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Peter Valent - One of the best experts on this subject based on the ideXlab platform.

  • Treatment of Patients with Aggressive Systemic Mastocytosis, Mast Cell Leukemia and Mast Cell Sarcoma: A Single Center Experience
    Blood, 2018
    Co-Authors: Karoline V. Gleixner, Peter Valent, Wolfgang R Sperr
    Abstract:

    Abstract Aggressive systemic Mastocytosis (ASM), Mast Cell Leukemia (MCL) and Mast Cell sarcoma (MCS) are rare, life-threatening Mast Cell disorders, characterized by an aggressive clinical course, drug resistance and a poor survival. Established disease-modifying therapies include interferon-alpha (INF-A), cladribine (2CdA) and midostaurin (PKC412). However, these treatment approaches are unable to exert curative effects in advanced Mastocytosis. Intensive therapy, including poly-chemotherapy and hematopoietic stem Cell transplantation (HSCT) have also been suggested for patients with rapidly progressing ASM and MCL (Ustun et al, J Clin Oncol 2014;32:3264-3274). However, little is known about long-term outcome and survival in these patients. We analyzed the clinical course and treatment responses in 24 patients with ASM, MCL and MCS seen at the Medical University of Vienna between May 1994 and December 2017. According to World Health Organization criteria, patients were diagnosed as ASM (n=11), ASM with associated chronic myelomonocytic Leukemia (ASM-CMML, n=6), ASM with associated chronic eosinophilic Leukemia (ASM-CEL, n=1), MCL (n=4) and MCS (n=2). The median age at diagnosis was 59 years (range 21-90 years) and the f:m ratio was 1:2.4. Patients received first-line therapy with INF-A (3x106 units three times a week, n=8), 2-CdA (0.13 mg/kg, days 1-5, n=5); CLAG (cladribine 5mg/m2, days 1-5, ARA-C 2g/m2 day 1-5, G-CSF, 300 µg from day 6 until recovery; n=2), alternating 2CdA and midostaurin (n=2), midostaurin alone (2x100 mg/day, n=2), FLAG (fludarabine, 30mg/m², days 1-5; ARA-C 2 g/m² days 1-5; G-CSF 300µg from day 6 until recovery, n=1) and brentuximab-vedotin (1.6 mg/kg every 3 weeks, n=1). In 3 patients (ASM, n=1; MCL, n=2) no therapy could be administered because of poor performance status. Detailed information on therapies and responses in our patients are provided in Figure 1. In 17 of 21 patients (81%) a response to therapy was observed, namely a complete remission (CR) in one female MCL patient, age 54 yrs (years) receiving 2 cycles of FLAG; a good partial response (GPR) of the remaining tumor mass (after surgery) in one female patient with MCS aged 33 yrs after 2 cycles of CLAG; a partial response (PR) in 5 additional patients; and a stable disease (SD) in 9 patients (Figure 1). Two patients, one female ASM patient, age 54 yrs with PR after 6 cycles of 2CdA and one female patient with MCS, age 30 yrs, with a GPR after CLAG, underwent HSCT and achieved long-term CR under maintenance with midostaurin. Median survival until loss of response to first-line therapy was 20 months (range: 3-73 months). Interestingly, in all 4 patients who had received both 2CdA and midostaurin, no progression of the disease occurred. In the follow up, 3 patients are still alive, 7 developed a secondary acute myeloid Leukemia (sAML) and in one patient with ASM-CMML, the CMML component progressed without overt AML. Three patients died due to unrelated (non-SM) events (age at death: 93, 90, and 67 yrs). The patient with CR following FLAG had a relapse of MCL after 4 months. In 3 patients receiving IFN-A, the disease showed progression under therapy and in 2 patients receiving midostaurin, therapy had to be withdrawn due to treatment-related toxicity prior to response evaluation. Interestingly, the risk to develop sAML was significantly higher in patients with ASM/CMML or ASM/CEL (71.4%) compared to patients with ASM (27.2%) or MCL/MCS without an associated hematologic neoplasm (0%) (p<0.05). Salvage therapy in patients with progressive disease (PD or toxicity under first-line therapy, n=4; PD/relapse following response to first-line therapy in patients eligible for further therapy, n=10) included 2CdA, polychemotherapy, INF-A, azacitidine and hydroxyurea. The median number of treatment lines of salvage therapy was 1.7 (range 1-4) and resulted in a median duration of response of 8 months (range: <1 to 44 months). The median survival of patients developing sAML was 4 months and was markedly shorter compared to patients without sAML (median survival 13 months). In conclusion, treatment of ASM, MCL and MCS remains a clinical challenge and unmet treatment-need. The combination of conventional therapy such as chemotherapy with novel tyrosine kinase inhibitors and/or HSCT may be a new promising approach in these patients and may lead to cure in some of them. However, controlled studies are necessary to confirm this hypothesis. Figure 1. Figure 1. Disclosures Valent: Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Sperr:Novartis: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria.

  • the clinical and molecular diversity of Mast Cell Leukemia with or without associated hematologic neoplasm
    Haematologica, 2017
    Co-Authors: Mohamad Jawhar, Hans-peter Horny, Karl Sotlar, Juliana Schwaab, Manja Meggendorfer, Nicole Naumann, Torsten Haferlach, Karla Schmitt, Alice Fabarius, Peter Valent
    Abstract:

    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 mu g/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 additio-nal mutations in SRSF2, ASXL1 or RUNX1 (S/A/R-pos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naIve 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/R-pos 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.

