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Novel Prognostic Markers in Previously Treated Chronic Lymphocytic Leukemia
Abstract Background: We need new biomarkers that manage CLL patients receiving novel chemotherapeutic agent treatments. In our earlier pilot study, we reported an association of inferior outcomes in those with higher IgM density, or those with IgG isotype expression, not explained by traditional markers such as unmutated IGHV or TP53 aberrations (Brander, et al., ASH abstract 118, 2011). The International Prognostic Index for CLL (CLL-IPI) was developed to provide CLL risk stratification, but this tool was largely studied in those treated conventionally (Lancet Oncol 17:779-790, 2016). Here we report studies of CLL cell IgM expression and outcomes in CLL patients treated with novel agents. We hypothesized that high IgM expression is associated with poor progression free survival (PFS) in patients treated with novel agents. Methods: We studied samples from 906 Duke University CLL patients. Fifty seven of 906 patients had received ibrutinib, acalabrutinib, and/or venetoclax. We classified CLL cell IgM expression surface isotype as low (<30%), moderate (31-60%), or high (>60%), and noted presence of class switching to IgG. We collected the following: social and geographical demographics, IGHV mutation status, CLL-IPI score, Rai staging, beta-2-microglobulin, FISH, cytogenetics, and treatment response per iwCLL definitions. PFS was defined as time from initiation of treatment with novel agents to progression of disease or death. Results: Of 57 CLL patients, 42 were alive at the time of followup. Median time for followup was 62 months for patients on BTK-inhibitors and 32 months for those on the Bcl-inhibitor venetoclax. Social demographics were similar across all treatment groups. Deaths were noted in each group (2/7 acalabrutinib, 13/45 ibrutinib, 6/13 venetoclax), with progression of disease as the leading cause. Many patients were not treatment naïve before starting novel agents. Specifically, 14/19 patients most recently on venetoclax had been exposed to a novel inhibitor. PFS did not correlate with surface IgM expression and outcomes for those treated with BTK inhibitors or venetoclax. Previously, approximately 25% of CLL patients with TP53 mut/del17p relapsed within 24 months of initiating traditional chemoimmunotherapeutics. Our TP53 mut/del17p group treated with BTK inhibitors had improved PFS (p=0.005) (Figure 1). Similarly, by univariate cox regression, we found statistically significant PFS in patients with high risk mutations treated with BTK inhibitors (p=0.042). There was no statistically significant correlation between CLL-IPI score and PFS, nor high IgM expression density and PFS for those treated with BTK inhibitors. Conclusions: We hypothesized that higher IgM expression density is associated with reduced PFS in patients treated with the novel agents. This was not identified in our study of 57 patients who had been treated with ibrutinib, acalabrutinib, or venetoclax. There was significantly shorter PFS for patients treated with BTK-inhibitors and TP53 mutand/or del17p compared to those without these genomic changes (p=0.005). This is consistent with prior studies. Historically, approximately 25% of CLL patients with TP53 mut/del17p relapsed within 24 months of initiating traditional chemoimmunotherapeutic agents. Our TP53 mut/del17p group treated with BTK inhibitors had improved PFS compared to the historical outcomes with a PFS of 66.5 months despite being a relapsed/refractory group. Our data supports prior studies identifying this as a high-risk subgroup of patients in need of investigational agent treatments (Catherwood MA, et al, J Clin Pathol, 72:343-346, 2019; and Gordon MJ, et al. Clin Cancer Res, In press, 2021). While the CLL-IPI score generally helps with prognostication of CLL patients, it was not significantly superior in our analyses in these patients. Other retrospective studies have also identified the limitations of the CLL-IPI score in the era of novel agents. Our work is limited by a small sample size of patients treated with the novel agents and by the retrospective nature of the study. With larger cohorts and longer followup, our future prospective studies will help clarify the role of surface immunoglobulin expression relative to CLL biology, and patient outcomes while receiving novel treatments. Figure 1 Figure 1. Disclosures Brander: BeiGene: Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; AstraZeneca: Research Funding; Verastem: Consultancy; Genentech: Consultancy, Research Funding; ArQule: Research Funding; Ascentage: Research Funding; DTRM: Research Funding; ArQule/Merck: Consultancy; LOXO: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; NCCN: Other: panel member.
