A JH CME Information: Systemic mastocytosis in adults: 2015 update on diagnosis, risk-stratification, and management Author: Animesh Pardanani M.B.B.S, Ph.D CME Editor: Ayalew Tefferi M.D.
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䊏 Educational Objectives Upon completion of this educational activity, participants will be better able to: 1. Identify the current pathogenetic concepts, classification, diagnosis and risk stratification of systemic mastocytosis. 2. Identify the current management of systemic mastocytosis, including updates in investigational therapies.
䊏 Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. CME Editor: Ayalew Tefferi, M.D., has no relevant financial relationships to disclose. Author: Animesh Pardanani, M.B.B.S, Ph.D, has no relevant financial relationships to disclose. This activity underwent peer review in line with the standards of editorial integrity and publication ethics maintained by American Journal of Hematology. The peer reviewers have no conflicts of interest to disclose. The peer review process for American Journal of Hematology is single blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’s Policy on Activity Disclosure and Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.
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Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management Animesh Pardanani1,2* Disease overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. Diagnosis: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk stratification: The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. Management: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-a (1/2corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases. Investigational Drugs: Recent data confirms midostaurin’s significant anti-MC activity in patients with advanced SM. C 2015 Wiley Periodicals, Inc. Am. J. Hematol. 90:251–262, 2015. V
䊏 Disease Overview and Pathogenesis Mastocytosis is one of eight subcategories of myeloproliferative neoplasms (MPN) per the 2008 World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues [1]. It results from a clonal, neoplastic proliferation of morphologically, and immunophenotypically abnormal mast cells (MC) that accumulate in one or more organ systems. The sine qua non of mastocytosis is the presence of multifocal clusters of abnormal MC, which in contrast to normal MC are variable in appearance, ranging from round to fusiform variants with long, polar cytoplasmic processes, and may display cytoplasmic hypogranularity with uneven distribution of fine granules, as well as atypical nuclei with monocytoid appearance [2–4]. The clinical presentation of mastocytosis is heterogeneous, ranging from skin-limited disease (cutaneous mastocytosis, CM), particularly in pediatric cases where the majority have disease-onset within the first 2 years of life and commonly experience spontaneous regression of skin lesions [5–8], to a more aggressive variant with extracutaneous involvement (systemic mastocytosis, SM) that may be associated with multiorgan dysfunction/failure and shortened survival, that is, generally seen in adult patients (Fig. 1) [9]. The WHO document distinguishes the usually KIT-mutated SM from a Philadelphia chromosome-negative MPN with hematological features of chronic eosinophilic leukemia associated with splenomegaly, marked elevation of serum vitamin B12, elevation of serum tryptase and increased bone marrow (BM) MC commonly in scattered or noncohesive clusters [10]. The latter entity is commonly associated with rearrangement of PDGFRA (i.e., FIP1L1-PDGFR) and less commonly, PDGFRB (e.g., PRKG2-PDGFRB), and is sensitive to treatment with imatinib [11–18]. WHOdefined SM is sometimes associated with a clonally related second myeloid neoplasm [19–22], which is not surprising considering its origin as a stem cell disease with multilineage clonal involvement [23–25]. Conversely, an otherwise well-defined myeloid malignancy, such as myelodysplastic syndrome (MDS) or a non-mast cell disease MPN, might also harbor neoplastic mast cells [26]. Mastocytosis is frequently associated with somatic gain-of-function point mutations within KIT. KIT (CD117) is a Type III receptor tyrosine kinase that is expressed by MC, hematopoietic progenitor cells, germ cells, melanocytes, and interstitial cells of Cajal in the gastrointestinal tract
Additional Supporting Information may be found in the online version of this article. 1
Division of Hematology, Mayo Clinic, Rochester, Minnesota; 2Department of Medicine, Mayo Clinic, Rochester, Minnesota
Conflict of interest: Nothing to report *Correspondence to: Animesh Pardanani, MBBS, PhD, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. E-mail: [email protected] Received for publication: 23 December 2014; Accepted: 24 December 2014 Am. J. Hematol. 90:251–262, 2015. Published online: in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23931 C 2015 Wiley Periodicals, Inc. V
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Figure 1. Clinical spectrum of patients with clonal mast cell disorders. Please refer to Tables I and II for the WHO classification of mastocytosis. “Prediagnostic” SM refers to an abnormal clonal BM mast cell infiltrate that falls short of the diagnostic threshold for SM (generally satisfies 1–2 minor criteria only). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Figure 2. Diagnostic algorithm for SM.
