Case Report: Evolution of KIT D816V-Positive Systemic Mastocytosis to Myeloid Neoplasm With PDGFRA Rearrangement Responsive to Imatinib

Systemic mastocytosis (SM) is a rare neoplasm resulting from extracutaneous infiltration of clonal mast cells (MC). The clinical features of SM are very heterogenous and treatment should be highly individualized. Up to 40% of all SM cases can be associated with another hematological neoplasm, most frequently myeloproliferative neoplasms. Here, we present a patient with indolent SM who subsequently developed a myeloid neoplasm with PDGFRA rearrangement with complete response to low-dose imatinib. The 63-year-old patient presented with eosinophilia and elevated serum tryptase level. Bone marrow analysis revealed aberrant MCs in aggregates co-expressing CD2/CD25 and KIT D816V mutation (0.01%), and the FIP1L1-PDGFRA fusion gene was not identified. In the absence of ‘B’ and ‘C’ findings, we diagnosed an indolent form of SM. For 2 years after the diagnosis, the absolute eosinophil count progressively increased. Bone marrow evaluation showed myeloid hyperplasia and the FIP1L1-PDGFRA fusion gene was detected. Thus, the diagnosis of myeloid neoplasm with PDGFRA rearrangement was established. The patient was treated with imatinib 100 mg daily and rapidly obtained a complete molecular remission. The clinical, biological, and therapeutic aspects of SM might be challenging, especially when another associated hematological disease is diagnosed. Little is known about the underlying molecular and immunological mechanisms that can promote one entity prevailing over the other one. Currently, the preferred concept of SM pathogenesis is a multimutated neoplasm in which KIT mutations represent a “phenotype modifier” toward SM. Our patient showed an evolution from KIT mutated indolent SM to a myeloid neoplasm with PDGFRA rearrangement; when the eosinophilic component expanded, a regression of the MC counterpart was observed. In conclusion, extensive clinical monitoring associated with molecular testing is essential to better define these rare diseases and consequently their prognosis and treatment.

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DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR IN CHILDREN: MR CHARACTERISTICS, CLINICAL FEATURES AND OUTCOME. FOUR CLINICAL CASES

Russian Journal of Biotherapy ◽

10.17650/1726-9784-2021-20-1-42-55 ◽

2021 ◽

Vol 20 (1) ◽

pp. 42-55

Author(s):

A. F. Valiakhmetova ◽

L. I. Papusha ◽

A. V. Artemov ◽

G. V. Tereshchenko ◽

E. A. Sal’nikova ◽

...

Keyword(s):

Fusion Gene ◽

Molecular Genetic ◽

Complete Response ◽

Mek Inhibitor ◽

Braf V600e ◽

Glioneuronal Tumor ◽

Molecular Testing ◽

Genetic Characteristics ◽

Diffuse Leptomeningeal Glioneuronal Tumor ◽

Braf Fusion

Background. Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare entity first officially recognized in 2016 WHO classification of tumors of the central nervous system. Magnetic resonance imaging (MRI) of this tumor usually visualizes diffuse meningeal infiltration with contrast enhancement, with the presence of multiple small contrast‑negative cysts, visible mainly in the T2 images. The main molecular markers of DLGNTs include the KIAA1549-BRAF fusion gene, BRAF V600E substitution is less common.The aim of this work is to describe the manifestation of DLGNT, its neuroimaging and molecular genetic characteristics, the experience of using anti‑BRAF and anti‑MEK therapy.Materials and methods. In this article are described four cases of DLGNT. The first patient with the presence of the KIAA1549-BRAF fusion in the tumor tissue received a full course of SIOP‑LGG / 2004 chemotherapy (carbo‑ platin and vincristine), the stabilization of the disease on the MRI remains for 4 years after completion of treatment. Second patient with KIAA1549-BRAF fusion gene in tumour tissue received MEK inhibitor trametinib as first line of treatment with the stabilization of the disease on control MRI which last for 2 years. A third patient with a mutation in the BRAF V600E gene. After disease progression on standard chemotherapy (carboplatin and vincristine) according to the SIOP‑LGG / 2004 protocol, anti‑BRAF therapy with vemurafenib was prescribed. After 10 months on MRI a complete response was recorded, which persists during the drug intake for 2.5 years. In the fourth patient, no molecular genetic aberrations were detected; a refractory / progressive course of the dis‑ ease was noted. To date, the stabilization of the disease is recorded on the fourth line of chemotherapy (everoli‑ mus and temozolomide).Conclusion. Given the rarity of this tumor and the lack of consensus about therapy, despite the limited number of observations, our experience allows us to recommend molecular testing of DLGNT to detect activating events in the BRAF gene, as well as consideration of anti‑BRAF / MEK therapy if either the BRAF V600E mutation is de‑ tected or KIAA1549-BRAF fusion.

