Mixed phenotype acute leukemia

INTRODUCTION — 

Mixed phenotype acute leukemia (MPAL) refers to acute leukemias that cannot be unequivocally assigned to one hematopoietic lineage because the malignant blasts express both myeloid and lymphoid antigens.

MPAL has previously been described as bilineage leukemia and biphenotypic acute leukemia.

This topic discusses clinical manifestations, diagnosis, classification, and management of MPAL in adults and children.

Related topics include:

●(See "Acute myeloid leukemia in adults: Overview".)

●(See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis".)

●(See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

●(See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)

OVERVIEW — 

MPAL describes acute leukemias in which the malignant blasts express antigens that are characteristic of the myeloid lineage plus antigens that are characteristic of a lymphoid lineage. Because of the ambiguous pattern of antigen expression, these leukemias cannot be unequivocally assigned to one hematopoietic lineage.

MPAL is rare, but it has been difficult to define its prevalence because its names and diagnostic criteria have evolved. It has not always been distinguished from acute undifferentiated leukemia, and it was previously called bilineage acute leukemia or biphenotypic acute leukemia. (See 'Epidemiology' below.)

The leukemic blasts are often morphologically bland with a nondiagnostic microscopic appearance. The biphenotypic nature of the leukemic blasts must be demonstrated by immunophenotypic, histochemical, karyotypic, and/or molecular methods. (See 'Diagnosis' below.)

MPAL shares clinical and/or pathologic features with other categories of acute leukemia and with mixed blast phase of chronic myeloid leukemia. Immunophenotypic and/or cytogenetic features are used to distinguish between these entities. (See 'Differential diagnosis' below.)

All patients who present with MPAL should have a lumbar puncture at diagnosis because of the substantial risk for central nervous system involvement. (See 'Lumbar puncture' below.)

The subtype of MPAL, which is based on the blast immunophenotype and certain cytogenic findings, must be determined for all cases. It is important to distinguish between cases that are Philadelphia chromosome positive (Ph+; t(9;22) and/or BCR::ABL1 rearrangement detected) versus those cases that are not (Ph-negative MPAL). (See 'Classification' below.)

Management is driven by whether the case is Ph+ MPAL versus Ph-negative MPAL. (See 'Ph+ MPAL' below and 'Ph-negative MPAL' below.)

EPIDEMIOLOGY — 

MPAL is rare, but the true incidence is uncertain because of changes in disease nomenclature and diagnostic criteria.

MPAL accounts for <3 percent of acute leukemia, according to retrospective studies [1-4]. A population-based study reported 0.35 cases of MPAL/1,000,000 person-years, based on United States Surveillance, Epidemiology, and End Results registry (SEER) data [5].

MPAL occurs more often in adults than in children, but it can be seen in patients of all ages. It has a bimodal age distribution, with peaks at ages 19 and ≥60 years [5-7]. A male preponderance (estimated as 1.5:1) is reported [7]. No familial cases of MPAL have been reported.

MPAL B/myeloid, not otherwise specified (NOS) accounts for approximately two-thirds of cases, while Philadelphia chromosome-positive MPAL accounts for approximately one-quarter of cases [7-9]. Less common subtypes of MPAL are discussed below. (See 'Classification' below.)

CLINICAL PRESENTATION — 

The clinical presentation of MPAL does not distinguish it from other forms of acute leukemia.

Patients generally present with clinical findings that reflect pancytopenia, such as fatigue, weakness, infections, and/or bleeding (eg, epistaxis, gingival bleeding, ecchymoses). Other presenting symptoms may relate to accumulation of leukemic cells in peripheral blood, bone marrow, or extramedullary sites (eg, abdominal fullness from splenomegaly, bone pain).

Other details of the clinical presentation of acute leukemia are presented separately. (See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis", section on 'Clinical presentation'.)

EVALUATION — 

Diagnosis of MPAL requires demonstration that the leukemic blasts express markers of more than one hematopoietic lineage (ie, expression of both myeloid and lymphoid antigens).

Peripheral blood — The white blood cell count at presentation is variable and can range from <1000 cells/microL with rare circulating leukemic blasts to >100,000 blasts/microL. Anemia and thrombocytopenia are almost invariably present.

