Lim, Ken‐Hong

Abstract Background: Current therapy in adult systemic mastocytosis (SM) includes observation alone, topical therapy for cutaneous disease, symptomatic non-cytoreductive therapy and cytoreductive therapy. The latter involves several drugs whose individual merit in the treatment of SM has not been well characterized. Patients and Methods: Diagnosis of SM was according to the 2001 WHO criteria (World Health Organization Classification of Tumours of Hematopoietic and Lymphoid Tissues, p 1–351. Lyon, France: IARC Press; 2001). Response to cytoreductive therapy was assessed by consensus criteria (Eur J Clin Invest.2007;37:435). The study population was selected from a series of 342 adult SM patients referred to our institution and seen between 1964 and 2008. KITD816V mutation analysis was performed by DNA sequencing. Results: A total of 134 study patients received treatment that included at least one cytoreductive drug as either first-line (n=105) or second-line (n=29) therapy. Interferon-alpha with or without prednisone (n=58), hydroxyurea (n=43), imatinib mesylate (n=42) and 2-chlorodeoxyadenosine (n=26) were the most frequently used cytoreductive agents accounting for 120 of the 134 study cases; the remaining 14 patients received other cytoreductive drugs, none of which were effective. i. Interferon-alfa (IFN-a) with or without prednisone IFN-a with or without prednisone (24 and 34 patients, respectively) was given to 12 patients with indolent SM (ISM), 14 aggressive SM (ASM), and 32 SM with associated clonal hematological non-mast cell lineage disease (SM-AHNMD). For all 58 patients receiving therapy, complete (CR), major (MR), and partial (PR) response/regression were achieved in 3, 7, and 14 patients, respectively, for an overall response rate (ORR) of 41%. ORR in ISM, ASM, and SM-AHNMD was 50%, 43%, and 38%, respectively. Median duration of response was 12 months (range, 1–117 months). Anemia and elevated ESR were significantly associated with inferior ORR; 29% vs. 56% (p=0.04) and 14% vs. 57% (p=0.01), respectively. BM detection of KITD816V did not appear to affect response rates (p=0.4). ii. Hydroxyurea (HU) HU was given to 2 ASM, 40 SM-AHNMD and 1 mast cell leukemia (MCL) patients. The drug was used as first-line therapy in 30 patients. MR and PR were achieved in 1 and 8 SM-AHNMD patients, respectively (ORR=21%). Median duration of response was 37 months (range, 5–84 months). iii. Imatinib mesylate (IM) in patients with SM and associated eosinophilia IM was given to 22 SM patients who had associated eosinophilia (SM-eos): 2 had ISM, 2 ASM, and 18 SM-AHNMD. The drug was used as first-line therapy in 9 patients. Ten of the 22 patients with SM-eos were known to harbor the FIP1L1-PDGFRA fusion mutation and all responded to IM (ORR=100%). None of 5 FIP1L1-PDGFRA-negative SM-eos patients had a response to IM. In the remaining 7 patients with unknown mutation status, 4 patients had a response to IM (1 CR, 1 MR, and 2 PR). iv. IM in patients with SM not associated with eosinophilia IM was administered to 20 SM patients without associated eosinophilia (7 ISM, 2 ASM, 10 SM-AHNMD, and 1 MCL). Response was documented in 4 (20%) patients (1 CR, 1 MR, and 2 PR) including 1 with ISM, 2 with ASM and 1 with SM-AHNMD. Median duration of response was 19.5 months (range, 9–69 months). Two patients developed interstitial pneumonitis. v. 2-Chlorodeoxyadenosine (2-CdA) 2-CdA was given to 10 ISM, 3 ASM, and 13 SM-AHNMD patients; the drug was used as first-line therapy in 8 patients. CR, MR and PR were achieved in 1, 7, and 4 patients, respectively (ORR=46%). ORR in ISM, ASM, and SM-AHNMD was 50%, 33%, and 46%, respectively. Median duration of response was 11 months (range, 3–74 months). Presence of leukocytosis (WBC > 10 x 109/L), monocytosis (absolute monocyte count > 0.9 x 109/L) or circulating immature myeloid cells was significantly associated with inferior response; 13% vs. 61% (p=0.02); 11% vs. 69% (p=0.006) and 0% vs. 71%, (p=0.001), respectively. Response was not affected by BM detection of KITD816V (p=1.0). Conclusions: Both IFN-a and 2-CdA are reasonable treatment options, with comparable efficacy, for symptomatic SM including the subcategories of ISM, ASM and SM-AHNMD. IFN-a response was significantly better in the absence of anemia or elevated ESR. 2-CdA response was similarly better in the absence of leukocytosis, monocytosis or circulating immature myeloid cells. The therapeutic value of IM was limited to FIP1L1-PDGFRA-positive disease.

