception to this principle is management of therapy-related acute promyelocytic leukemia (t-APL), as discussed above. (See 't-APL' above.)

Medically frail — Treatment of medically frail patients is focused primarily on relief of symptoms, prolongation of life, and improving the quality of life. Goals of care and management approach should be determined by shared decision-making between the patient and clinicians. (See 'Goals of care' above.)

For medically frail patients we suggest supportive care, with or without lower intensity treatment. Selection of an approach should reflect the individual's personal values and goals of care. Management options include:

●Lower intensity therapy – Treatment with a hypomethylating agent, a targeted agent, or other lower intensity treatments may provide symptomatic relief and/or prolong survival. (See 'Lower intensity treatments' below.)

●Hydroxyurea – Hydroxyurea is an oral agent with a favorable toxicity profile that may lessen symptoms caused by disease proliferation (eg, hyperleukocytosis, splenomegaly). (See "Hyperleukocytosis and leukostasis in hematologic malignancies", section on 'Hydroxyurea'.)

●Other measures – Other measures of supportive care include transfusions with red blood cells and platelets as needed, and the use of antibiotics to treat infections. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Frail patients'.)

MEDICAL THERAPY

Intensive treatments

Choice of intensive regimen — Intensive therapy offers the highest likelihood of achieving remission and prolonging survival but is generally associated with substantial toxicity. Anthracycline-containing regimens have the most robust track record for t-MNs, but some patients are not candidates for such treatment because of prior anthracycline therapy and/or cardiac toxicity.

The most common anthracycline-containing regimens are infusional cytarabine plus an anthracycline (so-called "7+3" therapy) or liposomal daunorubicin-cytarabine (ie, CPX-351); we consider either approach acceptable. Outcomes and toxicity with these approaches are described below. (See '7+3 anthracycline plus cytarabine' below and 'Liposomal daunorubicin-cytarabine' below.)

For patients who are not candidates for an anthracycline or a related agent because of comorbid heart disease or substantial prior anthracycline exposure, we favor participation in a clinical trial. Other options include intensive nonanthracycline-containing regimens or lower intensity approaches, as described below. (See 'Intensive nonanthracycline approaches' below and 'Choice of lower intensity treatment' below.)

7+3 anthracycline plus cytarabine — The most common intensive remission induction regimen (usually referred to as 7+3 therapy) is a seven-day continuous intravenous infusion of cytarabine plus an anthracycline on days 1 through 3 (table 6).

Daunorubicin is most commonly used, but idarubicin or mitoxantrone are acceptable alternatives. The dose of daunorubicin should be adjusted for patients ≥65 years of age. A targeted agent may be added for patients with specific molecular or immunophenotypic features. Descriptions of cytarabine and anthracycline dosing, addition of a targeted agent, and toxicity of 7+3 therapy are presented separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

Outcomes with 7+3 therapy or related intensive regimens for t-MNs come primarily from limited retrospective analyses, which demonstrate the importance of prognostic features in predicting response to therapy (see 'Prognostic factors' above):

●A phase 3 trial that compared 7+3 therapy versus liposomal daunorubicin-cytarabine (ie, CPX-351) and included patients with t-MNs is described below. (See 'Liposomal daunorubicin-cytarabine' below.)

●A retrospective study of 121 patients with t-MNs who were treated with intensive induction chemotherapy reported 27, 13, and 6 month median overall survival (OS) for patients with favorable, intermediate, and unfavorable cytogenetics, respectively [5].

●Favorable cytogenetic features were associated with superior outcomes in a report from an international workshop that included 511 patients with t-MNs [18]. For the favorable prognostic subsets, inv(16) and 21q22, the rates of median OS were 28 and 14 months, respectively, while the median OS for the unfavorable 11q23 subset was 8 months.  

●Another study reported 85 percent complete remission (CR) rate in 39 patients with inv(16) [19]. In that study, median OS was >3 years for the 26 patients who were <55 years old.

Compared with de novo acute myeloid leukemia (AML), patients with t-MNs generally have inferior outcomes. As an example, one study reported that median OS was 10 versus 15 months, respectively; however, more patients with therapy-related AML (t-AML) had unfavorable cytogenetic features (46 versus 20 percent) [20]. It is uncertain if outcomes with t-MNs are inferior to de novo AML when matched by prognostic features. Some studies have reported comparable outcomes for patients in the same risk category [1,5,20-22], while others report that patients with t-AML do worse than comparable patients with de novo AML [23-26].

Liposomal daunorubicin-cytarabine — Liposomal daunorubicin-cytarabine (also known as CPX-351) is a liposomal formulation of cytarabine and daunorubicin in a fixed 5:1 molar ratio.

