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PurposeWe aimed to develop a novel molecular imaging agent to monitor Multiple Myeloma (MM) using CD38, a target that has shown uniform expression in MM. However, only a few molecularly targeted imaging agents are available to take advantage of this high expression and the sensitivity of positron emission tomography (PET), and none of them fit into the standard clinical workflow. To address this, we developed and evaluated a first-in-class peptide-based radiotracer, [68Ga]Ga-AJ206, to non-invasively quantify CD38 levels in MM.Experimental designTo quantify CD38 levels non-invasively, we synthesized a peptide-based high-affinity binder, tested its affinity by surface plasmon resonance, and evaluated a gallium-68–labeled analog for in vitro specificity. We also performed in vivo distribution, pharmacokinetics, and CD38 specificity evaluations in MM preclinical models, and cross-validated imaging data with flow cytometry and immunohistochemistry-based analysis of CD38 expression.Results[68Ga]Ga-AJ206 demonstrated CD38 binding specificity with a dissociation constant (KD) of 19.1±0.99 nM and in vitro binding dependent on CD38 expression. PET imaging with [68Ga]Ga-AJ206 showed high contrast within 60 min and suitable radiation dose estimates for clinical use. Additionally, [68Ga]Ga-AJ206 detected CD38 expression in xenograft and disseminated disease models in a manner consistent with immunohistochemistry-based detection.Conclusions[68Ga]Ga-AJ206 exhibited the salient features required for clinical translation, providing CD38-specific high contrast images and detecting varying levels of CD38 expression in bone disease and soft tissue metastases.STATEMENT OF TRANSLATIONAL RELEVANCEMultiple myeloma is a challenging bone marrow plasma cell disease that is associated with heterogenous responses and universal recurrence. While minimal residual disease monitoring by blood and invasive bone marrow samples have improved prognostication of disease recurrence, molecularly targeted non-invasive imaging options remain limited. Additionally, there is an unmet need for functional imaging agents to monitor the effects of new therapeutics targeting CD38 protein, which is highly expressed on MM cells. To address this gap, we report the development of a high affinity first-in-class gallium-68 labeled peptide radiotracer for CD38, [68Ga]Ga-AJ206. [68Ga]Ga-AJ206 provides high-contrast images by PET within the standard clinical workflow of 60 minutes. Furthermore, we have demonstrated the potential of [68Ga]Ga-AJ206 PET to measure varying levels of CD38 expression. Further development of this new radiotracer may complement existing technologies and improve prognostication and monitoring of therapy response in MM patients.

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Purpose:This proof-of-principle clinical trial evaluated whether an allogeneic multiple myeloma GM-CSF–secreting vaccine (MM-GVAX) in combination with lenalidomide could deepen the clinical response in patients with multiple myeloma in sustained near complete remission (nCR).Patients and Methods:Fifteen patients on lenalidomide were treated with MM-GVAX and pneumococcal conjugate vaccine (PCV; Prevnar) at 1, 2, 3, and 6 months.Results:Eight patients (53.3%) achieved a true CR. With a median follow-up of 5 years, the median progression-free survival had not been reached, and the median overall survival was 7.8 years from enrollment. MM-GVAX induced clonal T-cell expansion and measurable cytokine responses that persisted up to 7 years in all patients. At baseline, a higher minimal residual disease was predictive of early relapse. After vaccination, a lack of both CD27−DNAM1−CD8+ T cells and antigen-presenting cells was associated with disease progression.Conclusions:MM-GVAX, along with lenalidomide, effectively primed durable immunity and resulted in long-term disease control, as suggested by the reappearance of a detectable, fluctuating M-spike without meeting the criteria for clinical relapse. For patients in a nCR, MM-GVAX administration was safe and resulted in prolonged clinical responses.