  • Mast Cell Leukemia clinical heterogeneity molecular aberrations treatment responses survival and prognostic factors
    Blood, 2016
    Co-Authors: Mohamad Jawhar, Hans-peter Horny, Karl Sotlar, Juliana Schwaab, Manja Meggendorfer, Nicole Naumann, Torsten Haferlach, Karla Schmitt, Alice Fabarius, Peter Valent
    Abstract:

    Mast Cell Leukemia (MCL) is a rare variant of advanced systemic Mastocytosis (advSM) characterized by ≥20% Mast Cells (MCs) in a bone marrow (BM) smear. Our current knowledge of MCL, including clinical and molecular characteristics, treatment options, survival, and prognostic factors is limited to case reports, small case-series and/or literature reviews. While the KIT D816V mutation is present in >80-90% of patients in other SM subtypes, it has only been reported in approximately 50% of patients with MCL. Of interest, recent data have highlighted that the molecular pathogenesis of advSM/MCL is complex. In particular, additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos), seen in 60-70% of advSM patients, have a significant adverse impact on disease phenotype and prognosis (Jawhar et al., Leukemia, 2016). Here, we sought to evaluate a) relevant clinical and molecular characteristics, b) treatment responses, and c) survival and prognostic factors in 28 MCL patients (median age 67 years; range, 45-82; male 57%), enrolled in the 9German Registry of Disorders on Eosinophils and Mast Cells9. The median percentages of MC in BM smears and trephine biopsies were 25% (range, 20-95) and 65% (range, 20-100; 82% ≥50%), respectively. MC in peripheral blood (PB) ≥10% (leukemic MCL) were seen in only 2/28 patients. Median serum tryptase level was 550 µg/L (range, 160-1850; 93% ≥200, normal value Disclosures Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Valent:Amgen: Honoraria; Novartis: Honoraria, Research Funding; Celegene: Honoraria, Research Funding.

  • chronic Mast Cell Leukemia mcl with kit s476i a rare entity defined by leukemic expansion of mature Mast Cells and absence of organ damage
    Annals of Hematology, 2015
    Co-Authors: Peter Valent, Sabine Cernyreiterer, Gregor Eisenwort, Leonhard Mullauer, Gregor Hoermann, Jorg Berger, Barbara Peter, Christine Mannhalter, Michael Steurer, P Bettelheim
    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 diagnosed in 2013. In February 2013, first symptoms, including flushing, headache, and diarrhea, were recorded. In addition, mild anemia was detected. The disease was characterized by a massive increase in well-granulated, mature, and often spindle-shaped MCs (80 %) in BM smears. The serum tryptase level amounted to 332 ng/mL. Like in most other MCL patients, no skin lesions were detected. However, unlike in other patients, tryptase levels remained stable, and no other signs or symptoms of MCL-induced organ damage were found. Sequencing studies revealed an isolated S476I point mutation in KIT but no mutation in codon 816. The patient received histamine receptor blockers but refused cytoreductive therapy. After 9 months, still no progression or organ damage was detected. However, progression with transformation to acute MCL occurred after 12 months. We propose that the chronic type of MCL with stable conditions, absence of organ damage, and a mature MC morphology is recognized as a distinct entity that should be distinguished from the acute variant of MCL.

  • chronic Mast Cell Leukemia a novel Leukemia variant with distinct morphological and clinical features
    Leukemia Research, 2015
    Co-Authors: Peter Valent, Karl Sotlar, Andreas Reiter, Wolfgang R Sperr, Michel Arock, Hans-peter Horny
    Abstract:

    Mast Cell Leukemia (MCL) is a rare form of systemic Mastocytosis characterized by leukemic expansion of mostly immature Mast Cells, organ damage, drug-resistance, and a poor prognosis. Even when treated with chemotherapy, most patients have a life-expectancy of less than one year. However, there are rare patients with MCL in whom the condition is less aggressive and does not cause organ damage within a short time. In these patients, Mast Cells exhibit a more mature morphology when compared to acute MCL. A recently proposed classification suggests that these cases are referred to as chronic MCL. In the present article, we discuss clinical, histopathological and morphological aspects of acute and chronic MCL.

Hans-peter Horny - One of the best experts on this subject based on the ideXlab platform.

  • Allogeneic Hematopoietic Stem Cell Transplantation in a Rare Case of Tonsillar Mast Cell Sarcoma
    Frontiers in Oncology, 2020
    Co-Authors: Anne Sophie Kubasch, Hans-peter Horny, Georg-nikolaus Franke, Ali Aldaoud, Konstantin Weibl, Madlen Jentzsch, Osama Sabri, Falko Fend, Gerhard Behre, Uwe Platzbecker
    Abstract:

    Mast Cell sarcoma comprises a rare aggressive Mast Cell neoplasia with histological, clinical, and genetic features distinct from other Mast Cell neoplasm. Until now, prognosis is still poor due to high rates of progression to Mast Cell Leukemia and failure of conventional chemotherapies. Our here presented first report about successful allogeneic hematopoietic stem Cell transplantation leading to remission in a case of tonsillar MCS represents a promising potential curative treatment option for this rare and often fatal disease.

  • the clinical and molecular diversity of Mast Cell Leukemia with or without associated hematologic neoplasm
    Haematologica, 2017
    Co-Authors: Mohamad Jawhar, Hans-peter Horny, Karl Sotlar, Juliana Schwaab, Manja Meggendorfer, Nicole Naumann, Torsten Haferlach, Karla Schmitt, Alice Fabarius, Peter Valent
    Abstract:

    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 mu g/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 additio-nal mutations in SRSF2, ASXL1 or RUNX1 (S/A/R-pos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naIve 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/R-pos 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.