CPX-351 is administered as daunorubicin (44 mg/m²) and cytarabine (100 mg/m²) over 90 minutes on days 1, 3, and 5; if needed, the same dose is administered on days 1 and 3 of a second cycle of induction therapy. Adverse reactions in >25 percent of patients included hemorrhage, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting [27]. The packaging label includes a boxed warning not to substitute liposomal daunorubicin-cytarabine with other daunorubicin- or cytarabine-containing products.

An open-label trial randomly assigned 309 patients (60 to 75 years old) with t-MN or secondary AML (arising from prior myelodysplastic syndrome [MDS]) to one to two induction cycles of CPX-351 versus 7+3 therapy [28]. However, the significance of the findings for t-MNs is uncertain, because only one-fifth of the patients had a t-MN. Compared with 7+3, CPX-351 achieved superior median OS (10 versus 6 months, respectively; hazard ratio [HR] 0.69; 95% CI, 0.52-0.90) and rate of overall remissions (48 versus 33 percent, respectively) across all age groups and AML subtypes. Early mortality rates with CPX-351 and 7+3 were 6 and 11 percent through day 30 and 14 and 21 through day 60, respectively. Response of t-MN was also reported in a phase 2 study of CPX-351 [29].

CPX-351 is approved by the US Food and Drug Administration (FDA) for adult patients with newly diagnosed t-AML or AML with myelodysplasia-related changes [27].

Intensive nonanthracycline approaches — There is no consensus regarding a preferred intensive, nonanthracycline-containing regimen in this setting, and institutions differ in their preferred regimens. High dose cytarabine-based regimens are most commonly used, but prior treatment and comorbid illnesses may influence the choice of regimen. Intensive nonanthracycline-containing regimens that may be used in this setting are discussed separately. (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Intensive chemotherapy'.)

Lower intensity treatments

Choice of lower intensity treatment — Lower intensity approaches may be suitable for patients with t-MNs who are unlikely to tolerate intensive remission induction therapy and for some patients with adverse prognostic features. These treatments can prolong life, alleviate symptoms, and/or improve the quality of life. Lower intensity approaches are generally associated with mild or moderate nausea, diarrhea, and/or myelosuppression. (See 'Management approach' above.)

Selection of a lower intensity regimen is mainly informed by molecular features, toxicity profile, patient preference, and availability. There is insufficient evidence to give priority to either a targeted therapy or a hypomethylating agent, so both are currently considered to be equally acceptable in this setting. No studies have directly compared various agents or regimens in this setting and no approach offers a clearly superior balance of outcomes and toxicity.

Hypomethylating agent-based therapy may be used to treat t-MN. Other approaches that may be selected on the basis of molecular or immunophenotypic features include various targeted agents for t-MNs with a mutation of IDH1, IDH2, or FLT3 or gemtuzumab ozogamicin when the malignant cells express CD33. (See 'Targeted or other treatments' below.)

Hypomethylating agents alone or with venetoclax — Azacitidine and decitabine are hypomethylating agents that are widely used for treatment of de novo MDS or AML, but they have not been well-characterized in patients with a t-MN. For patients with de novo AML, more than half had a clinically meaningful response with acceptable levels of toxicity when treated with azacitidine or decitabine combined with venetoclax, including patients with adverse cytogenetic/molecular profiles [30]. Several uncontrolled studies have reported that outcomes of therapy-related MDS (t-MDS) treated with hypomethylating agents were comparable to responses of de novo MDS [31-33]. Discussion of hypomethylating agents for de novo AML is presented separately. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Decitabine' and "Acute myeloid leukemia: Management of medically unfit adults", section on 'Azacitidine'.)

Targeted or other treatments — Efficacy of targeted agents for t-MNs is not well-characterized, but agents that have been used to treat de novo myeloid neoplasms include:

●Ivosidenib – Ivosidenib is an orally administered inhibitor of isocitrate dehydrogenase-1 (IDH1), but it is not available in all medical settings. Ivosidenib may be associated with differentiation syndrome (DS), QT prolongation on electrocardiogram (EKG), and rare cases of Guillain-Barre syndrome. Ivosidenib is approved for treatment of adults ≥75 years old with AML that has a susceptible IDH1 mutation detected by an FDA-approved diagnostic test. Details of administration, toxicities, and outcomes in AML are presented separately. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'IDH inhibitors'.)

