View source for HAEM4:Acute Panmyelosis with Myelofibrosis

{{DISPLAYTITLE:Acute Panmyelosis with Myelofibrosis}}


<blockquote class='blockedit'>{{Box-round|title=PREVIOUS EDITION|This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition [[HAEM5:Table_of_Contents|Table of Contents]].
}}</blockquote>
==Primary Author(s)*==

Jialing Huang, MD, PhD and Ying Zou, MD, PHD, FACMG

Johns Hopkins University, Baltimore, MD 

__TOC__

==Cancer Category/Type==

[[AML|Acute Myeloid Leukemia]]

==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<ref name=":0">Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405. PMID:27069254
</ref><ref name=":1">Arber DA, Brunning RD, Orazi A, Porwit A. Acute myeloid leukemia, NOS. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2017.
</ref><ref name=":2" />. 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]<ref name=":0" /><ref name=":1" /><ref name=":2" />. 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 [[HAEM4:Acute Myeloid Leukemia (AML), Not Otherwise Specified]]<ref name=":2">Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p165-166.</ref>.  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

Malignant myelosclerosis

Acute myelofibrosis

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 

==Clinical Features==

The common clinical presentations are related to acute onset of peripheral pancytopenia and bone marrow fibrosis in the absence of splenomegaly<ref name=":3">Orazi A, O’Malley DP, Jiang J, Vance GH, Thomas J, Czader M, et al. Acute panmyelosis with myelofibrosis: an entity distinct from acute megakaryoblastic leukemia. Mod Pathol. 2005;18:603–14. PMID: PMID:15578075
</ref><ref name=":4">Xu Z. AML with myelodysplasia-related changes masquerades as acute panmyelosis with myelofibrosis. Blood. 2017;130:1775. PMID:29025719
</ref><ref name=":5">Thiele J, Kvasnicka HM, Schmitt-Graeff A. Acute panmyelosis with myelofibrosis. Leuk Lymphoma. 2004;45:681–7. PMID:15160939
</ref>. Patients have severe and acute (sudden onset) systemic symptoms, including fever, pallor, dyspnea, fatigue, loss of weight and bleeding disorders. Splenomegaly is minimal.  

Previous history of myeloproliferative neoplasm (MPN) or myelodysplastic syndrome (MDS), and exposure to radiation or cytotoxic drugs are usually absent<ref name=":3" /><ref name=":4" /><ref name=":5" />.

==Sites of Involvement==

Bone marrow  

==Morphologic Features==

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. 

==Immunophenotype==

Cytochemistry 

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<ref name=":0" /><ref name=":3" /><ref name=":4" /><ref name=":6">Suvajdzic N, Marisavljevic D, Kraguljac N, Pantic M, Djordjevic V, Jankovic G, et al. Acute panmyelosis with myelofibrosis clinical, immunophenotypic and cytogenetic study of twelve cases. Leuk Lymphoma. 2004;45:1873–9. PMID:15223649
</ref><ref name=":7">Bae E, Park CJ, Cho YU, Seo EJ, Chi HS, Jang S, et al. Differential diagnosis of myelofibrosis based on WHO 2008 criteria: acute panmyelosis with myelofibrosis, acute megakaryoblastic

leukemia with myelofibrosis, primary myelofibrosis and myelodysplastic syndrome with myelofibrosis. Int J Lab Hematol.2013;35:629–36. PMID:23693053
</ref><ref name=":8">Grygalewicz B, Woroniecka R, Pastwinska A, Rygier J, Krawczyk P, Borg K, et al. Acute panmyelosis with myelofibrosis with EVI1 amplification. Cancer Genet. 2012;205:255–60. PMID:22682625
</ref><ref name=":9">Pantic M, Pfeifer D, Kapp-Schwoerer S, Ihorst G, Becker H, Zeiser R, Duyster J, Schmitt-Graeff A. TP53 abnormalities and chromosomal aneuploidy in acute panmyelosis with myelofibrosis. Leukemia. 2019 Dec;33(12):2956-2962. PMID:31350530
</ref>. These chromosomal aberrations are like AML with myelodysplasia related changes.  

==Genomic Gain/Loss/LOH==

1. Chromosomal aneuploidy is common. The gains of chromosome 3q, 8, 12q, 17q, and 21q, as well as losses of chromosome 5p, 7q, and 17p, are present in most cases<ref name=":0" /><ref name=":3" /><ref name=":4" /><ref name=":6" /><ref name=":7" /><ref name=":8" /><ref name=":9" />.  

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<ref name=":3" /><ref name=":6" /><ref name=":8" /><ref name=":9" />.

==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<ref name=":9" />.
===Other Mutations===
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<ref name=":9" /><ref>Kim SY, Im K, Park SN, et al. CALR, JAK2, and MPL mutation profiles in patients with four different subtypes of myeloproliferative neoplasms: primary myelofibrosis essential thrombocythemia, polycythemia vera, and myeloproliferative neoplasm, unclassifiable. Am J Clin Pathol 2015;143:635–44. PMID:25873496
</ref>.

==Epigenomics (Methylation)==

None

==Genes and Main Pathways Involved==

None

==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<ref>Konuma T, Kondo T, Kawata T, et al. Hematopoietic Cell Transplantation for Acute Panmyelosis with Myelofibrosis: A Retrospective Study in Japan. Biol Blood Marrow Transplant 2019;25(1):e23-e27. PMID:30103016
</ref>. 

==Familial Forms==

Put your text here

==Other Information==

The term “AML with TP53 mutations and chromosomal aneuploidy” can be used to describe majority of these patients and to distinguish from other diseases.  

==Links==

Put your links here

==References==
<references />

==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
[[Category:HAEM4]] [[Category:DISEASE]]