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MDS with 5q deletion and rare cKIT positive mastocytosis: a diagnostic and therapeutic challenge

BMJ Case Reports ◽

10.1136/bcr-2018-227768 ◽

2019 ◽

Vol 12 (4) ◽

pp. e227768

Author(s):

Daniel Steven Sanders ◽

Thomas Fennell ◽

Mohammad Muhsin Chisti

Keyword(s):

Bone Marrow ◽

Mast Cell ◽

Case Report ◽

Systemic Mastocytosis ◽

Molecular Testing ◽

Bone Marrow Biopsies ◽

Haematological Response ◽

Clonal Origin ◽

Mast Cell Population ◽

5Q Deletion

A patient with a diagnosis of myelodysplastic syndrome (MDS) with isolated 5q deletion underwent repeat bone marrow biopsy to assess haematological response after 6 months of initial lenalidomide therapy. Subsequent bone marrow biopsies revealed persistent MDS with del(5q) in addition to a small atypical mast cell population with >25% of mast cells with spindle-shaped morphology and immunohistochemistry characteristics consistent with mastocytosis. Molecular testing on the bone marrow was positive for cKIT D816V and the patient was diagnosed with systemic mastocytosis (SM) with an associated haematological neoplasm. MDS with SM is well known to be associated; however, to the best of our knowledge, only one prior case report identifies MDS with del(5q) and associated cKIT D816V positive mastocytosis. While the exact clonal origin of both chromosomal aberrations is unclear, this case illustrates the therapeutic efficacy of lenalidomide in a patient with MDS with del(5q) and rarely associated cKIT positive SM.

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Lineage Analysis of the FIPL1-PDGFRα Fusion Gene in Myeloproliferative Hypereosinophilic Syndrome.

Blood ◽

10.1182/blood.v104.11.2441.2441 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2441-2441 ◽

Cited By ~ 2

Author(s):

Steven J. Lemery ◽

Jamie A. Robyn ◽

J. Philip McCoy ◽

Joseph Kubofcik ◽

YaeJean Kim ◽

...

Keyword(s):

Bone Marrow ◽

Mast Cells ◽

Peripheral Blood ◽

Fusion Gene ◽

Tissue Injury ◽

Hypereosinophilic Syndrome ◽

Phenotypic Expression ◽

Elevated Serum ◽

Serum Tryptase ◽

Pdgfrα Mutation

Abstract Hypereosinophilic syndrome is a rare disorder characterized by hypereosinophilia and eosinophil-mediated tissue injury. An imatinib sensitive myeloproliferative variant (MHES) has been described which has a male predominance, and is associated with elevated serum tryptase levels, tissue fibrosis, increased atypical mast cells, and the presence of the fusion oncogene FIP1L1-PDGFRα which has tyrosine kinase activity. The FIP1L1-PDGFRα mutation has been detected in peripheral blood mononuclear cells, however, the hypercellular bone marrow and elevated serum tryptase levels suggest that multiple lineages might be involved in the clonal process. We analyzed peripheral blood from eight patients with the FIP1L1-PDGFRα mutation. Individual patient samples were sorted by flow cytometry to collect greater than 95% pure populations of CD3, CD14, and CD19 cells. Density gradient centrifugation followed by negative selection for CD16, CD3, CD14, and CD19 using an immunomagnetic bead column was used to purify eosinophils to > 99% purity. Bone marrow from one patient was obtained, and mast cells were cultured from CD34 positive cells. Three techniques were used to assay for the presence of the FIPL1-PDGFRα fusion gene: nested RT-PCR, TaqMan quantitative PCR, and FISH. Eosinophils were positive for the fusion gene in all patient samples that were analyzed. Monocytes were also positive in all but one instance. Surprisingly some patients showed positivity in lymphoid lineages as well. The bone marrow derived pure mast cell culture was positive for the mutation, consistent with the elevation of serum tryptase and atypical appearance of mast cells in MHES. In conclusion, although MHES seems to have a multilineage predilection, specific lineages involved may vary between patients. This may reflect differences in the progenitor stage at which the mutation occurs. Whether the pattern of lineage involvement has any relation to the phenotypic expression of the disease remains to be elucidated.

