Acute Basophilic Leukemia – Causes, Symptoms, Treatment

Acute Basophilic Leukemia
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Acute Basophilic Leukemia (ABL) is a rare and poorly characterized form of leukemia. A gastroscopy was conducted and indicated a gastric antral ulcer. The diagnosis of ABL was determined due to characteristic cytomorphological features, the myeloid immunophenotype of the blast cells (identified to be positive for cluster of differentiation [CD]25 and CD123) in addition to the absence of the Philadelphia chromosome and a c-kit D816V mutation. The patient initially demonstrated clinical improvement as a result of chemotherapy, however, subsequently deteriorated. The gastric and skin manifestations of ABL may be associated with excessive histamine release from basophilic cells. Thus, the administration of H1- and H2-receptor antagonists, proton pump inhibitors, and steroids is proposed in order to minimize these associated complications.

Acute basophilic leukemia (ABL) is listed as a separate entity in the acute myeloid leukemia (AML), not otherwise specified category in the 2008 WHO classification, comprising <1% of all cases of AML [rx]. The very recently proposed criteria of ABL are blasts ≄20% and immature basophils ≄40% of nucleated bone marrow (BM) or peripheral blood (PB) cells [rx]. However, as the disease is defined on the basis of morphology, limited information is currently available on specific cytogenetic and molecular markers.

The t(16;21)(p11;q22) translocation was initially described in a patient with AML characterized by a large number of abnormal eosinophils in BM [rx]. Sixty‐six cases carrying t(16;21) are currently listed in the Mitelman database, which shows that this translocation is present in all ages and is associated with poor survival [rx]. In 1994, two independent groups found that t(16;21) led to the generation of a fusion gene between FUS (FUS RNA binding protein) at 16p11 and ERG (ERG, ETS transcription factor) at 21q22, encoding the FUS‐ERG chimeric protein [rx, rx]. The leukemogenic activity of this chimeric protein was demonstrated by the retroviral transduction of FUS‐ERG to human umbilical cord blood cells, showing altered myeloid and arrested erythroid differentiation and marked increases in the proliferative and self‐renewal capacities of transduced myeloid progenitors [rx].

Cytogenetic analyses in the first patient showed a normal karyotype, while the second displayed a translocation t(2;6); (q23?4;p22?3), as well as a del (12)(p11). Earlier observations have linked bone marrow basophilia either to a deletion of the short arm of chromosome 12 (p11-13), to translocations involving the long arm of chromosome 6 at 6q23 or to the translocation t(6,9); (p23;q34). However, other translocations involving chromosome 6p23 have not been described before. Treatment of our patients consisted of supportive treatment in the one with normal karyotype and aggressive chemotherapy in the other patient. Both patients died within one year after diagnosis due to progressive or recurrent leukemia.

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Differential Diagnosis of Acute Basophilic Leukemia

Flow cytometry (FCM) revealed that leukemia blasts showed an immature myeloid cell phenotype, that is CD13+, CD33+, CD34+, and CD117+, but lacked HLA‐DR expression. Approximately, 20% of cells expressed CD203c, which was previously reported to be specific for basophils in PB and increased in response to IgE‐dependent cell activation [rx], and the acquisition of the antigen appeared to correlate with the loss of CD34. Other antigens expressed were CD7−, CD11bdim, CD25+, CD45RAdim, CD45RO+, CD56+, CD66c−, and CD123+.

Surface antigen expression of leukemia blasts in BM. (A) Single‐color FCM of leukemia blasts gated by SSC/FSC characteristics. Positive cell populations for each antigen are indicated by horizontal bars, and their percentages are shown. (B) Multicolor FCM of leukemia blasts gated by the weak expression of CD45 and low SSC characteristics. A CD203c/CD34 dot plot shows a broad range of expression levels of both antigens, while a CD7/CD56 dot plot shows the homogeneous expression of CD56 and lack of CD7. The percentages of each quadrant are shown.

Electron microscopy showed that leukemia blasts in BM were 6–12 Όm in diameter, and the nuclear‐cytoplasmic ratio ranged between 0.5 and 0.9. Cells had round, indented, or irregular nuclei with slightly condensed chromatin and small to medium‐sized nucleoli. In the cytoplasm, variable amounts of mitochondria, rough endoplasmic reticulum (ER), and Golgi apparatus were found among the cells. Twenty to 30% of leukemia blasts contained granules that were 0.3–1.2 mm in diameter with a variable appearance, representing immature basophils [rx]A and B) [rx, rx, rx]. The materials in the granules showed a similar electron density to the cytoplasm, more intense electron density, or a speckled appearance, and the materials were often extracted to display an electron‐lucent appearance. Occasional granules contained myelin‐like structures. Theta granules were not apparent. On the other hand, approximately 40% of the cells had primary granules of 0.25–0.6 mm in diameter, and MPO activity in these cells was detected in the nuclear cistern, rough ER, Golgi apparatus, and/or primary granules, showing the features of myeloblasts [rx]. In contrast, the contents of the granules, as well as cytoplasmic organelles in immature basophils, lacked MPO activity

