Risk Of Hematologic Malignancies Research Articles

Hematologic Malignancy Risk in Inflammatory Arthritis Patients Treated with TNF Inhibitors: The Real-Life Data from the HUR-BIO Registry.

This study aimed to assess the incidence of hematologic malignancy (HM) among inflammatory arthritis (IA) patients receiving tumor necrosis factor inhibitors (TNFi) compared with the general Turkish population. HUR-BIO (Hacettepe University Rheumatology Biologic Registry) is a single-center biological disease-modifying anti-rheumatic drug(bDMARD) registry since 2005. Patients with IA, including rheumatoid arthritis, spondyloarthritis, or psoriatic arthritis who had at least one visit after the TNFi were screened from 2005 to November 2021. Standardized incidence rates (SIR) were calculated after adjustment for age and gender and compared with the 2017 Turkish National Cancer Registry (TNCR). Of the 6139 patients registered in the HUR-BIO, 5355 used any TNFi at least once. The median follow-up duration was 2.6years for patients receiving TNFi. Thirteen patients developed a HM on follow-up. In these patients, the median age at the IA onset was 38 (range, 26-67), and the median age at the HM diagnosis was 55.5 (range, 38-76). Patients using TNFi had an increased HM incidence (SIR 4.23, 95% confidence interval (CI) 2.35-7.05). Ten patients with HM were under 65years of age. In this group, there was a higher incidence of HM in both men (SIR 5.15, 95% CI 1.88-11.43) and women (SIR 4.76, 95% CI 1.74-10.55). The risk of HMs in inflammatory arthritis patients receiving TNFi was four times higher than in the general Turkish population.

Integrating Mosaic Chromosomal Alterations and Single-Nucleotide Variants to Predict Evolution of Clonal Hematopoiesis

Background: Clonal hematopoiesis (CH) is an age-related expansion of mutated hematopoietic stem cells. Multiple studies have previously described distinct types of CH, CHIP (mutations in genes commonly associated with myeloid malignancies) as well as mosaic chromosomal alterations (mCA), that have been associated with increased risk of hematologic malignancies and cardiovascular morbidity. We hypothesized that the presence of both mCA and CHIP mutations may have an additive impact vis-à-vis risk of hematologic malignancy. Methods: Data on 91,335 patients from the BioVU repository, a Vanderbilt University Medical Center biobank with linked de-identified EHRs, spanning 2006 to 2021 were included in the analysis. Peripheral blood-derived DNA of 91,335 subjects from BioVU were genotyped on the Illumina Multi-Ethnic Global Array (MEGAEX) platform, which contains more than 2 million SNPs. CHIP mutation calls (DNMT3A R882/JAK2 V617F) were made by deconvoluting the MEGAEX array intensity data. Predetermined array intensity scores greater than a defined threshold for DNMT3A R882 and JAK2 V617F mutations were highly predictive of the corresponding mutation, so these mutations were included in the analysis. Individuals with a diagnosis of hematologic malignancy (HM) prior to blood draw were excluded, while those that went on to develop HM post-blood draw were included in the analyses. The relationship between independent variables and disease progression and death was assessed using Cox proportional hazards model. All statistical analyses were performed using R. Results: In this large cohort (n=91,335), CH is strongly age-related with an increased frequency in the elderly, as has been previously shown (eg., Bick et al, Nature 2021; Jaiswal et al NEJM 2014). In total, we identified mCA in 765 (0.8%) patients. DNMT3A R882 and JAK2 V617F SNV/indels were identified in 1167 (1.3%) and 347 (0.4%) patients, respectively. Most frequent mCA detected in this cohort include 9p CN-LOH (n=105, 6.9%), del (5q) (n=99, 6.5%), del (20q) (n=98, 6.4%), del (7q) (n=94, 6.2%), and del (13q) (n=67, 4.4%). Combined mCA and DNMT3A R882/JAK2 V617F mutations were reported in 147 (0.2%). Co-occurring JAK2 and 9p CN-LOH (n= 100, OR=5658, q<0.001) are consistent with the well-known mechanisms of biallelic alterations involved in the pathogenesis of HM. There were significant correlations between abnormal blood counts and CH lesions, for example, high platelet count had a higher frequency of JAK2 V617F and 9p CN-LOH (OR=2.57, q=3.41e-141). Individuals with mCA are associated with lower WBC and platelet count, and any blood count abnormality (Figure 1A). Finally, we looked at how presence of both mCA and JAK2/DNMT3A impact the risk of HM. In total, 1615 cases in the entire BioVU cohort were reported to develop HM: 947 myeloid, AML (n=210), CML (n=73), MDS (n=315), MPN (n=349) and 668 lymphoid, ALL (n=72), B-NHL (n=252), T-NHL (n=22), MM (n=322). The presence of mCA was associated with a higher incidence of HM (hazard ratio (HR) = 6.85, 95% confidence interval (CI) = 5.9-7.95, P < 0.001), and DNMT3A/JAK2 was associated with higher incidence of HM ( HR=5.7, 95% CI= 4.75-6.85, P<0.001), and presence of both (mCA and DNMT3A/JAK2) were significantly associated with higher incidence of HM (HR=26.67, 95% CI= 19.48-36.5, P<0.001) than observed in no CH patients (Figure 1B). Conclusion: In this large cohort of patients, the presence of CH (both mCA and DNMT3A/JAK2) in apparently healthy individuals positively correlated with blood count abnormalities and increased incidence of hematologic malignancy. The results from this large cohort of patients emphasize the significance of detecting both mCA and SNV/indels in clonal hematopoiesis. These results should be validated in large datasets to determine if detecting both mCAs and CH can augment clinical care and outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

