Citations

Abstract Introduction: Hematologic response criteria for light chain amyloidosis (AL) requires that difference in involved and uninvolved free light chains (dFLC) be at least 5 mg/dL (or 50 mg/L). However, many patients do not meet these criteria and are often excluded from clinical trials. These patients are challenging to follow clinically as organ response takes much longer and therefore response to treatment is difficult to evaluate in the first few cycles. This study aims to evaluate patients who had non-evaluable FLC (dFLC< 5 mg/dL) at diagnosis and compare them to those who had evaluable FLC (dFLC≥ 5 mg/dL). Methods: All patients with newly diagnosed AL seen within 90 days of diagnosis at our institution over a 10-year period (2006-2015) were identified from an institutional database. Data pertaining to demographics, diagnosis, treatment and follow-up was extracted from electronic medical records. Analysis was carried out by chi-square and Fisher's exact test for categorical variables and Kruskal-Wallis and Wilcoxon rank sum test for ordinal and continuous variables. Progression free survival (PFS) is defined as time to progression requiring treatment change or relapse requiring re-institution of treatment or death. PFS and overall survival (OS) were analyzed via the Kaplan-Meier method. Results: Of 1336 patients meeting inclusion criteria, dFLC at diagnosis was known in 1290. 85.4% (n=1101) had dFLC ≥ 5 mg/dL, while 14.6% (n=189) had non-evaluable FLC. Median age at diagnosis (65.2 vs. 63.9 years), gender distribution (males 56.1% vs.64.8%) and involved FLC (lambda: 72.2% vs. 72.9%) was similar in FLC < 5 mg/dL and FLC ≥ 5 mg/dL group. Cardiac (38.1 vs. 76.3%, p <0.0001) and liver (10.2% vs. 16.3%, p=0.03) organ involvement were less common in patients with non-evaluable FLC (table 1). NT-ProBNP was significantly lower in the group with dFLC < 5 mg/dL in patients with and without cardiac involvement, as was Mayo cardiac stage (table 1). A trend towards less gastrointestinal (GI) involvement (17.1% vs. 24%, p=0.09) was also seen with dFLC < 5 mg/dL. In contrast, a trend towards higher renal involvement was seen in patients with dFLC < 5 mg/dL (64.6% vs. 55.9%, p=0.08), though this was not statistically significant. Median 24 hour urine protein was significantly higher in all patients (with and without renal involvement) with dFLC < 5 mg/dL compared to dFLC ≥ 5 mg/dL group (table 1). Treatment details are listed in Table 1. ASCT (autologous stem cell transplant) was utilized more commonly in patients with dFLC < 5 mg/dL compared to patients with dFLC ≥ 5 mg/dL(43.2% vs. 26.1%, p <0.0001), including ASCT alone without chemotherapy (35.4% vs. 15.3%, p <0.0001).Rates of cardiac response (53.3% vs. 50.3%, p=0.88), and time to response (27.7 weeks vs. 35.6 weeks, p=0.67), were similar in both groups. Similarly, there was no difference in rates of renal and liver response and time taken to achieve a response (table 1). In patients with evaluable FLC, hematologic response was complete response (27.3%, n=245), very good partial response (21%, n=189), partial response (18%, n=160), no response (8%, n=74), progression (2%, n=15) and not known in 26.1% (n=216). In patients who had follow up data available, 30.6% (44/144) with dFLC < 5mg/dL experienced a relapse/progression with median PFS of 4.1 years (95% confidence interval (CI): 3 to 5.7), while 34.7% (304/875) with FLC ≥ 5 mg/dL experienced a relapse/progression with median PFS of 1.3 years (95% CI 1.1 to 1.5); p<0.0001. Median OS was higher in patients with dFLC < 5 mg/dL at diagnosis at 8.3 years compared to 2.4 years in patients with dFLC ≥ 5 mg/dL (p < 0.0001) as depicted in Figure 1. Conclusions: Patients with non-evaluable FLC at diagnosis have significant differences in organ involvement and survival compared to those with FLC ≥ 5 mg/dL at diagnosis. They have less cardiac and liver involvement and a trend towards less GI involvement, which may be secondary to low serum FLC burden and consequent less organ deposition. However, a trend towards higher renal involvement was seen in dFLC < 5 mg/dL group, with significantly higher urinary protein excretion. Loss of FLC in urine may result in lower serum FLC levels in this group. Survival was significantly better in patients with dFLC < 5 mg/dL, which may be explained by less cardiac involvement, lower cardiac stage and lower median FLC at diagnosis. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Jannsen: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; AbbVie: Research Funding; Noxxon: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

