Citations

Abstract Breast cancer survivorship guidelines recommend at least annual follow-up visits, yet the degree to which this occurs in clinical practice is uncertain. Claims data from a US commercial insurance database (OptumLabs) were used to identify women treated with curative intent surgery for newly diagnosed breast cancer between 2006 and 2014. In 25 035 women, median follow-up was 3 years. In the second year after surgery, 9.6% of the patients did not visit a primary care provider, an oncologist, or a surgeon (guideline-nonadherent). The guideline-nonadherent proportion increased from 7.8% in women diagnosed in 2006 to 12.2% in those diagnosed in 2014 (two-sided Wald P < .001). During years 2–6, guideline-nonadherence was also associated with older age, nonwhite race, no radiation, no chemotherapy, no endocrine therapy, and increasing time after surgery. There is a substantial and increasing rate of inadequate follow-up among breast cancer survivors. This has the potential to impair outcomes.

Abstract Relapse of malignancy and lethal graft versus host disease (GVHD) are the principal causes of failure of allogeneic hematopoietic cell transplant (HCT). Recently we have shown that at seven days after HCT an algorithm using two serum biomarkers (ST2 and REG3α) can predict severe GVHD (Hartwell et al. JCI Insight 2017). We determined whether serial testing (in the first month following HCT) of patients with low probability biomarkers would improve the predictive accuracy of the algorithm and identify patients with different risks of relapse and lethal GVHD. Patients who received an HCT at 18 centers in the Mount Sinai Acute GVHD International Consortium (MAGIC) for hematologic malignancy and who supplied three blood samples were divided into a training set and validation set with equal numbers of lethal GVHD events, which was defined as death from GVHD or infection during treatment for GVHD. Patients in the training set (n=702) underwent HCT from January 1, 2006 until June 30, 2015, whereas patients in the validation set (n=906) underwent HCT from July 1, 2015 to May 1, 2017. Serum samples were analyzed using the previously published algorithm of two biomarkers up to three times (day 7, day 14, day 28 or GVHD onset, if onset occurred within the first 28 days). The algorithm generates a predicted probability of lethal GVHD between 0 and 1 for each patient. Patients were categorized as either low probability (LP) or high probability (HP) for lethal GVHD. HP thresholds of 0.20 and 0.16 were used to classify patients with and without GVHD symptoms, respectively (once categorized as HP, patients remained in that category and were not retested). All results were similar between training and validation sets, and we present here the validation set results. Serial testing identified 28% of patients as HP with a three-fold greater cumulative incidence of lethal GVHD at one year (13% vs 4%, p<0.001, Figure 1). Relapse rates were the same in both probability groups, and thus LP patients experienced significantly better relapse free survival (RFS) (69% vs 53%, p<0.001). As expected, significantly fewer LP patients experienced severe GVHD at onset (as measured by Minnesota risk), maximum grade III/IV GVHD, or steroid resistant GVHD by day 180 after HCT (Figure 2, p<0.001 for all three parameters). To measure the accuracy of prediction, at each timepoint we calculated the area under the curve (AUC) of receiver operating characteristic curves; the AUC increased significantly with each subsequent evaluation, from 0.59 at one timepoint (dotted line) to 0.74 at the third timepoint (solid line) (p<0.001), with a final sensitivity of 65% and specificity of 74% (Figure 3A). Early development of GVHD (by day 28) is a risk factor for lethal GVHD. Therefore, we next plotted RFS (dashed line), relapse (solid line), and lethal GVHD (dotted line) rates in patients who developed GVHD by day 28. 25% of patients with GVHD were categorized as HP and had a cumulative incidence of lethal GVHD more than four times higher (28%) than that of relapse (6%); however the risks were reversed for the 75% of patients who were LP, where relapse (15%) occurred twice as often as lethal GVHD (7%) (Figure 3B). In patients who did not develop GVHD in the first month, this reversal of risks was even more dramatic. Approximately half (53%) of the entire validation cohort did not develop GVHD by day 28 and was LP at all three evaluations. These patients had an exceptionally low risk of lethal GVHD and thus they relapsed (25%) much more often than they died from GVHD (3%). When malignancies were classified according to risk for relapse by the disease risk index (DRI) (Figure 3C), the probability of relapse was three fold higher than lethal GVHD in malignancies with a low DRI (12%), six fold higher for intermediate DRI (20%), and eleven fold higher for high/very high DRI (33%). We conclude that a serial monitoring strategy using GVHD biomarkers for one month after HCT is able to identify two groups of patients with very different risks of lethal GVHD and relapse. For these patients, the intensity of immunosuppression after day 28 