The blood smear may reveal a morphologically uniform blast cell population, or there may be two distinct blast populations. When two populations are seen (ie, dimorphic blasts), the smaller blasts usually express lymphoid antigens, while the larger blasts exhibit myeloid or monocytic antigens. Either pattern (ie, uniform or dimorphic blasts) can be seen with any of the MPAL subtypes. (See 'Classification' below.)

Bone marrow — Bone marrow is evaluated for morphology, immunophenotype, and cytogenetic features.

Microscopy — Bone marrow is infiltrated with leukemic blasts, but the percentage varies.

Contemporary classification systems differ regarding the importance of the blast percentage for diagnosis of MPAL. The International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms requires ≥20 percent blasts in blood or bone marrow [10]. By contrast, the World Health Organization 5^th edition (WHO5) set no threshold blast percentage for diagnosing MPAL [11].

A single population of morphologically uniform blasts may be seen in bone marrow, or there may be a dimorphic population, as described above. (See 'Peripheral blood' above.)

The morphology of MPAL blasts can evolve, so relapsed or refractory MPAL may appear as pure acute lymphoblastic leukemia (ALL) or pure acute myeloid leukemia (AML) in the course of the disease.

Immunophenotype — Multiparameter flow cytometry is the preferred method for immunophenotyping MPAL. Blasts must express markers of more than one hematopoietic lineage; as with blast morphology, there may be a single population of uniform blasts, or there may be two or more blast populations.

Diagnosis of MPAL requires either a single blast population that expresses markers of >1 lineage, or there may be ≥2 completely separable single-lineage leukemia populations (when there are ≥2 populations, one must satisfy criteria for AML, and the other must meet criteria for ALL) [3,11]. The significance of small populations of blasts (eg, <5 percent of total blasts) with an aberrant phenotype should be interpreted with caution.

The following features are used to characterize the immunophenotype:

●B cell – Strong expression of CD19 (at least as bright as normal B cells) together with at least one other B cell marker (eg, CD10, cytoplasmic CD79a, CD22); if CD19 expression is dim or absent, ≥2 or ≥3 other B cell markers, respectively, must be expressed.

●T cell – Strong expression of cytoplasmic CD3 (with some blasts at least as bright as normal residual T lymphocytes); surface CD3 is usually negative.

●Myeloid – Myeloperoxidase (MPO) expression or ≥2 monocytic markers (CD11c, CD14, CD36, CD64).

In the absence of MPO expression or evidence of monocytic differentiation, expression of the myeloid markers CD13 and/or CD33 is not sufficient for a diagnosis of MPAL and must be supplemented by cytochemical studies:

•MPO – MPO positivity in >3 percent blasts is considered evidence for myeloid differentiation.

•Nonspecific esterase (NSE) – NSE positivity can be used as evidence of monocytic differentiation.

In the absence of lineage-defining results from flow cytometry or enzyme cytochemistry, immunohistochemistry should be used with caution for diagnosing MPAL because immunohistochemistry does not permit distinguishing between small numbers of residual normal cells and the leukemic blasts.

Cytogenetics — No chromosomal or genetic abnormality is exclusively associated with MPAL, but certain findings are used for classifying MPAL subtypes.

Karyotyping is also needed to exclude other leukemia diagnoses. Although fluorescence in situ hybridization (FISH) can define certain MPAL subtypes, it does not conclusively exclude other leukemia diagnoses based on cytogenetics. (See 'Differential diagnosis' below.)

Cytogenetic/molecular abnormalities that can be associated with MPAL include [3,11]:

●Philadelphia chromosome (Ph) – t(9;22) and/or BCR::ABL1

●KMT2A rearrangement

●ZNF384 rearrangement

●BCL11B activation

Cytogenetic abnormalities are reported in 59 to 91 percent of MPAL cases [2,7,8,12]. Other abnormalities have been reported, but complex karyotype and myelodysplasia-related AML-defining cytogenetics (eg, monosomy 5 or 7) should exclude the diagnosis of MPAL, since they would satisfy an alternative diagnosis, as discussed below. (See 'Differential diagnosis' below.)

MPAL is associated with a high frequency of somatic mutations in genes encoding epigenetic regulators, tumor suppressors, and transcription factors. Whole exome sequencing of 23 pediatric and adult MPAL specimens reported that one-third had mutations in epigenetic regulators (eg, DNMT3A, IDH2, EZH2); mutations were also identified in the RAS pathway, TP53, NOTCH1, and other genes [13]. Studies that used targeted sequencing reported similar findings [2,14].