Abstract Chimeric antigen receptor T (CART) cell therapy results in impressively high remission rates in B cell neoplasms but is limited by the development of cytokine release syndrome (CRS). CRS is characterized by the development of high-grade fevers, hypotension, fluid overload and respiratory compromise, coincides with T cell expansion and is associated with marked elevation of interleukin-6, interferon-ɣ and other inflammatory cytokines. Severe CRS is seen in 25-80% of patients treated with CD19 directed CART cell therapy and mortality has been reported. While the use of the anti-IL6 receptor antibody tocilizumab with or without steroids can usually reverse this syndrome, there is concern that the early introduction of immunosuppressive medications could impair the anti-tumor activity and therefore most investigators currently reserve tocilizumab as therapy for severe (grade 3-4) CRS. Ruxolitinib is a JAK/STAT pathway inhibitor that is FDA approved for myelofibrosis and polycythemia vera and has resulted in a significant reduction of inflammatory cytokines in clinical studies. In preclinical models, treatment with ruxolitinib ameliorates cytokine production and manifestations of hemophagocytic lymphohistiocytosis. Therefore, there is a compelling rationale to investigate and develop ruxolitinib as a modality to prevent CRS after CART cell therapy. To our knowledge, there are no relevant models for CRS after human CART therapy, thus severely limiting the development of CRS prevention modalities that would in turn enhance the clinical feasibility of CART therapy. In this study, we established a novel acute myeloid leukemia (AML) xenograft model to study the development of CRS. Here, NSG-S (Non Obese Diabetic, SCID ɣ -/- mice that are additionally transgenic for human stem cell factor, IL-3 and GM-CSF) are engrafted with blasts from AML patients and treated with 1x106 CD123-directed CART cells (CART123), ten-fold higher than we previously used in our primary AML xenograft models. These animals develop an illness characterized by progressive weight loss, generalized weakness, emaciation, hunched bodies, withdrawal and poor motor response. This illness starts within one week of CART cell injection, correlates with T cell expansion and rapidly evolves and results in the death of the animals in 7-14 days (Figure 1A). Serum from these mice seven days after CART123 shows an extreme elevation of human IL-6, Interferon-γ, tumor necrosis factor-α, and other inflammatory cytokines (Figure 1B), resembling human CRS after CART cell therapy. NSG-S mice bearing primary AML were treated with CART123 and randomized to receive different doses of ruxolitinib (30, 60, or 90 mg/kg) or vehicle by oral gavage twice a day. Treatment started on the day of CART123 injection and continued for a week. Mice treated with ruxolitinib 60 or 90 mg/kg exhibited less severe clinical illness as manifested by attenuated weight loss when compared with mice treated with CART123 alone (Figure 2A). With the exception of ruxolitinib-only treated mice, all other groups exhibited an equivalent anti-leukemic effect (Figure 2B). We therefore established ruxolitinib 60 mg/kg for further experimental use. Most importantly, ruxolitinib treatment attenuated inflammatory cytokines (figure 2C) and led to long-term survival (figure 2D). Here we have described for the first time a clinically relevant animal model of human CRS and demonstrated that the JAK/STAT inhibitor ruxolitinib can prevent the development of severe CRS without impairing the anti-tumor effect of CART cells. These findings provide a useful platform for the future study of CRS prevention and treatment modalities. These experiments indicate that ruxolitinib could also be combined with CART cell therapy for the prevention of CRS in patients identified to be at high risk for the development of CRS. Disclosures Kenderian: Novartis: Patents & Royalties, Research Funding. Ruella:novartis: Patents & Royalties: Novartis, Research Funding. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Patents & Royalties, Research Funding. June:Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; Pfizer: Honoraria; Johnson & Johnson: Research Funding; University of Pennsylvania: Patents & Royalties; Tmunity: Equity Ownership, Other: Founder, stockholder ; Celldex: Consultancy, Equity Ownership; Immune Design: Consultancy, Equity Ownership. Gill:Novartis: Patents & Royalties, Resear\ch Funding.

