Jackson, Amie E.

Abstract Background Familial myeloid neoplasms are rare causes of myeloid malignancies. Over the last few years germline mutations involving RUNX1, JAK2, GATA1, GATA2 and CEBPA genes have been associated with myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). We carried out this study to describe the spectrum of familial myeloid neoplasms seen at our institution. Methods After due IRB approval, the myeloid neoplasms data base (1990-2012) at the Mayo Clinic in Minnesota was queried for patients presenting with, or having a strong family history of myeloid neoplasms. Selective sequencing of germline DNA was done in appropriate patients. Germline mutations that were screened for included; RUNX1, JAK2, GATA1, GATA2 and CEBPA. In one family with none of the aforementioned gene mutations, exome sequencing was performed. Families with chromosomal breakage and primary telomere disorders were excluded. All patients had bone marrow and cytogenetic studies at diagnosis. Results We identified six families with familial myeloid neoplasms (table one). There were two with germline GATA2 mutations (no.1 and 2); one with a novel c1339A>C, pS447R, non-zinc finger gene abnormality. In this family nine members have developed MDS/AML. All members had profound B/NK cell deficiency, viral warts and one member had primary lymphedema (Embergers syndrome). Three of the 6 seen at the clinic have successfully undergone allo- SCT. The second GATA2 mutated family had a less extensive history of myeloid neoplasms. There was one patient (no.5) who presented with long standing thrombocytopenia, clinically diagnosed as ITP. She eventually developed MDS with trisomy 8. She had three first degree relatives with myeloid neoplasms. Germline sequencing identified a RUNX1 mutation. Platelet electron microscopy identified characteristic ultrastructural changes. There was one family (no.4) with a germline JAK2V617F mutation. The propositus was diagnosed to have primary myelofibrosis and then demonstrated clonal evolution to a concomitant BCR-ABL1 p190 driven chronic myeloid leukemia. His sister and mother have essential thrombocytosis (ET) and his brother has a detectable JAK2 mutation (no evidence for disease). The patient has successfully undergone an allo-SCT. The patient with a GATA1 mutation (no.3) presented with congenital anemia and had craniofacial anomaly, atrial septal defect and developmental delays. Red cell and platelet ultrastructural abnormalities lead to the diagnosis with an additional family member having chronic anemia and suspected MDS. One family (no.6) presented with seven first degree relatives affected by MDS/AML. Germline sequencing for the aforementioned genes was negative. Exome sequencing has been performed and results should be available at the time of the meeting. The prepositus has successfully undergone allo-SCT. Conclusion Familial myeloid neoplasms are uncommon but warrant early recognition. Clues to diagnosis include strong family history, associated primary immunodeficiency states, morphological/skeletal abnormalities and platelet ultrastructural defects (RUNX1, GATA2, and GATA1). Exome and whole genome sequencing is an exciting prospect for further discoveries. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Haploinsufficiency of GATA2 results in familial immunodeficiency and MDS/ AML. We identified a family with a novel c1339A>C, pS447R germline GATA2 mutation. Unlike most other disease-causing GATA2 mutations, this mutation occurred in the non-zinc finger domain. Methods: After due IRB approval, clinical and laboratory data were retrospectively abstracted. Results: Seven family members with the mutation are being followed at our institution. (Table 1), of whom two have MDS, one MDS/AML and one with isolated neutropenia. At the time of diagnosis 5/7(71%) pt had decreased monocyte count. 4/7(57%) patients had decreased NK cell count and/or function. Only 1/7(14%) patient had decreased CD4 count. 3/7(42%) patients had reduced B cell numbers and 5/7(71%) patients had persistent HPV warts. Other infections include invasive Absidia sinusitis, infectious mononucleosis, pertussis, and blood stream infections with S. maltophilia and S.aureus. One patient had the Emberger's syndrome presenting with lymphedema and congenital pulmonary stenosis. Pulmonary manifestation included a patient each with decreased DCLO and hyperreactive airway disease. Genitourinary manifestations included pelvic kidney/dysplastic kidney, posterior urethral valve, dermoid cyst and hydrocele. Two female patients developed primary infertility. One patient had a history of appendicular carcinoid. 4/7(57%) patients have successfully undergone allogenic stem-cell transplantation. Conclusion: Germline GATA2 mutations are associated with a high frequency of MDS/AML. We describe a family with a non-zinc finger GATA2 mutation causing MDS/AML, with a spectrum of hematological and non-hematological manifestations, once again, highlighting the heterogeneity of this syndrome and expanding the genotype-phenotype correlation in this disease. Abstract 5614. Table#Age/sexHemDAbso . MonoCount Abso. CD4 TCellNK cyto-toxicityAbso. NK CountAbso.B cell CountInfectiousDermCoag/VascularCVS/LungOthersNo.137/MAMLSeverely DecreasedNormalAbsentSeverely DecreasedAbsentAbsidia S.maltop- hilia S.aureusHPV WartsITP -Hydrocele 10 hyperparathyroidismNo.231/FMDSDecreasedNormalAbsentDecreasedNormalInfectious MonoHPV Warts-Hyper- reactive airwayInfertilityNo.317/FMDSSeverely DecreasedNormalUnknownDecreasedDecreasedHerpes stomatitisHPV Warts-Dec-DCLOPosterior urethral valveNo.49/MNeutropeniaSeverely DecreasedNormalNormalNormalNormalHSV-1HPV Warts Embergers syndrome Pul. Stenosis Congenital dysplastic Rt. Kidney Pelvic Lt. KidneyNo.531/F-DecreasedNormalDecreasedNormalNormal- -Qualitative platelet defectNoneInfertilityNo.635/F-NormalNormalDecreasedDecreasedDecreasedPertussisHPV Warts--Dermoid appendicular carcinoid No.756/F-NormalNormalNormalNormalNormalFrequent PNA---- Disclosures No relevant conflicts of interest to declare.

