Atypical Chronic Myeloid Leukemia: Where Are We Now?
<p>Peripheral blood (PB) and bone marrow (BM) smears of patient 1. Panels <b>a</b>-<b>b</b>-<b>c</b>: the PB shows hyperleukocytosis with neutrophil precursors (promyelocytes, myelocytes, and metamyelocytes) representing ≥ 10% of the leukocytes, with monocytes < 10% and rare blasts. The neutrophils show pseudo-Pelger-Huet nuclear abnormalities and hypogranulated cytoplasm. Panels <b>d</b>-<b>e</b>-<b>f</b>: the BM is hypercellular due to an increase of neutrophils and their precursors. The myeloid/erithroid ratio is > 10:1 due to myeloid hyperplasia. Of note, the myeloid lineage shows evident signs of dysplasia similar to those present in the PB. Moreover, the megakaryocytes show signs of dysplasia with micro-megakaryocyte and cells with hypolobated nuclei.</p> "> Figure 2
<p><b>Diagnostic algorithm for aCML.</b> The diagnostic work up should start with complete blood count with manual differential, morphological examination of PB smear, BM examination with assessment of dysplastic features, cytogenetic analysis, and fluorescence in situ hybridization (FISH) to exclude Ph<sup>+</sup> chromosome and rearrangements involving <span class="html-italic">PDGFRA</span> (4q12), <span class="html-italic">PDGFRB</span> (5q31–33), <span class="html-italic">FGFR1</span> (8p11), or <span class="html-italic">JAK2</span> (9p24). Second level testing should include NGS with a myeloid panel, not only to confirm diagnosis but also to open the possibility of identifying druggable targets. PB, peripheral blood; BM, bone Marrow; FISH, fluorescence in situ hybridization.</p> "> Figure 3
<p>Mutational landscape of aCML. The main genes found to be mutated in aCML are represented on the X axis of the graph. Bars represent the minimum and maximum percentage of mutated patients for each gene reported in different study populations [<a href="#B1-ijms-21-06862" class="html-bibr">1</a>,<a href="#B2-ijms-21-06862" class="html-bibr">2</a>,<a href="#B8-ijms-21-06862" class="html-bibr">8</a>,<a href="#B18-ijms-21-06862" class="html-bibr">18</a>,<a href="#B19-ijms-21-06862" class="html-bibr">19</a>,<a href="#B20-ijms-21-06862" class="html-bibr">20</a>,<a href="#B21-ijms-21-06862" class="html-bibr">21</a>,<a href="#B22-ijms-21-06862" class="html-bibr">22</a>].</p> "> Figure 4
<p>Molecular pathways involved in aCML. Mutations in the <span class="html-italic">ASXL1</span> and <span class="html-italic">EZH2</span> genes are mainly point mutations that lead to impaired function of the polycomb repressive complex 2 (PRC2), which translate in decreased epigenetic repression of key genes involved in stem cell renewal, thus promoting myeloid proliferation and differentiation. Mutations of both <span class="html-italic">NRAS</span> and <span class="html-italic">PTNP11</span> result in a constitutive activation of MAPK, promoting cancer cell survival and proliferation. <span class="html-italic">SETBP1</span> encodes a protein named SET binding protein 1 (SEB) that regulates the SET inhibitory activity on tumor suppressors, including PP2A. In aCML, all the <span class="html-italic">SETBP1</span> mutations result in an increased gene expression and, through SET, in a reduction of PP2A inhibitory activity on AKT and MAPK pathways, leading to increased cellular proliferation and survival. Fingolimod targets PP2A with an activating effect. <span class="html-italic">ETNK1</span> encodes an ethanolamine kinase, which catalyzes the first step of the de novo phosphatidylethanolamine biosynthesis pathway, critical for regulating membrane architecture and the topology of transmembrane domains of membrane binding proteins. Due to the fact that the ethanolamine kinase 1 contributes to different processes in the cell, the mechanisms by which the mutant protein induces myeloproliferation have not yet been clarified. <span class="html-italic">CSFR3</span> mutations may be membrane proximal mutations or truncation mutations or a combination of the two. All the activating missense mutations target the proximal domain leading to increased dimerization and activation of JAK-STAT pathway, sensitive to its kinase inhibitor ruxolitinib. Conversely, <span class="html-italic">CSFR3</span> truncating mutations induce receptor signaling through SRC family kinase rendering the cells sensitive to the multikinase inhibitor dasatinib. Green dot: activating mutation; red lightning: inactivating mutations. ETH: Ethanolamine; PETH: phosphatidylethanolamine.</p> "> Figure 5