  • Mast Cell Leukemia clinical heterogeneity molecular aberrations treatment responses survival and prognostic factors
    Blood, 2016
    Co-Authors: Mohamad Jawhar, Hans-peter Horny, Karl Sotlar, Juliana Schwaab, Manja Meggendorfer, Nicole Naumann, Torsten Haferlach, Karla Schmitt, Alice Fabarius, Peter Valent
    Abstract:

    Mast Cell Leukemia (MCL) is a rare variant of advanced systemic Mastocytosis (advSM) characterized by ≥20% Mast Cells (MCs) in a bone marrow (BM) smear. Our current knowledge of MCL, including clinical and molecular characteristics, treatment options, survival, and prognostic factors is limited to case reports, small case-series and/or literature reviews. While the KIT D816V mutation is present in >80-90% of patients in other SM subtypes, it has only been reported in approximately 50% of patients with MCL. Of interest, recent data have highlighted that the molecular pathogenesis of advSM/MCL is complex. In particular, additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos), seen in 60-70% of advSM patients, have a significant adverse impact on disease phenotype and prognosis (Jawhar et al., Leukemia, 2016). Here, we sought to evaluate a) relevant clinical and molecular characteristics, b) treatment responses, and c) survival and prognostic factors in 28 MCL patients (median age 67 years; range, 45-82; male 57%), enrolled in the 9German Registry of Disorders on Eosinophils and Mast Cells9. The median percentages of MC in BM smears and trephine biopsies were 25% (range, 20-95) and 65% (range, 20-100; 82% ≥50%), respectively. MC in peripheral blood (PB) ≥10% (leukemic MCL) were seen in only 2/28 patients. Median serum tryptase level was 550 µg/L (range, 160-1850; 93% ≥200, normal value Disclosures Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Valent:Amgen: Honoraria; Novartis: Honoraria, Research Funding; Celegene: Honoraria, Research Funding.

  • chronic Mast Cell Leukemia a novel Leukemia variant with distinct morphological and clinical features
    Leukemia Research, 2015
    Co-Authors: Peter Valent, Karl Sotlar, Andreas Reiter, Wolfgang R Sperr, Michel Arock, Hans-peter Horny
    Abstract:

    Mast Cell Leukemia (MCL) is a rare form of systemic Mastocytosis characterized by leukemic expansion of mostly immature Mast Cells, organ damage, drug-resistance, and a poor prognosis. Even when treated with chemotherapy, most patients have a life-expectancy of less than one year. However, there are rare patients with MCL in whom the condition is less aggressive and does not cause organ damage within a short time. In these patients, Mast Cells exhibit a more mature morphology when compared to acute MCL. A recently proposed classification suggests that these cases are referred to as chronic MCL. In the present article, we discuss clinical, histopathological and morphological aspects of acute and chronic MCL.

  • Mast Cell Leukemia a review
    International Journal of Hematologic Oncology, 2014
    Co-Authors: Hans-peter Horny, Karl Sotlar, Andreas Reiter, Peter Valent
    Abstract:

    SUMMARY  Mast Cell Leukemia (MCL) is a rare subtype of systemic Mastocytosis. In MCL the numbers of Mast Cells exceed 19% of nucleated Cells in bone marrow and/or 10% of circulating leukocytes in peripheral blood. Primary MCL must be distinguished from secondary MCL evolving from another subvariant of systemic Mastocytosis or from Mast Cell sarcoma. Acute MCL with a poor prognosis is distinguished from the more indolent chronic MCL. Serum tryptase is significantly elevated in almost all MCL patients and activating point mutations at codon 816 of KIT (usually KIT D816V) are encountered in about 70%. Regarding differential diagnosis, other ‘tryptase-positive’ or ‘metachromatic’ Leukemias must be considered, including myeloMastocytic Leukemia and tryptase-positive acute myeloid Leukemia but also acute and chronic basophilic Leukemias.

Karl Sotlar - One of the best experts on this subject based on the ideXlab platform.

  • the clinical and molecular diversity of Mast Cell Leukemia with or without associated hematologic neoplasm
    Haematologica, 2017
    Co-Authors: Mohamad Jawhar, Hans-peter Horny, Karl Sotlar, Juliana Schwaab, Manja Meggendorfer, Nicole Naumann, Torsten Haferlach, Karla Schmitt, Alice Fabarius, Peter Valent
    Abstract:

    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 mu g/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 additio-nal mutations in SRSF2, ASXL1 or RUNX1 (S/A/R-pos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naIve 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/R-pos 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.

  • Mast Cell Leukemia clinical heterogeneity molecular aberrations treatment responses survival and prognostic factors
    Blood, 2016
    Co-Authors: Mohamad Jawhar, Hans-peter Horny, Karl Sotlar, Juliana Schwaab, Manja Meggendorfer, Nicole Naumann, Torsten Haferlach, Karla Schmitt, Alice Fabarius, Peter Valent
    Abstract:

    Mast Cell Leukemia (MCL) is a rare variant of advanced systemic Mastocytosis (advSM) characterized by ≥20% Mast Cells (MCs) in a bone marrow (BM) smear. Our current knowledge of MCL, including clinical and molecular characteristics, treatment options, survival, and prognostic factors is limited to case reports, small case-series and/or literature reviews. While the KIT D816V mutation is present in >80-90% of patients in other SM subtypes, it has only been reported in approximately 50% of patients with MCL. Of interest, recent data have highlighted that the molecular pathogenesis of advSM/MCL is complex. In particular, additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos), seen in 60-70% of advSM patients, have a significant adverse impact on disease phenotype and prognosis (Jawhar et al., Leukemia, 2016). Here, we sought to evaluate a) relevant clinical and molecular characteristics, b) treatment responses, and c) survival and prognostic factors in 28 MCL patients (median age 67 years; range, 45-82; male 57%), enrolled in the 9German Registry of Disorders on Eosinophils and Mast Cells9. The median percentages of MC in BM smears and trephine biopsies were 25% (range, 20-95) and 65% (range, 20-100; 82% ≥50%), respectively. MC in peripheral blood (PB) ≥10% (leukemic MCL) were seen in only 2/28 patients. Median serum tryptase level was 550 µg/L (range, 160-1850; 93% ≥200, normal value Disclosures Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Valent:Amgen: Honoraria; Novartis: Honoraria, Research Funding; Celegene: Honoraria, Research Funding.