Abstract Introduction/Objective A career in the medical laboratory requires advanced education and technical training. To assist both employers and employees, several government organizations conduct demographic, education, and wage surveys for the general U.S. labor market. Through its workforce surveys, the American Society of Clinical Pathology (ASCP) does the same for the medical laboratory professions. Our aim was to compare the findings of these surveys and identify similarities and dissimilarities between the general labor pool and the medical laboratory workforce. Methods/Case Report Since the 2021 ASCP Wage survey is currently open, we reviewed the findings described in ASCP’s 2019 Wage Survey of Medical Laboratories in the United States (Am J Clin Pathol 2021;155:649-673) with the publicly available information (for 2019) on demographics, educational attainment, and average hourly earnings available on the websites of U.S. Bureau of Labor Statistics (www.bls.gov) as well as United States Census (www.census.gov). Results (if a Case Study enter NA) In 2019, the male: female ratio was 52.9:47.1 in general labor pool and 19.1:80.9 in the medical laboratory workforce. The average age of a worker in the general labor pool was 41.9 years and was 42 years in the medical laboratory workforce. The average hourly earnings were $27.99/hour in the general labor pool and ranged from $16.64/hour (phlebotomists) to $53.95/hour (pathologists assistants) in the medical laboratory workforce, with the MLS/MT/CLS earning $30.02/hour to $52.53/hour. While 33.1% adults in the U.S. have attained a bachelor’s degree or above, 73.79% have attained this in the medical laboratory workforce. Conclusion Compared to the general labor pool, the medical laboratory workforce is a highly educated workforce and has a higher participation by women. The average worker age and average hourly wage are comparable. We encourage laboratorians to participate in ASCP surveys since such surveys reveal data that can drive better prospects for the medical laboratory workforce.
Introduction Patients with chronic myelo-monocytic leukaemia (CMML) have been reported to have a relative predominance of classical or MO1 monocytes (CD14+/CD16-) at the expense of MO2 (CD14low/CD16+) and MO3 (CD14-/CD16+) monocytes (Selimoglu-Buet. Blood 2015). These authors suggested that an MO1 percentage cut-off of >94% could predict the diagnosis of CMML with high sensitivity and specificity (both >90%) from other causes of monocytosis. Since then, several independent groups have attempted to reproduce their protocol with variable results. Most recently, the Mayo Clinic (Pophali. Blood Cancer J. 2019) found that an MO1 cut off of > 94% in peripheral blood identified CMML with a sensitivity of 75% and a specificity of 95.4%. These figures were lower than previously reported - calling into question, the utility of flow cytometry to distinguish the aetiology of monocytosis in a real-world setting. Objective Our retrospective audit aimed to establish if monocyte subset repartitioning could be used to reliably diagnose CMML in a real-world sample of patients with monocytosis. Methods In this study, we assessed peripheral blood samples from 35 patients presenting with a monocytosis (absolute monocyte count > 1 x109/L) in a tertiary referral hospital in Brisbane, Australia between June 2015 and Sep 2019. The patients' final clinical diagnosis was extracted from the medical record by two clinicians (AM, PM) blinded to the results of the flow cytometry. Peripheral blood samples were subjected to MFC at a median of <24 hours (range, < 24 hours to 160 hours) after collection. Flow cytometry was performed using the BD FACS Canto II flow cytometer. Monocyte subsets were identified using Kaluza software (Beckman Coulter, USA). A CD45/ side scatter gate was set to locate the monocyte population and specific antibody combinations were used to identify and exclude other lineages; these were - CD24 to exclude granulocytes and B cells, CD16 to exclude neutrophils, CD2 to exclude T cells and CD56 to exclude NK cells. Based on the CD14 and CD16 expression, the monocytes were then divided into: MO1 (CD14+/CD16-), MO2 (CD14low/CD16+) and MO3 (CD14-/CD16+). Results are reported descriptively and Fishers Exact Test (IBM® SPSS® Statistics Version 26) was used to establish if there was any correlation between the percentage of classical monocytes and the diagnosis of CMML. Results Of the 35 patients included, 13 patients had CMML and four patients were diagnosed with another underlying myeloid neoplasm: one patient with myelodysplastic syndrome (MDS-RCMD), one patient with myeloproliferative neoplasm - not otherwise specified (MPN-NOS), one patient with multiple myeloma and one patient with acute myeloid leukaemia with myelodysplasia related changes (AML-MRC). Eighteen cases had non-clonal monocytosis. Six patients had a reactive monocytosis in the setting of autoimmune disease including: granulomatosis with polyangiitis (n=2), rheumatoid arthritis (n=1), IgG4 disease (n=1), mixed connective tissue disease (n=1) and polyarticular gout (n=1). Twelve cases of reactive monocytosis were due to infective and inflammatory causes. Among our 13 patients with CMML, seven cases (53.85%) had an MO1 percentage > 94%. In comparison, only four (18.18%) among the 22 cases of non-CMML were identified to have an MO1 percentage > 94%. There was no correlation between an MO1 percentage cut off of > 94% and a diagnosis of CMML (p = 0.057). Our study also examined the utility of an MO3 percentage cut off of < 1.13%, established by Hudson et al (Am J Clin Pathol 2018). Among our 13 cases of CMML, six patients (46.15%) were noted to have an MO3 percentage < 1.13%. Meanwhile, only eight, out of 22 non-CMML patients (36.36%) had MO3 percentage < 1.13%. There was no association between MO3 percentage and the diagnosis of CMML (p = 0.724). Conclusion Using the MO1 and MO3 percentage cut offs previously established, we were unable to reliably diagnose CMML. Given these findings, we suggest that more research with larger sample sizes is required before monocyte subset analysis can be applied in the clinical laboratory to discriminate reactive monocytosis from CMML. Disclosures Mollee: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees.