35225 Undifferentiated pruritus and the risk of hematologic malignancy

Background: Pruritus is common among patients with hematologic malignancies (HMs). However, the risk of HM among patients with pruritus is not established. Additionally, the diagnostic utility of serum lactate dehydrogenase (LDH), frequently ordered to assess malignancy in pruritic patients, remains uncertain. Methods: A population-level analysis from 2002-2020 was conducted with TriNetX, a global health research network. Patients were identified using ICD-9 and ICD-10 codes for undifferentiated pruritus, excluding patients with chronic pruritic dermatoses or systemic disease-associated pruritus. Patients were age-, sex-, race-, BMI-, and smoking/alcohol status-matched to controls without diagnosis of pruritus. SNOMED-CT and General Equivalence Mappings were used to map diagnostic codes prior to the introduction of ICD-10. P values were adjusted for multiple hypothesis testing using the Benjamini-Hochberg method. Results: 327,502 patients with undifferentiated pruritus and 8,934,671 controls were identified. Within 12 months of diagnosis with pruritus, patients had increased risk of Hodgkin’s lymphoma (relative risk [RR] 4.42, 95% confidence interval [CI] 2.83-6.88), non-Hodgkin’s lymphoma (RR 2.35, 95% CI 1.96-2.82), multiple myeloma (RR 2.38, 95% CI 1.66-3.41), lymphocytic leukemia (RR 1.47, 95% CI 1.07-2.02), myeloid leukemia (RR 2.56, 95% CI 1.79-3.67), monoclonal gammopathy (RR 1.90, 95% CI of 1.55-2.32), and myelodysplastic syndrome (RR 1.74, 95% CI 1.14-2.64). Pruritic patients had higher serum LDH (297.55 ± 310.9 units/liter) compared with controls (255.51 ± 223.73 units/liter), but LDH >250 units/liter did not confer a higher risk of developing HM in either group. Conclusion: Patients with undifferentiated pruritus have increased risk of developing HM, and LDH has limited diagnostic utility in these patients.

Association between Cholesterol Level and the Risk of Hematologic Malignancy According to Menopausal Status: A Korean Nationwide Cohort Study.

Recent studies have revealed the possible association between serum cholesterol levels and hematologic malignancy (HM). However, limited information is available about how reproductive factors interact with this association. Therefore, we investigated the roles of serum cholesterol in the risk of HM according to the menopausal status. We finally identified 1,189,806 premenopausal and 1,621,604 postmenopausal women who underwent a national health screening program in 2009 using data from the Korean National Health Insurance Service database. Overall, 5449 (0.19%) developed HM. Among postmenopausal women, the inverse associations were observed between total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) levels, and the risk of overall HM. In premenopausal women, the highest quartile of HDL-C was associated with a reduced risk of HM compared with the lowest quartile of HDL-C consistent with results in postmenopausal women (adjusted hazard ratio [aHR] 0.80, 95% confidence interval [CI] [0.68–0.95]), whereas the highest quartile of triglyceride (TG) showed an increased risk of HM compared to the lowest quartile of TG, (aHR 1.22, 95% CI [1.02,1.44]) only in premenopausal women. Our finding suggests that lipid profiles are differently associated with HM risk by menopausal status.

Abstract LB063: Duplex Sequencing reveals ubiquitous clonal hematopoiesis and complex donor-recipient clonal dynamics following HSCT

Abstract Clonal hematopoiesis (CH aka CHIP) is the process whereby otherwise healthy individuals accumulate clones bearing low-frequency somatic mutations in hematologic malignancy (HM) driver genes. Historically thought to be a phenomenon of the elderly that is associated with increased risk of HM and cardiovascular disease, CH has been observed in increasingly younger cohorts as sequencing technology has advanced. CH in hematopoietic stem cell transplant (HSCT) donors has also been associated with adverse recipient outcomes. In this retrospective analysis, we asked whether CH mutations preferentially expanded in recipients vs. donors in paired samples collected a median of 34 years post-HSCT (range 6-45). 16 donor-recipient pairs were analyzed, 11 of which had a donor sample collected pre-HSCT. All individuals were healthy at the time of contemporary sampling. Median donor age was 26 years (range 12-84) at time of HSCT. We took advantage of the ultra-low error rate (&amp;lt;1-in-10-million) of Duplex Sequencing (DS) to comprehensively assess CH in genomic DNA from blood. We targeted 29 genes recurrently mutated in acute myeloid leukemia (AML) plus 48 kilobases of randomly chosen neutral genomic regions. The mean DS error-corrected molecular depth across all samples was 26,731x for AML-associated genes and 32,812x in the neutral regions. CH was detected in 100% of donors and recipients, with a trend toward more CH clones in older vs. younger donors. We defined CH as mutations observed in at least 2 unique DNA molecules, rather than by a threshold variant allele frequency (VAF). Among the 11 donors with matched historical and contemporary DNA samples, CH mutations in the latter had a higher average VAF and comprised more unique mutations than in the former, reflecting clonal expansions over time. The magnitude of CH expansions was greater for the AML-associated genes than for neutral loci, consistent with positive selection. Post-HSCT the overall number of unique mutations was similar between donors and recipients. Most donor CH variants did not preferentially expand in the recipient. A minority of recipients had a modestly increased overall average VAF relative to paired donors in AML genes. While the VAF of some likely pathogenic variants increased in the recipient vs the donor, this was not the case for most CH mutations in most recipients and the reciprocal was sometimes observed. DS represents a powerful tool for the high-resolution study of CH evolution. In a unique historical cohort comprising longitudinal samples from some of the earliest patients and donors to undergo HSCT, we observed limited instances of accelerated CH in recipients relative to donors. While this cohort is biased due to enriched inclusion of long-term survivors, our data exemplifies how healthy hematopoiesis, indistinguishable between donors and recipients, can be maintained almost half a century following transplant. Citation Format: Masumi Ueda, Jake Higgins, Thomas Smith, Elizabeth Schmidt, Fang Y. Lo, Charles C. Valentine, Jesse J. Salk, Rainer Storb, Jerald P. Radich. Duplex Sequencing reveals ubiquitous clonal hematopoiesis and complex donor-recipient clonal dynamics following HSCT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB063.