could be tailored according to the probabilities of developing lethal GVHD and relapse in the context of clinical trials. Disclosures Aziz: Doris Duke Charitable Foundation: Research Funding. Ayuk:Therakos (Mallinckrodt): Honoraria; Novartis: Honoraria; Celgene: Consultancy; Gilead: Consultancy. Chen:REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Merli:Neovii Biotech: Honoraria; AMGEN: Honoraria. Roesler:Sanofi: Other: Travel, Accommodations, Expenses; Amgen: Equity Ownership; Jazz Pharmaceuticals: Other: Travel, Accommodations, Expenses; Immunomedics: Equity Ownership; Biogen: Equity Ownership; Merck: Consultancy; Pfizer: Consultancy. Kitko:Novartis: Consultancy, Honoraria; Mallinckrodt: Honoraria, Other: Travel, Accommodations, Expenses. Qayed:Novartis: Consultancy. Wölfl:Bristol-myers Squibb: Equity Ownership; Novartis: Equity Ownership; Taheda: Equity Ownership; Juno: Equity Ownership; Neovii: Other: Travel, Accommodations, Expenses. Mielke:Celgene: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau; Kiadis Pharma: Speakers Bureau; Miltenyi: Speakers Bureau. Wudhikarn:Takeda Oncology: Other: Travel, Accommodations, Expenses. Nakamura:Celgene: Honoraria; Molmed: Honoraria; Merck: Consultancy; Pharmacyclics: Consultancy; Atara: Consultancy; Jazz Pharmaceuticals: Consultancy. Pulsipher:CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotech: Consultancy, Research Funding; Amgen: Honoraria. Reshef:Pfizer: Consultancy; Atara Biotherapeutics: Consultancy; Kite Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy. Levine:Therakos: Consultancy; Novartis: Consultancy; Bluebird: Consultancy; Incyte: Consultancy; Kamada: Research Funding; Viracor: Patents & Royalties. Ferrara:Incyte: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Xenikos: Consultancy, Other: Travel, Accommodations, Expenses; Kamada: Consultancy, Research Funding; Viracor: Consultancy, Patents & Royalties.

Abstract Introduction Expanding treatment options for MDS have changed therapeutic decision-making for clinicians. To better characterize therapeutic choices in newly diagnosed MDS, we report the practice patterns captured during the first year of MDS diagnosis for patients enrolled in our statewide population-based study. We highlight a comparison of treatment in community and academic centers. Methods Adults in Minnesota with MDS (AIMMS) is a statewide prospective population-based study conducted by the University of Minnesota (UMN), Mayo Clinic, and Minnesota Department of Health. Starting in April 2010, all newly diagnosed adult cases (ages 20+) of MDS were invited to participate. After patient enrollment, central review was performed consisting of independent hematopathology and cytogenetic review coupled with oncologist chart review assigning prognostic risk scores [International Prognostic Scoring System (IPSS) and IPSS-R (Revised)] and abstracting treatment exposures. All enrolled patients with one year follow-up were included in this analysis. Treatment was divided into supportive, active, transplant, or other. Supportive care included observation, growth factors, and transfusions. Active care included azacitidine, decitabine, lenalidomide, or 7+3 chemotherapy. Academic centers were defined as the UMN and Mayo Clinic; all other centers were designated as community based practices. Results The median patient age was 73 years, with 68% males. IPSS and IPSS-R risk scores were calculated for 100% and 97% of patients, respectively. Treatment choices stratified by IPSS risk group showed 89% low risk, 53% INT-1, 31% INT-2, and 13% high risk with supportive care; active and transplant strategies were utilized for 9% low risk, 44% INT-1, 64% INT-2, and 88% high risk. INT-1 in the community received 70% supportive treatment, in academic 35%. Active treatment for INT-1 was 30% in community and 45% in academic. Community INT-2 received supportive care in 45% of cases, in academic 23%. Transplants were limited to academic centers, with the highest rate in INT-2 at 34%. Among community diagnoses, 100% of high risk, 52% INT-2, 26% INT-1, and 13% low risk were referred to an academic center. Comparison of age <65 and 65+ years showed 83% of transplants occurred in those <65. INT-2/high risk group patients <65 received 95% active therapy or transplant, compared to 51% of those 65+. Discussion This prospective, population based study provides a well-defined patient cohort based on central review of pathologic and clinical data. Evaluation of practice patterns during the first year after diagnosis showed higher utilization of active and transplant treatment strategies as IPSS risk score increased. Further, compared to community, higher utilization occurred for patients at academic centers, suggesting more aggressive treatment in these settings. Age was also a predictor of treatment choice. In addition, referral patterns followed IPSS score. Whether these treatment differences are driven by patient preference and/or translate into improved disease control and decreased mortality requires continued prospective analysis and will be detailed in future reports. Disclosures No relevant conflicts of interest to declare.