Background. CD5 expression is rare in MZL and has been historically characterized in case series of splenic (SMZL) and nodal (NMZL) MZL (Baseggio et al., haematologica, 2010; Jaso et al., Am J Clin Pathol, 2013; Salido et al., Blood 2010). These studies reported similar outcomes with CD5+ and CD5- MZL but did not examine the significance of CD5 in the context of modern immunochemotherapy. BR is a regimen increasingly used for treatment of MZL, but many patients can initially receive R monotherapy (R-mono) with no detriment to survival (Olszewski et al., ASH 2019). There are no biomarkers predictive of differential response to R-mono or BR. We examined outcomes of these treatments in MZL according to CD5 expression. Methods. We collected clinicopathologic data on patients with MZL (SMZL, NMZL, and extranodal MZL of the mucosa-associated lymphoid tissue [MALT]) diagnosed in our center between 2010 and 2020. CD5+ MZL was diagnosed by expert academic hematopathologists after excluding chronic lymphocytic leukemia and mantle cell lymphoma by immunophenotypic evaluation and cytogenetic/fluorescent in-situ hybridization studies. For prognostication, we assigned subtype-specific prognostic scores: MALT-IPI (Thieblemont et al., Blood 2017), IIL score for SMZL (Arcaini et al., Blood 2006), and standard IPI for NMZL. We examined overall response rate (ORR), progression-free (PFS) and overall survival (OS), calculated from the start of therapy, according to CD5 expression and first-line therapy. Survival was compared using log-rank tests stratified by age, MZL subtype, and stage. Results. The study included 213 patients with SMZL (N=51, 24%), NMZL (N=46, 22%), and MALT (N=116, 54%), with median age of 68 years at diagnosis, and with 52% women. Overall, 23 MZLs (10.8%) were CD5+. CD5 expression was most common in SMZL (24%), then NMZL (11%), and rare in MALT lymphoma (5%; P=.003). CD5+ cases showed del(7q) in 9%, trisomy 12 in 17%, and CD23 expression in 9%. All tested CD5+ cases had a positive peripheral blood flow cytometry (100% vs 65% of CD5- cases, P<.001) and bone marrow involvement (100% vs 64%, P=.004). Furthermore, adjusting for variable prevalence in MZL subtypes, CD5 expression was significantly associated with high lactate dehydrogenase (LDH, 56% vs 18%, adjusted odds ratio (aOR) 5.74, P=.0008), anemia (39% vs 20%, aOR 2.55, P=.044), monoclonal paraprotein (75% vs 36%, aOR 5.33, P=.016), advanced stage (83% vs 54%, aOR 4.10, P=.013), and blood involvement (78% vs 32%, aOR 7.80, P=.0001). CD5 expression also correlated with a higher IIL score in SMZL (P=.032 on test for trends of odds), higher IPI in NMZL (OR=2.84, P=.09), and higher MALT-IPI (OR=3.38, P=.10). CD5+ MZL had a numerically higher prevalence of 17p deletion (43% vs 21%, P=.35) and complex karyotype (42% vs 22%, P=.26) than CD5- MZL, when tested. Histologic transformation occurred in 2 (9%) CD5+ and 4 (2%) CD5- MZLs (P=.13). The most common first-line treatments were R-mono (29%), radiation therapy (23%), BR (20%), and surgery (15%). CD5 expression was not prognostic for PFS (stratified log-rank, P=.29, Fig. A) or OS (P=.08; Fig. B) in the entire cohort, or within the subgroup of NMZL/SMZL only (P=.46 for PFS and P=.31 for OS). However, outcomes differed according to CD5+/- status between patients treated with first-line R-mono or BR. ORR to R-mono was significantly lower for CD5+ than CD5- MZL (22% vs. 78%, P=.003), whereas ORR to BR did not differ (100% and 93%, respectively, P=.72). Similarly, PFS after R-mono was significantly worse for CD5+ than CD5- MZL (P=.036; Fig. C), while it did not significantly differ after BR (P=.64; P for interaction between treatments=.030). CD5 expression was also associated with significantly worse OS among patients receiving R-mono (P=.047) but not among those receiving BR (P=.56; Fig. D). Results were similar in the subgroup of SMZL/NMZL cases. Conclusions. To our knowledge, this is the first study examining CD5 expression as a prognostic and predictive biomarker for outcomes of R-based immunochemotherapy in MZL. CD5+ MZL was characterized by disseminated presentation with universal peripheral blood involvement, but after adjustment for other factors, CD5 expression was not independently prognostic. However, we observed worse response rates, PFS, and OS for CD5+ MZL treated with first-line R monotherapy, but not among those treated with BR, suggesting that the BR combination might be preferable in this subgroup. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding.