and is therefore functionally relevant for normal mast cell development, hematopoiesis, gametogenesis, melanogenesis, and regulation of slow gastric waves [27]. KIT expression is down regulated upon differentiation of hematopoietic progenitors into mature cells of all lineages, except mast cells, which retain high levels of cell surface KIT expression. The interaction between KIT and its ligand, stem cell factor, plays a key role in regulating mast cell proliferation, maturation, adhesion, chemotaxis, and survival [28]. Gain-of-function somatic mutations in the KIT tyrosine kinase domain, particularly the D816V mutation, have been found to occur 252
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in a majority of cases of adult SM, irrespective of WHO SM subtype [9,29]. Other less common (25% of the mast cells in the infiltrate are spindle-shaped or have atypical morphology or, of all mast cells in BM aspirate smears, >25% are immature or atypical b. Detection of an activating point mutation at codon 816 of KIT in BM, blood or other extracutaneous organ c. Mast cells in BM, blood or other extracutaneous organ express CD2 and/or CD25 in addition to normal mast cell markersa d. Serum total tryptase persistently exceeds 20 ng/mL (unless there is an associated clonal myeloid disorder, in which case this parameter is not valid) “B” findings 1. BM biopsy showing >30% infiltration by MC (focal, dense aggregates) and/or serum total tryptase level >200 ng/mL 2. Signs of dysplasia or myeloproliferation, in non-MC lineage(s), but insufficient criteria for definitive diagnosis of a hematopoietic neoplasm (AHNMD), with normal or slightly abnormal blood counts. 3. Hepatomegaly without impairment of liver function, and/or palpable splenomegaly without hypersplenism, and/or lymphadenopathy on palpation or imaging. “C” findings 1. BM dysfunction manifested by one or more cytopenia(s) (ANC MPN, AML > lymphoid neoplasms) [67]. Attempts at validating the WHO diagnostic criteria reveal that 20% of ISM patients lack mast cell clusters in the BM and 30% exhibit a serum tryptase level lower than 20 ng/mL [68]. In contrast, the sensitivity for detecting morphologic atypia, aberrant CD25 and/ or CD2 expression, or KITD816V in BM mast cells exceeds 90% when sensitive assays are used, thereby illustrating the increasing importance of these specific minor criteria in diagnosing SM [68,69]. Patients who have mast cell degranulation symptoms with clonal mast cells (i.e., mutated KIT gene and/or CD25 expression), but who do not meet criteria for SM (only 1 or 2 minor criteria satisfied, and no skin involvement), may have “prediagnostic ISM” or “monoclonal mast cell activation syndrome” (Fig. 3); these patients generally have normal or slightly elevated baseline serum tryptase level [70]. While the clinical characteristics of this entity may be indistinguishable from ISM, its true natural history remains to be defined. Rare SM cases may exhibit a well-differentiated phenotype (i.e., relatively normal BM MC morphology; absence of aberrant MC CD25/CD2 expression); these cases are associated with non-D816V KIT mutations (e.g., germline F522C or somatic I817V) and, in the case of KITF522C-associated SM, has been shown to be sensitive to imatinib therapy [29,45]. In the presence of blood eosinophilia, screening for FIP1L1PDGFRA, using either FISH or RT-PCR, is warranted [16]. In contrast, conventional cytogenetics analysis generally permits identification of cases of BMM associated with a PDGFRB rearrangement (i.e., chromosomal translocations involving 5q31-32) [18]. These cases with PDGFRA/PDGFRB-rearranged MPN with BM MC hyperplasia are appropriately classified as “Myeloid or lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1” per the WHO classification [10].
䊏 Risk Stratification This section focuses on adult SM patients; their life expectancy, when considered as a group, appears to be shorter as compared to doi:10.1002/ajh.23931
age- and gender-matched controls, with the excess deaths in this group occurring within the first 3–5 years after diagnosis (Fig. 4A) [9,71]. The categorization of adult SM patients per the 2008 WHO classification system remains the most practical first step in risk stratifying newly diagnosed patients [1]. The WHO classification recognizes seven mastocytosis categories (Table I) SM is subclassified into four subcategories: ISM (no evidence of extracutaneous organ dysfunction), ASM (presence of extracutaneous organ dysfunction), SM associated with another clonal hematological non-MC lineage disease (SM-AHNMD), and MCL. A recent study of 342 adult patients has validated the prognostic value of the WHO classification for SM [9].