Abstract Abstract 601 Background: Despite therapeutic advances and availability of novel agents, multiple myeloma (MM) remains an incurable malignant disorder and strategies to improve survival are being actively sought. One such approach is the use of maintenance therapy with lenalidomide (Revlimid®; R), which has shown PFS benefit, without conclusive evidence of OS benefit except in a selected population (CALGB100104). Shrinking resources with rising healthcare costs warrant careful assessment of the financial impact of expensive anticancer therapeutics in context with the true benefit to patients. Methods: This analysis was not supported or solicited by any pharmaceutical industry. For our pharmacoeconomic study we selected the MM-015 trial; a large (n=459) double-blind, randomized, placebo-controlled phase III study that investigated the efficacy of continuous R maintenance after initial therapy with melphalan/prednisone/lenalidomide (MPR) in a uniform cohort of patients (≥65 years, newly diagnosed MM, transplant ineligible). The three study arms were MP, MPR and MPR followed by R maintenance (MPR-R). The cost-effectiveness model included medical costs (drugs, office visits, laboratory tests) and costs of treatment-related adverse events (AEs) for an individual patient. Drug costs were calculated from the average wholesale price, using average US adult weight of 80kg. Office visit and laboratory test costs were obtained using Medicare reimbursement fees. Costs of AEs were obtained from peer-reviewed publications. Incidence of AEs was obtained from the published MM-015 trial. Costs were valued in 2011 US dollars. Cost calculations included: (1) computing distribution of the numbers of induction and maintenance courses completed by patients treated with each of these regimens; (2) computing the per-course probabilities of the occurrence of individual AEs during induction and maintenance for each of these toxicities; (3) combining these data with the treatment costs and costs of individual AEs to compute cumulative cost of treatment through 40 maintenance cycles and cumulative cost of treatment per progression-free survivor. Summary measures computed for each treatment: (1) average cumulative cost per patient (ACCP) treated; (2) average cumulative cost per progression free survivor (ACCPFS), representing the average cumulated cost/patient who is progression free at that time. The distribution of courses received was obtained from the MM-015 publication. Data on subsequent therapy at the time of disease progression was not available. Results: Median follow up reported in the published study was 30 months. Median PFS was 13 months (MP), 14 months (MPR) and 31 months (MPR-R) in the three arms. Table 1 summarizes the calculated ACCP and the ACCPFS of each regimen for induction and maintenance treatment. MPR-R was the most expensive of the three arms in terms of total cumulative costs, with an ACCP of $231,314, compared to $166,211 for MPR and $17,972 for MP. However, taking the efficacy of each regimen into account (ACCPFS), MPR greatly exceeds both MPR-R and MP ($1,540,139 vs. $516,322 vs. $309,346), while the difference between MPR-R and MP was less distinct. Figure 1 illustrates the exponential increase in ACCPFS of MPR, compared to MPR-R and MP. Conclusions: From a cost-effectiveness perspective, if MPR is used as the induction regimen, maintenance with R should be strongly considered, as MPR without maintenance does not confer any significant benefit over MP, while incurring a much higher cost. However, the overall cost of MPR-R is substantial with no reported OS benefit at present. In the absence of clear survival benefit the financial burden of prolonged treatment becomes an important factor to consider prior to adopting this therapeutic strategy in MM. As part of a global strategy for addressing healthcare costs, it is important to consider this in appropriate medical decision making for patients, and to include cost-effectiveness analyses as a part of large prospective clinical trial efforts. Disclosures: No relevant conflicts of interest to declare.

AbstractContrary to common perception, modern palliative care (PC) is applicable to all people with an incurable disease, not only cancer. PC is appropriate at every stage of disease progression, when PC needs emerge. These needs can be of physical, emotional, social, or spiritual nature. This document encourages the use of validated assessment tools to recognize such needs and ascertain efficacy of management. PC interventions should be provided alongside cardiologic management. Treating breathlessness is more effective, when cardiologic management is supported by PC interventions. Treating other symptoms like pain or depression requires predominantly PC interventions. Advance Care Planning aims to ensure that the future treatment and care the person receives is concordant with their personal values and goals, even after losing decision-making capacity. It should include also disease specific aspects, such as modification of implantable device activity at the end of life. The Whole Person Care concept describes the inseparability of the physical, emotional, and spiritual dimensions of the human being. Addressing psychological and spiritual needs, together with medical treatment, maintains personal integrity and promotes emotional healing. Most PC concerns can be addressed by the usual care team, supported by a PC specialist if needed. During dying, the persons’ needs may change dynamically and intensive PC is often required. Following the death of a person, bereavement services benefit loved ones. The authors conclude that the inclusion of PC within the regular clinical framework for people with heart failure results in a substantial improvement in quality of life as well as comfort and dignity whilst dying.