Abstract Background Patients with cancer may face a significant knowledge deficit as they battle their illness. We developed a first of its kind comprehensive patient symposia (Living with Cancer (LWC): A Mayo Clinic Symposia for Patients and Loved Ones) with 8 hours of general sessions (covering nutrition, exercise, cancer inheritance, financial and legal challenges, communication, survivorship, and cancer therapy) and a 4-hour disease specific breakout (myeloid diseases, myeloma, lymphoma, chronic lymphocytic leukemia, breast cancer, lung cancer, cutaneous malignancy, colorectal cancer, and prostate cancer). Through voluntary questionnaires, we studied the impact of this cancer symposium on quality of life, cancer specific knowledge, and symptom management among cancer patients. Methods LWC meeting attendees were provided surveys prior to and 3 months following the convention. Surveys included 1) EORTC-QLQ-C30; 2) new disease understanding tool developed specifically for this conference; 3) distress thermometer and problems checklist; 4) validated disease-specific questionnaires. Changes over time were assessed using McNemar’s tests and paired t-tests for categorical and continuous variables, respectively. Results Patients:158 attendees completed the pre-convention survey. The median age was 67.5 (range 30-86), 49% males, 76% over 1 year from diagnosis. Cancer type included 37% hematologic malignancies, 23% breast cancer, 23% prostate cancer, and 17% other. The hematologic malignancies were comprised of 34% leukemia, 31% CLL/lymphoma, 25% amyloid/multiple myeloma, and 9.3% myeloproliferative neoplasms. Baseline Disease Understanding, Symptoms, QOL: Most attendees endorsed understanding their disease quite a bit (54%) or very much (29%). Most respondents reported at least “quite a bit” of understanding regarding treatment options (84%), screening modalities (83%), symptomatology (74%), and cancer-related side effects (71%). Attendees endorsed the least understanding of disease-related stress (49%), risk factors (49%), management of disease related fatigue (41%), and legal issues related to disease/treatment (27%) Mean QLQ-C30 scores were 84.4 for physical functioning, 83 for role functioning, 80.7 for social functioning, and 72.7 for global health status. The symptoms with highest mean scores were insomnia, fatigue, and pain. Knowledge Improvement Durable at 3 Months: 115 (73%) patients completed the post-symposium survey. There was improvement in 12 of 14 areas of self-reported knowledge (Table 1) especially in areas of nutrition, and management of disease related stress and fatigue (all p<0.001). Symptomatic Changes at 3 Months: There was no significant change in QLQ-C30 physical/role/emotional functioning, fatigue, pain, or insomnia. Conclusions This first evaluation of a patient centered cancer symposium as an education intervention suggests patients selecting to participate in such an event seek to improve an already solid knowledge base regarding their malignant disease. Participating in the event improved disease specific knowledge in numerous areas. However, as a single intervention, function and symptoms tended not to improve with participation. Future efforts on 1) improving participation with disease knowledge “naïve” patients and 2) targeted efforts aimed at specific symptom management (i.e. insomnia, stress) are planned. This study serves as an avenue to empower patients and inform physicians to improve the experience of living with cancer. Disclosures: No relevant conflicts of interest to declare.

