Kochuparambil, Samith T.

Abstract Background: Multiple Myeloma (MM) patients have a substantially reduced Health related Quality of Life (HQOL) at diagnosis (dx) due to disease related symptoms like bone pain (58%) and fatigue (32%). HQOL monitoring is becoming increasingly important, owing to improved survival and the impact of treatment-related toxicity. As a result HQOL assessments are increasingly being used in clinical trials, but the literature regarding the relationship between HQOL and outcomes in MM is sparse. We used the Mayo Clinic “Hematology Patient Reported Symptom Screen” (HPRSS) to assess the impact of HQOL on outcomes in newly dx patients with MM. Methods:We retrospectively reviewed charts of 453 patients with newly dx MM seen at Mayo Clinic, Rochester from 2009 to 2014. All patients who visit Mayo clinic hematology clinic complete a 3-point questionnaire (HPRSS) on pain, fatigue and quality of life (QOL) (scored on a scale of 0-10; with 0 being the least fatigue or pain and 10 being the best QOL). Pain, fatigue and QOL scores documented at the time of dx and at 6 months were collected. JMP version 10 was used for the data analysis. Results: The median age at diagnosis was 67 years (range, 33-95); 60% were male. The estimated median OS for the cohort was 21 m (95% CI19, 23); 387 (85%) of the patients were alive at last follow up and the median OS for the population was not reached. The median (IQR) scores for pain, fatigue and QOL were 4 (2, 6), 3 (1, 5), and 7 (5, 9), respectively. First, we examined the relationship between each of the scores (dichotomized at the median) and the baseline characteristics. Higher fatigue scores were associated with lower Hb and serum albumin and higher beta 2 microglobulin, LDH and marrow plasmacytosis. Higher pain scores were seen in female patients, and associated with higher B2M, serum calcium and lytic bone lesions. Lower QOL scores were associated with lower absolute lymphocyte count and serum albumin levels. Next, we examined the relationship between the scores and the OS from diagnosis. The overall survival was inferior for patients with higher pain scores, fatigue scores and lower QOL scores (Figure). In a multivariable analysis, fatigue scores were most strongly associated with survival outcome. Patients with adverse scores in two or more of pain, fatigue and QOL had significantly inferior outcomes (Figure). In univariate analysis, age, B2M, LDH, FISH high risk and the presence of two or more adverse scores were all significantly associated with poorer OS. In a multivariable analysis, age, LDH and the presence >=2 adverse scores were all associated with shorter OS. Of the 453 patients included in the study, 222 patients had pain, fatigue and QOL scores at 6 month from diagnosis. At 6 months, the median (IQR) scores for pain, fatigue and QOL were 2 (1, 5), 4 (2, 5), and 7 (5, 9), respectively; suggesting improved pain, worsened fatigue and static QOL scores. Improvement in the scores by at least one point was seen in 50%, 49% and 38% for the fatigue, pain and QOL scores. While the pain and fatigue scores at 6 months correlated inversely with OS, improvements in the scores in any of the three were not associated with any improved outcomes. Conclusion: A simple, patient reported scoring system for pain, fatigue, and overall perceived QOL at the time of diagnosis is a powerful predictor of survival outcomes in patients with newly diagnosed MM and should be considered routinely in clinical practice. The results of these patient reported measures can be utilized to develop risk-adapted trials in patients with MM. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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: Proliferation rate of plasma cells (PC) is a powerful tool in evaluating all types of monoclonal gammopathies, predicting for progression as well as survival in all phases of the disease. A flow cytometry (FC)-based method to delineate the cell cycle of clonotypic PCs and determine the proportion in S-phase was developed. This method replaces a labor-intensive slide based methodology, but the prognostic power of this FC approach has not been clearly elucidated. Methods: A total of 1061 patients who had bone marrow (BM) FC PC proliferation analysis at Mayo Clinic, Rochester from May 2012 to December 2013 were studied. These included MGUS/ SMM (n=134), newly diagnosed (NMM; n=88), plateau in response (>=PR; n=544), and stable disease (n=38), and relapsed disease (RMM; n=257). PC proliferation was measured by 8-color FC using antibodies to CD19, CD38, CD138, CD45, and cytoplasmic kappa and lambda Ig light chains, and DAPI DNA staining. The DNA content of the abnormal, clonotypic PCs was specifically analyzed and the %S-phase was determined by measuring the proportion of cells between G0/G1 and G2/M. All studies collected 5x105 events on BD FACSCanto II instruments and analysis was performed with BD FACSDiva software. The CV of the DAPI staining of G0/G1 lymphocytes as an internal control population was always less than 3.5. Patients with fewer than 300 PCs for assessment of %SP were designated as 0%. Results: The median follow up from testing for the entire cohort was 13 months (95% CI; 12.7, 13.3); 156 (15%) had died. The proportion of patients with adequate numbers of plasma cells available for %SP estimation and the median (IQR) %SP for the different groups are as shown in table. As expected, patients with MGUS/SMM and those in a response state had slightly lower proportions of patients with sufficient PCs to estimate %SP. The clinical features and outcomes were further analyzed using two cutoffs, %SP ≥1 and ≥2, in the different patient groups. Among most of the disease groups, especially the newly diagnosed MM and relapsed disease, %SP was prognostic for OS using both cutoffs (Table). Among the NMM in univariate analysis, %SP ≥2, B2microglobulin >5.5, age >70 and creatinine > 2 mg/dl were all significant, but only B2microglobulin >5.5 retained significance in multivariable analysis. Among the RMM, in univariate analysis, %SP ≥2, B2microglobulin >5.5, HR FISH (t4; 14, t14;16, t14;20 & del17p) and LDH >221 were all significant, but only %SP ≥2 was significant in multivariable analysis. Conclusion: The %S-phase of clonal PCs determined by FC is of prognostic value in patients with MM, in all disease phases. This is particularly relevant among patients with relapsed disease, where it is independent of some of the other known poor prognostic factors such as high risk FISH. This is in sharp contrast with recent studies that have shown no prognostic value for slide based labeling index in patients treated with novel agents. Abstract 2053. Table MGUS/SMM NMM >=PR SD Relapse N 134 88 544 38 257 N (%) with PCs measurable for proliferation 103 (77%) 84 (96%) 245 (45%) 31 (82%) 210 (82%) %SP (IQR) 0.3(0.1-0.7) 0.8 (0.4- 1.5) 0(0- 0.9) 0.8(0.3-1.3) 1.2(0.4- 2.7) OS (%SP >1 vs. rest) NS NR for either(P<0.01) NR for either (P<0.001) NR for either(P=0.02) 19 vs. NR(P<0.001) OS (%SP >2 vs. rest) NS NR for either (P=0.03) 20 vs. NR(P<0.001) NR for either(P=NS) 16 vs. NR(P<0.001) Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