Electron microscopic appearance of leukemia blasts in BM. (A and B) Immature basophils containing cytoplasmic granules of 300–700 nm in diameter. The contents of the granules show a variable appearance, that is those with a similar degree of electron density to that of the cytoplasm, with more intense electron density, a speckled appearance, or electron‐lucent appearance resulting from the extraction of the materials. Occasional granules show myelin‐like figures. Uranyl acetate‐lead citrate staining. (C) MPO reaction in a myeloblast (left) and immature basophil (right). The myeloblast contains MPO‐positive primary granules in the cytoplasm and shows positivity in the nuclear cistern and rough ER, while the immature basophil was negative for the reaction. (D) An MPO‐stained immature basophil containing abundant granules with a variable appearance. The contents of the granules are negative for the MPO reaction, in contrast to an earlier study.

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G‐banding of the metaphase spreads obtained from the BM specimen revealed the der(21)t(16;21)(p11;q22) chromosome, while the reciprocal der(16)t(16;21)(p11;q22) was deleted. The karyotype according to the ISCN (2013) [rx] was 45,XY,−16,der(21)t(16;21)(p11;q22). A reverse transcriptase‐mediated polymerase chain reaction (RT‐PCR) using the nested primer pairs for the FUS‐ERG fusion transcripts generated three species of DNA, with molecular sizes of 255, 211, and 176 bp, as described earlier [rx]. The products were subjected to direct sequencing, demonstrating the in‐frame junction encompassing FUS exon 7 and ERG exon 10.

Morphologic Features of Acute Basophilic Leukemia

Differentiated (basophilic granules by light microscopy) and poorly differentiated cases; Majority are poorly differentiated. MPO negative by light microscopy; granules positive in a speckled pattern by electron microscopy. Myeloid antigens are expressed. Diagnosis of poorly differentiated cases made by electron microscopy. May manifest basophil and mast cell granules by EM. Cytogenetically heterogeneous but frequently associated with Philadelphia chromosome. There is no clinically distinguishing features but may be more common in children and young adults and carry a poor prognosis.[rx]

ABL features include immature basophils in the peripheral blood and blast cells with basophilic granules in the bone marrow[rx][rx]. These granules show metachromasia when stained with toluidine blue. Identification of the coarse basophilic granules may be the first step in the diagnosis of this rare disorder. Blasts are usually negative with Sudan Black B (SBB), myeloperoxidase (MPO), and neuron-specific enolase (NSE). Diffuse staining with acid phosphatase and peroxidase activity may be present in some cases.

Immunophenotype of Acute Basophilic Leukemia

Immunophenotyping is positive for myeloid markers such as CD9, CD13, CD33, CD123, CD203c, CD11b, and HLA-DR and negative for CD117 in some cases. The blasts may stain positive for toluidine blue, PAS, acid phosphatase, and myeloperoxidase. Immunophenotyping and electron microscopy may also identify a basophilic lineage; this is especially crucial to differentiate basophilic cells from closely related mast cells.

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Finding Marker
Positive (universal) CD13, CD33, CD34, Class II HLA-DR
Positive (subset) Mature basophils can be CD25+ and CD117-, mast cells can be CD117+ and CD25+, blasts can be CD9+ and TdT+.
Negative (universal) No B or T -lymphoid markers
Negative (subset) CD117

Chromosomal Rearrangements (Gene Fusions)

No consistent chromosomal abnormalities have been reported in ABL due to its rarity. Rearrangement of MYB/GATA1 with t(X;6)(p11;q23) has been reported in four male infants. The fusion gene leads to the downregulation of MYB, upregulation of GATA1, and commits myeloid cells to the granulocyte lineage and blocks their differentiation.

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
t(X;6)(p11;q23) 5’MYB / 3’GATA1 der(X) Rare (4 cases)

Characteristic Chromosomal Aberrations / Patterns

A few male patients have been reported with massive hyperdiploid or tetraploid karyotypes. Monosomy 7 was reported in a rare case.

Treatment of Acute Basophilic Leukemia

Although the initial treatment regimen consisting of idarubicin and cytarabine failed to eradicate leukemia cells, MEC (mitoxantrone, etoposide, and cytarabine) salvage treatment led to a hematological response. Cellulitis of the leg resolved during the induction treatment. After three cycles of MEC, FUS‐ERG fusion mRNA fell to below the level of detection. The patient then underwent hematopoietic stem cell transplantation from his daughter, who was HLA‐A locus mismatched in the graft‐versus‐host direction and HLA‐C and DR loci‐mismatched in the host‐versus‐graft direction. Although the course of the transplant was uneventful, his leukemia briefly relapsed on day 56 of transplantation. A reduction in the dosage and withdrawal of tacrolimus led to the elimination of circulating leukemia blasts; however, he developed severe graft‐versus‐host disease involving the entire gastrointestinal tract. He finally died of Pseudomonas aeruginosa septicemia on day 419 of the initial presentation.

References

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