Maternal ancestry and hematological cancer risk: case-control study in an Argentinean population.

Aim: We investigated the role of maternal ancestry in neoplastic hematological malignancies (HMs) risk in a population from Central Argentina. Materials & methods: We analyzed 125cases with HMs and 310 controls from a public hospital, and a set of 202 colorectal, breast, lung, and hematologic cancer patients from a private hospital. Results: A decreased risk for HMs was associated with the Native American haplogroup B2 (odds ratio =0.49;95% CI: 0.25-0.92;p=0.02). The sub-Saharan African parahaplogroup L was associated with higher susceptibility for disease (odds ratio=3.10;95% CI: 1.04-9.31;p=0.043). Although the mean ancestral proportions in the total studied population was as published (61.7% Native American, 34.6% Europeanand 3.7% African), an unequal distribution was observed between hospitals. Conclusion: We confirmed the tri-hybrid nature of the Argentinean population, with proportions varying within the country. Our finding supports the notion that associated haplogroup is population and cancer specific.

Cancer risk in patients with primary immune thrombocytopenia – A Swedish nationwide register study

BackgroundImmune thrombocytopenia (ITP) is an autoimmune disease treated with immunosuppressive agents, thrombopoietin receptor agonists, immunomodulation drugs and/or splenectomy. Patients with ITP have been found to have increased risk ofhematological malignancies. Studies investigating stomach/liver cancer are contradictory and the risk of developing other solid tumors is largely unknown. We aimed at estimating risk of overall and organ-specific cancers in patients with primary ITP. MethodsThe study population was Swedish patients with at least one ITP diagnosis recorded in the National Patient Register and a 1:10 matched comparison cohort from the population. The study period covers 1997−2016. The Cancer Register and the Cause of Death Register provided data on malignancies and deaths, respectively. Primary ITP was identified using an established algorithm. We used time-split Cox models to estimate hazard ratios (HRs) with 95 % confidence intervals (CIs), adjusted for age, sex, index-year, county, income, education, Charlson score and number of in- and outpatient contacts. ResultsIn total 66,134 individuals were included in the study. Patients with ITP had higher risk of gastro-intestinal, skin (all morphologies), lymphoid and hematological cancers. Adjusted HR (95 % CI) for cancer was 1.37 (1.27–1.48), with highest risk during the first year, but with increased risk remaining for up to 20 years for men. For women, the overall risk was increased during the first year, HR (95 % CI) 2.00 (1.55–2.60). A significantly increased liver cancer risk was seen up to 9 years after diagnosis. ConclusionPatients with primary ITP have higher risk of cancer than the population. The observed increased risk does not seem to be solely due to surveillance bias, but might be associated with ITP or its treatments. Treating hematologists need to have high index of suspicion for cancer.

Hematologic malignancy in tanker crewmembers: A case-referent study among male Swedish seafarers.

Work on Swedish petroleum tankers before the late 1980s has been associated with an increased risk of hematologic malignancy (HM). Since then, ship modernizations have decreased occupational exposure to gases, including the carcinogen benzene. We explored the risk of HMs in Swedish seafarers who had worked on newer types of tankers. A case-referent study in male seafarers from a cohort of all Swedish seafarers was set up by record linkage with the Swedish Cancer Registry using the subjects' personal identification number. For each case (N = 315), five referents were randomly chosen from within the cohort, matched by birth year and three different periods of first sea service (<1985, 1985-1991, and ≥1992). Information on the type of ship and dates of service was retrieved from the Swedish Seafarers' Registry. Odds ratios (OR) were calculated by conditional logistic regression together with 95% confidence intervals (CI). The OR of HM was 1.07 (95% CI, 0.80-1.42) for work on tankers. In seafarers that had started to work on tankers ≥1985, the OR was 0.85 (95% CI, 0.50-1.43). For those who started to work on tankers before 1985, the OR was 1.17 (95% CI, 0.84-1.21) and 1.32 (95% CI, 0.86-2.03) if the cumulative time on tankers exceeded 5 years of service. In this last group, the OR of multiple myeloma was 5.39 (95% CI, 1.11-26.1). Although limited by crude exposure contrast and a short follow-up, work on tankers after 1985 was not associated with an increased risk of HM among Swedish seafarers.

Childhood body mass index is associated with the risk of adult hematologic malignancies in men-The best Gothenburg cohort.

Hematologic malignancies are common and the incidence is increasing. Adult obesity has been associated with hematologic malignancies (HM), but the importance of body mass index (BMI) in childhood and during puberty has not been evaluated. The aim of the present study was to evaluate the relative contribution of BMI and height in childhood and during puberty for the risk of adult HM. 37 669 men born in 1946 to 1961 who had weight and height measured at 8 (childhood) and 20 (young adult age) years of age available from the BMI Epidemiology Study were included in the study. Pubertal BMI change was calculated as BMI at 20 years of age minus BMI at 8 years of age. Information on HM was retrieved from Swedish registers (459 cases of HM). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regressions. Childhood BMI (HR 1.11 per SD increase [95% CI 1.02-1.23]), but not pubertal BMI change, was associated with hematologic malignancies in a linear manner. Childhood BMI was, independent of childhood height, associated with the diagnostic entities Non-Hodgkin lymphoma (HR 1.14 [95% CI 1.00-1.30]) and its largest subgroup diffuse large B-cell lymphoma (HR 1.31 [95% CI 1.03-1.67]). Childhood height was associated with multiple myeloma (HR 1.30 [95% CI 1.04-1.64]) independent of childhood BMI. We conclude that childhood but not puberty is the critical developmental period regarding future risk of HM and we suggest that elevated childhood BMI is a determinant of Non-Hodgkin lymphoma and diffuse large B-cell lymphoma.