Introdução: O adenoma pleomórfico (AP) é um tumor de glândulas salivares, misto, benigno composto de células epiteliais e mioepiteliais dispostas em vários padrões morfológicos, demarcadas dos tecidos circundantes por uma cápsula fibrosa. Dentre as glândulas salivares, é predominante nas intraorais com maior frequência no palato. Sua etiopatologia ainda é controversa. Objetivo: Relatar um caso clínico de adenoma pleomórfico localizado em região póstero lateral direito, do palato tratado cirurgicamente. Relato do Caso: Paciente, sexo feminino, 55 anos, foi encaminhada com laudo histopatológico de adenoma pleomórfico. Ao exame físico, foi observou um aumento de volume caracterizado como um nódulo séssil, consistente à palpação, localizado em palato duro direito, com aproximadamente 4cm de extensão em seu maior diâmetro, superfície íntegra, coloração normal e indolor. Ao exame tomográfico, imagem unilocular, bem delimitada, com reabsorção óssea local. Como tratamento, optou-se pela exérese cirúrgica da lesão sob anestesia geral, a qual foi realizada sem intercorrências. Paciente atualmente se encontra com 1 ano de pós-operatório sem sinais de recidiva. Conclusão: O tipo de tratamento descrito apresenta excelente prognóstico, com baixas taxas de recidiva.Descritores: Adenoma Pleomorfo; Cirurgia Bucal; Patologia Bucal.ReferênciasSharma A, Deshmukh S, Shaikh A, Dabholkar J. Pleomorphic adenoma of the minor salivary gland of the cheek. Singapore Med J. 2013;54(9):e183-4. Arumugam P, Christopher PJ, Kumar S, Kengasubbiah S, Shenoy V. Pleomorphic adenoma of the palate: a. case report. Cureus 11(3):e4308.Khan MN, Raza SS, Hussain Zaidi SA, Haq IU, Hussain AK, Nadeem MD, Farid K. Pleomorphic Adenoma Of Minor Salivary Glands. J Ayub Med Coll Abbottabad. 2016;28(3):620-22. Chaturvedi M, Jaidev A, Thaddanee R, Khilnani AK. Large Pleomorphic Adenoma of Hard Palate. Ann Maxillofac Surg. 2018;8(1):124-126.Oliveira LJ, Castro HHO, Leão PLR, Leal RM, Horta MCR, Souza PEA. Tratamento de adenoma pleomórfico em palato: relato de 2 casos e revisão de literatura. Rev Port Estomatol Med Dent Cir Maxilofac. 2016;57(1):55-61.Porto DE, Cavalcante JR, Cavalcante Júnior JR, Costa MCF, Pereira SM. Adenoma Pleomórfico de Parótida – Relato de Caso. Rev cir traumatol buco-maxilo-fac. 2014;14(2):15-18;Melo MNB, Nogueira Neto JN, Souza SR, Dultra FKAA, Dultra JA. Adenoma pleomórfico em lábio superior: Relato de caso. Rev. cir. traumatol. buco-maxilo-fac.2016;16(2):40-3.Erdem MA, Cankaya AB, Güven G, Olgaç V, Kasapoğlu C. Pleomorphic adenoma of the palate. J Craniofac Surg. 2011;22(3):1131-4.Takahashi H, Fujita S, Tsuda N, Tezuka F, Okabe H. Intraoral minor salivary gland tumors: a demographic and histologic study of 200 cases. Tohoku J Exp Med. 1990;161(2):111-28. Loiola RF, Matos FR, Nonaka CFW, Lopes FF, Cruz MCFN. Perfil epidemiológico das neoplasias de glândulas salivares diagnosticadas em São Luís-MA. J Bras Patol Med Lab. 2009;45(5):413-20.Tiago RSL, Castro GA, Ricardo LAC, Bühler RB, Fava AS. Adenoma pleomórfico de parótida: aspectos clínicos, diagnósticos e terapêuticos. Rev Bras Otorrinolaringol. 2003;69(4):485-89.Khan MN, Raza SS, Hussain Zaidi SA, Haq IU, Hussain AK, Nadeem MD, Farid K. Pleomorphic Adenoma Of Minor Salivary Glands. J Ayub Med Coll Abbottabad. 2016;28(3):620-22. Soares AB, Demasi APD, Altemani A, Araújo VC. Increased mucin 1 expression in recurrence and malignant transformation of salivary gland pleomorphic adenoma. Histopathology. 2011; 58(3):377-82.Soares AB, Demasi AP, Tincani AJ, Martins AS, Altemani A, de Araújo VC. The increased PDGF-A, PDGF-B and FGF-2 expression in recurrence of salivary gland pleomorphic adenoma. J Clin Pathol. 2012;65(3):272-77.Maia FPA, Oliveira PRK, Santos JVQM, Costa DFN, Andrade ESS. Abordagem minimamente invasiva para tratamento de adenoma pleomórfico em palato: caso clínico. Rev Cir Traumatol Bucomaxilofac. 2019;19(3):21-4.