Summary Improvement in survival in Light chain (AL) amyloidosis has been seen over recent decades, enabling more patients to achieve long‐term survival. Patients with AL amyloidosis who survived ≥10 years from time of diagnosis ( n = 186) were the subject of this study. Ten‐year survivors represented 22% of the total population. These patients were characterized by favourable patient, organ and plasma cell features. Of note, trisomies were less common among 10‐year survivors compared to those who did not survive to 10 years. All‐time best haematological response was complete response in 67%, very good partial response in 30%, partial response in 2% and no response in 1%, with 11% having received a consolidative strategy for inadequate response to first line therapy. The overall organ response rate to first‐line therapy was 76%, which increased to 86% when considering subsequent line(s) of therapy. Forty‐seven percent of the 10‐year survivors did not require a second‐line therapy. The median treatment‐free survival (TFS) among the 10‐year survivors was 10·5 years (interquartile range 7·4‐12·2). On multivariate analysis independent predictors for TFS were the achievement of complete haematological response and lack of cardiac involvement. Long‐term survivors are increasingly seen in AL amyloidosis and present distinct patient, organ and clonal disease features.

Abstract The high-risk abnormality del(17p) can be detected by fluorescence in situ hybridization on malignant plasma cells (PCs) and has an adverse prognostic impact in patients with multiple myeloma (MM). Patients with del(17p) have reduced overall survival (OS). Patients who acquire del(17p) later during the disease course are not well described. The disease characteristics at diagnosis predicting for acquired del(17p) and its overall impact on patient survival is not known. We compared 76 patients with MM who were negative for del(17p) at diagnosis and acquired it later with 152 control MM patients who did not acquire del(17p) at a comparable time point. Patients acquired del(17p) at a median of 35.6 months (range, 4.6-116.1 months) from diagnosis of MM after a median of 2 lines of therapy (range, 1-10 lines of therapy). When compared with controls, patients with acquired del(17p) had shorter median progression-free survival (PFS) (30.1 vs 23.0 months; P = .032) and OS (106.1 vs 68.2 months; P &lt; .001) from diagnosis. After the detection of del(17p), the median PFS was 5.4 months and the median OS was 18.1 months. High lactate dehydrogenase level (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.11-12.24) and presence of t(4;14) (OR, 2.66; 95% CI, 1.09-6.48) or any high-risk translocation (OR, 2.23; 95% CI, 1.00-4.95) at diagnosis predicted acquisition of del(17p). High PC proliferative rate predicted shorter OS from detection of del(17p) (hazard ratio, 2.28; 95% CI, 1.31-3.96; P = .004). Our study shows that acquisition of del(17p) is an important molecular event associated with reduction in OS in MM. Certain baseline factors may predict acquisition of del(17p). This needs validation in prospective data sets.

Significance Statement Targeting plasma cells to reduce the risk of antibody-mediated rejection and decreased allograft survival due to anti-HLA donor-specific antibodies has not been explored in transplantation. After sensitizing eight rhesus macaques with two sequential mismatched skin allografts, the authors desensitized four with daratumumab (anti-CD38 mAb) and plerixafor (anti-CXCR4) before transplant. Compared with controls, the daratumumab-treated animals had significantly reduced donor-specific antibody levels and prolonged renal graft survival; however, this reduction was not maintained. Two patients treated with daratumumab—one with therapy-resistant acute kidney antibody-mediated rejection and a highly sensitized heart transplant candidate—exhibited a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and heart graft access. These findings suggest daratumumab merits investigation as a potential therapeutic strategy, although further research is needed. Background Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production. Methods To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant. Results The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P <0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P <0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell–mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access. Conclusions Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.