While allogeneic blood or marrow transplantation (alloBMT) is an effective therapy for peripheral T-cell lymphoma (PTCL), the optimal approach in this patient population remains to be determined. Here we review outcomes in 65 consecutive patients with PTCL who underwent alloBMT with non-myeloablative (NMA) conditioning and post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis. The graft source was bone marrow (BM) in 46 patients (71%) and peripheral blood (PB) in 19 patients (29%); all patients in the BM cohort received 200 cGy TBI, and most in the PB cohort (15/19) received 400 cGy TBI. With a median follow up of 2.8 years (range, 290 days-14.2 years), the 2-year PFS for the entire cohort was 49% (95% confidence interval [CI] 38–64%), and the 2-year OS was 55% (95% CI 44–69%). Outcomes were significantly improved in those receiving PB, including 2-year PFS of 79% (95% CI 63–100%) vs. 39% (95% CI 27–56%), 2-year OS of 84% (95% CI 69–100%) vs. 46% (95% CI 33–63%), and 1-year cumulative incidence of (CuI) relapse of 5% (95% CI 0–16%) vs. 33% (95% CI 19–46%), with no difference in GVHD or non-relapse mortality (NRM).

When confronted with a major physical stressor, some older adults are able to recover to baseline with minimal changes, while others undergo irreversible declines. The ability to adapt and recover well from physical stress is called physical resilience and may be impeded by altered glucose-insulin dynamics. Among 55 participants in the pilot phase of the Study of Physical Resilience IN Geriatrics(SPRING), we examined associations between metabolic syndrome and/or diabetes status to physical resiliency recovery parameters after the clinical stressors total knee replacement and bone marrow transplant. These parameters included health outcomes, functional recovery, and pain in the weeks after the intervention. Additionally, we hypothesized that less resilient individuals would have abnormal glucose and insulin responses to a 75-gram oral glucose tolerance test at 0, 30, 60, 120 minutes and tested this in a subset (n=40) without known diabetes. Exploratory analyses of this pilot study will be presented during this session.

We describe outcomes after post-transplantation cyclophosphamide and nonmyeloablative conditioning-based allogeneic blood or marrow transplantation for myelofibrosis using matched or mismatched related or unrelated donors. The conditioning regimen consisted of fludarabine, cyclophosphamide, and total body irradiation. Forty-two patients were included, with a median age of 63 years, of whom 19% had Dynamic International Prognostic Scoring System (DIPSS)-plus intermediate-1 risk, 60% had intermediate-2 risk, and 21% had high-risk disease, and 60% had at least 1 high-risk somatic mutation. More than 90% of patients engrafted neutrophils, at a median of 19.5 days, and 7% experienced graft failure. At 1 year and 3 years, respectively, overall survival was 65% and 60%, relapse-free survival was 65% and 31%, relapse was 5% and 40%, and nonrelapse mortality was 30% and 30%. Acute graft-versus-host disease grade 3-4 was seen in 17% of patients at 1 year, and chronic graft-versus-host disease requiring systemic therapy in occurred in 12% patients. Spleen size ≥17 cm or prior splenectomy was associated with inferior relapse-free survival (hazard ratio [HR], 3.50; 95% confidence interval [CI], 1.18 to 10.37; P = .02) and higher relapse rate (subdistribution HR [SDHR] not calculable; P = .01). Age60 years (SDHR, 0.26; 95% CI, 0.08 to 0.80, P = .02) and receipt of peripheral blood grafts (SDHR, 0.34; 95% CI, 0.11 to 0.99; P = .05) were associated with a lower risk of relapse. In our limited sample, the presence of a high-risk mutation was not statistically significantly associated with an inferior outcome, although ASXL1 was suggestive of inferior survival (SDHR, 2.36; 95% CI, 0.85 to 6.6; P = .09). Overall, this approach shows outcomes comparable those of to previously reported approaches and underscores the importance of spleen size in the evaluation of transplantation candidates.

Objectives This study aimed to determine the diagnostic and prognostic value of urinary biomarkers of intrinsic acute kidney injury (AKI) when patients were triaged in the emergency department. Background Intrinsic AKI is associated with nephron injury and results in poor clinical outcomes. Several urinary biomarkers have been proposed to detect and measure intrinsic AKI. Methods In a multicenter prospective cohort study, 5 urinary biomarkers (urinary neutrophil gelatinase–associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid binding protein, urinary interleukin-18, and cystatin C) were measured in 1,635 unselected emergency department patients at the time of hospital admission. We determined whether the biomarkers diagnosed intrinsic AKI and predicted adverse outcomes during hospitalization. Results All biomarkers were elevated in intrinsic AKI, but urinary neutrophil gelatinase–associated lipocalin was most useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) and predictive of the severity and duration of AKI. Intrinsic AKI was strongly associated with adverse in-hospital outcomes. Urinary neutrophil gelatinase–associated lipocalin and urinary kidney injury molecule 1 predicted a composite outcome of dialysis initiation or death during hospitalization, and both improved the net risk classification compared with conventional assessments. These biomarkers also identified a substantial subpopulation with low serum creatinine at hospital admission, but who were at risk of adverse events. Conclusions Urinary biomarkers of nephron damage enable prospective diagnostic and prognostic stratification in the emergency department.