255 Background: In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with overall survival (OS) in CRPC stage in a North American cohort of 519 subjects. We attempt to replicate these findings in an independent cohort of Portuguese patients. Methods: A hundred and forty CRPC stage patients in the new cohort were genotyped fort he candidate SNPs. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. For SNP level results we estimated hazard ratios (HR) and 95% confidence intervals (CI) under the dominant allele model using Cox regression and adjusted for age and Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 53-84). The GS distribution was 48% subjects with GS≥8; 35% with GS=7 and 17% with GS<7. Median time from castration resistance to death for the cohort was 2.2 years (IQ range: 0.8-3.4, 93 deaths). One of the 3 SNPs (rs2295005; C>G; MAF = 0.16) in the TRMT11gene was associated with OS after adjustment for age and GS: (dominant model p=0.05, HR=0.56; 95 CI=0.31-1.00). No other SNP was observed to have statistical significance with OS (Table 1). Conclusions: Variation in the TRMT11 gene is significantly associated with overall survival in patients with CRPC and warrants further validation as a potential prognostic biomarker. [Table: see text]

209 Background: Predictive markers of response to AA are not known. In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with response to AA in HSPC in a North American cohort of 519 subjects. We attempt to replicate these findings in a cohort of Portuguese patients. Methods: The Portuguese cohort consisted of 308 HSPC patients, and the primary endpoint was time to AA failure, defined as time from initiating continuous AA to two serial PSA increases over the nadir, initiation of chemotherapy for progressive disease, or clinical or imaging based progression, whichever came first. For each SNP, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for time to AA failure using a recessive model with adjustment for Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 43, 85). The GS distribution was 35% subjects with GS≥8; 35% with GS=7 and 30% with GS<7. Median time to AA failure for the cohort was 1.8 years (IQ range: 0.3, 3.6). Association of each SNP with time to AA failure is shown in the Table. None of the SNPs replicated. However, there was a suggestive inverse association for rs10503733 (NKX3.1) with time to AA failure (P=0.07). Conclusions: While we were not able to replicate our initial findings, there was an unexpected association with rs10503733 (NKX3.1 gene) that may warrant additional clinical validation. [Table: see text]

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.