Abstract Autologous stem cell transplantation (ASCT) remains an important consolidation treatment for multiple myeloma (MM) patients, even in the era of novel agents. The prolongation of plateau-phase induced by ASCT is generally attributed to intensive cytoreduction. However, ASCT generates inflammation and profound lymphodepletion, which may result in hitherto unexpected immunological effects. To investigate potential immunological contributions to myeloma control after ASCT, we developed preclinical models of transplantation for MM using Vk*MYC myeloma that generates bony lytic lesions, a serum M band and marrow plasmacytosis that are hallmarks of clinical disease. Myeloma-bearing B6 recipients underwent myeloablative conditioning and were transplanted with naïve B6 bone marrow (BM) grafts with or without T cells from donors that were myeloma-naïve (SCT) or had low M bands at the time of harvest to mimic ASCT. Surprisingly, we demonstrate the broad induction of T cell-dependent myeloma control with enhanced median survival in recipients of grafts containing T cells compared to T cell depleted (TCD) BM alone (SCT= 91 days and ASCT > 100 days post-transplant vs TCD BM alone= 44 days; p<0.0001). Myeloma was most efficiently controlled when recipients were transplanted with memory T cells (CD44+) from autologous grafts (median survival: ASCT-CD44+ T cells >90 days post-transplant vs. CD44─ T cells = 50 days; p = 0.0006). Importantly, T cells adoptively transferred from recipients surviving > 120 days (MM-primed) protected secondary recipients compared to T cells from naïve donors (median survival: MM-primed > 120 days post-transplant vs 65 days naïve T cells; p = 0.0003). Furthermore, MM-primed CD8 T cells were restricted in TCR repertoire and provided protection in a myeloma clone-specific fashion, indicative of a tumor-specific T cell response. Despite this immune-mediated control of myeloma after SCT, progression still occurred in the majority of recipients. We phenotyped CD8+ T cells from the BM of MM-relapsed, MM-controlled and MM-free (that had never seen myeloma) mice 8 weeks after SCT. Expression of the inhibitory receptors, programmed cell death protein 1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) on BM CD8+ T-cells strongly correlated with myeloma cell number (r = 0.729, p<0.0001 and r = 0.796, p<0.0001 respectively). Additionally, the co-stimulatory/adhesion receptor CD226 (DNAM-1) was markedly downregulated as myeloma progressed (r = - 0.865, p<0.0001), as was interferon-γ secretion (r = - 0.76, p = 0.0022). t-SNE analysis confirmed an irreversible exhaustion signature at myeloma progression, characterized by the absence of DNAM-1 and co-expression of PD-1, TIM-3, TIGIT together with CD101 and CD38. Immune-checkpoint inhibition (CPI) early post-SCT, using antibodies against PD-1 or TIGIT facilitated long-term myeloma control (median survival in both treatment arms > 120 days post-SCT vs. 60 and 68 days respectively; p <0.05). Furthermore, TIGIT blockade limited CD8+ T cell exhaustion, increased CD107a and IFNγ secretion and expanded a memory CD8+ T cell population in the BM. Genetic deletion of either IFNγ or the IFNγ receptor from the donor graft resulted in dramatic myeloma progression after SCT. Consequently, treatment with a CD137 (4-IBB) agonist early after SCT profoundly augmented CD8+IFNγ+GranzymeB+ T-cell expansion in the BM, such that majority of treated animals eliminated myeloma and survived long-term. These data provide insights into an unappreciated mechanism of action of ASCT whereby myeloma immune-equilibrium is established and suggest that combination with immunotherapeutic strategies is a rational approach to generate long term disease control. Disclosures Smyth: Bristol Myers Squibb: Other: Research agreement; Tizona Therapeutics: Research Funding.