Background:Idiopathic granulomatous mastitis (IGM) is a rare inflammatory disease of the breast [1], for which there is a lack of consensus on the treatment protocol [2, 3]; it requires long-term follow-up and is associated with a high rate of relapse after surgical treatment. In this study, we report on the largest single-center cohort of idiopathic granulomatous mastitis treated with steroids + methotrexate.Objectives:We present this study believing that our experience with patients with IGM and use of steroid + methotrexate treatment in them will contribute to the literature.Methods:We retrospectively examined the data of 33 patients histopathologically diagnosed with idiopathic granulomatous mastitis who were evaluated by our Rheumatology or General Surgery Clinics between 2013 and 2016.Results:Of the 33 female patients (age: 38.64 ± 6.9 years), 24 were admitted with an initial diagnosis of Idiopathic granulomatous mastitis, whereas 9 were admitted after surgical treatment. The breast symptoms and laboratory values of the patients before and after the steroid and methotrexate treatment are shown in Table 1. Remission was achieved in 87.9% patients with steroid + methotrexate treatment, and there were no relapses during the 24-month follow-up.Table 2.Pre- and post-treatment laboratuary and clinical findings.Pre-treatmentPost-treatmentP valueESR (mm/h)42.45±28.8817.24±11.31<0.001*CRP (mg/L)24.72±35.325.37±6.50.004*Mass Size (mm)36.94±16.4010.79±15.01<0.001*Fistula (n)15/33 (45%)2/33(6%)<0.001**Nipple discharge(n)17/33(52%)1/33(3%)<0.001**ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein; *Paired T Test;**Chi-Square test.Conclusion:Methotrexate has so far been added to IGM treatment in order to decrease steroid dosage or to treat relapses, and it has been reported to be effective in case study and a limited number of studies with few patients [2, 4, 5]. Steroid + methotrexate treatment used by us in patients with IGM, which is a rare disease and for which no consensus exists regarding the treatment protocol, is effective and reliable in providing clinical improvement and long-term remission. Therefore, this treatment appears to be successful owing to long-term remission outcomes and very low relapse rates, without the patients having to undergo a surgical procedure and experience the associated anxiety and complications.References:[1]Kessler, E. and Y. Wolloch, Granulomatous mastitis: a lesion clinically simulating carcinoma. Am J Clin Pathol, 1972. 58(6): p. 642-6.[2]Schmajuk, G. and M.C. Genovese, First report of idiopathic granulomatous mastitis treated with methotrexate monotherapy. J Rheumatol, 2009. 36(7): p. 1559-60.[3]Patel, R.A., et al., Idiopathic granulomatous mastitis: case reports and review of literature. J Gen Intern Med, 2010. 25(3): p. 270-3.[4]Sheybani, F., et al., Treatment for and clinical characteristics of granulomatous mastitis. Obstet Gynecol, 2015. 125(4): p. 801-7.[5]Aghajanzadeh, M., et al., Granulomatous mastitis: Presentations, diagnosis, treatment and outcome in 206 patients from the north of Iran. Breast, 2015. 24(4): p. 456-60.Disclosure of Interests:None declared
Abstract Background: IGF-I is the most widely used biomarker for management of GH related diseases. Reproducible assays and method-specific reference intervals (RIs) are crucial determinants of its clinical utility. Assay validation and RIs based on >15,000 subjects were published for the IDS iSYS IGF-I assay (J Clin Endocrinol Metab 2014). We now analyzed distribution of IGF-I results obtained in routine samples analyzed by accredited laboratories in the US and Europe, all using the IDS iSYS assay. Methods: All results from routine IGF-I measurements during the past 5 years in 4 laboratories were included (US lab n=778,173 males/710,752 females; European labs (Germany/Belgium, n=23,220 males/40,183 females). Assay performance across laboratories was confirmed through proficiency testing schemes and exchange of patient samples. We constructed RIs adjusted for age/sex from European and US cohorts separately using a modified Hoffmann approach (Am J Clin Pathol 2015), and compared to the originally published RIs (n=6697 males/8317 females, adults from Europe). A subset of US samples was used to compare IGF-I between regions with lower (Colorado) and higher (Alabama) mean body mass index (BMI). Results: Lower limits (LLs) of RIs calculated from routine results are superimposable to LLs from the original publication for all ages and sexes, regardless whether IGF-I results were from Europe or the US. For groups with sufficient n, upper limits (ULs) of RIs calculated from European routine data were also not statistically different from the originally published central 95%. However, a striking difference exists in calculated ULs from data of European and US origin: For ages 10-18 years, calculated