Abstract Background: Systemic mastocytosis (SM) has a varied presentation ranging from indolent forms with limited morbidity over many years to the rapidly fatal mast cell leukemia (MCL). This heterogeneity complicates clinical decision making regarding choice and timing of therapy. The aim of this study was to evaluate the prognostic value of the 2001 World Health Organization (WHO) classification of SM, and to refine risk stratification within SM sub-groups to facilitate clinical decision making. Information on KITD816V and JAK2V617F mutation analysis and clinical correlates is also provided. Methods: Patient records in the institutional electronic database from January 1976 to October 2007 were reviewed and SM patients 18 years of age or older identified; the date of diagnosis ranged from July 1964 to October 2007. Only those patients where diagnosis was confirmed by bone marrow (BM) histology were included in the analysis. KITD816V mutation analysis was performed by DNA sequencing. JAK2V617F was screened by allele-specific quantitative PCR analysis. Results: i. Clinical characteristics at presentation: A total of 342 SM patients were identified (154 female; median age at diagnosis=57 years; range 19 to 87 years). Per the 2001 WHO classification, 159 had indolent SM (ISM; median age=49 years), 41 aggressive SM (ASM; median age=65 years), 138 SM with associated clonal hematological non-mast cell lineage disease (SM-AHNMD; median age=65 years), and 4 MCL (median age=55 years) (p-value for age <0.0001). 140 (41%) patients had urticaria pigmentosa (UP) (63% with ISM; p<0.0001), 160 (47%) mast cell (MC) mediator release symptoms (69% with ISM; p<0.0001), 107 (31%) skeletal symptoms, and 142 (42%) constitutional symptoms (61% with ASM/SM-AHNMD versus 19% with ISM; p<0.0001). 123 patients (36%) had palpable splenomegaly (57% with SM-AHNMD; p<0.0001). 56 patients (16%) exhibited prominent eosinophilia (absolute eosinophil count >1500/mcl) – 31% and 22% with SM-AHNMD and ASM, respectively, versus 3% with ISM (p<0.0001); 12 of 23 patients (52%) with eosinophilia who were tested carried the FIP1L1-PDGFRA mutation. Serum tryptase (normal <11.5 ng/mL) was measured in 160 patients (47%) and almost all (96%) had an elevated level (median=64 ng/mL; range=4 to 2000 ng/mL; 33 patients had >200 ng/mL). ii. Disease course and prognostic factors After a median follow-up of 20.7 months (range=0–417), 153 deaths were recorded. 17 patients (5%) transformed to acute myeloid leukemia (AML; n=14) or MCL (n=3), most frequently with SM-AHNMD (11% versus 0% for ISM; p<0.0001). The median overall survival was 63 months (ISM=198 months, ASM=41 months; SM-AHNMD=24 months, and MCL=2 months; p<0.0001). Multivariate analysis of parameters at the time of diagnosis showed a significant and independent association between inferior survival and WHO sub-type (p<0.0001), age at diagnosis (p<0.0001), history of weight loss (p=0.01), anemia (p=0.007), thrombocytopenia (p=0.0008), hypoalbuminemia (p=0.0008), and excess BM blasts (>5%; p=0.004). A similar analysis in ISM identified anemia (p=0.04), hypoalbuminemia (P=0.002), and BM MC ≥ 30% (p=0.03) as independent predictors of inferior survival; the corresponding parameters in ASM were age at diagnosis (p=0.002) and history of weight loss (p=0.003). iii)KITD816V andJAK2V617F analysis Archived bone marrow was available in 165 patients for KITD816V and JAK2V617F analysis. By DNA sequencing, overall KITD816V detection rate was 28%: ISM 20%, ASM 29%, SM-AHNMD 33% (p=0.4). In patients with ASM (p=0.003) and SM-AHNMD (p=0.001), detection of KITD816V was associated with inferior survival. Greater than 1% (range 1–57) JAK2V617F allele burden was detected in 6 patients (4%); all belonged to SM-AHNMD including 4 with non-MC lineage myeloproliferative neoplasm. Conclusions: The current study confirms the prognostic value of the WHO subclassification of SM and identifies advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess BM blasts as additional adverse prognostic factors. In ISM, presence of anemia, hypoalbuminemia, or BM MC ≥ 30% is associated with inferior survival. In ASM and SM-AHNMD, BM KITD816V allele burden might influence survival. JAK2V617F is rare in SM and when found, it is almost always in the context of SM-AHNMD.