Abstract The JAK2V617F mutation is present in the majority of cases of myeloproliferative disease, including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), and is an attractive candidate for molecularly targeted therapy. However, the potential toxicities of JAK2 inhibition in vivo, and identification of appropriate surrogate endpoints for response, are challenges that may limit clinical usefulness in treatment of these relatively indolent diseases. We report efficacy and assessment of surrogate endpoints for response of a small molecule JAK2 inhibitor, TG101348 in a murine model of polycythemia vera. TG101348 is selective for JAK2 with an in vitro IC50 of ∼3 nM that is ∼334 fold more potent than for inhibition of JAK3. TG101348 showed therapeutic efficacy in the murine model of PV that included a statistically significant reduction in hematocrit, normalization of white blood cell count, a dose dependent reduction/elimination of extramedullary hematopoiesis in the spleen and liver, and marked attenuation of myelofibrosis. Consistent with its selective inhibition of JAK2 and not JAK3, there was no significant change in T-cell number in treated animals. These clinical responses correlated with surrogate endpoints for response, including reduction or elimination of JAK2V617F expressing clones based on quantitative genomic PCR, suppression of JAK2V617F positive endogenous erythroid colony growth of JAK2V617F MPD bone marrow, and inhibition of JAK-STAT signal transduction as assessed by phosphoflow cytometry for phosphorylated STAT5. Thus, TG101348 is efficacious in treatment of a murine model of PV, and surrogate endpoints have been identified that may be of value in clinical trials in humans.

Abstract Abstract 1024 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004. Sixteen North American member institutions with expertise in multiple myeloma (MM) work collaboratively with the MMRC Inc. (Norwalk, CT) and numerous pharmaceutical partners to speed development of new treatment options to MM patients. In December 2007, MMRC Inc. implemented business solutions to address barriers to rapid activation of phase I-II trials and established benchmarks for initiating and conducting these studies. In December 2010, we reported significantly faster trial start up and accrual data from previous years1,2. Today, we update and expand on MMRC performance data and analysis of progress. Methods: Twenty-five (25) trials conducted within the Consortium from May 2006 to July 2011 had sufficient start up trial data for review. FPFD was defined as the time from the member institutions' receipt of the final protocol (FP) from the trial sponsor, to the time the first patient was dosed on the trial at any participating MMRC member institution. With respect to enrollment, pre-study enrollment commitment (EC) established between MMRC and the study sponsor was defined as the total number of subjects committed to receive at least one dose of study drug across all participating MMRC centers on a trial; baseline enrollment timeline (BET) was prospectively defined as the target time period to attain EC. Results: Mean time to FPFD in the recent group of trials (RG; n=18; Sept 08-Jul 11) held steady at 131 calendar days from receipt of FP as compared to 181 days for the early group of trials (EG; n=7; Jun06-Sept08) representing a 28% reduction in time to FPFD. More importantly, there was a 20% decrease in time to FPFD by all participating MMRC centers on any MMRC trial from 189 days in the RG compared to 236 days in the EG representing an important achievement especially in the Phase I/II arena. MMRC trial accrual data was available for 17/25 trials (2 EG trials were missing data and 6 RG trials continue enrolling). The pre-study mean MMRC EC was 44 subjects per trial (n=19 trials; 849 patients); the mean actual MMRC enrollment was 49 subjects per trial (n=19; 935 patients through July 11) representing a 10% over enrollment versus committed enrollment. A total of 17/19 evaluable trials (89%) met their EC; 12/19 trials met EC within BET (71%) of which 8/12 trials (67%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 19 trials was 13.6 months. MMRC's actual mean enrollment timeline was 12.8 months for the group of 17 evaluable trials representing improvement over the original BET by a mean of 10%. Discussion: MMRC's acceleration of clinical trials provides physicians and patients with rapid access to novel compounds; industry with data for important drug development decisions; and academic institutions with more trials of high scientific interest. Even so, our data uncovered opportunities for improvement. The submission time from receipt of the final protocol from the trial sponsor to Scientific Review Committee (SRC) took an average 30 calendar days across all trials. A reduction to half this time could make a difference to patients and therefore warrants further exploration. Conclusion: Today, drug development in multiple myeloma is fast-paced and highly competitive. MMRC's frequent review of trial metrics provides valuable insight to continually speed answers to physicians, patients and industry. Disclosures: Richardson: Multiple Myeloma Research Consortium: Annual grant in support Clinical Trial Project Management. Vij:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Lonial:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Siegel:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jakubowiak:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Reece:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jagannath:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Hofmeister:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Stewart:Multiple Myeloma Research Consortium: Annual Grant in support of clinical trial Project Management. Wolf:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Krishnan:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Zimmerman:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Kumar:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Roy:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Fay:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Anderson:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management.