MPAL exhibits a pattern of gene expression that is distinct from other acute leukemias [15], but gene expression is not a diagnostic criterion for MPAL.

DIAGNOSIS — 

MPAL should be suspected in patients with unexplained cytopenia- or organomegaly-related symptoms that suggest an acute leukemia, but there are no clinical manifestations that are seen exclusively with MPAL.

Diagnosis of MPAL requires morphologic, immunophenotypic, cytogenetic, and molecular testing that demonstrates:

●Leukemic blasts express markers of more than one hematopoietic lineage

This pattern of antigen expression can be due to a single blast population that expresses markers of >1 lineage, or it can be due to ≥2 distinct single-lineage leukemia populations, one that meets criteria for acute myeloid leukemia (AML) and another that can be defined as acute lymphoblastic leukemia (ALL). (See 'Immunophenotype' above.)

Importantly, neither expression of a single lymphoid antigen on a myeloblast nor expression of a single myeloid antigen by a lymphoblast is sufficient to diagnose MPAL. As examples, AML with t(8;21) often expresses CD19 (a B cell antigen), while some cases of T cell ALL express a single myeloid antigen; neither of these scenarios would qualify as MPAL.

●Exclusion of other specific categories of leukemia

Immunophenotypic, cytogenetic, and molecular criteria that distinguish MPAL from other leukemias are discussed below. (See 'Differential diagnosis' below.)

Note that the International Consensus Classification (ICC) requires ≥20 percent blasts in bone marrow or blood to diagnose MPAL [10], while the World Health Organization 5^th edition (WHO5) set no blast threshold for diagnosis [11].

DIFFERENTIAL DIAGNOSIS — 

Distinguishing MPAL from other types of leukemia is challenging and requires expert pathology support.

MPAL is difficult to distinguish from other leukemias because:

●Morphologic features of leukemic blasts are generally nondiagnostic

●Immunophenotype is, by definition, ambiguous; blasts may be either bilineal or biphenotypic

●There are no pathognomonic cytogenetic or molecular findings

●Lineage switching may occur spontaneously or after treatment

Disorders that should be distinguished from MPAL include:

●Acute undifferentiated leukemia (AUL) – AUL is distinguished from MPAL by immunophenotype since neither blast morphology nor cytogenetic/molecular findings distinguish these acute leukemias.

AUL is defined by the absence of lineage-specific antigens by flow cytometry or immunohistochemistry. By contrast, MPAL blasts express both myeloid and lymphoid antigens.

●Acute myeloid leukemia (AML) – AML shares morphologic, immunophenotypic, and genetic findings with MPAL.

AML subtypes are defined and distinguished from MPAL by cytogenetic/molecular findings, the degree of blast differentiation, and/or clinical context (eg, prior cytotoxic therapy, associated dysplasia, germline/inherited genetic alterations), as discussed in detail separately. (See "Acute myeloid leukemia: Classification".)

●Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusions – These neoplasms may be morphologically and immunophenotypically indistinguishable from MPAL, but they are defined by tyrosine kinase fusion genes (eg, FGFR1, PDGFRA, PDGFRB), with or without associated chromosomal abnormalities. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

●Acute lymphoblastic leukemia (ALL) – ALL may morphologically resemble MPAL, but it can be distinguished by the pattern of antigen expression and certain cytogenetic findings.

ALL leukemic blasts express lymphoid antigens, and they generally do not express myeloid antigens. However, exceptions include B cell ALL with t(12;21)(p13.2;q22.1); ETV6::RUNX1, which can express both lymphoid and myeloid antigens, but it is distinguished by the diagnostic cytogenetic findings. Early T cell precursor ALL can express multiple myeloid antigens, but it is distinguished from T/myeloid MPAL by the lack of myeloperoxidase (MPO) expression.

Philadelphia chromosome-positive (Ph+) ALL may have the same chromosomal and molecular rearrangements as Ph+ MPAL, but the blasts do express myeloid antigens. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma", section on 'Ph+; t(9;22)(q34.1; q11.2); BCR::ABL1'.)

Further details of diagnosis of ALL are presented separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

●Chronic myeloid leukemia (CML) with mixed blast phase – CML with mixed blast phase may be indistinguishable from Ph+ MPAL by morphology, immunophenotype, and cytogenetic features, but it is distinguished by the clinical context (ie, prior chronic phase or accelerated-phase CML).