Abstract Background: Systemic mastocytosis (SM) sometimes coexists with an associated clonal hematological non mast cell lineage disease and such an occurrence is recognized by the 2001 World Health organization (WHO) classification system as SM-AHNMD (Leuk Res. 2001 25:603). However, SM-AHNMD has not been further stratified into prognostically relevant subgroups. This was the major objective of the current study, which also provides information on prevalence and relevance of detecting KITD816V and JAK2V617F mutations. Methods: Patient records in the institutional electronic database from January 1976 to October 2007 were reviewed and SM patients 18 years of age or older identified; the date of diagnosis ranged from July 1964 to October 2007. Only those cases where diagnosis was confirmed by bone marrow (BM) histology were included in the analysis. SM- and AHNMD-components were classified according to WHO criteria. Results: AHNMD sub-classification: Of 342 consecutive cases of SM that were screened, 138 (40%) were identified as having SM-AHNMD (median age 65 years, range 20–87). The most frequent AHNMD was chronic myelomonocytic leukemia (SM-CMML) seen in 38 (28%) patients. 23 (17%) patients had SM associated with myelodysplastic syndrome (SM-MDS), 22 (16%) with hypereosinophilic syndrome/chronic eosinophilic leukemia (SM-HES/CEL) and 33 (24%) with another myeloproliferative neoplasm (SM-MPN). The number of cases with other SM-AHNMD was much lower and included lymphoma 8 (6%), acute leukemia 3 (2%), MDS/MPN 3 (2%), and 8 (6%) cases of multiple myeloma, primary amyloidosis or chronic lymphocytic leukemia. Of the 33 SM-MPN patients, 2 had polycythemia vera, 6 essential thrombocythemia, and 2 myelofibrosis; the remaining 23 patients had an unclassified MPN in association with SM. Clinical characteristics at presentation: The combined incidence of urticaria pigmentosa (UP) was 18%, mast cell mediator release symptoms 28% and constitutional symptoms 62%. 76 patients (57%) had palpable splenomegaly. 99 patients (72%) had anemia, 18 (13%) leukopenia (43% with SM-MDS; p<0.0001) and 76 (55%) thrombocytopenia. 70 (51%) patients had leukocytosis and 63 (55%) displayed circulating immature myeloid cells (78% with CMML; p=0.001). 59 (54%) patients had elevated serum alkaline phosphatase level: SM-CMML 70%, SM-MPN 60%, SM-HES/CEL 40%, and SM-MDS 30% (p=0.01). Where evaluated, serum tryptase was elevated in 92% of the patients (median=75 ng/mL; range=4–1360). BM blasts were ≥5% in 25 patients (22%), including 48% with SM-MDS (p=0.004). 12 of 35 patients tested carried the FIP1L1-PDGFRA mutation (all had SM-HES/CEL; p<0.0001). Disease course and prognostic factors At a median follow up of 15 months (range 0–182), 99 deaths were recorded and the combined median survival was 24 months: SM-CMML 15 months; SM-MDS 15 months, SM-MPN 30 months; and SM-HES/CEL 87 months (p=0.003). Fifteen patients (11%) transformed to acute leukemia or mast cell leukemia. Multivariate analysis of parameters at the time of diagnosis showed a significant and independent association between inferior survival and SM-AHNMD sub-type (p=0.007), presence of constitutional symptoms (p=0.04), thrombocytopenia (p=0.01), presence of circulating immature myeloid cells (p=0.006), and hypoalbuminemia (p<0.0001). In SM-CMML, hypoalbuminemia was associated with inferior survival (p=0.03). KIT D816V and JAK2 V617F analysis: Archived BM was available in 88 patients for KITD816V and JAK2V617F analysis. By DNA sequencing, overall KITD816V detection rate was 33%: SM-CMML 48%, SM-MDS 21%, SM-HES 8%, and SM-MPN 45% (p=0.03). In patients with SM-HES/CEL (p=0.0009) and SM-MPN (p=0.04), detection of