  • chronic Mast Cell Leukemia a novel Leukemia variant with distinct morphological and clinical features
    Leukemia Research, 2015
    Co-Authors: Peter Valent, Karl Sotlar, Andreas Reiter, Wolfgang R Sperr, Michel Arock, Hans-peter Horny
    Abstract:

    Mast Cell Leukemia (MCL) is a rare form of systemic Mastocytosis characterized by leukemic expansion of mostly immature Mast Cells, organ damage, drug-resistance, and a poor prognosis. Even when treated with chemotherapy, most patients have a life-expectancy of less than one year. However, there are rare patients with MCL in whom the condition is less aggressive and does not cause organ damage within a short time. In these patients, Mast Cells exhibit a more mature morphology when compared to acute MCL. A recently proposed classification suggests that these cases are referred to as chronic MCL. In the present article, we discuss clinical, histopathological and morphological aspects of acute and chronic MCL.

  • Mast Cell Leukemia a review
    International Journal of Hematologic Oncology, 2014
    Co-Authors: Hans-peter Horny, Karl Sotlar, Andreas Reiter, Peter Valent
    Abstract:

    SUMMARY  Mast Cell Leukemia (MCL) is a rare subtype of systemic Mastocytosis. In MCL the numbers of Mast Cells exceed 19% of nucleated Cells in bone marrow and/or 10% of circulating leukocytes in peripheral blood. Primary MCL must be distinguished from secondary MCL evolving from another subvariant of systemic Mastocytosis or from Mast Cell sarcoma. Acute MCL with a poor prognosis is distinguished from the more indolent chronic MCL. Serum tryptase is significantly elevated in almost all MCL patients and activating point mutations at codon 816 of KIT (usually KIT D816V) are encountered in about 70%. Regarding differential diagnosis, other ‘tryptase-positive’ or ‘metachromatic’ Leukemias must be considered, including myeloMastocytic Leukemia and tryptase-positive acute myeloid Leukemia but also acute and chronic basophilic Leukemias.

  • refined diagnostic criteria and classification of Mast Cell Leukemia mcl and myeloMastocytic Leukemia mml a consensus proposal
    Annals of Oncology, 2014
    Co-Authors: Peter Valent, Karl Sotlar, Olivier Hermine, Andreas Reiter, Wolfgang R Sperr, Tracy I George, Hanneke C Kluinnelemans, Luis Escribano, Selim Yavuz, Joseph H Butterfield
    Abstract:

    Mast Cell Leukemia (MCL), the leukemic manifestation of systemic Mastocytosis (SM), is characterized by leukemic expansion of immature Mast Cells (MCs) in the bone marrow (BM) and other internal organs; and a poor prognosis. In a subset of patients, circulating MCs are detectable. A major differential diagnosis to MCL is myeloMastocytic Leukemia (MML). Although criteria for both MCL and MML have been published, several questions remain concerning terminologies and subvariants. To discuss open issues, the EU/US-consensus group and the European Competence Network on Mastocytosis (ECNM) launched a series of meetings and workshops in 2011-2013. Resulting discussions and outcomes are provided in this article. The group recommends that MML be recognized as a distinct condition defined by Mastocytic differentiation in advanced myeloid neoplasms without evidence of SM. The group also proposes that MCL be divided into acute MCL and chronic MCL, based on the presence or absence of C-Findings. In addition, a primary (de novo) form of MCL should be separated from secondary MCL that typically develops in the presence of a known antecedent MC neoplasm, usually aggressive SM (ASM) or MC sarcoma. For MCL, an imminent prephase is also proposed. This prephase represents ASM with rapid progression and 5%-19% MCs in BM smears, which is generally accepted to be of prognostic significance. We recommend that this condition be termed ASM in transformation to MCL (ASM-t). The refined classification of MCL fits within and extends the current WHO classification; and should improve prognostication and patient selection in practice as well as in clinical trials.

Wolfgang R Sperr - One of the best experts on this subject based on the ideXlab platform.

  • Treatment of Patients with Aggressive Systemic Mastocytosis, Mast Cell Leukemia and Mast Cell Sarcoma: A Single Center Experience
    Blood, 2018
    Co-Authors: Karoline V. Gleixner, Peter Valent, Wolfgang R Sperr
    Abstract:

    Abstract Aggressive systemic Mastocytosis (ASM), Mast Cell Leukemia (MCL) and Mast Cell sarcoma (MCS) are rare, life-threatening Mast Cell disorders, characterized by an aggressive clinical course, drug resistance and a poor survival. Established disease-modifying therapies include interferon-alpha (INF-A), cladribine (2CdA) and midostaurin (PKC412). However, these treatment approaches are unable to exert curative effects in advanced Mastocytosis. Intensive therapy, including poly-chemotherapy and hematopoietic stem Cell transplantation (HSCT) have also been suggested for patients with rapidly progressing ASM and MCL (Ustun et al, J Clin Oncol 2014;32:3264-3274). However, little is known about long-term outcome and survival in these patients. We analyzed the clinical course and treatment responses in 24 patients with ASM, MCL and MCS seen at the Medical University of Vienna between May 1994 and December 2017. According to World Health Organization criteria, patients were diagnosed as ASM (n=11), ASM with associated chronic myelomonocytic Leukemia (ASM-CMML, n=6), ASM with associated chronic eosinophilic Leukemia (ASM-CEL, n=1), MCL (n=4) and MCS (n=2). The median age at diagnosis was 59 years (range 21-90 years) and the f:m ratio was 1:2.4. Patients received first-line therapy with INF-A (3x106 units three times a week, n=8), 2-CdA (0.13 mg/kg, days 1-5, n=5); CLAG (cladribine 5mg/m2, days 1-5, ARA-C 2g/m2 day 1-5, G-CSF, 300 µg from day 6 until recovery; n=2), alternating 2CdA and midostaurin (n=2), midostaurin alone (2x100 mg/day, n=2), FLAG (fludarabine, 30mg/m², days 1-5; ARA-C 2 g/m² days 1-5; G-CSF 300µg from day 6 until recovery, n=1) and brentuximab-vedotin (1.6 mg/kg every 3 weeks, n=1). In 3 patients (ASM, n=1; MCL, n=2) no therapy could be administered because of poor performance status. Detailed information on therapies and responses in our patients are provided in Figure 1. In 17 of 21 patients (81%) a response to therapy was observed, namely a complete remission (CR) in one female MCL patient, age 54 yrs (years) receiving 2 cycles of FLAG; a good partial response (GPR) of the remaining tumor mass (after surgery) in one female patient with MCS aged 33 yrs after 2 cycles of CLAG; a partial response (PR) in 5 additional patients; and a stable disease (SD) in 9 patients (Figure 1). Two patients, one female ASM patient, age 54 yrs with PR after 6 cycles of 2CdA and one female patient with MCS, age 30 yrs, with a GPR after CLAG, underwent HSCT and achieved long-term CR under maintenance with midostaurin. Median survival until loss of response to first-line therapy was 20 months (range: 3-73 months). Interestingly, in all 4 patients who had received both 2CdA and midostaurin, no progression of the disease occurred. In the follow up, 3 patients are still alive, 7 developed a secondary acute myeloid Leukemia (sAML) and in one patient with ASM-CMML, the CMML component progressed without overt AML. Three patients died due to unrelated (non-SM) events (age at death: 93, 90, and 67 yrs). The patient with CR following FLAG had a relapse of MCL after 4 months. In 3 patients receiving IFN-A, the disease showed progression under therapy and in 2 patients receiving midostaurin, therapy had to be withdrawn due to treatment-related toxicity prior to response evaluation. Interestingly, the risk to develop sAML was significantly higher in patients with ASM/CMML or ASM/CEL (71.4%) compared to patients with ASM (27.2%) or MCL/MCS without an associated hematologic neoplasm (0%) (p<0.05). Salvage therapy in patients with progressive disease (PD or toxicity under first-line therapy, n=4; PD/relapse following response to first-line therapy in patients eligible for further therapy, n=10) included 2CdA, polychemotherapy, INF-A, azacitidine and hydroxyurea. The median number of treatment lines of salvage therapy was 1.7 (range 1-4) and resulted in a median duration of response of 8 months (range: <1 to 44 months). The median survival of patients developing sAML was 4 months and was markedly shorter compared to patients without sAML (median survival 13 months). In conclusion, treatment of ASM, MCL and MCS remains a clinical challenge and unmet treatment-need. The combination of conventional therapy such as chemotherapy with novel tyrosine kinase inhibitors and/or HSCT may be a new promising approach in these patients and may lead to cure in some of them. However, controlled studies are necessary to confirm this hypothesis. Figure 1. Figure 1. Disclosures Valent: Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Sperr:Novartis: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria.

  • chronic Mast Cell Leukemia a novel Leukemia variant with distinct morphological and clinical features
    Leukemia Research, 2015
    Co-Authors: Peter Valent, Karl Sotlar, Andreas Reiter, Wolfgang R Sperr, Michel Arock, Hans-peter Horny
    Abstract:

    Mast Cell Leukemia (MCL) is a rare form of systemic Mastocytosis characterized by leukemic expansion of mostly immature Mast Cells, organ damage, drug-resistance, and a poor prognosis. Even when treated with chemotherapy, most patients have a life-expectancy of less than one year. However, there are rare patients with MCL in whom the condition is less aggressive and does not cause organ damage within a short time. In these patients, Mast Cells exhibit a more mature morphology when compared to acute MCL. A recently proposed classification suggests that these cases are referred to as chronic MCL. In the present article, we discuss clinical, histopathological and morphological aspects of acute and chronic MCL.

  • refined diagnostic criteria and classification of Mast Cell Leukemia mcl and myeloMastocytic Leukemia mml a consensus proposal
    Annals of Oncology, 2014
    Co-Authors: Peter Valent, Karl Sotlar, Olivier Hermine, Andreas Reiter, Wolfgang R Sperr, Tracy I George, Hanneke C Kluinnelemans, Luis Escribano, Selim Yavuz, Joseph H Butterfield
    Abstract:

    Mast Cell Leukemia (MCL), the leukemic manifestation of systemic Mastocytosis (SM), is characterized by leukemic expansion of immature Mast Cells (MCs) in the bone marrow (BM) and other internal organs; and a poor prognosis. In a subset of patients, circulating MCs are detectable. A major differential diagnosis to MCL is myeloMastocytic Leukemia (MML). Although criteria for both MCL and MML have been published, several questions remain concerning terminologies and subvariants. To discuss open issues, the EU/US-consensus group and the European Competence Network on Mastocytosis (ECNM) launched a series of meetings and workshops in 2011-2013. Resulting discussions and outcomes are provided in this article. The group recommends that MML be recognized as a distinct condition defined by Mastocytic differentiation in advanced myeloid neoplasms without evidence of SM. The group also proposes that MCL be divided into acute MCL and chronic MCL, based on the presence or absence of C-Findings. In addition, a primary (de novo) form of MCL should be separated from secondary MCL that typically develops in the presence of a known antecedent MC neoplasm, usually aggressive SM (ASM) or MC sarcoma. For MCL, an imminent prephase is also proposed. This prephase represents ASM with rapid progression and 5%-19% MCs in BM smears, which is generally accepted to be of prognostic significance. We recommend that this condition be termed ASM in transformation to MCL (ASM-t). The refined classification of MCL fits within and extends the current WHO classification; and should improve prognostication and patient selection in practice as well as in clinical trials.

