Acute Panmyelosis with Myelofibrosis
Jialing Huang, MD, PhD and Ying Zou, MD, PHD, FACMG
Johns Hopkins University, Baltimore, MD
Cancer Sub-Classification / Subtype
Acute panmyelosis with myelofibrosis
Definition / Description of Disease
Acute panmyelosis with myelofibrosis (APMF) is a rare form of acute myeloid leukemia (AML), characterized by acute onset of pan-myeloid proliferation with increased blasts ( ⩾20% of cells in the bone marrow or peripheral blood) and extensive bone marrow fibrosis in the absence of splenomegaly. It shows hyperplasia of all three lineages, an increase in megakaryocyte count with dysplasia, and frequent abnormal karyotypes with chromosomal aneuploidy. In the 2016 revision to the World Health Organization (WHO) classification system, acute panmyelosis with myelofibrosis is a distinct entity within the section of [:File:///C:/index.php/Acute Myeloid Leukemia (AML), Not Otherwise Specified Acute Myeloid Leukemia (AML), Not Otherwise Specified]. This entity is distinct and does not meet the criteria for acute megakaryoblastic leukemia (AML-M7), myelodysplastic syndrome - refractory anemia with excess blast II ( MDS-RAEB-II) with fibrosis, primary myelofibrosis (PMF), AML with myelodysplasia related changes, or therapy-related AML. The clinical course of this entity is rapidly progressive, and the prognosis is poor with overall survival of only a few months (range 1.8–11.3 months).
This is a distinct entity in the World Health Organization (WHO) classification system within the section of Acute Myeloid Leukemia (AML), Not Otherwise Specified. This entity does not meet the criteria for inclusion in any of the other AML groups (i.e. AML with Recurrent Genetic Abnormalities, AML with Myelodysplasia-Related Changes, or Therapy-Related Myeloid Neoplasms).
Synonyms / Terminology
French-American-Brirish (FAB) classification M4, NOS
Acute panmyelosis, NOS
Acute (malignant) myelofibrosis
Acute (malignant) myelosclerosis, NOS
Acute myelosclerosis, NOS
Epidemiology / Prevalence
Approximately 1% of AML cases
1. Occur in all age groups but is more common in adults.
2. Median patient age is 40 - 50 years
3. Male-to-female ratio is unknown, male predominance may occur
The common clinical presentations are related to acute onset of peripheral pancytopenia and bone marrow fibrosis in the absence of splenomegaly. Patients have severe and acute (sudden onset) systemic symptoms, including fever, pallor, dyspnea, fatigue, loss of weight and bleeding disorders. Splenomegaly is minimal.
Sites of Involvement
1. Bone marrow aspirate smear is often hypocellular due to marked fibrosis.
2. Prominent panmyelosis with myelofibrosis in the bone marrow (≥ grade 2 on a 0–3 scale, reticulin > collagen). Different degrees of reticulin-collagen fibrosis and wide ranges of cellularity with a prominent left-shifted and macrocytic erythropoiesis associated with a reduction and maturation defects of the neutrophil series.
3. A marked increase in atypical megakaryocytes including loose clustering, dislocation towards the endosteal border and appearance of atypical microforms with compact nuclei.
4. Besides myelofibrosis, the interstitial compartment displays an inflammatory reaction with lymphoid nodules, abundant iron-laden macrophages, perivascular plasmacytosis and increase in micro vessels.
5. An accumulation of dispersed or clustered CD34+ and lysozyme-expressing blasts in the bone marrow.
6. The peripheral blood typically shows pancytopenia, such as schistocytes and giant or hypogranular platelets. Dysplastic myeloid cells are frequent.
1. MPO is usually negative in the blasts.
2. PAS stain highlights erythroblast and megakaryocytes.
3. Monoblasts, promonocytes and monocytes usually show non-specific esterase reactivity.
Often a complex immunophenotype with multiple blast populations seen, including:
1. Immature blasts with high CD34 and/or KIT (CD117) expression
2. Populations with myeloid markers: CD13, CD33, CD15, CD65
3. Populations with monocytic markers: CD4, CD11b, CD11c, CD14, CD64, CD36, CD68 (PGM1), CD163 and lysozyme
4. Populations with megakaryocytic markers: CD41, CD42b, CD61, von Willebrand factor
5. Populations with erythroblastic markers: glycophorin A, hemoglobin A
6. In most cases, blasts are positive for HLA-DR
7. Approximately 30% of cases, blasts are positive for CD7
Chromosomal Rearrangements (Gene Fusions)
Cytogenetic abnormality was common, but no known recurring or common cytogenetic abnormality except chromosomal aneuploidy.
Characteristic Chromosomal Aberrations / Patterns
The gains of chromosome 3q, 8, 12q, 17q, and 21q, as well as loss of 5q, 7q, and 17p, are present in most cases. These chromosomal aberrations are like AML with myelodysplasia related changes.
2. Chromosomal aneuploidy can be divided into two groups including a low genomic complexity (with ≤ 3 copy number abnormalities) and a high genomic complexity group (with >3 copy number abnormalities). The low genomic complexity group may have mostly single but heterogeneous copy number abnormalities. The high genomic complexity group has frequent losses of 5q, 7q, and 17p. The gains of chromosome 3q, 8, 12q, 17q, and 21q, as well as loss of 7q were present in both groups.
Gene Mutations (SNV/INDEL)
Acute panmyelosis with myelofibrosis has genetic heterogeneity at the molecular level and the genetic alterations underlying acute panmyelosis with myelofibrosis are not well characterized. Although there is no specific gene identified that is frequently associated with this subset of AML, TP53 abnormalities (i.e. loss of 17p and/or TP53 mutation (such as Exons 7 and 10 splicing mutations), and/or biallelic inactivation of both TP53 alleles) has been reported in these patients.
Acute panmyelosis with myelofibrosis occasionally has mutations in DNMT3A, TET2, CBL, and BCOR genes, and usually does not have JAK2 V617F, MPL, or CALR mutations according to limited studies.
Genes and Main Pathways Involved
Diagnostic Testing Methods
1. Conventional chromosome analysis
2. FISH myeloid panel
3. Myeloid mutation panel
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
The clinical course of this disease is rapidly progressive and fatal. Therefore, it is essential to distinguish it from its mimickers including acute megakaryoblastic leukemia (AML-M7), myelodysplastic syndrome - refractory anemia with excess blast II (MDS-RAEB-II) with fibrosis, primary myelofibrosis (PMF), and AML with myelodysplasia related changes. Detailed clinical history and hematological/cytogenetics work up can be helpful to differentiate this disease from its mimickers. Since the prognosis of these patients is poor, it is important to aggressively manage these patients with timely diagnosis as it can reduce morbidity and prolong life. Hematopoietic cell transplantation (HCT) prolongs overall survival to 3 years in 24% of patients.
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The term “AML with TP53 mutations and chromosomal aneuploidy” can be used to describe majority of these patients and to distinguish from other diseases.
Put your links here
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