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Acute myeloid leukemia

Systemic mastocytosis with acute myeloid leukemia occurs from mutually exclusive clones expressing KITD816V and FLT3-ITD

To the Editor:

We read with great interest the article by Jawhar et al. [1]. They identified KIT D816V mutated/CBF-negative acute myeloid leukemia (AML) as an adverse risk group associated with systematic mastocytosis (SM) [1]. The KIT p.Asp816Val (KITD816V) driver and other myeloid genes such as transcription factors or epigenetic modifiers are frequently mutated in the mast cells (MC) and associated hematological neoplasm (AHN) components of SM-AHN [2,3,4]. Here, we sought to explore the origin of SM-AHN in a SM-AML patient with a FLT3-ITD (internal tandem duplication) and KITD816V, among other myeloid variants.

Different hypotheses have been explored to explain the genesis of SM-AHN (Fig. 1A-I-IV); one possibility is that the SM and AHN components are derived from two separate clones with unique mutation profile (Model I, Fig. 1A-I). Other studies suggest SM-AHN originates from a common precursor with combined features of SM and AHN (Model II, Fig. 1A-II). This assignment is due to the observation that various subtypes of SM-AHN bear KITD816V and myeloid biomarkers, in both their MC and AHN cellular fractions [3]. Others postulate that SM-AHN is derived from a pre-existing AHN clone that subsequently acquire KITD816V, as late event (Model III, Fig. 1A-III). This is because myeloid genes were mutated in SM-AHN progenitor cells, while KIT variants were only detected in some of these founder clones [1, 4,5,6,7]. We herein report on a different model for SM-AHN, where SM and AHN are driven by mutually exclusive clones expressing KITD816V and FLT3-ITD, expanding from a common progenitor (Model IV, Fig. 1A-IV).

Fig. 1: Systemic mastocytosis with acute myeloid leukemia.

(A & B) A. Models depicting the biogenesis of systemic mastocytosis (SM) with an associated hematologic myeloid neoplasm (AHN) (I) 2 independent clones whereby SM and AHN coexist. II 1 common myeloid precursor and KIT variant is an early event. III 1 common myeloid precursor and KIT variant is a late event. IV 1 common myeloid precursor, KIT and FLT3-ITD are late-event drivers in 2 mutually exclusive AHN and SM clones. B. (ai) Bone marrow aspirate showing leukemic blasts admixed with atypical mast cells; original magnification ×100, May-Grünwald-Giemsa stain. bii Representative micrograph of the bone marrow biopsy; original magnification ×20 hematoxylin and eosin (H&E) stain shows paratrabecular formation of new bone. There is a paratrabecular and interstitial infiltration of atypical mast cells (arrow) and blasts (arrowhead) expressing CD34. The atypical mast cells are Tryptase (+), CD117 (+) and CD25 (+). In addition, there is a patchy increase in reticulin fibrosis around the atypical mast cells; original magnification ×10, reticulin stain.

An 82-year-old male with no history of a hematologic malignancy presented with shortness of breath on mild exertion and occasional bruising. Physical examination revealed pallor, axillary lymphadenopathy and splenomegaly with no hepatomegaly or skin lesions. A full blood count showed hemoglobin concentration of 72 g/l, white blood cell count of 36.4 × 109/l and platelet count of 11 × 109/l. The peripheral blood film showed 23% blasts and marked thrombocytopenia.

A final diagnosis of systemic mastocytosis with acute myeloid leukemia (SM-AML) was made based on the following findings. The bone marrow (BM) aspirate was markedly hypercellular with 45% myeloblasts (Fig. 1B-i), which were positive for CD34, CD13, CD33, CD36, CD64, CD117 and HLA-DR by flow cytometry; these observations were compatible with the diagnosis of AML. In addition, a subset (2%) of cells were positive for CD117 (bright), CD33, CD25 (bright), CD64, CD123, and HLA DR+(dim) which was consistent with atypical MC. The BM biopsy was markedly hypercellular with osteosclerosis, blasts and a paratrabecular infiltration by atypical MC occupying ~30% of the total intertrabecular area (Fig. 1B-ii). By immunohistochemistry, these MC were positive for tryptase, CD117 and CD25 while the blasts were CD34 positive. The BM biopsy stained positive for Bcl-2, both in the myeloblasts (MB, bright) and MC (weak). There was also an increase in reticulin fibrosis around the atypical MC. Further investigations revealed a serum tryptase of 710 ng/ml (normal range, <11.4 ng/ml) and alkaline phosphatase of 342 U/L (norma125–200 U/L). In addition, a CT scan of the chest showed diffusely sclerotic ribs and middle third of the clavicle.