KITD816V was associated with inferior survival. Greater than 1% (range 5–57) JAK2V617F allele burden was detected in 6 patients (9%): 4 in SM-MPN, 1 in SM-CMML and 1 in SM-MDS. Conclusions: The WHO-defined SM-AHNMD comprises prognostically diverse subcategories among which SM-CMML is the most frequent. Survival is favorable in SM-HES/CEL and significantly worse in SM-CMML and SM-MDS. Additional independent predictors of inferior survival include constitutional symptoms, thrombocytopenia, circulating immature myeloid cells, and hypoalbuminemia. In SM-HES/CEL and SM-MPN, BM KITD816V allele burden may influence survival. JAK2V617F occurs infrequently in SM-AHNMD and when it does, it clusters with SM-MPN.

Abstract Abstract 3903 Poster Board III-839 Background A peripheral blood (PB) absolute eosinophil count (AEC) of ≥ 1.5 × 109/L is operationally referred to as “hypereosinophilia”. In general, one can classify hypereosinophilia into 3 major categories: i) secondary, ii) clonal, and iii) idiopathic. The 2008 WHO proposal provides a modern-era framework for the classification of clonal eosinophilia and subcategories include (i) myeloid/lymphoid neoplasms associated with eosinophilia and PDGFRA-, PDGFRB-, or FGFR1-rearrangement; (ii) clonal eosinophilia associated with an otherwise WHO-defined myeloid malignancy such as systemic mastocytosis (MN-eo), and (iii) chronic eosinophilic leukemia, otherwise not specified (CEL-NOS). Idiopathic hypereosinophilia (IH) with organ damage and without clonal/abnormal lymphocytes is referred to as hypereosinophilic syndrome (HES). In the current study, we define the spectrum of disease phenotypes and survival in 357 consecutive patients with hypereosinophilia seen at a single institution. Methods Mayo Clinic patient records from January 1994 to October 2008 were reviewed, and those with persistent eosinophilia ≥1.5 × 109/L identified. Clinical data and bone marrow (BM) histology were reviewed, and the eosinophilic disorder classified as above. The aims of the current study were to: (i) study the spectrum of eosinophilic disorders within the context of the WHO proposal; (ii) describe the clinical, laboratory, and molecular/cytogenetic characteristics of patients with primary eosinophilia (i.e. clonal and idiopathic); and (iii) assess the prognostic relevance of the WHO proposal from the standpoint of life expectancy and risk of leukemic transformation. Results (i) Disease spectrum and clinical characteristics: A total of 357 cases (median age=52 years) were identified: (i) secondary eosinophilia 165 (46%; male ∼52%) (autoimmune 33%, non-myeloid malignancy 19%, drugs 12%, allergies 10%, parasitosis 2%, others 24%); (ii) PDGFRA- or PDGFRB-rearranged myeloid neoplasm 17 (5%; male 100%); (iii) CEL-NOS 6 (2%; male 67%); (iv) MN/eo 36 (10%; male 69%) (systemic mastocytosis 50%, chronic myeloproliferative neoplasm 33%, AML 6%, others 11%); (v) IH 115 (32%; male 58%); and (vi) eosinophilia associated with clonal/abnormal lymphocytes 14 (4%; male 57%). Of the 115 patients with IH, 72 (63%) had evidence of end-organ damage, and could be classified as having HES: 36 patients had 1 organ involved, 21 had 2, and 15 had 3-4. In HES patients, the major organs involved were: lung 23%, skin/mucosa 22%, cardiac 14%, nervous system 10%, and thrombosis 9%. (ii) Molecular and cytogenetic abnormalities: Complete karyotype information was available for 144 (77%) patients; 21 (15%) patients had an abnormal karyotype; MN/eo 12 (35%), PDGFRA- or PDGFRB-rearranged myeloid neoplasm 4 (31%), CEL-NOS 5 (83%), IH and eosinophilia associated with clonal/abnormal lymphocytes 0 (p<0.01). Of the 126 (67%) patients screened for FIP1L1-PDGFRA, 16 (13%) tested positive. Two patients (1%) harbored t(5;12). Of the 108 (57%) patients screened for presence of an occult T-cell clone (PCR for TCR gene rearrangement), 14 (13%) tested positive. (iii) Survival and risk of disease transformation: At a median follow of 21 months (range <1-174), 56 (30%) deaths were recorded; MN/eo 23 (64%), IH 25 (22%), PDGFRA- or PDGFRB-rearranged myeloid neoplasm 3 (18%), CEL-NOS 3 (50%), and T-cell/eo 2 (14%). The combined median survival was 95 months: MN/eo 34 months, CEL-NOS 13 months, IH 151 months, PDGFRA- or PDGFRB-rearranged myeloid neoplasm and eosinophilia associated with an abnormal lymphocyte clone (not reached) (p<0.01; Figure). Transformation to acute leukemia was seen in 4 patients (2 with PDGFRA- or PDGFRB-rearranged myeloid neoplasm, and 1 each with CEL-NOS and IH) (p<0.01). Conclusions In a major tertiary center in the United States, the two major causes of hypereosinophilia were secondary (46%) and idiopathic (32%). Regarding the former, autoimmune diseases and parasitic infections were the most and least frequent causes, respectively. Cases with clonal eosinophilia were predominantly male while the sex ratio was more balanced in the other subcategories. Among primary hypereosinophilia, survival was the worst in clonal eosinophilia not associated with the imatinib-sensitive PDGFR mutations. Additional data regarding clinical characteristics, laboratory findings, and treatment outcome of idiopathic hypereosinophilia patients will be presented at the meeting. Disclosures: Pardanani: TargeGen: Research Funding; Cytopia: Research Funding.

Abstract Abstract 2906 Poster Board II-882 Background: The World Health Organization (WHO) classification system recognizes indolent SM (ISM) as an entity characterized by low systemic mast cell (MC) burden but frequent skin involvement. The WHO system also recognizes 2 provisional ISM sub-variants: smoldering SM (SSM) and bone marrow (BM) mastocytosis (BMM). The two are respectively characterized by increased systemic MC burden (presence of ≥ 2 ‘B-findings') and BM MC infiltration in the absence of skin or multiorgan visceral lesions. The prognostic relevance of this sub-classification remains unclear. Methods: The study population was drawn from a larger cohort of 342 adult SM patients (Blood. 2009 Jun 4;113(23):5727). Clinical data and BM histology were reviewed, and the diagnosis of ISM and its subclassification confirmed per the 2008 WHO proposal. The primary objectives of the study were to: (i) describe the clinical characteristics of a large cohort of ISM patients, within the context of the WHO classification; (ii) evaluate the prevalence of molecular and cytogenetic abnormalities; (iii) evaluate whether ISM subclassification is prognostically relevant on the basis of survival and risk of transformation to acute leukemia or aggressive SM (ASM). Results: (i) Clinical characteristics: 159 ISM patients were evaluated (69 males; median age 49 years, range 19-84); 22 (14%) had SSM, 36 (23%) BMM, and 101 (63%) ‘ISM-other' (ISMo). By definition, ‘B-findings' were absent in BMM patients. ‘B-findings' in SSM (and ISMo) patients was as follows: hepatosplenomegaly and/or lymphadenopathy 91% (21%), BM MC >30% or serum tryptase level >200ng/mL 68% (8%), and hypercellular BM or dysmyelopoiesis without cytopenias 50% (2%). SSM patients were older (p<0.01) and more frequently displayed constitutional symptoms (p<0.01), and anemia (p<0.01). MC mediator-release symptoms (p=0.01), including anaphylaxis (p<0.01), were more frequent in BMM. The following MC-mediators were studied: serum tryptase (57%), beta prostaglandin F2alpha (45%), urine methylhistamine (32%), and urine