●Enasidenib – Enasidenib is an orally administered inhibitor of isocitrate dehydrogenase-2 (IDH2), but it is not available in all medical settings. Enasidenib may be associated with DS, QT prolongation on EKG, and rare cases of Guillain-Barre syndrome. Enasidenib is approved by the FDA for relapsed or refractory AML with IDH2 mutation, but it has also been used off-label for frontline treatment. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'IDH inhibitors'.)

●Venetoclax – Venetoclax is an orally available inhibitor of BCL2 and related anti-apoptotic proteins that is effective for initial treatment of AML in combination with azacitidine, decitabine, or low dose cytarabine. Venetoclax does not have a demonstrated role as a single agent for myeloid malignancies. Venetoclax plus a hypomethylating agent is described above. (See 'Hypomethylating agents alone or with venetoclax' above.)

●Glasdegib – Glasdegib is an orally available inhibitor of the hedgehog pathway that is effective for treatment of newly diagnosed AML in combination with low dose cytarabine; it does not have a demonstrated role as a single agent in this setting. Glasdegib was approved by the FDA for treatment of newly diagnosed AML in adults ≥75 years old or for patients who have comorbidities that preclude use of intensive induction chemotherapy. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Low-dose cytarabine (LoDAC)'.)

●Gemtuzumab ozogamicin – Gemtuzumab ozogamicin (GO) as a single agent is an acceptable remission induction therapy for selected patients who are unlikely to tolerate intensive remission induction therapy.

●Clofarabine – We consider clofarabine an acceptable option for patients who seek remission induction therapy but are unlikely to tolerate more intensive regimens. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Other agents'.)

Further discussion of treatment, toxicity, and outcomes with targeted or other agents are presented separately. (See "Acute myeloid leukemia: Management of medically unfit adults".)

RESPONSE EVALUATION — Response evaluation is informed by the goals of therapy and the type of initial treatment.

Response to intensive treatments — The goal of intensive therapy is long-term disease control. This typically requires achieving a complete remission (CR), with or without restoration of normal hematopoietic function.

Bone marrow examination is typically performed seven days after the final dose of induction chemotherapy and repeated after recovery of blood counts (eg, approximately four weeks after treatment began). For patients who have cleared their blasts in the day 7 marrow but show prolonged pancytopenia with no signs of hematological recovery, bone marrow examination should be repeated in order to exclude leukemic regrowth. In patients treated with intensive remission induction therapy, we suggest assessment of measurable residual disease (MRD). Criteria for CR and assessment of MRD are discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Remission status' and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Introduction'.)

Management for patients who achieve CR and for those who do not respond adequately to initial therapy (ie, resistant disease) are discussed below. (See 'Post-remission management' below and 'Relapsed/refractory disease' below.)

Response to lower intensity treatment — For patients treated with lower intensity treatment, assessment generally focuses on achieving a functional response, such as reducing transfusion needs, avoiding hospitalization, and controlling symptoms of the t-MN. It is generally not necessary to perform routine bone marrow examinations to assess treatment response or to measure MRD. However, bone marrow examination may be performed after several cycles of therapy if warranted by changes in the peripheral blood counts.

POST-REMISSION MANAGEMENT — Post-remission therapy aims to destroy leukemic cells that survived induction therapy. Virtually all patients with a t-MN who achieve remission will relapse within weeks to months unless they receive further treatment.

Selection of post-remission therapy — Our preferred approach to post-remission management is participation in a clinical trial of post-remission management.

Outside of a clinical trial, selection of post-remission management must be individualized and should consider medical fitness for further therapy, response to initial therapy, prognostic features of the t-MN, and the individual's goals of care. We suggest reassessing medical fitness and goals of care before selecting a post-remission strategy. Risks, benefits, and likely outcomes of various post-remission options should be discussed and treatment selection should be finalized soon after achieving remission, as most patients will otherwise soon relapse. (See 'Pretreatment evaluation' above.)

We suggest stratification of post-remission care based on medical fitness, prognostic category (table 5), and response to initial therapy:

●Medically fit for further intensive treatment:

•Favorable or intermediate prognosis – For patients who achieve complete remission (CR) with favorable or intermediate prognostic features (table 5), we select therapy on the basis of measurable residual disease (MRD):

-MRD not detected – For patients with no detectable MRD, we consider consolidation chemotherapy, maintenance therapy with a targeted agent (if appropriate, based on the molecular features), or observation to be acceptable options. This suggestion is informed by the relatively favorable prognosis and a desire to limit toxicity, compared with allogeneic hematopoietic cell transplantation (HCT). This approach requires continued monitoring for relapse; if relapse is detected, salvage therapy followed by early transplantation will be required. Some patients may, instead, choose allogeneic HCT in first CR because they value the lower likelihood for relapse more than concerns about associated toxicity.