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FIP1L1/PDGFRa Synergizes with SCF/c-Kit Signaling To Induce Systemic Mastocytosis in a Chronic Eosinophilic Leukemia Murine Model

Blood ◽

10.1182/blood.v110.11.1540.1540 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1540-1540

Author(s):

Yoshiyuki Yamada ◽

Jose A. Cancelas ◽

Eric B. Brandt ◽

Abel Sanchez-Aguilera ◽

Melissa McBride ◽

...

Keyword(s):

Bone Marrow ◽

Small Intestine ◽

Murine Model ◽

Fusion Gene ◽

Systemic Mastocytosis ◽

Wild Type ◽

Chronic Eosinophilic Leukemia

Abstract Systemic mastocytosis (SM) associated with chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES) is a result of expression of the Fip1-like1 (FIP1L1)/platelet-derived growth factor receptor alpha (PDGFRa) (F/P) fusion gene. We have previously described a murine CEL/HES model (CEL-like mice) induced by F/P fusion gene transduction and T-cell overexpression of IL-5 (Yamada Y et al., Blood 2006). We have now validated a preclinical murine model of F/P-induced SM/CEL and analyzed the pathogenesis of SM in this model. F/P+ mast cells (MC, defined as EGFP+/c-kit+/FceRI+) were significantly increased in the small intestine, bone marrow (BM) and spleen of CEL-like mice compared to wild-type mice (Table). CEL-like mice also developed cutaneous MC infiltration. In addition, mMCP-1 serum levels, which correlate well with MC expansion and activation in vivo, were significantly higher in CEL-like mice than in wild-type mice (64,000 ± 23,800 and 38 ± 41.4 pg/ml, respectively). F/P induces increased expansion of BM-derived MC in vitro (∼2,000-fold) and F/P+ BM-derived MC survive longer than wild-type MC in cytokine-deprived medium (28.0 ± 2.3% vs. 8.7 ± 3.1% 7AAD−/Annexin V− cells after 48 hours). This correlated with increased Akt phosphorylation in the F/P+ MC. Since c-kit mutations are the most frequent cause of SM, we analyzed the possible synergistic role of SCF and F/P signaling. F/P and SCF/c-kit signaling indeed synergize in the development of BM-derived MC (16-fold greater expansion than in the absence of SCF) and F/P+ BM-derived MC showed a 3.7-fold greater migratory response to SCF than wild-type BM-derived MC. In order to determine the role of SCF/c-kit signaling in F/P+ MC development, activation and tissue infiltration in vivo,these responses were evaluated in mice that were treated with a blocking anti-c-kit blocking antibody, ACK-2, or an isotype-matched control antibody. ACK-2 treatment suppressed intestinal MC infiltration and elevated plasma levels of mMCP-1 induced by F/P expression by 95 ± 6.0% and 98 ± 0.76%, respectively, whereas MC and plasma mMCP-1 were completely undetectable in wild-type mice treated with ACK2. This suggests that SCF/c-kit interactions may synergize with F/P to induce SM. In summary, mice with CEL-like disease also develop SM. F/P-induced SM is a result of increased in vivo MC proliferation, survival, activation and tissue infiltration. SCF/c-kit signaling synergizes with F/P in vivo and in vitro to promote mast cell development, activation and survival. EGFP+/c-kit+/FcεRI+ cell frequency in tissues of control and CEL-like mice (%) Control mice CEL-like mice Small intestine 1.0±0.95 47±21.4* Bone marrow 0.2±0.14 3±1.9* Spleen 0.05±0.01 3±0.8*

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Change In Mast Cell Bone Marrow Burden and In Serum Tryptase Level Are Not Accurate Markers of Response In Patients with Systemic Mastocytosis

Blood ◽

10.1182/blood.v116.21.3073.3073 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3073-3073

Author(s):

Alfonso QuintÁs-Cardama, ◽

Matjaz Sever ◽

Jorge E. Cortes ◽

Hagop M. Kantarjian ◽

Srdan Verstovsek

Keyword(s):