Although the BCR::ABL1 isoform may be helpful, this does not unequivocally distinguish between these entities. CML usually expresses the p210 isoform, but it can express p190, which is the most common isoform in MPAL; conversely, MPAL can express the BCR::ABL1 p210 isoform.

CLASSIFICATION — 

MPAL is classified according to defining genetic alterations or defining immunophenotypic findings.

Because of distinctly different approaches to management, it is most important to distinguish between:

●Philadelphia chromosome-positive (Ph+) MPAL – Cases that exhibit t(9;22) and/or express BCR::ABL1. (See 'Ph+ MPAL' below.)

●Ph-negative MPAL – All other cases of MPAL. (See 'Ph-negative MPAL' below.)

The International Consensus Classification (ICC) and the World Health Organization 5th edition (WHO5) agree about how to classify MPAL, but there are slight differences in names for various subtypes [10,11,16]:

●MPAL with defining genetic alterations

•MPAL with BCR::ABL1 – Ph+ MPAL accounts for one-quarter of cases of MPAL, and it is more common in adults than in children [7-9]. Ph+ MPAL is often associated with dimorphic morphology of leukemic blasts, most cases have a B/myeloid phenotype, and most express the p190 BCR::ABL1 transcript [7-9]. Some series report that patients with Ph+ MPAL have a high incidence of central nervous system involvement at presentation [17-20].

•MPAL with t(v;11q23.3); KMT2A rearranged – This subtype, which accounts for <10 percent of MPAL, is more common in children than in adults [2,7,8]. It is typically bilineal (two distinct populations of blasts) and only rarely biphenotypic (coexpression of lymphoid and myeloid markers on the same cell). Most cases have B lymphoblasts, and the myeloid blasts are usually monoblastic [21].

•MPAL with ZNF384 rearrangement.

•MPAL with BCL11B activation.

●MPAL with defining immunophenotypic changes

•B/myeloid MPAL – This subtype accounts for approximately two-thirds of MPAL cases [7].

•T/myeloid MPAL – Mutations of DNMT3A and FLT3 have been reported in T/myeloid MPAL [13,22], and outcomes with the T/myeloid subtype were reported to be inferior to B/myeloid MPAL [23].

•B/T/myeloid MPAL.

•B/T MPAL.

MPAL is grouped with acute undifferentiated leukemia into a larger category called acute leukemia of ambiguous lineage in both ICC and WHO5 [10,11].

PRETREATMENT EVALUATION

Clinical/laboratory testing — Pretreatment evaluation is like that for acute myeloid leukemia, as discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Pretreatment'.)

Lumbar puncture — An initial diagnostic lumbar puncture (LP), including cytology and flow cytometry, should be performed for all patients with MPAL.

The first dose of intrathecal (IT) chemotherapy should be administered at the time of the initial diagnostic LP, as described below. (See 'Central nervous system management' below.)

The following cautions about the LP should be noted:

●Computed tomography (CT) should be performed prior to LP to assess possible causes of elevated intracranial pressure for patients with focal neurologic findings, altered mental status, recent seizure, or papilledema on retinal exam. (See "Lumbar puncture: Technique, contraindications, and complications in adults", section on 'Cerebral herniation'.)

●For patients with a platelet count ≤20,000/microL, we suggest platelet transfusion immediately prior to the procedure. There is controversy regarding what constitutes a "safe" platelet count, as discussed separately. (See "Acute myeloid leukemia: Involvement of the central nervous system", section on 'Lumbar puncture'.)

●LP should be performed regardless of the peripheral blood leukemic blast count.

●LP should be performed before beginning leukemia therapy (or as soon as possible), but initiation of chemotherapy should not be delayed to perform the LP.

Ph+ MPAL — 

We recommend incorporation of a tyrosine kinase inhibitor (TKI) into all phases of treatment for patients with Philadelphia chromosome-positive (Ph+) MPAL, based on improved outcomes compared with chemotherapy alone.

The choice of TKI is individualized, based on toxicity profile and comorbidities, but we generally favor dasatinib (because it may effectively penetrate the central nervous system [CNS]) or ponatinib (based on superior efficacy and similar toxicity compared with imatinib in a phase 3 trial for Ph+ ALL [24]). Selection of a TKI is discussed separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Selection of a tyrosine kinase inhibitor'.)