Abstract Background The timing of SCT for treatment of AML after first relapse is controversial, i.e.,whether to proceed to SCT at the time of relapse or to proceed to chemotherapy re-induction first in an attempt to reach a second remission. The purpose of this study is to determine the optimal time of allogeneic SCT in AML patients in first relapse by comparing outcomes of allogeneic SCT between patients untreated and patients post re-induction chemotherapy. Method This retrospective study was approved by the Mayo Foundation IRB. Between February 1983 and March 2003, 60 patients with AML in untreated first relapse (REL1) or post re-induction chemotherapy (CT) underwent allogeneic SCT in Mayo Clinic, Rochester. Study outcome included overall survival (OS), disease free survival (DFS), and transplant related mortality (TRM). The outcome was compared between the patients who underwent allogeneic SCT at REL1 and CT. Survival was analyzed using Kaplan-Meier (KM) and groups were compared statistically with the log-rank test. Result Of the 60 patients receiving allogeneic SCT , 25 patients and 35 patients underwent SCT at REL1 and CT, respectively. In the group of CT, 23 patients (66%) achieved CR2 while 12 patients (34%) had refractory disease. Forty-nine of 60 patients received cyclophosphamide and total body irradiation (Cy/TBI) as a conditioning regimen and the remainder received busulfan and cyclophosphamide( Bu/Cy). Patients in REL1 were older at SCT (median age 38 vs 31 years p= 0.024 ) and had lower percentage blast cells in bone marrow at first relapse (median 15% vs 50% p=0.00095) than in CT group. Difference in other baseline characteristics were not significant. KM analysis showed that the two groups did not show statistically differences in OS (p=0.43), DFS (p=0.68), and TRM (p=0.25). However, there were trends toward longer median OS (26.2 vs 5.4 months) and DFS (11.9 vs 3.3 months) with REL1 versus CT. OS at 1 year was 56 % for REL1 and 34.3 % for CT and at 5 year 32.1 % and 28.6 %, respectively. DFS at 1 year was 48 % for REL1 and 31.4 % for CT and at 5 years 22.9 % and 24.5 % respectively. TRM at 1 year was 25% for REL1 and 40 % for CT. A univariate Cox Proportional Hazard analysis for survival showed that unfavorable cytogenetics at diagnosis and relapse, antecedent MDS, and shorter duration of CR1 were significantly associated with a higher risk of death. Higher percentage of blast cells in bone marrow at first relapse was not significantly associated with a higher risk of death. In a multivariate model, unfavorable cytogenetics at first relapse and shorter duration of CR1 were both significantly associated with an increased risk of death. In this study, even after adjusting for other factors in a multivariate model, the difference between REL1 and CT groups was not statistically significant. Conclusion This study suggests that outcome of allogeneic SCT was comparable between REL1 and CT. Patients with AML in first relapse may proceed to allogeneic SCT because there appear to be no statistical differences in REL1 versus re-induction chemotherapy before SCT. REL1 patients tended to have a better outcome than CT patients.

Abstract In individuals with the plasma cell malignancy multiple myeloma, there is evidence that bone formation rates are reduced and that increased ostoeclastic bone resorption is associated with impaired osteoblast function. We investigated the osteogenic differentiation capacity of myeloma bone marrow mesenchymal progenitor cells (MPCs). We also examined the expression levels and activity of Runx2, the transcription factor required for osteogenesis. Bone marrow MPCs were cultured in osteogenic induction medium and assessed for bone alkaline phosphatase (bALP) expression (Sigma kit), induction of osteoblast specific genes like osteocalcin (RT-PCR) and mineralization by von Kossa staining. Immunoblot analysis and electrophoretic mobility shift assays (EMSA) were used to determine Runx2 expression and DNA-binding activity respectively. RT-PCR was used to sequence Runx2 and detect any mutations or deletions present within its domains. Transactivation ability of Runx2 was measured by its ability to activate osteocalcin promoter in transient transfection assays. Myeloma -derived MPCs showed reduced levels of bALP and osteocalcin transcript and a lower degree of mineralization, in osteogenic induction medium, as compared to that of the healthy donors. Immunoblot analysis and EMSA indicated equivalent Runx2 expression and DNA-binding capacity, respectively, in both healthy donor and myeloma-derived MPCs. Sequence analysis of Runx2 indentified a splice variant of Runx2 lacking exon 8 (Runx2D8) in myeloma patients with reduced transactivation ability. Co-transfection of the splice variant led to reduced transcriptional activity of the full-length Runx2. The reduced transactivation ability of spliced Runx2, as well as its suppressive action on the transactivation function of full-length Runx2, likely contributes to the defective osteogenesis clinically observed in myeloma pateints.

