Acute megakaryoblastic leukemia

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Acute megakaryoblastic leukemia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Israr Khan, M.D.[2]

Synonyms and keywords: Leukemia, megakaryoblastic, acute; megakaryoblastic leukemia, acute; AMKL; leukemia, myeloid, acute, M7; megakaryocytic leukemia; megakaryocytic leukemia, acute; myeloid leukemia, acute, M7


Acute megakaryoblastic leukemia is a rare type of hematological malignancy that results from the clonal proliferation of megakaryoblasts in the bone marrow. Prof. Dr. Von Boros first described it in 1931. In 1985, the French-British-American classification of Acute myeloid leukemia (AML) included it as (M7 subtype). Later in 2008, acute megakaryoblastic leukemia was classified under AML otherwise not specified category by World Health Organization. It results from a mutation involving several genes, particularly the GATA1 gene, and transforming growth factor-β (TG-β). AMKL has commonly associated with Down syndrome. It has a bimodal distribution and is more common in children (<4) 15% than adults 0.6%. AMKL has a wide range of presentations which has either acute or insidious onset. It is characterized by fever, irritability, headache, fatigue, bone pain, generalized body aches, bruises, and difficulty walking. Physical exam findings include pallor, Hepatosplenomegaly (HSM), and lymphadenopathy, bruises and purpura, and sometimes temporal or orbital swelling. It is diagnosed by bone marrow biopsy showing 30% or more leukemic cells of megakaryocytic lineage and detection of platelet-specific peroxidase antibodies. Other lab findings include pancytopenia and megakaryocytic progenitors in the peripheral smear. Other diagnostic studies include; Immunophenotyping using MoAb to megakaryocyte restricted antigen (CD41 and CD61), complex karyotypic (t(1;22)(p13;q13) involvement, radiologic features of the osteolytic lesion, metaphyseal lucency, pathologic fractures using CXR, CT scan, bone scan, and MRI modalities. Currently, chemotherapy and allogeneic bone marrow transplant (Allo-BMT) are mainstay therapy. However, treatment-related toxicity is a big challenge. Different drug combination regimens are available for AMKL. The commonly used drugs are Cytarabine, mitoxantrone, etoposide, vincristine, fludarabine, and pirarubicin. The prognosis of AMKL in Down syndrome patients is favorable as compared with non-Down syndrome patients.

The following complications can be observed in patients with AMKL; periosteal elevation, osteolytic lesions, especially in long bones, e.g., femur, osteoporosis with pathologic fractures, Sweet syndrome (SS), leukemia cutis, and hypercalcemia.

Historical Perspective

J. Von Boros first described acute megakaryoblastic leukemia in 1931.


For established French-British-American (FAB) classification, refer to acute myeloid leukemia classification.


  • It is associated with GATA1, and risks are increased in individuals with Down syndrome. However, not all cases are associated with Down syndrome, and other genes can also be associated with AMKL. However, not all cases are associated with Down syndrome, and other genes can also be associated with AMKL.
  • Myelofibrosis is usually associated with AMKL; however, the exact underlying pathophysiology is controversial. The investigators did not find any direct correlation between acute myelofibrosis and the fibroblasts obtained from the bone marrow of patients with AMKL. Nevertheless, it was proposed that some humoral factors may play a key role in developing bone marrow fibrosis.
  • Transforming Growth Factor-β (TG-β) was identified to be the significant contributor in AMKL associated myelofibrosis in addition to some other unknown factors due to the strong stimulatory effects on collagen.


Mutations involving

Differentiating AMKL from other Diseases

Distinguishing features from other subtypes of AML are following:

  • Presence of megakaryocytic specific antigens (CD41, CD61) and markers (glycoprotein 1b) and platelets peroxidase activity. Karyotype analysis also helpful due to its complex and unusual karyotypic presentation t(1;22)(p13;q13).

Differential Diagnoses:

Acute myeloid leukemia otherwise not specified as per WHO classification:

  1. Acute myeloid leukemia with minimal differentiation
  2. Acute myeloid leukemia without maturation
  3. Acute myeloid leukemia with maturation
  4. Acute myelomonocytic leukemia
  5. Acute monoblastic/monocytic leukemia
  6.  Acute erythroid leukemia
  7. Pure erythroid leukemia
  8. Erythroleukemia, erythroid/myeloid
  9.  Acute basophilic leukemia
  10. Acute panmyelosis with myelofibrosis (a.k.a acute myelofibrosis)

Epidemiology and Demographics

  • AMKL is the most common subtype of AML reported in Down syndrome patients. It is more common in children compared with adults. The prevalence in children and adults is ~15% and 0.6%, respectively.
  • Down syndrome patients carry a 200 fold increased risk of developing AMKL vs. non-Down syndrome patients. Similarly, another review proposed a 500 fold increased risk. It almost exclusively occurs in the first 3 years of life.
  • Transient leukemia (TL) occurs in approximately 10% of Down syndrome infants, which is also attributed to transient myeloproliferative disorder. In most cases, TL spontaneously resolves; however, during the first four years of life, it progresses to acute megakaryoblastic leukemia in 13% to 33% of patients.

Risk Factors

  • Risk of development of AMKL increases in patients with Down syndrome .

Natural History

  • Clonal proliferation of early megakaryoblasts in the bone marrow results in acute megakaryoblastic leukemia (AMKL). It has a bimodal onset of presentation—occurs both in the pediatric age group (<4 years) and adults.
  • In childhood, it is more prevalent in patients with Down syndrome. While it is rare in adults, approximately 0.6% (24/3603) reported in the GIMEMA trial.
  • Cases of AMKL secondary to chronic myelogenous leukemia and essential thrombocytosis have been reported in the medical literature.