Bone Marrow ◽

Mast Cell ◽

Mast Cells ◽

Systemic Mastocytosis ◽

Median Number ◽

Response To Therapy ◽

Serum Tryptase ◽

Bone Marrow Biopsies ◽

Tryptase Level ◽

Bone Marrow Mast Cell

Abstract Abstract 3073 Background: Bone marrow involvement, with or without cutaneous or visceral involvement, is almost universal in patients with systemic mastocytosis (SM). The KITD816V mutation is present in most patients with SM, thus confirming its clonal nature. Patients with ASM are usually managed with cytoreductive agents such as hydroxyurea (HU), cladribine (2CDA), or interferon-alpha (IFN-α), although the activity of these therapies is limited as they do not target specifically the malignant clone. Response assessment in SM relies on symptom improvement and reduction in serum tryptase levels and visceral and/or bone marrow mast cell burden (percent mast cell involvement). We contend that the later two relatively objective metrics may not be appropriate markers of response because serum tryptase levels may vary significantly at different time-points in the same patient in the absence of intervention, do not correlate accurately with mast cell burden, and bone marrow mast cell burden determination is subject to sampling bias given the patchy infiltration observed in many cases of SM. Objectives: To assess the utility of bone marrow mast cell burden reduction and serum tryptase level reduction as criteria for response in patients with SM. Patients and Therapy: We studied a cohort of 50 patients with SM for whom at least 2 sequential bone marrow biopsies and 2 serum tryptase level determinations were available at our center. The KITD816V mutation was present in 20 (59%) of 34 assessable patients. No patient carried the JAK2V617F mutation or the FIP1L1-PDGFRA rearrangement. Patients had a diagnosis of indolent SM (ISM, n=25), aggressive SM (ASM, n=16), or SM-AHNMD (n=9). All but 1 patient received SM-directed therapy (median number of therapies 2, range 1–5), including: imatinib (n=16), dasatinib (n=23), RAD001 (n=8), denileukin diftitox (n=7). The median number of bone marrow biopsies available per patient was 4 (range, 2–14) and the median number of tryptase measurements was 6 (range, 2–18), which were obtained both on and off SM-directed therapies. Results: Four patients had a bone marrow complete response: 1 with imatinib, 2 with dasatinib, and 1 with decitabine (with SM-MDS). However none of the responders normalized their tryptase levels. We used the coefficient of variation (CV) as a normalized measure of dispersion of a probability distribution for the percentage of mast cells in bone marrow biopsies and serum tryptase levels. In this manner, the CV summarizes/describes the variation in tryptase levels and bone marrow mast cell percentage from the baseline (first recorded value) in the patients evaluated. We found that among the 49 treated patients, the percentage of bone marrow mast cells varied significantly with a CV ranging from 6 – 173% and an average of 65%. Forty-four percent of patients had a CV equal or higher to the average. Similar results were observed regarding tryptase levels, with an average CV of 19% that ranged from 0 to 96%. Thirty-six percent of patients had a CV higher than average. Conclusion: While most patients fail to respond to currently available SM-directed therapies, sequential bone marrow biopsies and tryptase level determinations exhibit remarkable variation both during and in the absence of SM-directed therapy. Therefore, it seems that single time point measurements of these values do not represent proper tools to assess accurately response to therapy. Disclosures: No relevant conflicts of interest to declare.

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Pentostatine Is a Safe and Active Agent in Chronic Lymphocytic Leukemia CLL with Minimal Toxicity.

Blood ◽

10.1182/blood.v106.11.5042.5042 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5042-5042

Author(s):

Ahmad Jajeh ◽

Deimante Tamkus ◽

Ebinezer Berko ◽

Alusola Ogandipe ◽

David Osafo ◽

...

Keyword(s):