A t(2;21) (p13;q22) translocation involving RUNX1 was detected by cytogenetic analyses. Next-Generation Sequencing (NGS) of the bulk BM using a panel of 49 myeloid genes identified KITD816V, a FLT3-ITD and 3 deleterious variants in RUNX1, SRSF2 and BCORL1 (Table 1). MB (CD34+) and MC (CD117+bright, CD25+) were isolated (purity of 95%) by fluorescence activated cell sorting (FACS). NGS showed that the MB and MC cellular fractions harbor the same 3 variants in RUNX1, SRSF2, and BCORL1. Of interest, KITD816V was only detected in the MC; whereas the FLT3-ITD was only seen in the MB (Table 1). T cells (CD3+) and B-cells (CD20+) were also isolated from the bulk BM. We did not detect KITD816V, FLT3-ITD or any oncogenic variant in the T-cell fraction (6% of the bulk BM) analyzed (Table 1). In the B-cells, that constituted a very small fraction of the bulk BM (<1%), NGS was inconclusive with no interpretable data.

Table 1 Genomic profiling in systemic-mastocytosis with acute myeloid leukemia.

Variants in transcription factors (RUNX1, BCORL1) and epigenetic modifiers (SRSF2) are well-established oncogenic drivers in AML and SM-AHN [1, 3]. NGS detected alterations of these genes in both the MB and MC of this patient (Table 1), indicating that SM-AML originates from a common ancestor that bears myeloid features. This suggests a different mechanism than presented in Model I (Fig. 1A-I); where 2 separate coexisting MB and MC clones evolve to give rise to SM-AML. Instead, in our proposed scheme (Fig. 1A-IV), clonal evolution to SM-AML requires additional hits in KIT and FLT3, but in different cells. Acquisition of late event mutations in 2 separate clones (one with KITD816V and another bearing FLT3-ITD) is also against Model II (Fig. 1A-II). This paradigm differs from Model III (Fig. 1A-III), in that KITD816V is not the sole determinant for SM-AML in the evolution of this multi-mutated neoplasm. In model IV, we are providing evidence of 2 co-occurring and mutually exclusive entities in the MC and MB cellular fractions that progress to give raise to SM-AML.

Given the diagnosis of SM-AML, chemotherapy with Azacitidine 75 mg/m2 subcutaneous for 6 days and Venetoclax 400 mg once daily for 21 days was initiated for three cycles with the subsequent addition of Midostaurin 100 mg twice daily in his fourth treatment cycle. Complete remission (CR) from AML was achieved after 2 cycles of chemotherapy, but persistence of the MC infiltration was still observed. This patient is still undergoing chemotherapy. NGS testing on the bulk BM post induction showed the same 3 variants in RUNX1, SRSF2 and BCORL1 identified at diagnosis (Table 1). Of interest, the FLT3-ITD previously detected was not identified post-induction; however, KITD816V persisted. As NGS analyses are semi-quantitative we could not fully measure the fluctuation in variant allele frequencies (VAF) observed at diagnosis at CR. We were not able to recover sufficient DNA material to perform absolute quantitation of this variants, using alternative approaches.

Nevertheless, NGS results corroborate the pathophysiological findings and support the presence of 2 mutually exclusive MB and MC clones driving SM-AML. The absence of the FLT3-ITD post-induction is in keeping with resorption of MB in AML CR. The increased VAF of KITD816V from diagnosis to post-induction suggests a possible expansion of the MC, or at the very least persistence of SM. These opposite trajectories of the KITD816V and FLT3-ITD clones is expected, considering that the percentage of MB in the bulk BM dropped from 45% (diagnosis) to less than 1% (post-induction); while, the proportion of MC rose from 2% (diagnosis) to 23% (post-induction).

Deleterious variants in RUNX1, SRSF2 are indicative of poor prognosis in SM-AHN [2, 3, 8,9,10]. The clinical course of SM in this patient could also be explained by the acquisition of a truncating variant in TET2, which was not previously detected at diagnosis (Table 1). It is possible that this TET2 clone was present at very low levels at diagnosis and expanded post-treatment; although, NGS results obtained do not show evidence of this.

SM-AHN regroups clinically and genetically heterogeneous neoplasms. Herein, clinical and pathophysiological findings combined with genomic analyses in a single SM-AML case suggest in this instance one example of molecular ontogeny for SM-AHN development. In this model, SM-AML is derived from 2 distinct MC and MB clones following clonal evolution from a common myeloid precursor.


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The study was supported in part by the grants from Leukemia and Lymphoma Research Society of Canada (LLSC), and Cancer Research Society (CRS).

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CJM, EK, RN, DZ carried out experiments, analysis and interpretation of data, MD provided clinical sample and helpful discussions. CJM, EK, and HC wrote the manuscript. HC conceived and designed the study, analyzed the data and supervised the project.

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Correspondence to Hong Chang.

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Capo-Chichi, JM., Kagotho, E., Nayyar, R. et al. Systemic mastocytosis with acute myeloid leukemia occurs from mutually exclusive clones expressing KITD816V and FLT3-ITD. Leukemia 35, 282–285 (2021).

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