UL on average was 149.3 ng/mL (34.6%) higher in boys and 94.9 ng/mL (19.8%) in girls from the US. In adults (19-95 years), calculated UL on average was 45 ng/mL (20.3%) higher in males and 29.7 ng/mL (13.8%) in females from the US. Within the US, mean IGF-I was significantly higher in samples from Colorado (lower mean BMI) than in Alabama (p<0.0001) across age- and sex groups, although the difference between the two states was smaller than between each of them and Europe. Conclusion: This study provides evidence that in sufficiently large datasets, both, direct sampling (as in the original publication) and the indirect Hoffmann algorithms provide statistically comparable RI limits and may be considered as accurate representation of results distribution in the disease-free populations. More importantly, we demonstrate that even with tight cross-correlation and continuous monitoring of IGF-I assay performance RIs generated in different populations can be different. Notably, in our extremely large study, the difference between Europe and the US was clinically relevant only at the UL. Although our study cannot reveal the cause of the difference, we suggest using adapted RIs for the US.
Assisted reproductive technologies (ART) are being extensively used to produce cattle offspring. However, as shown by Siqueira et al. (2017 J. Dairy Sci. 100, 5899-5908; https://doi.org/10.3168/jds.2016-12539), phenotypical and performance differences between cows derived from distinct ART can be found at different stages of development. Thus, in an attempt to mimic the natural environment, reproductive fluids (oviductal (SOF) and uterine fluids) were added as supplementation to embryo culture media. Our hypothesis was that this improved culture media would produce calves more similar to the ones produced by AI. Invitro-produced (IVP) beef embryos were produced using SOF media supplemented with reproductive fluids (RF) or standard protocol (BSA), vitrified and later warmed and transferred to synchronized dairy recipients. Simultaneously, other dairy recipients were inseminated (AI) with the same bull used to produce IVP embryos. A total of 19 calves are included in this study (RF n=5, BSA n=7, AI n=7). Calves that did not reach 45 days of life were excluded from these data. All animals received the same feeding and housing conditions. Calves were examined at Days 0, 3, 7, 15, 30, and 45 of life. Each examination included weight, height at withers, thorax circumference, heart and respiratory rates, body temperature, and a blood sample from the jugular vein to perform a general haematological analysis (Siemens ADVIA 120) and glucose levels. A non-parametric test (Mann-Whitney U) was used to compare paired samples, with significance assumed when P<0.05. Since day is a factor that influences growth, it was assumed as a fixed factor, and data were analysed per day. In terms of growth development, AI calves were significantly taller than BSA calves in all days, and in general taller than RF calves, with the exception of Days 3 and 7. Thorax circumference was significantly smaller for BSA versus AI calves only on Days 15 and 45. Respiratory rate was higher for RF calves at birth and for BSA calves at Day 3 when both were compared with AI calves, but we found no difference between them. Heart rate was higher for RF calves on Day 7 compared with BSA and AI, and higher again on Day 15 compared with AI. Regarding haematological parameters, significant differences were found on Day 0, with platelet counts being lower for BSA calves. On Day 7, mean corpuscular volume from AI calves was lower than either BSA or RF calves, and on Day 15, eosinophils were lower for RF calves compared with AI. At Day 30, white blood cells and lymphocyte concentration were lower for BSA than for AI calves. Glucose levels were higher for RF calves than for AI calves on Day 45. Overall, all haematology and clinical values seem to match the values of healthy calves (Brun-Hansen et al. 2006 Vet. Clin. Pathol. 35, 182-187; https://doi.org/10.1111/j.1939-165X.2006.tb00111.x), and the differences found were not clinically relevant. In conclusion, at the moment and from the analysed criteria of development during the first 45 days of life, there seems to exist no difference between calves born by IVP with RF as supplement to culture media and their invitro or invivo controls.