Abstract Background: The salivary gland is one of the most common sites of involvement by non-gastric extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). This multicenter, international trial sought to characterize the clinical course, treatment and outcome of patients with salivary gland MALT lymphoma. Methods: Patients were identified from multiple international sites including the Mayo Clinic Lymphoma Database (n=89), three International Extranodal Lymphoma Study Group (IELSG) cohorts (n=138), and the University of Athens (n=21). All patients had biopsy-confirmed MALT lymphoma of the salivary gland by WHO criteria. Clinical characteristics, treatment, and outcomes were obtained from the respective patient databases. Survival probability was estimated using the Kaplan-Meier method and compared between groups with the Wilcoxon or log-rank. The impact of variables on survival was assessed by the Cox proportional hazards model. Results: Patients and clinical features: From 1983 to 2012, 247 patients with MALT lymphoma were included. Clinical characteristics are shown in Table 1. The median age at diagnosis was 59, and the male-to-female ratio was 1:3. The majority of patients (76%) presented with limited stage disease, and the parotid gland was the most common site of involvement (78%). There was a history of antecedent autoimmune disease in 41% of patients, and Sjögren’s disease was the most common (83%). Treatment: Information on initial treatment was available on 242 patients. 137/242 patients (57%) initially received local therapy with either surgery (n=81), radiation (n=26), or both (n=30). Of these, 25 received adjuvant systemic therapy. 90/242 patients (37%) were treated initially with systemic therapy, of whom 54% had localized and 46% had stage IV disease. Rituximab was used alone (n=16) or in combination with chemotherapy (n=26) in 42 of the 90. 15/242 patients (6%) were initially observed. Survival: The median OS for all patients was 18.3 years. PFS following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first line for all patients, or for those with stage I or II disease. On univariate analysis age <60, stage, IPI, normal LDH, the presence of Sjögren’s disease, and treatment with rituximab were associated with improved overall survival. Age <60, low to intermediate IPI and normal LDH were associated with improved PFS. On multivariate analysis, age<60, and IPI were associated with improved OS and PFS and Sjögren’s disease was associated with improved OS. Relapse/progression: The site of progression was known in 51 of 76 patients who progressed. 15 (29%) patients progressed in the same salivary gland or regional nodes; in 16 (21%) recurrence involved the contralateral salivary gland; 20 (31%) had distant progression. Relapse histology was identified in 30. The most common pathology at relapse was MALT (n=28), with one patient progressing to diffuse large B-cell lymphoma. A second patient developed a mantle cell lymphoma. Conclusions: Salivary gland MALT lymphoma commonly presents at an early stage, and has a favorable prognosis with a median OS of 18 years. Surgical or radiation therapy does not appear to have benefit over systemic therapy. Patients with Sjögren’s disease appear to have a better survival. The role of rituximab and optimal first-line therapy should be evaluated further in prospective trials. Table 1: Characteristics of 247 patients with salivary MALT Characteristic N (%) Age, median; range 59; 18-93 Sex, Male: Female 62: 185 (25: 75) Primary site of involvement Parotid 193 (78) Submandibular 12 (5) Other/not specified 42 (17) Extent (unilateral: bilateral) 89:21 Missing data 137 Autoimmune disorder* 101(41) Sjögren’s 84 (33) Rheumatoid arthritis 9 (4) Raynaud’s phenomenon 8 (3) Scleroderma 5 (2) Other 19 (8) Stage IE 147 (59) IIE 42 (17) IV 56 (23) Missing data 2 (1) IPI Score Low (0-1) 126 (51) Low-Intermediate (2) 20 (8) High-intermediate (3) 21 (8) High (4-5) 5 (2) Missing data 75 (31) Elevated LDH 17 (7) ECOG PS 0-1 246 2 1 Extranodal sites 1 58 (23) 2 187 (76) Missing data 2 (1) B symptoms 9 (4) * Percents may not equal 100 as some patients had more than one disorder. Figure One: Overall survival of patients with and without Sjögren’s disease Figure One:. Overall survival of patients with and without Sjögren’s disease Disclosures Nowakowski: Celgene, Morphosis: Consultancy. Zucca:Roche, Mundipharma, Novartis, Jannsen, Celgene: Consultancy, Honoraria, Research Funding.