-MRD detected – For patients with detectable MRD, we favor allogeneic HCT rather than consolidation chemotherapy, maintenance therapy, or observation. This judgment weighs potential long-term disease control more heavily than short-term and long-term toxicities of transplantation. (See 'Allogeneic transplantation' below.)

-MRD not measured – For patients in whom MRD was not evaluated, there is no consensus regarding a preferred approach to post-remission care, and shared decision-making should weigh personal values and goals. If consolidation chemotherapy is selected rather than early HCT, then repeat monitoring of blood and bone marrow for signs of relapse should be performed.

•Adverse prognosis – For patients with adverse prognosis who achieve CR or CR with incomplete recovery of blood counts (regardless of MRD status), we suggest allogeneic HCT, based on the poor outcomes associated with approaches other than transplantation.

●Less medically fit – For patients who are unable to tolerate allogeneic HCT, we suggest maintenance therapy with a targeted agent (as appropriate) or observation. For patients whose medical condition improves after achieving CR, some may be able and willing to receive consolidation chemotherapy.

For patients who do not achieve CR, regardless of prognostic features, we manage for refractory t-MN or offer supportive care alone. (See 'Relapsed/refractory disease' below and 'Medically frail' above.)

Allogeneic transplantation — Allogeneic HCT offers the greatest possibility of long-term disease control for patients with t-MNs. Nevertheless, transplantation is associated with considerable toxicity and there remains a high rate of relapse after transplantation. Allogeneic HCT has not been directly compared to consolidation chemotherapy in this setting, and patients with t-MN appear to have a higher rate of adverse outcomes with HCT when compared with patients with de novo acute myeloid leukemia (AML). Selection of patients for transplantation is described above. (See 'Selection of post-remission therapy' above.)

We consider medical fitness rather than age per se in judging eligibility for transplantation, but some centers limit transplantation to patients ≤65 years old. It should be recognized that cumulative toxicities from prior therapy may preclude HCT for some potential candidates. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

There is no consensus regarding the optimal approach to transplantation in this setting. Aspects that may vary between institutions include the conditioning regimen (eg, myeloablative versus reduced intensity versus nonmyeloablative conditioning), degree of immunologic match (eg, complete or partially matched related or unrelated donor, haploidentical donor), extent of disease control (eg, CR versus partial remission versus undetectable MRD), and post-transplant maintenance therapy with a targeted agent, if that was a component of remission induction therapy. (See "Acute myeloid leukemia in younger adults: Post-remission therapy".)

No randomized trials have directly compared allogeneic HCT versus alternative approaches for t-MNs. Retrospective and population-based studies suggest that allogeneic HCT is beneficial for selected patients with t-MN, but such studies lack appropriate control groups and are subject to bias regarding patient selection. Informative studies include:

●An international retrospective analysis reported outcomes of 868 persons who underwent allogeneic HCT for a t-MN [34]. Outcomes after one and five years included 37 and 22 percent overall survival (OS), respectively; 32 and 21 percent disease-free survival (DFS); 27 and 31 percent rates of relapse; and 41 and 48 percent treatment-related mortality. Grade II to IV acute graft-versus-host disease (GVHD) was reported in 39 percent, and approximately one-third of patients had chronic GVHD at one, three, and five years. There was no significant difference between outcomes after reduced intensity conditioning versus myeloablative conditioning. Risk factors associated with inferior OS and DFS included age >35 years, adverse-risk cytogenetics, t-MN not in remission, and donor other than a human leukocyte antigen (HLA)-identical sibling or a partially/well-matched unrelated donor. OS at five years for patients with 0, 1, 2, 3, or 4 of these risk factors was 50, 26, 21, 10, and 4 percent respectively.

●An international registry study of 461 patients with t-MN reported an estimated 35 percent three-year OS [35]. The cumulative incidence of relapse at three years was 31 percent, and nonrelapse mortality at one and three years were 32 and 37 percent, respectively.

●Other registry studies report that outcomes with transplantation are superior to other approaches, but such analyses are not well-controlled for prognostic features or medical fitness. As an example, an Italian Network registry study reported 58.8 month OS for transplant recipients, compared with 12.1 months for nontransplant approaches [2]. Similarly, a German study reported median OS with nontransplant approaches was 7.2 months, while median OS for transplanted t-MN had not been reached after median follow-up of 41 months [36].

