Abstract:Mast cell leukemia (MCL) is a rare, life-threatening malignancy defined by a substantial increase in neoplastic mast cells (MCs) in bone marrow (BM) smears, drug-resistance and a poor prognosis. In most patients, the survival-time is less than 1 year. However, exceptional cases may present with a less malignant course. We report on a 49-year-old female patient with MCL
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“…In our series, the proposed subtypes of MCL without C-findings (chronic MCL) and leukemic MCL were only observed in 2 patients each, in line with previously published series, 14 , 15 the latter clearly demonstrating that presence or absence of MCs in PB is only of minor importance for the diagnosis of MCL. We have, however, observed a much higher relative frequency of MCL-AHN than that reported in the literature (71% vs .…”
Mast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by at least 20% of mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 520 μg/L. C-findings were identified in 26 of 28 (93%) patients. Mutations in KIT (D816V, n=19; D816H/Y, n=5; F522C, n=1) were detected in 25 of 28 (89%) patients and prognostically relevant additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naïve patients was 5 of 12 (42%) on midostaurin and 1 of 6 (17%) on cladribine, and after switch 1 of 4 (25%) on midostaurin and 0 of 3 on cladribine, respectively. S/A/Rpos adversely affected response to treatment and progression to secondary mast cell leukemia (n=6) or acute myeloid leukemia (n=3) while on treatment (P<0.05). The median overall survival from mast cell leukemia diagnosis was 17 months as compared to 44 months in a control group of 124 patients with advanced systemic mastocytosis but without mast cell leukemia (P=0.03). In multivariate analyses, S/A/Rpos remained the only independent poor prognostic variable predicting overall survival (P=0.007). In conclusion, the molecular signature should be determined in all patients with mast cell leukemia because of its significant clinical and prognostic relevance.
“…In our series, the proposed subtypes of MCL without C-findings (chronic MCL) and leukemic MCL were only observed in 2 patients each, in line with previously published series, 14 , 15 the latter clearly demonstrating that presence or absence of MCs in PB is only of minor importance for the diagnosis of MCL. We have, however, observed a much higher relative frequency of MCL-AHN than that reported in the literature (71% vs .…”
Mast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by at least 20% of mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 520 μg/L. C-findings were identified in 26 of 28 (93%) patients. Mutations in KIT (D816V, n=19; D816H/Y, n=5; F522C, n=1) were detected in 25 of 28 (89%) patients and prognostically relevant additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naïve patients was 5 of 12 (42%) on midostaurin and 1 of 6 (17%) on cladribine, and after switch 1 of 4 (25%) on midostaurin and 0 of 3 on cladribine, respectively. S/A/Rpos adversely affected response to treatment and progression to secondary mast cell leukemia (n=6) or acute myeloid leukemia (n=3) while on treatment (P<0.05). The median overall survival from mast cell leukemia diagnosis was 17 months as compared to 44 months in a control group of 124 patients with advanced systemic mastocytosis but without mast cell leukemia (P=0.03). In multivariate analyses, S/A/Rpos remained the only independent poor prognostic variable predicting overall survival (P=0.007). In conclusion, the molecular signature should be determined in all patients with mast cell leukemia because of its significant clinical and prognostic relevance.
“…Notably, the KIT mutation is the most important and prevalent pro-oncogenic mutation in MCL. In this study, we found the presence of a KIT S476I mutation, which has been discovered previously in chronic MCL [ 15 ]. With our finding, this point mutation becomes the second most common point mutation in MCL, following KIT D816V, which is located in the tyrosine kinase domain.…”
Section: Discussionsupporting
confidence: 77%
“…Almost 40% of de novo patients with MCL had the KIT D816V mutation [ 1 ]. In addition, S476I, F522C, V654A, V560G, duplication of amino acids 501–502 and 502–503, and deletion of amino acids 501–502 were also reported in a case report [ 10 11 12 13 14 15 ]. Besides the KIT mutation, a TET2 mutation has been investigated in aggressive SM [ 16 ].…”
BackgroundMast cell leukemia (MCL) is the most aggressive form of systemic mastocytosis disorders. Owing to its rarity, neither pathogenesis nor standard treatment is established for this orphan disease. Hence, we tried to treat a patient with MCL based on the exome and transcriptome sequencing results of the patient's own DNA and RNA.MethodsFirst, tumor DNA and RNA were extracted from bone marrow at the time of diagnosis. Germline DNA was extracted from the patient's saliva 45 days after induction chemotherapy and used as a control. Then, we performed whole-exome sequencing (WES) using the DNA and whole transcriptome sequencing (WTS) using the RNA. Single nucleotide variants (SNVs) were called using MuTect and GATK. Samtools, FusionMap, and Gene Set Enrichment Analysis were utilized to analyze WTS results.ResultsWES and WTS results revealed mutation in KIT S476I. Fusion analysis was performed using WTS data, which suggested a possible RARα-B2M fusion. When RNA expression analysis was performed using WTS data, upregulation of PIK3/AKT pathway, downstream of KIT and mTOR, was observed. Based on our WES and WTS results, we first administered all-trans retinoic acid, then dasatinib, and finally, an mTOR inhibitor.ConclusionWe present a case of orphan disease where we used a targeted approach using WES and WTS data of the patient. Even though our treatment was not successful, use of our approach warrants further validation.
“…2 Chronic MCL is defined as MCL without C-findings/organ damage and may display a more indolent course over time, but its natural history requires more study. [24][25][26] Immunostaining with Ki-67 has been shown to differentiate between the acute and chronic variants, since most mast cells in chronic MCL stain negative for Ki-67 whereas mast cells in acute MCL frequently display Ki-67. 24 These findings require validation in additional studies.…”
Section: Mast Cell Leukemiamentioning
confidence: 99%
“…In some cases, organdirected biopsy may be useful to determine whether organ damage is related to the SM or AHN or both (eg, liver biopsy in a patient with liver function abnormalities). Although chronic MCL may follow a more indolent disease course compared with acute MCL with organ damage, [24][25][26] cytoreductive therapy should still be considered for such patients given the poor prognosis of both MCL subtypes (see "Treatment for MCL," page 1509, [SM-8]).…”
Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/ or in various extracutaneous organs. 1 In the revised 2017 WHO classification, mastocytosis was removed as one of the subtypes of myeloproliferative neoplasms (MPN) and listed as a separate major disease entity with distinctive clinical and pathologic features. 2 Mastocytosis is divided into 3 broad subtypes, depending on pathology, distribution of disease, and clinical manifestations. Cutaneous mastocytosis NCCN
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