<p>Bone marrow smears after 3 cycles of decitabine of clinical case 1. The reduction of marrow blasts with persistence of trilineage dysplasia and a residual thrombocytopenia are consistent with an optimal marrow response according to proposed international criteria [<a href="#B36-ijms-21-06862" class="html-bibr">36</a>].</p> "> Figure 6
<p>Treatment algorithm for aCML. This flow-chart summarizes the treatment management of aCML. Treatment choices are made according to few key variables: eligibility for allogeneic hematopoietic stem cell transplantation (HSCT); mutations identified by next generation sequencing (NGS) panel; availability and eligibility for clinical trials; possibility to adopt therapies used for myelodysplastic syndrome (MDS) or MPN (e.g., hypomethylating agents or second-line/adjunctive therapies). * Patients should be enrolled in a clinical trial whenever possible.</p> ">
Abstract
:1. General Concepts
2. Clinical Case 1: aCML in Younger Patients
3. Clinical Case 2: aCML in the Elderly Patient/Unfit for Allogeneic Stem Cell Transplantation
4. Characteristics of aCML at Presentation and Prognosis
5. Diagnostic Tools in aCML
6. Cytogenetics in aCML
7. Molecular Landscape of aCML
8. Clinical Case 1: Treatment Choices in a Transplant Eligible Patient
9. Clinical Case 2: Treatment Approach in a Transplant Ineligible Patient
10. Treatment
10.1. Hematopoietic Stem Cell Transplant
10.2. Hypomethylating Agents
10.3. AML-Like Chemotherapy
10.4. Interferon-Alpha and Hydroxyurea
10.5. Target Therapy
11. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Clinical Case 1 | Clinical Case 2 | |
---|---|---|
Age (years) | 41 | 71 |
WBC | 32.12 × 109/L | 29.35 × 109/L |
Differential (PB) | hypogranulated neutrophils 46% band-cells 12% eosinophils 2% basophils - monocytes 6% lymphocytes 14% myeloblasts - promyelocytes 2% metamyelocytes 12% myelocites 6% | neutrophils with P-H abnormality 30% band-cells 17% eosinophils - basophils - monocytes 15% lymphocytes 9% myeloblasts 1% promyelocytes 14% metamyelocytes 6% myelocites 8% |
Hb | 13.5 g/dL | 14.9 g/dL |
Plts | 103 × 109/L | 239 × 109/L |
BM blasts | 2% | 4% |
Screening for mutations in JAK2, CALR and MPL | negative | negative |
BCR/ABL | negative | negative |
Gene mutations identified by NGS panel | TET2
p.Q635* (VAF 37.09%) TET2 p.C1221Y (VAF 42.23%) EZH2 p.R690H (VAF 82.89%) | SETBP1 p.D868N (VAF 47.1%) SRSF2 p.P95H (VAF 52.34%) TET2 p.Y1245Lfs*22 (VAF 52.8%) |
Screening for ETNK1 mutations | negative | ETNK1 p.H243P |
Karyotype | 46, XY (20) | 46, XY (20) |
Treatment | Decitabine 3cycles PR with residual thrombocytopenia HSCT | Peghilated IFN alpha PR |
Follow-up time (months after diagnosis) | 8 months | 10 months |
Status at last follow up | Alive in complete remission | Alive with stable disease and partial hematological response |
WHO 2016 Diagnostic Criteria for aCML |
---|
Peripheral blood leukocytosis (WBC count ≥ 13 × 109/L) because of increased numbers of neutrophils and their precursors with prominent dysgranulopoiesis |
Neutrophil precursors (promyelocytes, myelocytes, metamyelocytes) ≥ 10% of leukocytes |
No Ph chromosome or BCR-ABL1 fusion gene and not meeting criteria for PV, ET, or PMF * |
No evidence of PDGFRA, PDGFRB, FGFR1 rearrangement, or PCM1-JAK2 |
Minimal absolute basophilia; basophils usually < 2% of leukocytes |
No or minimal absolute monocytosis; monocytes usually < 10% of leukocytes |
Hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia, with or without dysplasia in the erythroid and megakaryocytic lineages |
Less than 20% blasts in the blood and bone marrow |
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Crisà, E.; Nicolosi, M.; Ferri, V.; Favini, C.; Gaidano, G.; Patriarca, A. Atypical Chronic Myeloid Leukemia: Where Are We Now? Int. J. Mol. Sci. 2020, 21, 6862. https://doi.org/10.3390/ijms21186862
Crisà E, Nicolosi M, Ferri V, Favini C, Gaidano G, Patriarca A. Atypical Chronic Myeloid Leukemia: Where Are We Now? International Journal of Molecular Sciences. 2020; 21(18):6862. https://doi.org/10.3390/ijms21186862
Chicago/Turabian StyleCrisà, Elena, Maura Nicolosi, Valentina Ferri, Chiara Favini, Gianluca Gaidano, and Andrea Patriarca. 2020. "Atypical Chronic Myeloid Leukemia: Where Are We Now?" International Journal of Molecular Sciences 21, no. 18: 6862. https://doi.org/10.3390/ijms21186862