Indolent SM It comprised the largest subgroup (n 5 159; 46%) [9]. Compared with patients with ASM and SM-AHNMD, ISM patients were significantly younger at presentation (median age 49 years) and had a higher prevalence (66–75%) of UP-like skin lesions, MCMRS and gastrointestinal symptoms; ISM patients were significantly less likely however to exhibit constitutional symptoms or hepatosplenomegaly ( val in microdissected pooled single mast cells and leukemic cells in a patient with systemic mastocytosis and concomitant chronic myelomonocytic leukemia. Leuk Res 2002;26:979–984. 21. Travis WD, Li CY, Yam LT, et al. Significance of systemic mast cell disease with associated hematologic disorders. Cancer 1988;62:965–972.
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96. Lim KH, Pardanani A, Butterfield JH, et al. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol 2009;84:790–794. 97. Simon J, Lortholary O, Caillat-Vigneron N, et al. Interest of interferon alpha in systemic mastocytosis. The french experience and review of the literature. Pathol Biol (Paris) 2004;52: 294–299. 98. Bohm A, Sonneck K, Gleixner KV, et al. In vitro and in vivo growth-inhibitory effects of cladribine on neoplastic mast cells exhibiting the imatinib-resistant KIT mutation D816V. Exp Hematol 2010;38:744–755. 99. Gleixner KV, Mayerhofer M, Aichberger KJ, et al. PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816Vmutated variant of KIT: Comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood 2006;107:752–759. 100. Penack O, Sotlar K, Noack F, et al. Cladribine therapy in a patient with an aleukemic subvariant of mast cell leukemia. Ann Hematol 2005; 84:692–693. 101. Tefferi A, Li CY, Butterfield JH, et al. Treatment of systemic mast-cell disease with cladribine. N Engl J Med 2001;344:307–309. 102. Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ, et al. Cladribine therapy for systemic mastocytosis. Blood 2003;102:4270–4276. 103. Pardanani A, Hoffbr AV, Butterfield JH, et al. Treatment of systemic mast cell disease with 2chlorodeoxyadenosine. Leuk Res 2004;28:127– 131. 104. Hermine O, Hirsh I, Damaj G, et al. Long term efficacy and safety of cladribine in adult systemic mastocytosis: A French Multicenter Study of 44 Patients. Blood ASH Annual Meeting Abstracts 2010;116:1982. 105. Zermati Y, De Sepulveda P, Feger F, et al. Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms. Oncogene 2003;22:660–664. 106. Akin C, Brockow K, D’Ambrosio C, et al. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol 2003;31:686–692. 107. Ma Y, Zeng S, Metcalfe DD, et al. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatorytype mutations. Blood 2002;99:1741–1744. 108. Nakagomi N, Hirota S. Juxtamembrane-type ckit gene mutation found in aggressive systemic mastocytosis induces imatinib-resistant constitutive KIT activation. Lab Invest 2007;87:365– 371. 109. Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, et al. Imatinib mesylate in the treatment of systemic mastocytosis: A phase II trial. Cancer 2006;107:345–351. 110. Vega-Ruiz A, Cortes JE, Sever M, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res 2009;33:1481–1484. 111. Pagano L, Valentini CG, Caira M, et al. Advanced mast cell disease: An Italian hemato-
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䊏 Accreditation and Designation Statement: Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Blackwell Futura Media Services designates this journal-based CME for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.
䊏 Educational Objectives Upon completion of this educational activity, participants will be better able to: 1. Identify the current pathogenetic concepts, classification, diagnosis and risk stratification of systemic mastocytosis. 2. Identify the current management of systemic mastocytosis, including updates in investigational therapies.
䊏 Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. CME Editor: Ayalew Tefferi, M.D., has no relevant financial relationships to disclose. Author: Animesh Pardanani, M.B.B.S, Ph.D, has no relevant financial relationships to disclose. This activity underwent peer review in line with the standards of editorial integrity and publication ethics maintained by American Journal of Hematology. The peer reviewers have no conflicts of interest to disclose. The peer review process for American Journal of Hematology is single blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’s Policy on Activity Disclosure and Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.