Abstract Background. The salivary gland is one of the most common sites involved by nongastric, extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). A large series of patients with long-term follow-up has not been documented. This multicenter, international study sought to characterize the clinical characteristics, treatment, and natural history of salivary gland MALT lymphoma. Methods. Patients with biopsy-confirmed salivary gland MALT lymphoma were identified from multiple international sites. Risk factors, treatment, and long-term outcomes were evaluated. Results. A total of 247 patients were evaluated; 76% presented with limited-stage disease. There was a history of autoimmune disorder in 41%, with Sjögren disease being the most common (83%). Fifty-seven percent of patients were initially treated with local therapy with surgery, radiation, or both; 37 of patients were treated with systemic therapy initially, with 47% of those receiving rituximab; and 6% of patients were observed. The median overall survival (OS) was 18.3 years. The median progression-free survival (PFS) following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first-line management. On multivariate analysis, age &lt;60 years and low to intermediate international prognostic index were associated with improved OS and PFS; Sjögren disease was associated with improved OS. Conclusion. Salivary gland MALT lymphoma has an excellent prognosis regardless of initial treatment, and patients with Sjögren disease have improved survival. Risks for long-term complications must be weighed when determining initial therapy. Implications for Practice: Patients with salivary gland extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) have an excellent prognosis, particularly those with associated Sjögren's disease. A wide range of available therapies may provide similar durable rates of disease control and survival. Therefore, an important goal in selection of therapy should be to minimize morbidity from treatment. When determining initial therapy for these patients, practitioners should consider the potential side effects and long-term toxicities of treatment.

AbstractGuanine‐adenine‐thymine‐adenine 2 (GATA2) mutated disorders include the recently described MonoMAC syndrome (Monocytopenia and Mycobacterium avium complex infections), DCML (dendritic cell, monocyte, and lymphocyte deficiency), familial MDS/AML (myelodysplastic syndrome/acute myeloid leukemia) (myeloid neoplasms), congenital neutropenia, congenital lymphedema (Emberger's syndrome), sensorineural deafness, viral warts, and a spectrum of aggressive infections seen across all age groups. While considerable efforts have been made to identify the mutations that characterize this disorder, pathogenesis remains a work in progress with less than 100 patients described in current literature. Varying clinical presentations offer diagnostic challenges. Allogeneic stem cell transplant remains the treatment of choice. Morbidity, mortality, and social costs due to the familial nature of the disease are considerable. We describe our experience with the disorder in three affected families and a comprehensive review of current literature.

Patients with diffuse large B‐cell lymphoma (DLBCL) and pre‐treatment bone marrow (BM) involvement require a restaging BM biopsy to document complete remission (CR). We investigated whether BM assessment by restaging PET‐CT could obviate the need for a repeat BM biopsy. Patients with DLBCL and a positive BM biopsy at diagnosis were identified from the Mayo Clinic Lymphoma Data Base. The concordance of BM status on restaging histopathology and PET‐CT reports and the positive (PPV) and negative predictive value (NPV) of PET‐CT were determined. One thousand eighty patients with DLBCL were evaluated and 69 patients (6%) had DLBCL involving the BM at diagnosis. Of 46 patients who completed frontline chemoimmunotherapy, 34 had a restaging PET‐CT and BM biopsy and were included in the analysis. Thirty‐three patients had a negative BM by both PET‐CT and BM biopsy; one patient had persistent BM involvement by biopsy and PET‐CT. Thus, restaging PET‐CT had 100% PPV and 100% NPV for assessing residual BM disease. The findings were validated in a prospective cohort of 68 DLBCL patients treated on a phase II clinical trial where four patients (6%) had DLBCL involving the BM at diagnosis. All had a negative BM by both restaging BM biopsy and PET‐CT. Compared with the gold standard of BM biopsy, PET‐CT had a 100% NPV to exclude residual BM disease after frontline therapy. If further validated, DLBCL practice guidelines and response criteria could be modified so that BM biopsy is no longer required to document CR if the restaging PET‐CT is negative. Am. J. Hematol. 89:865–867, 2014. © 2014 Wiley Periodicals, Inc.