histamine (21%) – significant differences were noted amongst the ISM subgroups with the following relationship: SSM>ISMo>BMM (p<0.01). (ii) Molecular and cytogenetic abnormalities: Complete karyotype information was available for 55 patients; only 1 patient (with ISMo) had an abnormal karyotype. Fifty nine patients were screened for KITD816V and JAK2V617F; JAK2V617F was universally absent, and distribution of KITD816V was not significantly different amongst the ISM subgroups: SSM (100%), BMM (92%), and ISMo (69%). (iii) Survival and risk of disease transformation: At a median follow of 27 months (range <1-417), 26 deaths were recorded (ISMo 14, SSM 10, and BMM 2), and the combined median survival was 198 months: ISMo 301 months, SSM 120 months, and BMM (not reached) (p<0.01; Figure). Transformation to acute leukemia and ASM was seen in 1 patient (SSM) and 3 patients (2 SSM and 1 ISMo), respectively. Conclusions: Among WHO-defined ISM patients, SSM is associated with significantly shorter survival whereas BMM and ISMo are prognostically similar. If these observations are confirmed by others, consideration may be given to classifying SSM as a distinct subcategory of SM, instead of a sub-variant of ISM as it currently stands. Disclosures: No relevant conflicts of interest to declare.

Abstract The prognostic heterogeneity of the World Health Organization category of “systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease” (SM-AHNMD) has not been systematically validated by primary data. Among 138 consecutive cases with SM-AHNMD, 123 (89%) had associated myeloid neoplasm: 55 (45%) myeloproliferative neoplasm (SM-MPN), 36 (29%) chronic myelomonocytic leukemia, 28 (23%) myelodysplastic syndrome (SM-MDS), and 4 (3%) acute leukemia. Of the myeloid subgroups, SM-MPN displayed a 2- to 3-fold better life expectancy (P = .003), whereas leukemic transformation was more frequent in SM-MDS (29%; P = .02). The presence of eosinophilia, although prevalent (34%), was prognostically neutral, and the overall results were not affected by exclusion of FIP1L1-PDGFRA-positive cases. We conclude that it is clinically more useful to consider specific entities, such as SM-MPN, systemic mastocytosis with chronic myelomonocytic leukemia, SM-MDS, and systemic mastocytosis with-acute leukemia, rather than their broad reference as SM-AHNMD.

Abstract Clinical phenotype in systemic mastocytosis (SM) is markedly variable, which complicates prognostication and decision making regarding the choice and timing of therapy. In a retrospective study of 342 consecutive adult patients with SM seen at the Mayo Clinic between 1976 and 2007, disease subdesignation according to the World Health Organization (WHO) proposal was indolent (ISM) in 159 (46%), with associated clonal hematologic non–mast cell lineage disease (SM-AHNMD) in 138 (40%), aggressive (ASM) in 41 (12%), and mast cell leukemia in 4 (1%). KITD816V was detected in bone marrow–derived DNA by allele-specific polymerase chain reaction (PCR) in 68% of 165 patients evaluated (ISM, 78%; ASM, 82%; SM-AHNMD, 60%; P = .03); JAK2V617F was detected in 4%, all in SM-AHNMD. Compared with those with nonindolent SM, life expectancy in ISM was superior and not significantly different from that of the age- and sex-matched US population. In addition, multivariable analysis identified advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts as independent adverse prognostic factors for survival. The current study validates the prognostic relevance of the WHO subclassification of SM and provides additional information of value in terms of both risk stratification and interpretation of clinical presentation and laboratory results.