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Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management Animesh Pardanani1,2* Disease overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. Diagnosis: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk stratification: The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. Management: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-a (1/2corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases. Investigational Drugs: Recent data confirms midostaurin’s significant anti-MC activity in patients with advanced SM. C 2015 Wiley Periodicals, Inc. Am. J. Hematol. 90:251–262, 2015. V
䊏 Disease Overview and Pathogenesis Mastocytosis is one of eight subcategories of myeloproliferative neoplasms (MPN) per the 2008 World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues [1]. It results from a clonal, neoplastic proliferation of morphologically, and immunophenotypically abnormal mast cells (MC) that accumulate in one or more organ systems. The sine qua non of mastocytosis is the presence of multifocal clusters of abnormal MC, which in contrast to normal MC are variable in appearance, ranging from round to fusiform variants with long, polar cytoplasmic processes, and may display cytoplasmic hypogranularity with uneven distribution of fine granules, as well as atypical nuclei with monocytoid appearance [2–4]. The clinical presentation of mastocytosis is heterogeneous, ranging from skin-limited disease (cutaneous mastocytosis, CM), particularly in pediatric cases where the majority have disease-onset within the first 2 years of life and commonly experience spontaneous regression of skin lesions [5–8], to a more aggressive variant with extracutaneous involvement (systemic mastocytosis, SM) that may be associated with multiorgan dysfunction/failure and shortened survival, that is, generally seen in adult patients (Fig. 1) [9]. The WHO document distinguishes the usually KIT-mutated SM from a Philadelphia chromosome-negative MPN with hematological features of chronic eosinophilic leukemia associated with splenomegaly, marked elevation of serum vitamin B12, elevation of serum tryptase and increased bone marrow (BM) MC commonly in scattered or noncohesive clusters [10]. The latter entity is commonly associated with rearrangement of PDGFRA (i.e., FIP1L1-PDGFR) and less commonly, PDGFRB (e.g., PRKG2-PDGFRB), and is sensitive to treatment with imatinib [11–18]. WHOdefined SM is sometimes associated with a clonally related second myeloid neoplasm [19–22], which is not surprising considering its origin as a stem cell disease with multilineage clonal involvement [23–25]. Conversely, an otherwise well-defined myeloid malignancy, such as myelodysplastic syndrome (MDS) or a non-mast cell disease MPN, might also harbor neoplastic mast cells [26]. Mastocytosis is frequently associated with somatic gain-of-function point mutations within KIT. KIT (CD117) is a Type III receptor tyrosine kinase that is expressed by MC, hematopoietic progenitor cells, germ cells, melanocytes, and interstitial cells of Cajal in the gastrointestinal tract
Additional Supporting Information may be found in the online version of this article. 1
Division of Hematology, Mayo Clinic, Rochester, Minnesota; 2Department of Medicine, Mayo Clinic, Rochester, Minnesota
Conflict of interest: Nothing to report *Correspondence to: Animesh Pardanani, MBBS, PhD, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. E-mail: [email protected] Received for publication: 23 December 2014; Accepted: 24 December 2014 Am. J. Hematol. 90:251–262, 2015. Published online: in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23931 C 2015 Wiley Periodicals, Inc. V
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Figure 1. Clinical spectrum of patients with clonal mast cell disorders. Please refer to Tables I and II for the WHO classification of mastocytosis. “Prediagnostic” SM refers to an abnormal clonal BM mast cell infiltrate that falls short of the diagnostic threshold for SM (generally satisfies 1–2 minor criteria only). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Figure 2. Diagnostic algorithm for SM.