  • the classification of systemic Mastocytosis should include Mast Cell Leukemia mcl and systemic Mastocytosis with a clonal hematologic non Mast Cell lineage disease sm ahnmd
    Blood, 2010
    Co-Authors: Peter Valent, Karl Sotlar, Andreas Reiter, Wolfgang R Sperr, Michel Arock, Cem Akin, Karin Hartmann, Tracy I George, Knut Brockow, Hanneke C Kluinnelemans
    Abstract:

    To the editor: We have read with interest the letter of Drs Pardanani and Tefferi, suggesting that the current World Health Organization (WHO) classification of systemic Mastocytosis (SM) should be revised.[1][1] They suggest eliminating Mast Cell Leukemia (MCL) and SM with associated clonal

  • Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic Mastocytosis: report of five cases and review of the literature
    Leukemia Research, 2004
    Co-Authors: Alexander W. Hauswirth, Wolfgang R Sperr, Ingrid Simonitsch-klupp, Martin Uffmann, Elisabeth Koller, Klaus Lechner, Peter Valent
    Abstract:

    Aggressive systemic Mastocytosis (ASM) is a hematopoietic neoplasm characterized by infiltration of visceral organs by neoplastic Mast Cells (MCs) with consecutive organopathy and respective clinical and laboratory findings (so called C-Findings). Whereas, it is generally appreciated that patients with ASM are candidates for pharmacological intervention, no ideal drug or drug combination have been identified yet. One drug proposed to work in ASM is interferon alpha-2b (IFN-α2b). However, little is known so far about the quality of responses to IFN-α2b and actual response rates. We here report on five ASM patients treated with either a combination of IFN-α2b (3×3 million units per week) and prednisolone (n=4), or IFN-α2b alone (n=1). During therapy, two of the five patients showed a major response defined by complete resolution of C-Finding(s), one a partial response (partial regression of C-Findings), and one a stable disease (no changes in C-Findings). In one patient, progression to Mast Cell Leukemia was seen after 3 months. In contrast to the other patients, this patient exhibited >10% MCs in his bone marrow (bm) smear at first presentation. In summary, our data confirm beneficial effects of IFN-α2b (plus prednisolone) for a group of patients with ASM, whereas patients with Mast Cell Leukemia may require more aggressive therapy. Prospective trials with more patients are now required to further document these drug effects and to better define subgroups of patients with ASM who show good and long-lasting responses to IFN-α2b.

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  • genome wide molecular portrait of aggressive systemic Mastocytosis and Mast Cell Leukemia depicted by whole exome sequencing and copy number variation analysis
    Blood, 2015
    Co-Authors: Simona Soverini, Giorgina Specchia, Michela Rondoni, Caterina De Benedittis, Manuela Mancini, Cristina Papayannidis, Antonella Padella, Roberta Zanotti, Livio Pagano, Viviana Guadagnuolo
    Abstract:

    Background and Aims: The term Systemic Mastocytosis (SM) identifies a poorly understood group of rare and clinically heterogenous myeloproliferative neoplasms characterized by abnormal growth and activation of Mast Cells (MCs) and their precursors in the bone marrow and in various tissues and organs. Based on phenotype and extent of organ infiltration/dysfunction, a spectrum of disease variants can be recognized ranging from indolent SM (ISM) to aggressive SM (ASM) and Mast Cell Leukemia (MCL). The fact that in all cases, including ISM who have a (near) normal life expectancy, neoplastic MCs display the same D816V KIT gene mutation points to additional mechanisms and molecular defects as responsible for ASM and MCL. So far, however, this issue has mainly been addressed with targeted resequencing studies of candidate gene panels. We thus decided to undertake an integrated molecular characterization study of ASM and MCL to identify novel, functionally relevant molecular lesions and/or clinically actionable signaling pathways. Methods: A discovery panel including 6 patients with ASM and 6 patients with MCL was studied using whole exome sequencing (WES) and copy number variation (CNV) analysis. WES (80x) was performed on a Hiseq 2500 (Illumina). CNV was done using Cytoscan HD Arrays (Affymetrix). Paired normal/MC DNA was analyzed in all but 2 archival MCL cases for whom germline DNA was not available. A validation panel of 30 ISM, 5 smoldering SM and 20 additional ASM was also included in this study. Results: In the discovery panel, WES identified a total of 1554 point mutations, small insertions and deletions. Seven hundred and eighty-five were non-silent mutations in 698 genes, with an average of 51 (range, 30-186) non-silent mutations per patient. Non-silent mutations included 354 missense mutations, 188 nonsense mutations, 145 frameshift insertions/deletions, 98 non-frameshift insertions/deletions. C to T transitions were by far the most frequent. Orthogonal validation estimated the accuracy of mutation calls at >95%. Interrogation of the COSMIC and OMIM databases revealed 42 known cancer genes. Among the missense mutations, 87 were predicted to have a high probability of being deleterious by Condel. MCL cases were found not to harbour a higher mutation load as compared to ASM cases. High resolution CN analysis showed that focal amplifications/deletions/loss-of-heterozygosity (LOH) were prevalent over arm-level alterations (found in 3 patients only). Genes were selected for further assessment when recurrently mutated in ≥2 patients or concurrently identified in WES and CNV analyses or previously associated with leukemogenesis or cancer pathogenesis. Among these, genes already reported to be affected by mutations in SM included TET2, NRAS, ASXL1, CBL, IDH1, SRSF2, SF3B1, RUNX1. We also identified genetic alterations in genes not previously implicated in SM pathogenesis including TP53BP1, RUNX3, NCOR2, CDC27, CCND3, EI24, MLL3, ARID1B, ARID3B, ARID4A, SETD1A, SETD1B, KDM1B, PRDM1, ATM, WRN. A long tail of infrequently mutated genes dominated, resulting in significant intertumoural heterogeneity. However, when genes were assigned to functional pathways to discern patterns of mutations across different patients, we found that PI3K/Akt and MAPK pathways, calcium pathway, chromatin modification, DNA methylation, and DNA damage repair were consistently affected (Figure 1). Further assessment of the mutation frequency of selected genes within each pathway and functional validation at the protein level are currently ongoing in the validation panel. Preliminary findings on a tumor suppressor selected among those identified by WES show transcript and/or protein downmodulation due to inactivating mutations, transcriptional silencing or enhanced degradation in 17/20 ASM. Detailed results will be presented at the meeting. Conclusions: WES and CNV analyses of ASM and MCL revealed a complex landscape, not unexpected when considering the clinical heterogeneity of these patients. Nonetheless, key pathways were found to be recurrently altered. Further investigation of selected candidate genes and pathways is warranted and will cast light on the cooperative genetic (and epigenetic?) events underlying the more aggressive forms of SM - paving the way to a better prognostic stratification and more effective treatment. This study was supported by ELN, AIL, AIRC, progetto Regione-Universita 2010-12 (L. Bolondi), FP7 NGS-PTL project. Disclosures Soverini:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; ROCHE: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; AMGEN: Consultancy; MSD: Consultancy.