Consolidation chemotherapy — There are few reports of post-remission consolidation chemotherapy for t-MNs and no consensus regarding selection of patients, optimal regimen, or number of treatment cycles in this setting. Selection of patients for consolidation chemotherapy is discussed above. (See 'Selection of post-remission therapy' above.)

For patients who received remission induction therapy with CPX-351, the suggested dose for each cycle of consolidation therapy is daunorubicin 29 mg/m² and cytarabine 65 mg/m² via intravenous infusion over 90 minutes on days 1 and 3. Other consolidation chemotherapy regimens are discussed separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy".)

Maintenance therapy — Maintenance therapy with a targeted agent may be administered for post-remission treatment or post-transplant, but the benefit has not yet been demonstrated for patients with a t-MN. Settings where maintenance therapy with a targeted agent may be considered are discussed above. (See 'Selection of post-remission therapy' above.)

MONITORING — There is no consensus regarding the frequency of follow-up visits or protocol for monitoring a patient after treatment for a t-MN. Monitoring should include both surveillance for disease relapse and long-term complications of therapy.

The frequency of visits should be informed by clinical judgment. We generally schedule patient visits every one to two months for the first two years when the disease is most likely to relapse, and then every three to six months for up to five years post-consolidation. At these visits we perform a complete blood count and differential count and review of the peripheral blood smear. Bone marrow biopsy and aspirate is not routinely performed but may be informative if the peripheral smear demonstrates abnormalities or if unexplained cytopenias develop. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Post-consolidation management'.)

Monitoring disease status, including the use of measurable residual disease (MRD) in patients with acute myeloid leukemia, is discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Introduction'.)

RELAPSED/REFRACTORY DISEASE — The prognosis for patients who relapse with a t-MN is generally grim. There is no consensus regarding the optimal therapeutic approach, and treatment is guided by medical fitness and prior therapies. In circumstances where they relapse without a prior allogeneic HCT, one may still try to induce a remission and lead the patient to transplant. We encourage participation in a clinical trial, when possible. Potential treatment approaches are discussed separately. (See "Treatment of relapsed or refractory acute myeloid leukemia".)

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health [37].

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 5^th to 6^th 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 10^th to 12^th 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

●Therapy-related myeloid neoplasms (t-MN) can arise in patients who were previously treated with DNA-damaging agents. 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).

●Therapy-related acute promyelocytic leukemia (t-APL) is a distinct category of t-MN that should be suspected in a patient with bleeding/bruising, when leukemic blasts have coarse or dense cytoplasmic granules, and when there are few circulating leukemic cells or a low white blood cell count. (See 't-APL' above.)

●Goals of care should be determined by shared decision-making between clinicians and the patient. For most medically fit patients the goal is to achieve long-term survival with the possibility of cure, while for others, the goals are to prolong life, alleviate symptoms, and/or improve quality of life. (See 'Goals of care' above.)

●Management – Outside of a clinical trial, selection of treatment is based on medical fitness for intensive treatment, cytogenetic and molecular features (table 5), prior therapy, and the patient's goals and preferences. Importantly, treatment selection is not based on age per se or the specific category of t-MN (ie, t-AML, t-MDS, or t-MDS/MPN).

Our approach follows:

•Medically fit – For medically fit patients, we suggest stratifying treatment on the basis of prognostic category (table 5) (see 'Medically fit' above):

-Favorable or intermediate prognosis – For medically fit patients with favorable or intermediate prognostic features (table 5), we suggest intensive remission induction therapy, rather than lower intensity treatment (eg, targeted therapy, hypomethylating agent) (Grade 2C). (See 'Choice of intensive regimen' above.)

-Adverse prognosis – For medically fit patients with adverse prognostic features (table 5), we strongly encourage participation in a clinical trial. Outside of a clinical trial, there is no consensus regarding a preferred approach, and we consider intensive regimens, targeted treatments, or hypomethylating agents to be acceptable options.

•Medically frail – Treatment is focused on relief of symptoms, prolongation of life, and improving the quality of life, using supportive care, with or without lower intensity treatments. (See 'Medically frail' above.)

●Treatments – Specific intensive and lower-intensity treatments are described above. (See 'Intensive treatments' above and 'Lower intensity treatments' above.)

●Response evaluation after initial therapy for a t-MN is described above. (See 'Response evaluation' above.)

●Post-remission management – Virtually all patients who achieve remission will relapse within weeks to months unless they receive further treatment. Treatment options include allogeneic hematopoietic cell transplantation, consolidation chemotherapy, maintenance therapy with a targeted agent, or observation, based on medical fitness, prognostic category (table 5), and response to initial therapy. (See 'Selection of post-remission therapy' above.)