and is therefore functionally relevant for normal mast cell development, hematopoiesis, gametogenesis, melanogenesis, and regulation of slow gastric waves [27]. KIT expression is down regulated upon differentiation of hematopoietic progenitors into mature cells of all lineages, except mast cells, which retain high levels of cell surface KIT expression. The interaction between KIT and its ligand, stem cell factor, plays a key role in regulating mast cell proliferation, maturation, adhesion, chemotaxis, and survival [28]. Gain-of-function somatic mutations in the KIT tyrosine kinase domain, particularly the D816V mutation, have been found to occur 252
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in a majority of cases of adult SM, irrespective of WHO SM subtype [9,29]. Other less common (25% of the mast cells in the infiltrate are spindle-shaped or have atypical morphology or, of all mast cells in BM aspirate smears, >25% are immature or atypical b. Detection of an activating point mutation at codon 816 of KIT in BM, blood or other extracutaneous organ c. Mast cells in BM, blood or other extracutaneous organ express CD2 and/or CD25 in addition to normal mast cell markersa d. Serum total tryptase persistently exceeds 20 ng/mL (unless there is an associated clonal myeloid disorder, in which case this parameter is not valid) “B” findings 1. BM biopsy showing >30% infiltration by MC (focal, dense aggregates) and/or serum total tryptase level >200 ng/mL 2. Signs of dysplasia or myeloproliferation, in non-MC lineage(s), but insufficient criteria for definitive diagnosis of a hematopoietic neoplasm (AHNMD), with normal or slightly abnormal blood counts. 3. Hepatomegaly without impairment of liver function, and/or palpable splenomegaly without hypersplenism, and/or lymphadenopathy on palpation or imaging. “C” findings 1. BM dysfunction manifested by one or more cytopenia(s) (ANC MPN, AML > lymphoid neoplasms) [67]. Attempts at validating the WHO diagnostic criteria reveal that 20% of ISM patients lack mast cell clusters in the BM and 30% exhibit a serum tryptase level lower than 20 ng/mL [68]. In contrast, the sensitivity for detecting morphologic atypia, aberrant CD25 and/ or CD2 expression, or KITD816V in BM mast cells exceeds 90% when sensitive assays are used, thereby illustrating the increasing importance of these specific minor criteria in diagnosing SM [68,69]. Patients who have mast cell degranulation symptoms with clonal mast cells (i.e., mutated KIT gene and/or CD25 expression), but who do not meet criteria for SM (only 1 or 2 minor criteria satisfied, and no skin involvement), may have “prediagnostic ISM” or “monoclonal mast cell activation syndrome” (Fig. 3); these patients generally have normal or slightly elevated baseline serum tryptase level [70]. While the clinical characteristics of this entity may be indistinguishable from ISM, its true natural history remains to be defined. Rare SM cases may exhibit a well-differentiated phenotype (i.e., relatively normal BM MC morphology; absence of aberrant MC CD25/CD2 expression); these cases are associated with non-D816V KIT mutations (e.g., germline F522C or somatic I817V) and, in the case of KITF522C-associated SM, has been shown to be sensitive to imatinib therapy [29,45]. In the presence of blood eosinophilia, screening for FIP1L1PDGFRA, using either FISH or RT-PCR, is warranted [16]. In contrast, conventional cytogenetics analysis generally permits identification of cases of BMM associated with a PDGFRB rearrangement (i.e., chromosomal translocations involving 5q31-32) [18]. These cases with PDGFRA/PDGFRB-rearranged MPN with BM MC hyperplasia are appropriately classified as “Myeloid or lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1” per the WHO classification [10].
䊏 Risk Stratification This section focuses on adult SM patients; their life expectancy, when considered as a group, appears to be shorter as compared to doi:10.1002/ajh.23931
age- and gender-matched controls, with the excess deaths in this group occurring within the first 3–5 years after diagnosis (Fig. 4A) [9,71]. The categorization of adult SM patients per the 2008 WHO classification system remains the most practical first step in risk stratifying newly diagnosed patients [1]. The WHO classification recognizes seven mastocytosis categories (Table I) SM is subclassified into four subcategories: ISM (no evidence of extracutaneous organ dysfunction), ASM (presence of extracutaneous organ dysfunction), SM associated with another clonal hematological non-MC lineage disease (SM-AHNMD), and MCL. A recent study of 342 adult patients has validated the prognostic value of the WHO classification for SM [9].
Indolent SM It comprised the largest subgroup (n 5 159; 46%) [9]. Compared with patients with ASM and SM-AHNMD, ISM patients were significantly younger at presentation (median age 49 years) and had a higher prevalence (66–75%) of UP-like skin lesions, MCMRS and gastrointestinal symptoms; ISM patients were significantly less likely however to exhibit constitutional symptoms or hepatosplenomegaly ( val in microdissected pooled single mast cells and leukemic cells in a patient with systemic mastocytosis and concomitant chronic myelomonocytic leukemia. Leuk Res 2002;26:979–984. 21. Travis WD, Li CY, Yam LT, et al. Significance of systemic mast cell disease with associated hematologic disorders. Cancer 1988;62:965–972.
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