Patients should undergo human leukocyte antigen (HLA) typing early in the course of disease in anticipation of possible allogeneic hematopoietic cell transplantation (HCT). Eligibility for allogeneic HCT is discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

MPAL is rare, and there are few clinical studies of Ph+ MPAL from the TKI era. Management is largely extrapolated from treatment of Ph+ ALL. Our approach follows:

●Remission induction therapy – Remission induction should include a TKI plus age-based Ph+ acute lymphoblastic leukemia (ALL) remission induction therapy, as described separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Remission induction therapy' and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

●Response assessment – Bone marrow examination is performed on day 29 (ie, immediately after completing remission induction therapy) and should include blast percentage and assessment of BCR::ABL1 for measurable residual disease (MRD), as discussed separately. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma", section on 'Methods for detecting MRD'.)

●CNS management – The first dose of intrathecal (IT) chemotherapy is given at the time of the initial diagnostic lumbar puncture (LP). Further details of CNS management are described above. (See 'Central nervous system management' below.)

●Post-remission therapy – For patients who achieve complete remission (CR), post-remission management is guided by age and fitness.

•Adults

-Transplant eligible – For transplant-eligible adults, we suggest allogeneic HCT rather than consolidation chemotherapy plus a TKI, treatment with a TKI alone, or observation, based on extrapolation from the superior outcomes with allogeneic HCT in Ph+ ALL, as discussed separately. (See "Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: Post-remission management".)

-Not transplant eligible – We suggest consolidation chemotherapy plus a TKI rather than a TKI alone or observation.

•Children – Post-remission management in children is guided by the level of MRD, like the approach used for pediatric ALL, as discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

Patients who do not achieve CR are managed as refractory MPAL. (See 'Relapsed/refractory MPAL' below.)

●Maintenance therapy – We suggest maintenance therapy with a TKI.

While maintenance therapy has not been proven to be beneficial for Ph+ MPAL, this treatment suggestion is based on improved outcomes with TKI-based maintenance therapy for Ph+ ALL. (See "Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: Post-remission management", section on 'Maintenance therapy regimens'.)

Surveillance after post-remission therapy is described below. (See 'Surveillance' below.)

Routine use of TKIs to treat Ph+ MPAL has improved survival compared with the dismal outcomes from the pre-TKI era. (See 'Prognostic factors' below.)

●A study from the US SEER (Surveillance, Epidemiology, and End Results) registry reported outcomes of 241 cases of MPAL [25]. Ph+ MPAL patients had a lower risk of death compared with Ph-negative MPAL patients (hazard ratio [HR] 0.28 [95% CI 0.13-0.62]). In a 1:1 matched case-control analysis, outcomes of Ph+ MPAL were comparable to those of Ph+ ALL.

●A retrospective analysis reported that outcomes for 13 patients with Ph+ MPAL were comparable to those of 27 patients with Ph+ ALL, including CR rate (100 versus 85 percent), five-year overall survival (55 versus 53 percent), and five-year disease-free survival (46 versus 42 percent) [26].

Ph-NEGATIVE MPAL — 

All cases of MPAL that do not manifest the Philadelphia chromosome (Ph; ie, t(9;22)) and/or expression of BCR::ABL1 are considered Ph-negative MPAL.

Patients should undergo human leukocyte antigen (HLA) typing early in the course of disease to prepare for possible allogeneic hematopoietic cell transplantation (HCT). Eligibility for allogeneic HCT is discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

Our approach to treatment of Ph-negative acute lymphoblastic leukemia (ALL) is consistent with a consensus statement from the Children's Oncology Group (COG) [27].

Remission induction — We suggest ALL-like remission induction therapy rather than an acute myeloid leukemia (AML)-like regimen or a hybrid (ALL-AML) regimen, based on more favorable outcomes and less toxicity.

Management is evolving with the availability of effective immunotherapy (eg, blinatumomab) for ALL, but no studies have reported such treatment for Ph-negative ALL at present.

●Management of Ph-negative MPAL is guided by age:

•<40 years – Treat with a pediatric-type ALL regimen, as described separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

•≥40 years – Treat with an adult-type ALL regimen, as described separately. (See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults", section on 'Chemotherapy'.)