  • abstract 3957 integrated molecular characterization of Mast Cell Leukemia reveals recurrent inactivation of the setd2 tumor suppressor gene
    Cancer Research, 2015
    Co-Authors: Simona Soverini, Michela Rondoni, Caterina De Benedittis, Manuela Mancini, Cristina Papayannidis, Luca Zazzeroni, Viviana Guadagnuolo, Elisa Zago, Francesca Griggio, Alberto Ferrarini
    Abstract:

    Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Systemic Mastocytosis (SM) includes a heterogeneous group of disorders ranging from indolent SM to the rare and aggressive Mast Cell Leukemia (MCL). Somatic mutations in the KIT receptor kinase (most frequently, D816V) can be detected in >90% of patients and are thought to play an important pathogenetic role. Nevertheless, morphological and clinical diversity, as well as the fact that some patients are negative for KIT mutations, suggest that the underlying molecular picture is far from being fully elucidated. To shed further light on this issue, we undertook an integrated molecular genetic study of a KIT gene mutation-negative MCL case who came to our attention in 2012. After having obtained written informed consent, we extracted genomic DNA and total RNA from purified Mast Cells (MCs) isolated from bone marrow at diagnosis and at progression, as well as DNA from saliva, and performed whole exome sequencing (WES) and RNA-seq on an HiSeq1000 (Illumina, San Diego CA). High resolution karyotyping was also performed with Cytoscan HD arrays (Affymetrix, Santa Clara CA). Among the mutated genes detected in MCs but not in saliva by WES, SETD2 stood out among others because two loss-of-function mutations (a nonsense and a frameshift mutation) inactivating both alleles of the gene were identified. Western Blotting (WB) confirmed the expression of the truncated SETD2 isoform resulting from the nonsense mutation. The SETD2 gene encodes a histone methyltransferase responsible for trimethylation of Lysine 36 of histone H3 (H3K36Me3), a key hystone mark associated not only with active chromatin but also with transcriptional elongation, alternative splicing, DNA replication and repair. Loss of the highly conserved WW and SRI domains was predicted to impair SETD2 binding with RNA polymeraseII and hNRNP L, as confirmed by co-immunoprecipitation. Accordingly, RNA-seq showed evidence of spurious transcripts initiated from cryptic promoter-like sequences within genes as well as non-canonical splice isoforms. More importantly, WB confirmed that H3K36Me3 was completely abrogated. In line with the role of SETD2-dependent H3K36Me3 in DNA repair and genome stability, Cytoscan HD arrays and WES showed that several losses at many chromosomal loci, together with more than 70 additional point mutations, undetectable at diagnosis, were acquired at the time of progression. Absence of SETD2 protein expression and/or reduced H3K36Me3 were detected in 3/3 additional MCLs and in 6/8 aggressive SMs so far screened. Our data point to epigenetic regulation and/or DNA repair as candidate pathways deserving further investigation in SM - in an attempt to elucidate the mechanisms underlying enhanced clinical aggressiveness and to identify more effective treatment modalities. Molecular characterization of 10 additional MCLs and aggressive SMs is ongoing. Supported by FP7 NGS-PTL project and Progetto Regione-Universita 2010-12(L. Bolondi) Citation Format: Simona Soverini, Caterina De Benedittis, Michela Rondoni, Manuela Mancini, Cristina Papayannidis, Luca Zazzeroni, Viviana Guadagnuolo, Elisa Zago, Francesca Griggio, Alberto Ferrarini, Marianna Garonzi, Massimo Delledonne, Giorgina Specchia, Roberta Zanotti, Omar Perbellini, Livio Pagano, Michele Cavo, Peter Valent, Giovanni Martinelli. Integrated molecular characterization of Mast Cell Leukemia reveals recurrent inactivation of the SETD2 tumor suppressor gene. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3957. doi:10.1158/1538-7445.AM2015-3957

  • Serum total tryptase level confirms itself as a more reliable marker of Mast Cells burden in Mast Cell leukaemia (aleukaemic variant).
    Case reports in hematology, 2015
    Co-Authors: Paolo Savini, Michela Rondoni, Giovanni Martinelli, Simona Soverini, Giovanni Poletti, Arianna Lanzi, O. Quercia, C De Benedittis, G. Musardo, Giuseppe Francesco Stefanini
    Abstract:

    Mast Cell Leukemia (MCL) is a very rare form of systemic Mastocytosis (SM) with a short median survival of 6 months. We describe a case of a 65-year-old woman with aleukaemic variant of MCL with a very high serum total tryptase level of 2255 μg/L at diagnosis, which occurred following an episode of hypotensive shock. She fulfilled the diagnostic criteria of SM, with a bone marrow smear infiltration of 50–60% of atypical Mast Cells (MCs). She tested negative for the KIT D816V mutation, without any sign of organ damage (no B- or C-findings) and only few mediator-related symptoms. She was treated with antihistamine alone and then with imatinib for the appearance of anemia. She maintained stable tryptase level and a very indolent clinical course for twenty-two months; then, she suddenly progressed to acute MCL with a serum tryptase level up to 12960 μg/L. The patient died due to haemorrhagic diathesis twenty-four months after diagnosis. This clinical case maybe represents an example of the chronic form of Mast Cell Leukemia, described as unpredictable disease, in which the serum total tryptase level has confirmed itself as a reliable marker of Mast Cells burden regardless of the presence of other signs or symptoms.

  • inactivation of the setd2 tumor suppressor gene in Mast Cell Leukemia
    Blood, 2014
    Co-Authors: Simona Soverini, Michela Rondoni, Caterina De Benedittis, Manuela Mancini, Cristina Papayannidis, Luca Zazzeroni, Viviana Guadagnuolo, Elisa Zago, Raffaele A Calogero, Anna Scandola
    Abstract:

    Systemic Mastocytosis (SM) includes a heterogeneous group of disorders ranging from indolent SM to Mast Cell Leukemia (MCL). Somatic mutations in the Kit receptor tyrosine kinase (most frequently, D816V) can be detected in >90% of patients with SM and are thought to play a key pathogenetic role. Nevertheless, morphological and clinical diversity, as well as the fact that some patients are negative for KIT mutations, suggest that the underlying molecular picture is far from being fully elucidated. To shed further light on this issue, we undertook an integrated molecular genetic study of a KIT gene mutation-negative MCL patient who came to our attention in 2012 – a 63 year-old woman diagnosed with MCL, aleukemic variant (50-60% atypical Mast-Cells in the bone marrow [BM] smear; CD117+/CD2+/CD13+-/CD33+/CD59+ immunophenotype; serum tryptase, 2500 µg/L; no C-findings). The patient had received imatinib for 6 months, with no clinical benefit. The disease, however, had had an overall chronic clinical course for 6 more months until severe anemia occurred. The patient rapidly progressed and died after 21 months from diagnosis. After having obtained written informed consent, we extracted genomic DNA and total RNA from purified MCs isolated from BM at diagnosis and at progression, as well as DNA from saliva, and performed whole exome sequencing (WES) and RNA sequencing on an HiSeq1000 (Illumina, San Diego CA). Cytoscan HD arrays (Affymetrix, Santa Clara CA) were also used to scan for chromosomal gains and losses as well as for loss of heterozigosity (LOH). Among the mutated genes detected by WES, SETD2 stood out among others because two distinct putatively inactivating heterozygous mutations were identified, a frameshift insertion of a C in exon 20 (NM_014159:c.7595_7596insC: p.Gly2515ArgfsTer5) and a nonsense mutation in exon 15 (NM_014159:c.G6753T:p.Glu2234Ter). The two mutations were found to hit distinct alleles, pointing to a loss-of-function event. Western Blotting (WB), however, showed that only the 2234 a.a. Setd2 truncated isoform resulting from the nonsense mutation, losing the highly conserved WW and SRI functional domains, was detectable in the sample. The SETD2 gene encodes a histone methyltransferase nonredundantly responsible for trimethylation of lysine 36 of histone H3, a key hystone mark associated not only with active chromatin but also with transcriptional elongation, alternative splicing, DNA replication and repair. SETD2 gene mutations have been described in a variety of cancers and, more recently, have been found to be cooperating events in acute Leukemia initiation and progression. In yeast, deletion of the SRI domain abolishes Set2-RNA polymerase II (PolII) interaction causing transcription elongation defects and abolishes K36 methylation. The truncated SETD2 isoform was actually found to lose the ability to bind RNAPolII, as shown by co-immunoprecipitation. Accordingly, RNA-sequencing showed evidence of spurious transcripts initiated from cryptic promoter-like sequences within genes rather than from canonical promoters. More importantly, WB confirmed that H3K36Me3 was completely abrogated. In line with the recently reported role of SETD2-dependent H3K36Me3 in homologous recombination (HR) repair and genome stability, Cytoscan HD arrays showed that LOH and several gains and losses at many chromosomal loci, undetectable at diagnosis, had been acquired at the time of progression. Haploinsufficiency of PSIP1 (recruiting HR machinery at double strand breaks) at 9p24.3 might have represented a cooperating event. Downmodulation of the Setd2 protein (in the presence of LOH but in the apparent absence of sequence variations other than polymorphisms) and reduced H3K36Me3 levels were detected in two more MCL cases, in which putative cooperative lesions were also identified. Results of WES and high resolution karyotyping of additional SM cases will be presented. Our findings point to epigenetic regulation and/or DNA repair as two candidate pathways deserving further investigation in an attempt to identify novel actors or mechanisms contributing to the pathogenesis and progression of SM, or novel modulators of disease phenotype. They also extend the recent observation that the molecular landscape of SM is much more complex than the initial finding of KIT mutations allowed to imagine. Supported by FP7 NGS-PTL project and Progetto Regione-Universita 2010-12 (L. Bolondi) Disclosures Soverini:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Speakers Bureau.