  1. Periorbital swelling
  2. Periosteal elevation
  3. Osteolytic lesions, especially in long bones, e.g., femur
  4. Osteoporosis with pathologic fractures
  5. Sweet syndrome (SS)
  6. Leukemia cutis
  7. Hypercalcemia


Due to the rarity of this subtype of hematological malignancy, limited data is available on the natural course or prognosis.

  • Apart from AMKL in Down syndrome patients, the prognosis of AMKL is poor. The efficacy profile of AMKL in Down syndrome patients is favorable, but it comes with a lot of treatment-related toxicity.
  • According to the Children’s Oncology Group (COG) AML0431 trial results, the 5-year event-free survival and overall survival rates were 90% and 93% in 204 eligible Down syndrome with AMKL patients.
  • Similarly, the reported 3-year overall survival rate was 100% among 3 AMKL with Down syndrome patients while (47±12%) in non-Down syndrome patients.


Diagnostic Study of Choice

History and Symptoms

  • Greater than 50% of leukemia patients demonstrate skeletal features and are mostly related to the AMKL subtype.

Physical Examination

  • Physical exam findings include:

Down syndrome features are present in patients with Down syndrome associated AMKL.

Laboratory Findings

The diagnosis of AMKL (M7) is based on the following:

  1. Bone marrow biopsy demonstrating 30% or more leukemic cells of megakaryocytic lineage
  2. Conducting tests that detect platelet-specific antibodies which could be monoclonal or polyclonal.
  3. Bone marrow biopsy is recommended in patients who developed myelofibrosis. Visualization of blasts and mature megakaryocytes on biopsy sections is diagnostic.

Other Diagnostic Studies

  • In children, the same clinical presentation but with variable course especially in very young children; both leukocytosis and organomegaly may be present in children with M7. Complete remission and long term survival are more common in children than adults.
  • In blood and bone marrow smears megakaryoblasts are usually medium sized to large cells with a high nuclear- cytoplasmic ratio. Nuclear chromatin is dense and homogeneous. There is scanty, variable basophilic cytoplasm which may be vacuolated. An irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present. The megakaryoblasts lack myeloperoxidase activity and stain negatively with Sudan black B (SBB).
  • They are alpha naphthyl butyrate esterase negative and manifest variable alpha naphthyl acetate esterase activity usually in scattered clumps or granules in the cytoplasm. PAS staining also varies from negative to focal or granular positivity, to strongly positive staining.
  • A marrow aspirate is difficult to obtain in many cases because of variable degree of myelofibrosis.
  • More precise identification by immunophenotyping or with electron microscopy (EM). Immunophenotyping using MoAb to megakaryocyte restricted antigen (CD41 and CD61) may be diagnostic.

Karyotype analysis:

Radiographic features:


Medical Therapy

  • According to the AML-BFM (Berlin–Frankfurt–Münster) 98 and AML-BFM ((Berlin–Frankfurt–Münster) 93 clinical studies, intensive AML targeted chemotherapy in Down syndrome-associated AMKL results in high event-free survival rates versus non-Down syndrome patients. However, they are also prone to develop treatment-related toxicity at standard doses due to chemo sensitivity.

The treatment is divided into induction therapy and consolidation therapy.

  • Induction therapy — involves two cycles (four weeks apart ) of Ara-Cytarabine (Ara-C) at 100 mg/m2 /day continuous infusion for 7 days, vincristine at 0.7 mg/m2 on day 7, and pirarubicin at 25 mg/m2 by 60 min infusion on days 2, and 4 (AVC1).
  • Consolidation therapy — follows once complete remission is achieved with the following regimen; etoposide & high-dose Ara-C (EC), mitoxantrone and continuous-dose Ara-C (MC), and pirarubicin, vincristine, and continuous-dose Ara-C (AVC2).

The doses are given below:

MC regimen:

  • Ara-C at 100 mg/m2 /day continuous infusion for 5 days and
  • Mitoxantrone at 3.5 mg/m2 by 60 min infusion on days 2–4

EC regimen

  • High-dose Ara-C 1 g/m2 every 12 hrs on days 1–5,
  • Etoposide 66 mg/m2 by 2 h infusion on days 2–4), and

AVC2 regimen

  • Ara-C at 100 mg/m2 /day on days 1–5,
  • Pirarubicin 35 mg/m2 by 60 min infusion on day 2, and
  • Vincristine at 0.7 mg/m2 on day 5

In relapsed state, re-induction with fludarabine and Ara-C combination or same AVC regimen can be utilized. Allogenic bone marrow transplant (Allo-BMT) from a suitable donor is justified if the patients achieved second complete remission. Currently, there is no recommended definitive therapy for non-Down syndrome with AMKL cohort. Novel therapeutic interventions are undertaken.

  • Some study groups proposed that non-Down syndrome with AMKL is a high-risk condition; therefore, allogeneic hematopoietic stem cell transplantation (Allo-HSCT) during first complete remission is recommended to benefit the patients. In contrast, no benefit of Allo-HSCT is evident over chemotherapy without remission.
  • In AML-BFM 04 trial, patients were randomized to receive induction therapy with either (Ara-C), liposomal daunorubicin, and etoposide (ADxE) or Ara-C, idarubicin, and etoposide (AIE) regimen. Consolidation therapy with 2-chloro-2-deoxyadenosine (2-CDA) and Ara-C and idarubicin was preceded by second induction therapy with HAM (high-dose Ara-C, mitoxantrone, cytarabine However, no significant results were obtained regarding event-free survival (EFS) and overall survival (OS).


There is no established surgical intervention for acute megakaryoblastic leukemia.


There is no established method for prevention of acute megakaryoblastic leukemia.


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