All patients should receive prophylaxis for central nervous system (CNS) involvement beginning with the initiation of remission induction therapy. Further details of CNS management are presented below. (See 'Central nervous system management' below.)

Bone marrow examination should be performed on day 29 (immediately after completing remission induction therapy), including blast percentage and assessment for measurable residual disease (MRD), as discussed separately. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma", section on 'Methods for detecting MRD'.)

●Outcomes – Clinical studies of Ph-negative MPAL are limited, and it is difficult to compare results from different studies, in part, because of changes in disease nosology, as described above. (See 'Overview' above.)

•Efficacy – Most studies of MPAL indicate that ALL-like remission induction therapy is associated with better outcomes than AML-like regimens, although results are not entirely consistent across all studies.

-A meta-analysis of 1351 patients with MPAL reported that ALL-like and AML-like treatment strategies were associated with similar overall survival (OS), but the complete remission (CR) rate was lower with AML-like induction therapy [28]. Patients who received AML-like therapy were less likely to achieve CR (odds ratio [OR] 0.33 [95% CI 0.18-0.58]).

-A study of 100 patients with MPAL (32 children, 68 adults) reported that response rates were higher with ALL-like remission induction therapy than AML-like therapy [7]. Median survival was 18 months, and 37 percent of patients were alive at five years. Among 27 patients treated with ALL-like therapy, 85 percent achieved CR compared with 41 percent CR of 34 patients treated with AML-like therapy (two of whom also received imatinib); three of five patients responded to treatment with hybrid ALL-AML therapy. Other studies also reported superior remission rates with ALL-like therapy versus AML-like approaches [29-32].

-Responses did not differ with ALL-like and AML-like induction regimens (90 versus 84 percent, respectively) among 36 patients with MPAL in a single-institution study; CR rates for adults and children were 87 and 85 percent [33].

-Hybrid ALL/AML remission induction approaches for MPAL achieve CR rates that are comparable to ALL-like therapy, but long-term survival is less certain, and these treatment strategies are often associated with greater toxicity [2,17,23,29,30,34].

•Toxicity – No studies have directly compared toxicity of ALL-like and AML-like regimens in the setting of MPAL, but AML-like regimens are generally associated with more prolonged/profound cytopenias, infections, and cardiac complications but less neuropathy.

For patients who are medically frail, acceptable options include participation in a clinical trial or approaches that focus on palliation of symptoms, as described separately.

Central nervous system management — All patients with MPAL should have a lumbar puncture (LP) at the time of diagnosis, as described above. (See 'Lumbar puncture' above.)

The first dose of intrathecal (IT) chemotherapy should be given at the time of the initial diagnostic LP or on day 1 of remission induction therapy. IT chemotherapy is repeated on day 8.

Each IT treatment should include 12 to 15 mg of preservative-free methotrexate or 30 to 50 mg of cytarabine, with or without 50 mg of hydrocortisone.

Four additional IT treatments should be administered. Our suggestions for the schedule are informed by the initial diagnostic LP:

●Positive cerebrospinal fluid – Initial LP: >5 white blood cells (WBC)/microL or cytospin positive for lymphoblasts:

•IT chemotherapy on days 15 and 22 of remission induction and days 1 and 8 after completing remission induction therapy

●Negative cerebrospinal fluid – Initial LP: ≤5 WBC/microL and cytospin negative for lymphoblasts:

•IT chemotherapy on days 1, 8, 15, and 22 following recovery from remission induction therapy

If new neurologic symptoms appear at any time during or after treatment of acute leukemia, an LP should be performed.

Post-remission management — We stratify post-remission management according to results from the day 29 bone marrow examination, age, and transplant eligibility. Eligibility for allogeneic HCT is discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

We do not treat with maintenance chemotherapy, as there is no evidence that it provides a benefit with Ph-negative MPAL.

Patients who do not achieve CR are managed as refractory MPAL. (See 'Relapsed/refractory MPAL' below.)

There are no prospective studies of post-remission management of Ph-negative MPAL. Our treatment suggestions are based on limited retrospective studies (discussed below) and extrapolation from treatment of Ph-negative ALL.

●CR with MRD ≤10^-4

•Transplant eligible – Either consolidation therapy or allogeneic HCT is acceptable. The decision is individualized and informed by comorbidities and individual values and preferences.