Introduction B-cell post-transplant lymphoproliferative disorders (B-PTLD) represent a spectrum of lymphoid neoplasms arising as a consequence of impaired T-cell surveillance secondary to immunosuppressive medications. Epstein-Barr Virus (EBV) has been implicated in the development of B-PTLD. B-PTLDs diagnosed within one year post-transplant are more likely to be associated with EBV whereas B-PTLD diagnosed after a year are more likely to be EBV-negative and are associated with worse prognosis. Studies have shown that EBV up-regulates CD30 expression, a member of the TNF-receptor superfamily (Haque et al 2011). Novel agents are now available that target cells expressing CD30. Hence, knowledge of the expression profiles and the clinical characteristics of CD30+ neoplasms is warranted. In this study, we evaluated CD30 expression in 59 cases of B-PTLD and correlated CD30 and EBV status with clinical characteristics. Methods Consecutive cases of B-PTLD diagnosed between 1997 and 2013 were retrieved from our archives. Immunohistochemistry (ISH) for CD30 was performed on formalin-fixed, paraffin embedded biopsies using the BerH2 monoclonal antibody (BioSB, Santa Barbara, CA) according to standard methods. Positive expression was pre-defined as CD30 expression by ≥20% of the lesional cells (Figure 1). Log-rank and Fischer's Exact 2-sided Test were performed in STATA 11, as appropriate. Results The 59 B-PTLDs occurred in 54 patients. Three patients had two different sites biopsied during the diagnostic workup. Two other patients had recurrent B-PTLD. The median age at diagnosis was 22.8 years old (range 1.2 to 75.9 years); 65% were male. The median time from transplant to diagnosis was 2.6 years (range 6 weeks to 15.9 years, mean 4.2 years). Eighteen cases (35%) were diagnosed within the first year of transplantation. The organs transplanted are detailed in Table 1 with the percentage of CD30+ cases noted. Prior to transplantation, only 25/44 (57%) patients were EBV IgG seropositive, likely reflecting the number of children who were younger than age ten when transplanted (21/52; 40%). (Orjuela et al 2011). Serum EBV Polymerase Chain Reaction (PCR) was positive in 18/27 (67%) cases analyzed. Pathological data are summarized in Table 2. In total, 39 of 59 cases (66%) showed 20% or more CD30 expression. Positive EBV ISH was significantly associated with CD30 expression (r=0.38, p< 0.01). Of 59 tumors informative for CD30 and EBV (by ISH), 32/41 of EBV-positive tumors were CD30 positive (78%) while 7 of 18 tumors that were EBV negative were CD30 positive (39%) (r=0.38 for the association of EBV and CD30 status, p=0.01). Detectable serum viremia was associated with CD30 status (r=0.49, p=0.02). There was no association found between CD20 status and CD30 status. There was no significant association between CD30 status and ki67 index or c-myc expression either (data not shown). Conclusion We observed a high frequency of CD30 expression in patients with B-PTLD. Expression of CD30 correlates with ISH evidence of EBV infection in B-PTLD. In addition, positive serum EBV PCR was associated with CD30 expression. These two findings further support the link between EBV infection and CD30 expression. CD30 positivity was still found in 39% of EBER – negative cases, suggesting that CD30 ISH should be considered on all cases of B-PTLD. A monoclonal antibody conjugated to the cytotoxic agent MMAE,Brentuximab Vedotin (SGN-35), has shown activity in clinical trials against CD30 positive lymphomas (Jacobson et al 2012). Considering the relatively common prevalence of CD30+ expression in PTLD, brentuximab vedotin could be considered for study in combination with traditional front-line therapies or as an alternative therapy for relapsed/refractory disease. A prospective clinical trial (NCT 01805037) at Northwestern University is ongoing. Disclosures: Schecter: Seattle Genetics: Research Funding, Speakers Bureau. O'Connor:Seattle Genetics: Research Funding.