Characterization of Clonal Dynamics after Hematopoietic Cell Transplantation Using Ultra-Sensitive Duplex Sequencing

Hematopoietic cell transplantation (HCT) is used in the treatment of hematologic malignancies (HM). Clonal hematopoiesis of indeterminate potential (CHIP) is the age-associated process whereby healthy individuals accumulate low-frequency clones driven by mutations in genes recurrently mutated in myeloid cancers; CHIP is associated with an increased risk of HM and cardiovascular disease. It has been hypothesized that CHIP clones present in an HCT donor might disproportionately proliferate in the recipient due to a relative growth advantage during immune reconstitution. Here we use Duplex Sequencing (DS) to investigate, years after HCT, whether the clonal makeup of CHIP in prior donors differs from that of the donor-derived hematopoietic system long after allogeneic transfer to a recipient. DS is an ultra-sensitive NGS error-correction technology that relies on sequencing of the individual paired strands of original source DNA molecules to dramatically reduce technical background compared to other NGS methodologies. Here we performed DS on 10 pairs of donor/recipient peripheral blood DNA samples collected 7-46 years post-transplant, as well as DNA from a healthy young control. We used a sequencing panel comprising 29 genes recurrently mutated in acute myeloid leukemia (AML) and generated mean DS molecular depth of 27,580x per sample, with maximum DS depth reaching 45,402x. We detected an average of 356 and 283 total variants per donor and recipient, respectively, and 462 total variants in the control. These included 291 single-count exonic variants (SEV) in the control and an average of 215 SEVs in donors (Fig. A). To enrich for CHIP (clonal) variants, we filtered out single-count (non-clonal) events, as well as intronic (non-splice site) variants and germline SNPs. Whereas the young control had only 5 clonal exonic variants (CEV), meaning nearly all of the variants in the control were SEVs, SNPs or intronic (Fig. A,B), HCT donors and recipients respectively averaged 44 and 38 CEVs. 91% of CEVs were non-synonymous (Fig. B), which is higher than expected by chance. The average age of the donors was 36 years old at the time of HCT (range 12-84), and the oldest donor (M1) had the most CEVs. 24/29 genes in the panel exhibited CEVs in the control or HCT donors (Fig. C). DNMT3A, TET2, BRINP3 (FAM5C) and ASXL1 had the greatest number of CEVs and this imbalance was not explained purely by gene size. The young control sample had an overall somatic mutation frequency (MF) of 4.7x10-7. HCT donors and recipients had average MFs of 1.0x10-6 and 1.7x10-6, respectively. 154 CEVs were shared in at least 1 donor-recipient pair, with the majority present at variant allele frequencies (VAFs) &lt;0.1% (Fig. D). 60 and 71 variants respectively increased or decreased by at least 20% in recipients compared to donors. The average increase was 3.9-fold and the average decrease was 3.1-fold. The greatest fold-increase was 136-fold for DNMT3A W297* in recipient M2 (2.2x10-4 to 3.0x10-2). 9 CEVs increased &gt;10-fold, all in DNMT3A, TET2 and RAD21. Only 1 CEV decreased &gt;10-fold: TP53 R273H (4.9x10-4 to 4.2x10-5). Analysis of the same 10 donor-recipient pairs using a commercial sequencing service found that, with a VAF cutoff of 2% and filtering for SNPs, only 7 shared CEVs could be detected that increased or decreased in any recipient. Our ultra-high accuracy DS data indicates that the structure of CHIP is more polyclonal than has been previously reported. In a handful of older healthy donors we detected dozens of concurrent CHIP mutations, with a relative gene distribution nearly identical to that previously reported in studies on thousands of patients using less sensitive method. We observed a similar age-dependent effect. Furthermore, our findings indicate that the clonal dynamics of CHIP clones between HCT donors and recipients are substantially more complex than previously known. Nearly all somatic variants shared between HCT donors and recipients were observed at &lt;2% VAF, with most &lt;0.1%, which is well-below the detection limit of other NGS assays. Many shared variants increase or decrease in the recipient but, contrary to our expectation, there was not an overall trend for clones carrying likely-drivers (i.e. pathogenic CHIP-associated mutations) to be larger in the recipient than the donor, as compared with probably passengers (i.e. synonymous mutations). This suggests that the evolution of CHIP is not accelerated as a result of HCT. Figure Disclosures Higgins: TwinStrand Biosciences: Employment. Pratt:TwinStrand Biosciences: Employment. Valentine:TwinStrand Biosciences: Employment. Williams:TwinStrand Biosciences: Employment. Radich:Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Salk:TwinStrand Biosciences: Employment.

Clonal Hematopoiesis and Premalignant Diseases.

Clonal hematopoiesis (CH) arises when mutations in the hematopoietic system confer a fitness advantage to specific clones, thereby favoring their disproportionate growth. The presence of CH increases with age and environmental exposures such as cytotoxic chemotherapy or radiotherapy. The most frequent mutations occur in epigenetic regulators, such as DNMT3A, TET2, and ASXL1, leading to dysregulation of tumor suppressor function, pathogen response, and inflammation. These dysregulated processes elevate risk of overall mortality, cardiovascular disease, and eventual hematologic malignancy (HM). CH is likely acting as an initiating event leading to HM when followed by cooperating mutations. However, further evidence suggests that CH exerts a bystander influence through its pro-inflammatory properties. Delineating the mechanisms that lead to the onset and expansion of CH as well as its contribution to risk of HM is crucial to defining a management and intervention strategy. In this review, we discuss the potential causes, consequences, technical considerations, and possible management strategies for CH in the context of HMs and pre-HMs.