Abstract Introduction: The prevalence of venous thrombosis and pulmonary embolism (VTE) increases with age. Definitive VTE diagnosis or exclusion relies on imaging modalities, which are found to be negative in a high proportion of tested patients. Algorithms based on pretest clinical probability (low and intermediate) in conjunction with negative d-dimer test results have reliably excluded VTE sparing the need for additional imaging studies. Currently, the cutoff for a negative d-dimer is based on reference ranges regardless of age of the donor population. Since baseline d-dimer increases with aging, an age-adjusted d-dimer (AADD) cutoff for patients older than 50 years (age*10 ng/mL FEU) has been shown to improve specificity of diagnosis while still maintaining a high sensitivity (>97%) of detecting VTE/PE (Righini, et al. JAMA, 2014). Due to FDA restrictions, clinical laboratories cannot implement and report such AADD cutoffs. Major hurdles include: AADD cutoffs are assay-dependent, and there is a lack of feasible strategy for laboratories to verify the AADD cutoffs. We hypothesize that an adequate study of age-distribution of baseline d-dimer levels of healthy donors can assist the verification of AADD cutoffs and ultimately ensure patient safety in the VTE patient population. Objective: Establish an age dependent reference range for patients 50 years or older with the HemosIL HS 500 D-dimer reagent on the ACL TOP 700 (Instrumentation Laboratory, Bedford MA, USA); and compare this range with the manufacturer provided and literature recommended AADD cutoffs. Methods: D-dimer assay was performed on plasma samples from normal adult donors per the manufacturers' instructions. D-Dimer age, gender distribution and association were analyzed using non-parametric Wilcoxon rank sum, Kolmogorov-Smirnov tests, and quantile regression methods to estimate the 95th percentile to establish a reference range. Results: We studied 241 healthy donors, ranging from 21-91 years of age. Statistically significant differences between males and females (100 [42%] male) were detected (p-value <0.001; p-value =0.0009). Using CLSI guidelines, these statistical differences (median d-dimer for men = 200, while median d-dimer for women = 300) are not considered clinically significant, since only 6% of women would be outside an overall reference range (CLSI guideline states to partition if over 8% for either group would be outside the overall reference range). Using the quantile regression method, a significant association between d-dimer and age was found at the median (P<0.0001). We then established a reference range (95th percentile) for donors younger than age 50 at 635 ng/mL FEU for both men and women and AADD reference range for patients 50 and older (635 + (age - 50)*10 ng/mL) (Figure 1). This reference range was verified with our sample set, with only 6.2% of donors higher than the established reference limit. If we used the non-AADD cutoff provided by the manufacturer for donors younger than 50 (500 ng/mL FEU) and the literature recommended AADD cutoffs for older donors (age*10 ng/mL FEU), 13.3% of our normal donors were above the limits, resulting in not validating this literature reference range per CLSI guidelines in EP28-A3c. These data imply that if both manufacturer and literature recommended AADD cutoffs were adopted, HemosIL HS 500 D-dimer assay should have sufficient sensitivity and negative predictive value, although with slightly lower specificity than those reported by Righini, et al. for detecting VTE/PE. Conclusion: Our study verifies the association between d-dimer level and age and for the first time, to our knowledge, determined AADD normal range for the HemosIL HS 500 D-dimer assay. The manufacturer and literature recommended AADD cutoffs should provide sufficient sensitivity and negative predictive value for VTE/PE exclusion. Figure 1 Age distribution of D-Dimer values (n=241). Figure 1. Age distribution of D-Dimer values (n=241). Disclosures No relevant conflicts of interest to declare.