•Not transplant eligible – Treat with consolidation therapy, as guided by the patient's age. (See "Philadelphia chromosome-negative acute lymphoblastic leukemia in adults: Post-remission management" and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

●CR with MRD ≥10^-4

•Transplant eligible – We suggest allogeneic HCT rather than observation or consolidation chemotherapy, based on superior outcomes and acceptable toxicity.

Allogeneic HCT for Ph-negative ALL in children and adults is discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents" and "Philadelphia chromosome-negative acute lymphoblastic leukemia in adults: Post-remission management".)

•Not transplant eligible – Treat with consolidation therapy, as guided by the patient's age. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents" and "Philadelphia chromosome-negative acute lymphoblastic leukemia in adults: Post-remission management".)

Surveillance after post-remission therapy is described below. (See 'Surveillance' below.)

In general, allogeneic HCT is associated with improved outcomes compared with consolidation chemotherapy. Outcomes with allogeneic HCT for MPAL are similar to those of patients who undergo allogeneic HCT for AML and ALL [34-37]. Informative studies of post-remission management in MPAL include:

●A single-center study of 66 patients with MPAL reported that, compared with consolidation chemotherapy, allogeneic HCT in first CR was associated with superior three-year OS (77 versus 16 percent) [29]. Rates of relapse and nonrelapse mortality (NRM) following HCT were 21 and 10 percent, respectively. A smaller study reported comparable results [14].

●A study of 95 patients with MPAL from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry reported that at three years, OS, NRM, relapse rate, and leukemia-free survival were 67, 15, 29, and 56 percent, respectively [36]. Outcomes were comparable for patients 20 to 40 years versus >40 years and for patients transplanted in first CR versus second remission.

SURVEILLANCE — 

There is no consensus protocol of surveillance for either Philadelphia chromosome (Ph)-positive or Ph-negative MPAL.

Our approach to surveillance for relapse and complications of therapy is like that for acute lymphoblastic leukemia, as discussed separately. (See "Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: Post-remission management", section on 'Surveillance' and "Philadelphia chromosome-negative acute lymphoblastic leukemia in adults: Post-remission management", section on 'Follow-up'.)

PROGNOSTIC FACTORS — 

Limited data are available, but factors associated with less favorable outcomes in MPAL are like those in other categories of acute leukemia, including:

●Older age [5,7,9,15,17-19,34,38,39]

●High white blood cell count at diagnosis [17,23,33]

●Adverse cytogenetics [7,8,19,32] and KMT2A rearrangement [33]

●Failure to achieve remission [17,29,37-39]

●T/myeloid MPAL had less favorable outcomes than B/myeloid MPAL, according to one report [23]

Philadelphia chromosome-positive MPAL was considered a poor prognostic feature in the past, but its prognostic significance in the era of routine use of tyrosine kinase inhibitors is uncertain [7].

RELAPSED/REFRACTORY MPAL — 

For patients who did not achieve complete remission (CR) after remission induction therapy (refractory MPAL) or who relapse after an initial CR, we encourage participation in a clinical trial.

There is no consensus treatment, and management should be individualized according to cytogenetic and immunophenotypic findings, prior therapy, and fitness.

●Immunophenotyping, cytogenetics, and molecular profiling should be repeated at relapse to see if the immunophenotype or genotype has evolved after prior treatment. If relapsed or refractory (r/r) MPAL undergoes a lineage switch, selection of salvage therapy may be guided by immunophenotypic findings.

●For patients with r/r Philadelphia chromosome-positive (Ph+) MPAL, mutation analysis of the BCR::ABL1 kinase domain should guide the choice of tyrosine kinase inhibitor, as discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor", section on 'TKI resistance'.)

●We generally favor an acute myeloid leukemia (AML)-like regimen for patients who failed to achieve remission with an acute lymphoblastic leukemia (ALL)-like remission induction regimen. However, immunotherapy with blinatumomab or inotuzumab should be considered if there is expression of CD19 or CD22, respectively. Chimeric antigen receptor T cell therapy may be considered if the target antigen is expressed.

Treatment strategies for r/r AML and ALL are discussed separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults" and "Treatment of relapsed or refractory acute myeloid leukemia".)

Patients who achieve a remission with salvage therapy should be considered for allogeneic hematopoietic cell transplantation.

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".)