Primary Versus Secondary Autoimmune Hemolytic Anemia: A Retrospective Analysis of Diagnostic Patterns and Treatment Outcomes

Introduction: Autoimmune hemolytic anemia (AIHA) is an acquired autoimmune disorder caused by development of antibodies against antigens on erythrocytes. AIHA is divided into primary (idiopathic) and secondary type, the latter of which is often associated with hematologic malignancy (HM). Previous studies estimate that between 5-10% of people with HM develop AIHA at some point, but the temporal relationship between HM and AIHA has, to our knowledge, not been explicitly studied. Furthermore, only one small study has compared the treatment protocols and complication rates for primary AIHA to those for secondary AIHA. This study suggested that treating AIHA secondary to HM with corticosteroids may not be the most effective first-line strategy due to complications and frequent treatment failure. Instead, treating the underlying malignancy may be more beneficial. This study aims to shed light on the temporal relationship between diagnosis of AIHA and HM, and to compare and contrast the treatments and treatment outcomes for primary and secondary AIHA.Methods: Patients with AIHA diagnosed between January 2000 and December 2010 were retrospectively identified by a search of ICD codes. Patients were excluded if they did not have a positive direct antibody test (DAT), anemia, or laboratory findings of hemolysis. We recorded the date of AIHA diagnosis, lab findings at diagnosis, the treatments and duration of each therapy, and number and frequency of blood transfusions. The medical record was then analyzed for any diagnosis of HM during the patient's life. If HM was diagnosed, the date of diagnosis and type of HM were documented. The means or medians of continuous variables were compared using Student's t tests, Wilcoxon's rank-sum tests, ANOVA, or Kruskal-Wallis tests, depending on the distribution of the data. Categorical variables were analyzed using chi-square or Fisher's exact tests. Univariate and multivariate Cox proportional-hazards models were used to assess the effect of different first AIHA treatment types on PFS and OS, adjusting for baseline characteristics. Statistical significance was considered to be P <0.05.Results: A total of 67 patients were included in this study. Of these patients, 38 (56.7%) did not have HM, while 29 (43.3%) did. Within the HM group, 14 (48.3%) were diagnosed before developing AIHA, 6 (20.7%) were diagnosed after, and 9 (31%) were diagnosed within the same encounter. Demographically, the patients with HM were significantly older when diagnosed with AIHA (70.8 years of age for HM, compared to 60.7 years of age for AIHA only) and were more likely to be male. Between the two groups, there were no significant differences in hemoglobin, bilirubin, haptoglobin, lactate dehydrogenase, or reticulocyte count at AIHA diagnosis. The volume of blood transfusions was significantly higher in the HM group, with a mean of 26.1 units of packed red blood cells compared to 7.4 units in the AIHA only group. Regarding first treatment for AIHA, 38 (56.7%) of patients were treated with steroids alone, 9 (13.4%) were treated with intravenous immunoglobulin (IV Ig), and 16 (23.8%) were treated with observation or blood transfusions only. Only 2 patients were treated with rituximab before steroid or IV Ig therapy as a first treatment. There was no significant difference in first treatment for AIHA between the HM and AIHA only groups.Discussion: Nearly half of our study population had AIHA associated with HM. Most of the patients with HM were diagnosed with AIHA months to years after diagnosis of their malignancy. However, of the 44 patients presenting with AIHA without a known diagnosis of HM, 15 (34.1%) were found to have HM during that encounter, or in the years following. This reinforces the need to search for underlying malignancy in a patient with newly diagnosed AIHA. This study was unable to identify specific markers that were associated with an increased risk of HM. Regarding treatment, there was a great deal of variety in first treatment for AIHA, with a similar variety in response. Treatment that included IV Ig was associated with a statistically significant increase in relapse rate than treatment with steroids alone. This finding is likely confounded to some degree, the patients who received IV Ig as a first treatment had slightly, although non-significantly, lower presenting reticulocyte counts and required more transfusions, indicating they may have had more severe disease. DisclosuresNo relevant conflicts of interest to declare.

Body composition measurements and risk of hematological malignancies: A population-based cohort study during 20 years of follow-up

High body mass index (BMI) is associated with development of hematological malignancies (HMs). However, although BMI is a well-established measurement of excess weight, it does not fully reflect body composition and can sometimes misclassify individuals. This study aimed at investigating what body composition measurements had highest association with development of HM. Body composition measurements on 27,557 individuals recorded by healthcare professionals as part of the Malmö Diet and Cancer study conducted in Sweden between 1991–1996 were matched with data from national registers on cancer incidence and causes of death. Cox regression models adjusted for age and sex were used to test the association between one standard deviation increments in body composition measurements and risk of HM. During a median follow-up of 20 years, 564 persons developed an HM. Several body composition measurements were associated with risk of developing an HM, but the strongest association was found for multiple myeloma (MM). Waist circumference (HR 1.31, p = 0.04) and waist-hip ratio (HR 1.61, p = 0.05) had higher risk estimates than BMI (HR 1.18, p = 0.07) for MM. In conclusion, our study shows that measurements of abdominal adiposity better predict the risk of developing HM, particularly MM, compared to BMI.

Incidence of hematologic malignancy and cause-specific mortality in the Women's Health Initiative randomized controlled trial of calcium and vitamin D supplementation.