Background: Multiple Myeloma (MM) is defined as a clonal proliferation of malignant bone marrow plasma cells with high and uniform expression of CD 38 (Kumar et al, J Natl Compr Canc Netw. 2019; 3 and Lin et al, Am J Clin Pathol. 2004; 121:482-488). Daratumumab, a human IgGk monoclonal antibody, targets and binds to CD38, induces antibody dependent cell mediated cytotoxicity, complement activation, and antibody mediated phagocytosis (Prescribing information. Daratumumab; Janssen Biotech, Inc 2016). Daratumumab is associated with infusion related reactions (IRRs), which present with symptoms of rhinitis, cough, dyspnea, bronchospasm, chills and nausea. In two phase 3 trials, CASTOR (Palumbo et al, N Engl J Med. 2016; 375:754-66) and POLLUX (Dimopolous et al, N Engl J Med. 2016; 375(14):1319-31), IRRs occurred in 45% and 48% of patients, respectively. Of these, 98% and 96%, respectively, occurred during the first infusion. Grade 3 IRRs occurred in 5.3% and 8.6% of patients in CASTOR and POLLUX, respectively. No grade 4 IRRs were observed in either trial. Standard of care includes extended infusion times for the first, second, and subsequent infusions with a three-drug pre-infusion prophylaxis strategy including diphenhydramine, dexamethasone or methylprednisolone, and acetaminophen with slow prolonged infusion times is recommended(Bhatnagar et al, Oncologist. 2017; 22:1347-53). A single-arm safety study of accelerated infusion rate indicate that administering daratumumab using a time-saving 90-minute infusion protocol can be safe. Of 28 patients treated with accelerated daratumumab infusion during their third and subsequent infusions, no IRRs were observed, and there was only one mild reaction with no further reactions during subsequent infusions at the 90-minute rate (Barr et al, Leukemia. Mar. 2018). Subsequently, a similar protocol for all daratumumab infusions was implemented at The Johns Hopkins Health System including five premedications and three medications (5+3) during the first two infusions. Premedication can be eliminated for lack of tolerance. The purpose of this study is to evaluate the safety and success of rapid daratumumab administration in clinical practice based on infusion times, IRRs prophylaxis medication administration, IRRs frequency, and management of IRRs in the ambulatory setting of the Johns Hopkins Health System, pre- and post-implementation of the 90-minute infusion protocol using a more robust premedication regimen (5+3) than previously published. Study Design and Methods: This study is approved by the institutional review board at The Johns Hopkins Hospital (IRB 00195519). This is a retrospective, chart review of daratumumab infusions prior to implementing the accelerated infusion rate. The inclusion criterion was adult patients who received daratumumab infusion in the ambulatory infusion clinic July 1, 2016 to May 25, 2018 for pre-implementation and July 1 2018 to June 30 2019 for the post-implementation period. Patients who only received inpatient administration of daratumumab were excluded due to limited infusion related documentation. The primary endpoint is the proportion of patients who experienced IRRs after daratumumab infusion. Secondary endpoints include proportion of patients with grade 1/2 or grade 3/4 IRRs, infusion duration (hours), and the number of pre and post infusion prophylaxis medications given. Other data collected will include but not limited to demographics, prior history of anaphylaxis, eczema, asthma, or other drug allergies to identify risk factors not previously defined. Results: Data collection and analysis are ongoing. The sample size for pre-implementation of rapid infusion is ninety-three patients. Documented IRRs occurred in 18 (19%) patients. The mean infusion time was 7.4 hours for first infusions (n=70), 8 hours for patients with IRRs in the first infusion (n=18) and 7.1 hours for patients without IRRs in the first infusion (n=52). The mean number of IRR prophylaxis medications given was 7.8 (range 2-9) for first or second infusions. All IRRs documented were grade 1 or 2. Additional data analysis will include descriptive statistics as well as comparison of infusion duration, and will use paired t-test within samples and student t-test across different samples. Final results will report safety of daratumumab rapid infusion in largest single center patient population to date. Disclosures Ali: Celgene: Research Funding; Poseida: Research Funding.