SUMMARY AND RECOMMENDATIONS

●Description – Mixed phenotype acute leukemia (MPAL) describes acute leukemias that express antigens of more than one hematopoietic lineage and cannot be unequivocally assigned to one lineage.

●Presentation – Fatigue, infections, or bleeding (from pancytopenia) or bone/abdominal pain (from leukemic infiltration) are common. (See 'Clinical presentation' above.)

●Pathology

•Microscopy – Leukemic blasts may be uniform or dimorphic (two distinct populations). (See 'Bone marrow' above.)

•Immunophenotype – Expression of both:

-Myeloid antigens – Myeloperoxidase (MPO) or ≥2 monocytic markers (eg, CD11c, CD14, CD36, CD64)

-Lymphoid antigens – B lineage (eg, strong CD19 and ≥1 other B cell markers) and/or T lineage (cytoplasmic CD3)

•Cytogenetics – Cytogenetic/molecular features (eg, Philadelphia chromosome [Ph]) define some subtypes of MPAL.

●Diagnosis – MPAL may be suspected in patients with unexplained findings related to acute leukemias. (See 'Diagnosis' above.)

Diagnosis requires expression of both myeloid and lymphoid antigens, the blasts cannot be unequivocally assigned a single lineage, and other categories of leukemia are excluded.

●Differential diagnosis – Criteria for distinguishing MPAL from acute undifferentiated leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusions, and chronic myeloid leukemia with mixed blast phase are discussed. (See 'Differential diagnosis' above.)

●Classification – Specific subtypes are labeled according to defining genetic alterations or immunophenotypic findings. MPAL is broadly categorized as Philadelphia chromosome positive (Ph+) versus Ph negative. (See 'Classification' above.)

●Pretreatment – All patients should have a lumbar puncture at diagnosis because of high risk for central nervous system (CNS) involvement. (See 'Lumbar puncture' above.)

●Ph+ MPAL – For Ph+ MPAL (ie, t(9;22) and/or BCR::ABL1 detected), we recommend incorporation of a BCR::ABL1 tyrosine kinase inhibitor (TKI) into all phases of treatment (Grade 1B). The choice of TKI is individualized according to toxicity and comorbidities, but we generally favor dasatinib or ponatinib. (See 'Ph+ MPAL' above.)

•Remission induction therapy – We suggest age-based Ph+ ALL-like remission induction therapy rather than AML-like induction therapy (Grade 2C).

•CNS prophylaxis – Treatment should include CNS prophylaxis (Grade 2C). (See 'Central nervous system management' above.)

•Post-remission management – Following achievement of complete remission (CR), we suggest allogeneic hematopoietic cell transplantation (HCT) rather than consolidation chemotherapy plus TKI, a TKI alone, or observation (Grade 2C).

•Maintenance therapy – We suggest TKI maintenance therapy after either allogeneic HCT or consolidation chemotherapy (Grade 2C). Duration of maintenance therapy is guided by BCR::ABL1 measurable residual disease (MRD), as discussed above.

●Ph-negative MPAL – Ph-negative MPAL describes any case where neither t(9;22) nor BCR::ABL1 is detected. (See 'Ph-negative MPAL' above.)

•Remission induction – We suggest ALL-like, rather than AML-like, induction therapy (Grade 2C). (See 'Remission induction' above.)

•CNS – We suggest CNS prophylaxis (Grade 2C). (See 'Central nervous system management' above.)

•Post-remission – Guided by fitness and MRD (see 'Post-remission management' above):

-MRD ≤10^-4

For transplant-eligible patients, either allogeneic HCT or consolidation therapy is acceptable (Grade 2C).

For less-fit patients, we suggest consolidation therapy rather than observation (Grade 2C).

-MRD >10^-4

For transplant-eligible patients, we suggest allogeneic HCT rather than consolidation therapy (Grade 2C).

For less-fit patients, we suggest consolidation therapy rather than observation (Grade 2C).

●Relapsed/refractory MPAL – We favor participation in a clinical trial. Immunophenotyping, cytogenetics, and molecular profiling are repeated; patients with relapsed/refractory Ph+ MPAL should have BCR::ABL1 kinase domain sequencing (to guide TKI selection); and management is individualized by cytogenetic/molecular findings, prior therapy, and fitness. (See 'Relapsed/refractory MPAL' above.)