Bone Marrow ◽

Single Agent ◽

Tumor Lysis Syndrome ◽

Elevated Serum ◽

Active Agent ◽

Autologous Bone Marrow ◽

Complete Response ◽

Marrow Transplant ◽

Lymphocytic Leukemia ◽

Irreversible Inhibitor

Abstract Pentostatin is a nucleoside analogue, it is a potent irreversible inhibitor of adenosine diaminase ADA. The triphosphate form of pentostatin is incorporated into DNA strand breaks. This effect is potentiated by the presence of an alkylating agent such as Cytoxan. Combination approaches will maximize the inhibition of DNA repair with less myelosuppression. A total of twenty five patients diagnosed with chronic lymphocytic leukmia treated with pentostatin combination in the last four years, nineteen patients had refractory CLL. Six patients has newely diagnosis with adverse features such as high risk cytogenetic/FISH abnormality, elevated serum Beta 2 microglobuline, elevated LDH, presence of the B symptoms, doubling time less than a year and progressive enlargment of spleen and lymph nodes. All patients had stage III-IV Rai classification. Fifteen males and ten females, eighty five percent were african american. Mean age is 52 years (range 46–70). Median follow up was eighteen months (range4–42 months). Thirteen patients recieved the combination of Pentostatin, Cytoxan and Rituxan. Rituxan or Rituximab is a chiemeric human monoclonal antibodies against CD expressing B cell lymphocytes. Pentostatin 4 mg/M2, Cytoxan 300 mg/M2 and Rituxan 375 mg/M2 given one day one every 28 days. Three patients recieved pentostatin and cytoxan. Nine patients recieved pentostatin and rituxan. Eighty percent of the patients recieved a minimum of six cycles. Complete response CR and near complete response nCR were confirmed by peripheral blood flowcytometric study. Ten patients achieved CR, nCR and fifteen patients achieved PR. One patient had short PR response less than six months post completing therapy. Five patients had autologous bone marrow transplant post CR, nCR response. Median time to progression is not reached. Toxicity observed with pentostain combination was minimal as compaired to retrospective analysis of Fludarabin whether as a single agent or in combination with cytoxan or rituxan. Bone marrow necrosis and tumor lysis syndrome were not seen. Neutropenic fever that required hospitaliztion is less than 10% as compaired to Fludarabin 40%. Growth factor G-CSF required less with pentostin combination. However, warm autoimmune hemolytic anemia was seen more during pentostatin therapy rather than prior to initiating therapy. Conclusion: Pentostatin has less myelosuppressive effect and equal response as compaired retrospectively to Fludarabine. Head to head randomized prospective study is needed.

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International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis

Blood ◽

10.1182/blood-2012-09-458521 ◽

2013 ◽

Vol 121 (13) ◽

pp. 2393-2401 ◽

Cited By ~ 65

Author(s):

Jason Gotlib ◽

Animesh Pardanani ◽

Cem Akin ◽

Andreas Reiter ◽

Tracy George ◽

...

Keyword(s):

Systemic Mastocytosis ◽

Myeloproliferative Neoplasms ◽

Organ Damage ◽

Response Criteria ◽

Survival Duration ◽

Response Evaluation ◽

Cell Leukemia ◽

Competence Network ◽

Myeloid Neoplasm ◽

Mast Cell Leukemia

Abstract Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SM for the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials.

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FIP1L1/PDGFRα synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome

Blood ◽

10.1182/blood-2007-11-126268 ◽

2008 ◽

Vol 112 (6) ◽

pp. 2500-2507 ◽

Cited By ~ 8

Author(s):

Yoshiyuki Yamada ◽

Abel Sanchez-Aguilera ◽

Eric B. Brandt ◽

Melissa McBride ◽

Nabeel J. H. Al-Moamen ◽

...

Keyword(s):

Bone Marrow ◽

Fusion Gene ◽

Systemic Mastocytosis ◽

Hypereosinophilic Syndrome ◽

Growth Factor Receptor ◽

Hematopoietic Stem ◽

Chronic Eosinophilic Leukemia ◽

Factor Receptor Alpha

Abstract Expression of the fusion gene FIP1-like 1/platelet-derived growth factor receptor alpha (FIP1L1/PDGFRα, F/P) and dysregulated c-kit tyrosine kinase activity are associated with systemic mastocytosis (SM) and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES). We analyzed SM development and pathogenesis in a murine CEL model induced by F/P in hematopoietic stem cells and progenitors (HSCs/Ps) and T-cell overexpression of IL-5 (F/P-positive CEL mice). These mice had more mast cell (MC) infiltration in the bone marrow (BM), spleen, skin, and small intestine than control mice that received a transplant of IL-5 transgenic HSCs/Ps. Moreover, intestinal MC infiltration induced by F/P expression was severely diminished, but not abolished, in mice injected with neutralizing anti–c-kit antibody, suggesting that endogenous stem cell factor (SCF)/c-kit interaction synergizes with F/P expression to induce SM. F/P-expressing BM HSCs/Ps showed proliferation and MC differentiation in vitro in the absence of cytokines. SCF stimulated greater migration of F/P-expressing MCs than mock vector–transduced MCs. F/P-expressing bone marrow–derived mast cells (BMMCs) survived longer than mock vector control BMMCs in cytokine-deprived conditions. The increased proliferation and survival correlated with increased SCF-induced Akt activation. In summary, F/P synergistically promotes MC development, activation, and survival in vivo and in vitro in response to SCF.