Background: The myelodysplastic syndromes (MDS) represent heterogeneous disorders with varied clinical courses. The major prognostic tool in MDS is the IPSS-R, which helps estimate survival outcome and estimate risk for AML transformation. In low or intermediate risk pts, the IPSS-R has shortcomings; in these pts, the development of transfusion dependent anemia is the major disease associated complication, and this is not addressed by IPSS-R stratification. Previous studies have indicated that aberrancies detected by flow cytometry can risk stratify pts with MDS. The purpose of this study was to determine whether detection of neoplastic-specific blast aberrancies in pts diagnosed with low or intermediate risk MDS can identify pts at higher risk for transfusion dependent anemia after MDS diagnosis. Methods: We performed a retrospective chart review on MDS patients initially diagnosed at our institution between 1/2010 and 12/31/2017. Patients with low/intermediate risk by IPSS-R were identified. Flow cytometry findings on initial diagnostic BM biopsies performed at our institution only were reviewed. Flow cytometry (4- and 8-color) was performed on bone marrow aspirates for the following antigens: CD3, CD7, CD11b, CD13, CD14, CD15, CD19, CD20, CD33, CD34, CD36, CD38, CD45, CD56, CD64, CD117, and HLA-DR using FACS Calibur or FACSCanto II flow cytometers. Myeloblasts were identified by cluster analysis, as previously described (Am J Clin Pathol. 2010 Nov; 134(5):749-61), and compared to 20 control cases. Blast aberrancies were defined as an immunophenotypic difference of > ¼ log compared to the blasts in the controls. Neoplasia-specific blast aberrancies were defined as: expression of CD7, CD11b, CD15, and/or CD56 and/or under expression of CD38 and CD45. We estimated probability of transfusion dependent anemia using Kaplan Meier product limit method and compared survival curves using log-rank test. Analyses were performed using Stata v12.0. Results: A total of 63 patients were identified, with median age of 68 years (range 31-89 years). Median hemoglobin (Hg) at diagnosis was 9.8 (range 5.2-15.3). Cytogenetic risk categories were very good, good, intermediate and poor in 3%, 71% 16%, and 10% respectively. IPSS-R category was very low or low in 70% (44 pts), and intermediate in 30% (19 pts). The presence of blast aberrancies was similar in proportion among low risk patients (61%, n=27) compared to intermediate risk patients (68%, n=13). Overall, the presence of only one blast aberrancy, whether neoplasia-specific or not, did not significantly segregate patients at greater risk for transfusion dependence. However, the presence of 2 or more aberrancies statistically defined two populations. Those possessing 0-1 blast aberrancy did not reach a median time to transfusion dependence, whereas those possessing 2+ aberrancies had a median time to transfusion dependence of 1.2 years (p=0.02). Additionally, when looking at neoplasia-specific blast aberrancies, pts with 0-1 aberrancy had a median time to transfusion of 4.7 years, compared to 2+ aberrancies, at 0.8 years (p=0.02). Figure 1 illustrates this finding. Conclusion: The determination of blast aberrancies by flow at time of MDS diagnosis may provide prognostic information in low/intermediate risk MDS patient and could help predict risk for early red blood cell transfusion dependence. Upfront risk stratification would be valuable information to plan follow-up for these patients, as well as treatment decision making including early initiation of ESAs. Disclosures Michaelis: Novartis: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; BMS: Research Funding; Bioline: Research Funding; ASTEX: Research Funding; Janssen: Research Funding; Millenium: Research Funding; Macrogeneics: Research Funding; Pfizer: Equity Ownership, Research Funding; Incyte: Consultancy, Research Funding. Runaas:Agios: Honoraria; Blueprint Medicine: Honoraria. Atallah:Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Helsinn: Consultancy. Abedin:Actinium Pharmaceuticals: Research Funding; Pfizer Inc: Research Funding; Helsinn Healthcare: Research Funding; Agios: Honoraria; Jazz Pharmaceuticals: Honoraria.