Prior evidence of a possible link between vitamin D status and hematologic malignancy (HM) in humans comes from observational studies, leaving unresolved the question of whether a true causal relationship exists. The authors performed a secondary analysis of data from the Women's Health Initiative Calcium/Vitamin D (CaD) trial, a large randomized controlled trial of CaD supplementation compared with placebo in older women. Kaplan-Meier and Cox proportional hazards survival analysis methods were used to evaluate the relationship between treatment assignment and 1) incident HM and 2) HM-specific mortality over 10 years following randomization. HMs were classified by cell type (lymphoid, myeloid, or plasma cell) and analyzed as distinct endpoints in secondary analyses. A total of 34,763 Women's Health Initiative CaD trial participants (median age, 63 years) had complete baseline covariate data and were eligible for analysis. Women assigned to CaD supplementation had a significantly lower risk of incident HM (hazard ratio [HR], 0.80; 95% confidence interval [95% CI], 0.65-0.99) but not HM-specific mortality (HR, 0.77 [95% CI, 0.53-1.11] for the entire cohort; and HR, 1.03 [95% CI, 0.70-1.51] among incident HM cases after diagnosis). In secondary analyses, protective associations were found to be most robust for lymphoid malignancies, with HRs of 0.77 (95% CI, 0.59-1.01) and 0.46 (95% CI, 0.24-0.89), respectively, for cancer incidence and mortality in those assigned to CaD supplementation. The current post hoc analysis of data from a large and well-executed randomized controlled trial demonstrates a protective association between modest CaD supplementation and HM risk in older women. Additional research concerning the relationship between vitamin D and HM is warranted. Cancer 2017;123:4168-4177. © 2017 American Cancer Society.

205 - Immune Reconstitution and Outcomes after Peripheral Blood Haploidentical Transplantation with Novel Conditioning and Post-Transplant Cyclophosphomide (PTCY)

The outcomes after Haploidentical HCT with Flu-CY-TBI and PTCY using BM as a graft source have been associated with high relapse and delayed immune recovery. Additionally, there is limited knowledge regarding immune reconstitution post haploidentical HCT with the use of mobilized peripheral blood. We hypothesized that the immunogenic properties of pre-transplant low dose Cyclophosphamide along with immunomodulatory effects of Melphalan would enhance early post-transplant engraftment and early peripheral T cell recovery through enhanced cytokine release and antigen alloreactivity. We examined the clinical outcomes and immune reconstitution recovery of 12 consecutive haploidentical HCT patients with high-risk hematological malignancies. Patients and Graft characteristics is as shown in Table 1. Conditioning regimen was low dose Cy 14.5 mg/m2 on day -6 & day −5, Flu 30 mg/m2 day −6 to Day −2 and Mel 70 mg/m2 on day −3 & −2. Graft versus host disease prophylaxis (GVHD) was PTCY 50 mg/Kg on day +3 and day +4 along with Tacrolimus and Mycophenolate starting at day +5. Immune reconstitution performed on days +60, +120 and +180 post HCT. All the patients treated according to an institutional protocol and records reviewed retrospectively after IRB approval.Table 1 All patients engrafted with median time to engraftment of 17 days (range 12-23). Chimerism studies revealed enhanced engraftment with 100% donor in bone marrow and peripheral blood at day 30 in all 12 patients. Post HCT immune recovery shown in Table 2. There was significant early recovery at day 60 of all T cell subsets, most pronounced in activated T cells. While we have observed a progressive reduction in the median number of early-activated T cells at day 120 & 180, the number CD4 and NK cells has improved (Figure 1).Table 2Table 2 With median duration of follow up of 323 days, range (123-451), the overall survival at day 100 and projected one year is 92% and 81% respectively. Only 2/12 had relapsed at 95 and 321 days post- transplant. Treatment related mortality (TRM) was limited to 1/12 patients. Acute GVHD grade 2-4 developed in six of 12 patients, two of whom were grade 3-4. Chronic GVHD has developed in four patients (1 serositis, 1 pericardial effusion and 2 nephrotic range proteinuria). CMV reactivation occurred in 9/12 patient with no CMV disease. Aspergillus antigen positivity in serum occurred in 4 /12 but only two of them developed clinical fungal infection. Conclusion: In this limited series of patients with high- risk hematological malignancies who underwent haploidentical HCT with Cy/Flu and Melphalan with PTCY, the regimen was well tolerated and resulted in effective disease control. The regimen has also demonstrated enhanced early engraftment and robust immune recovery in comparison to other studies, Table 3. The study provide unavailable knowledge about immune reconstitution post Haplo-identical HCT with PTCY with the use of mobilized peripheral blood.Table 3

Pre-Transplant Low Dose Cyclophosphamide Enhances Engraftment and Immune Reconstitution in Haploidentical Hematopoietic Stem Cell Transplant (HCT) Recipients Receiving Total Body Radiation (TBI) Free Reduced Intensity Conditioning with Post- Transplant Cyclophosphamide (PTCY)