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Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms22062983 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2983

Author(s):

William Shomali ◽

Jason Gotlib

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Systemic Mastocytosis ◽

Myeloproliferative Neoplasms ◽

Organ Damage ◽

Response Criteria ◽

Molecular Response ◽

Tryptase Level ◽

Hematologic Neoplasm ◽

Kit D816v

Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating KIT D816V mutation that leads to the growth and accumulation of neoplastic mast cells. While patients with advanced forms of SM have a poor prognosis, the introduction of KIT inhibitors (e.g., midostaurin, and avapritinib) has changed their outlook. Because of the heterogenous nature of advanced SM (advSM), successive iterations of response criteria have tried to capture different dimensions of the disease, including measures of mast cell burden (percentage of bone marrow mast cells and serum tryptase level), and mast cell-related organ damage (referred to as C findings). Historically, response criteria have been anchored to reversion of one or more organ damage finding(s) as a minimal criterion for response. This is a central principle of the Valent criteria, Mayo criteria, and International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Irrespective of the response criteria, an ever-present challenge is how to apply response criteria in patients with SM and an associated hematologic neoplasm, where the presence of both diseases complicates assignment of organ damage and adjudication of response. In the context of trials with the selective KIT D816V inhibitor avapritinib, pure pathologic response (PPR) criteria, which rely solely on measures of mast cell burden and exclude consideration of organ damage findings, are being explored as more robust surrogate of overall survival. In addition, the finding that avapritinib can elicit complete molecular responses of KIT D816V allele burden, establishes a new benchmark for advSM and motivates the inclusion of definitions for molecular response in future criteria. Herein, we also outline how the concept of PPR can inform a proposal for new response criteria which use a tiered evaluation of pathologic, molecular, and clinical responses.

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Clinical Discernment, Bone Marrow, and Molecular Diagnostics Are Equally Important to Solve the Phenotypic Mimicry among Subtypes of Myeloproliferative Neoplasms

Reports ◽

10.3390/reports4030027 ◽

2021 ◽

Vol 4 (3) ◽

pp. 27

Author(s):

Susann Schulze ◽

Nadia Jaekel ◽

Christin Le Hoa Naumann ◽

Anja Haak ◽

Marcus Bauer ◽

...

Keyword(s):

Bone Marrow ◽

Clinical Judgment ◽

Systemic Mastocytosis ◽

Myeloproliferative Neoplasms ◽

Accurate Diagnosis ◽

Molecular Techniques ◽

Driver Mutations ◽

Therapeutic Consequences ◽

Molecular Features ◽

Disease Entities

The 2016 WHO classification integrates clinical, bone marrow (BM)-morphology, and molecular features to define disease entities. This together with the advancements in molecular detection and standardization of BM features enable an accurate diagnosis of myeloproliferative neoplasms (MPN) in the majority of patients. Diagnostic challenges remain due to phenotypic mimicry of MPN, failing specificity of BM-morphology, and the fact that phenotype-driver mutations, such as JAK2V617F, are not exclusive to a particular MPN, and their absence does not preclude any of these. We present a series of cases to illustrate themes to be considered in complex cases of MPN, such as triple-negative (TN)-MPN or MPN-unclassifiable (MPN-U). Eleven patients labelled as TN-MPN or MPN-U were included. Serum tryptase and NGS were part of a systematic/sequential multidisciplinary evaluation. Results were clustered into four categories based on diagnostic entities and/or how these diagnoses were made: (A) With expanding molecular techniques, BCR-ABL1 and karyotyping should not be missed; (B) systemic mastocytosis is underdiagnosed and often missed; (C) benign non-clonal disorders could mimic MPN; and (D) NGS could prove clonality in some “TN”-MPN cases. The prognostic/therapeutic consequences of an accurate diagnosis are immense. In TN-MPN or MPN-U cases, a multidisciplinary re-evaluation integrating molecular results, BM-morphology, and clinical judgment is crucial.

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