The outcomes after Haploidentical HCT with Fludarabine (Flu)/Cyclophosphamide (Cy)/TBI and PTCY as pioneered by the Hopkins group have been associated with higher risk of relapse and delayed immune reconstitution. Multiple groups have explored the potential benefits of more intensive conditioning regimens with or without TBI. However, none of these regimens to our knowledge has exploited the immunogenic properties of pre-transplant low dose Cy while avoiding the immune-suppressive effect of TBI. Additionally, there is limited knowledge regarding immune reconstitution post haploidentical HCT with the use of mobilized peripheral blood stem cells. Accordingly, we designed a protocol modification of the Hopkins regimen by replacing TBI with Melphalan (Mel) without adding Thiotepa in contrast to the MD Anderson regimen (Ciurea et al). We hypothesized that the immunogenic properties of pre-transplant low dose Cy along with the immunomodulatory effects of Mel would enhance early post-transplant engraftment and early peripheral T cell recovery through enhanced cytokine release and antigen alloreactivityWe examined the clinical outcomes and immune reconstitution recovery of 12 consecutive haploidentical HCT patients with high-risk hematological malignancies. Patient and graft characteristics are as shown in table-1. The conditioning regimen was low dose Cy 14.5 mg/m2 on day -6 & day -5, Flu 30 mg/m2 on days -6 to Days -2 and Mel 70 mg/m2 on day -3 & -2. Graft versus host disease prophylaxis (GVHD) was PTCY 50 mg/Kg on day +3 and day +4 along with Tacrolimus and Mycophenolate starting at day +5 as previously described by the Hopkins group. An immune reconstitution panel of absolute lymphocyte count (ALC), CD3, CD4, CD8, Activated T cell (CD3-HLA Dr + T cells) & NK cell (CD56/16) was performed by 4 color flow-cytometry on days +60, +120 and +180 post HCT. Chimerism studies were performed at day +30 and +100 post HCT by variable number tandem repeat PCR analysis of peripheral blood & bone marrow. All of the patients were treated according to an institutional protocol and records were reviewed retrospectively after IRB approval.All patients engrafted with a median time to engraftment of 17 days (range 12-23). Chimerism studies revealed enhanced engraftment with 100% donor in bone marrow (unsorted) and peripheral blood (CD3, CD33 & CD 56) at day +30 in all 12 patients. All patients with active disease at time of transplant (5 Pts) achieved complete remission at day +30 evaluation. Post HCT immune recovery is shown in table 2. There was significant early recovery at day + 60 of the median ALC and all T cell subsets. This recovery was most pronounced in activated T cells. While we have observed a progressive reduction in the median number of early activated T cells at day 120 & 180, the number of helper T cells (CD4) and NK cells (CD56/16) did not decline (Figure 1).With a median duration of follow up of 261 days (range 62-390), the overall survival at day 100 and projected one year survival is 96% and 81% respectively. Only one of 12 patients had relapsed. Acute GVHD grade 2-4 developed in six of 12 patients, two of whom were grade 3-4. Chronic GVHD developed in four patients (1 serositis, 1 pericardial effusion and 2 nephrotic range proteinuria). Cytokine storm developed in 5/12 patients after stem cell infusion and resolved after PTCY. BK cystitis developed in four patients but continuous bladder irrigation was only required in two patients. All cases of BK cystitis were transient and resolved with supportive measures. CMV reactivation occurred in 9/12 patients; no CMV disease or CMV mortality was observed. Aspergillus antigen positivity in serum occurred in 4 /12 but only two developed clinical fungal infection.Conclusion: In this limited series of patients with high- risk hematological malignancies who underwent haploidentical HCT with low dose Cy/Flu/Mel and PTCY, the regimen was well tolerated and resulted in effective disease control. The regimen has also demonstrated enhanced early engraftment and robust immune recovery in comparison to other studies, table 3. However, it is not clear if this enhanced immune recovery is related to the conditioning regimen modification or the use of mobilized stem cells. The results are intriguing and need further confirmation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Viral co-infections and paraproteins in HIV: effect on development of hematological malignancies.

The role of viral co-infections and paraproteins in the development of hematological malignancies (HMs) in HIV remains unclear. Using our large database of HIV+ patients, we investigated whether co-infection and paraproteinemia increase the risk of HM. Data on demographics, hepatitis B (HBV) and hepatitis C virus (HCV) co-infections, paraproteinemia, HIV characteristics, and biopsy proven malignant hematological disorders for HIV+ patients were collected over a 10-year period in a large urban hospital setting. We identified 10,293 HIV+ patients who were followed for a median duration of 53 months. Of the 10,293 patients with HIV, 229 (2.2 %) were diagnosed with a HM. Over 85% of patients in both groups were tested; no significant difference in the prevalence of chronic HBV or HCV was noted between the HM positive (n = 229) and HM negative (n = 9992) patients. The serum protein electrophoresis test was performed for 1371 of the 10,221 patients. HM positive patients, compared to HM negative, were more likely to be tested for paraproteins (OR 3.3, 95% CI 2.5-4.4) and more likely to have a discrete paraprotein band (OR 3.3, 95% CI 1.2-8.9). Discrete paraproteins exclusively correlated with the development of plasma cell malignancies. Faint or oligoclonal protein bands were seen in high grade B cell lymphomas but did not show a significant correlation with HM development. Chronic hepatitis B or C infections did not correlate with the development of HM in HIV; however, viral influence on host gene transformation may have been impacted by anti-viral therapy limiting the duration of high viremic states.

Abstract 5594: Progression of paraproteinemia in HIV-positive versus HIV-negative patients

Abstract BACKGROUND: Paraproteinemias occur in 1 to 3% of people over the age of 50 and progress to hematological malignancies (HM) at the rate of about 1% per year. In HIV+ patients a higher incidence of paraproteinemia has been reported however the rate of progression to HM remains unclear. We studied a large database comparing HIV+ and HIV- patients with paraproteinemia for incidence of HM. METHODS: Patients tested for HIV who also had a serum protein electrophoresis test (SPEP) performed between January 1st 2001 and December 31st 2011 were identified using a medical database at a large tertiary care center. SPEP+ patients were stratified into distinct (D-SPEP) or faint/multiple/oligoclonal (F-SPEP) bands by an independent laboratory technician. Demographics, coinfections and biopsy data were reviewed. RESULTS: 181,851 patients underwent a HIV test and 10,293 were HIV+. Significantly greater number of HIV+ patients (1381 of 10,293) compared to HIV- (6512 of 171,588) were tested for paraprotein (13.4% vs 3.8%, p&amp;lt;0.0001). Of those tested, the prevalence of SPEP positivity was higher in HIV+ (266 of 1381) versus HIV- (537 of 6512) (19.3% vs 8.2%, p&amp;lt;0.0001). HIV+ SPEP+ patients were more likely to have F-SPEP and light chain paraproteins compared to their HIV- counterparts. HIV+SPEP+ patients were significantly more likely to be tested and more likely to be positive for hepatitis B and C co infections. HIV- SPEP+ patients were more likely to have a D-SPEP and IgA and IgM subtype paraproteins than HIV+ patients. HIV- patients also had a higher incidence of HM which persisted when adjusted for year of SPEP and duration of follow up (p&amp;lt;0.0001). CONCLUSIONS: While a higher prevalence of paraproteinemia was noted in the HIV+, HM incidence was lower in the HIV+ compared to HIV-, suggesting that nonmalignant virus-dependent proliferation may lead to paraproteinemia in some HIV+ cases. Identification of HIV+SPEP+ cases with higher risk of HM will be clinically relevant. Table 1.Comparison of HIV+SPEP+ and HIV- SPEP+ patientsCharacteristicHIV+ SPEP+ (n = 266)HIV- SPEP+ (n = 537)p value(Chi square/ Fishers exact/ t-test)Age at SPEP test (yrs)50 (SE: 0.54)59 (SE: 0.55)&amp;lt;0.0001*F-SPEP (n,%)234 (88%)342 (63.7%)&amp;lt;0.0001D-SPEP (n,%)32 (12%)195 (36.3%)&amp;lt;0.0001*IgG (n,%)209 (78.6%)372 (73.5%)0.136IgM (n,%)4 (1.5%)42 (8.3%)&amp;lt;0.0001*IgA (n,%)3 (1.1%)40 (7.9%)&amp;lt;0.0001*Light chain (n,%)24 (9%)23 (4.5%)0.013Hepatitis C positive by serology/ viral load of those tested113/246 (45.9%)78/412 (18.9%)&amp;lt;0.0001HBsAg/ Hepatitis B viral load positive of those tested22/241 (9.1%)4/254 (2.6%)0.012Follow up after SPEP test (months)23360.003HM (n,%)17 (6.5%)83 (16.1%)&amp;lt;0.0002HM+ of F-SPEP+12/234 (5.1%)34/342 (9.9%)0.042HM+ of D-SPEP+5/32 (15.6%)49/195 (25%)0.369 Citation Format: Erin Jou, Oleg Gligich, Alvita CY Chan, Diwakar Mohan, Uriel R. Felsen, Sabarish Ayyappan, Henny H. Billett, Edwin P. Hui, Anthony TC Chan, Radha Raghupathy. Progression of paraproteinemia in HIV-positive versus HIV-negative patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5594. doi:10.1158/1538-7445.AM2015-5594

LINAC-based intensity modulated total marrow irradiation (TMI) in addition to myeloablative fludarabine/IV busulfan conditioning prior to allogeneic stem cell transplant for high-risk hematologic malignancies: A phase I study.

7045 Background: Total body irradiation (TBI) currently has limited use in stem cell transplant due to significant extra-hematologic toxicity. Intensity modulated total marrow irradiation (TMI) represents an innovative technique to selectively irradiate the bone marrow. We combined a fully myeloablative chemotherapy regimen with escalating doses of TMI in a Phase I trial in allogeneic stem cell transplant. (Id: Clinicaltrials.gov NCT00988013). Methods: A Phase 1 trial (3+3 design) for adult patients with high risk (HR) hematologic malignancies enrolled 14 patients who were transplanted from related (n=9) or unrelated (n=5) donors and included: HR acute lymphoblastic (ALL) (n=2) or myeloid (AML) (n=9) leukemia, HR multiple myeloma (n=2) and chronic myeloid leukemia (CML) (n=1) resistant to TKI. Median age was 52 years (range 20-65). Patients received fludarabine 160mg/m2, targeted i.v. busulfan (AUC 4800 μM/min) and IM-TMI (from 3 to 12 Gy). Dose Limiting Toxicity was defined as any grade 3 or 4 toxicity u...

Associations between allergies and risk of hematologic malignancies: Results from the VITamins and lifestyle cohort study

Immune dysregulations associated with allergies may affect cancer cell biology but studies on the relationship between allergies and risk of hematologic malignancies (HM) yielded inconsistent results. Herein, we used the vitamins and Lifestyle (VITAL) cohort to examine this association. From 2000 to 2002, 66,212 participants, aged 50-76, completed a baseline questionnaire on cancer risk factors, medical conditions, allergies, and asthma. Through 2009, incident HMs (n = 681) were identified via linkage to the surveillance, epidemiology, and end results cancer registry. After adjustment for factors possibly associated with HMs, a history of airborne allergy was associated with increased risk of HMs (hazard ratio [HR] = 1.19 [95% confidence interval: 1.01-1.41], P = 0.039) in Cox proportional hazards models. This association was limited to allergies to plants/grass/trees (HR = 1.26 [1.05-1.50], P = 0.011) and was strongest for some mature B-cell lymphomas (HR = 1.50 [1.14-2.00], P = 0.005). Gender-stratified analyses revealed that the associations between airborne allergies overall and those to plants, grass, and trees were only seen in women (HR = 1.47 [1.14-1.91], P = 0.004; and HR = 1.73 [1.32-2.25], P < 0.001) but not men (HR = 1.03 [0.82-1.29], P = 0.782; and HR = 0.99 [0.77-1.27], P = 0.960). Together, our study indicates a moderately increased risk of HMs in women but not men with a history of allergies to airborne allergens, especially to plant, grass, or trees.