ALBERT

Description: Background: The amyloidoses comprise a heterogeneous group of diseases characterized by misfolding of amyloidogenic proteins and subsequent deposition as amyloid fibrils. To date, over 30 proteins are known to be amyloidogenic (Sipe Amyloid 2014). Immunoglobulin light chain (AL) amyloidosis, a plasma cell dyscrasia, is the most common subtype. The standard diagnostic algorithm in AL amyloidosis is to obtain a biopsy of a clinically involve organ, and once Congo red positivity is confirmed, perform subtyping analyses with immunohistochemistry or mass spectrometry. Accurate subtyping of amyloidosis is essential to appropriate treatment, as misdiagnosis occurs in up to 10% of patients and may lead to inappropriate administration of chemotherapy (Comenzo Blood 2006; Lachmann NEJM 2002). We sought to determine the patterns of amyloid subtyping among patients with a diagnosis of AL amyloidosis referred to a tertiary referral center for HDM/SCT. Methods: Sequential patients with confirmed amyloidosis, age ≥ 18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were eligible. Presence of a Congo red-positive biopsy for each patient referred for transplant was confirmed and the pathology reports and medical records were reviewed to determine if subtyping was performed, and which modality was used. Results: Fifty-one patients with AL amyloidosis were referred for transplant; of these, 45 proceeded with HDM/SCT. The organ systems most commonly involved were renal in 34/51, and gastrointestinal in 5/51. Of the biopsies, subtyping was performed in 35 (68.6%), and no subtyping was performed in 16 patients (31.3%). Immunofluorescence was the most common modality used for subtyping in 33 biopsies (94.2%) and laser capture/mass spectrometry (LC/MS) was used in 2 patients (5.7%). All patients had evidence of a clonal plasma cell dyscrasia by bone marrow biopsy and peripheral blood testing. Of the patients without subtyping, 8 (50%) were diagnosed before 2008. Discussion: Misdiagnosis of amyloidosis due to a lack of appropriate subtyping is a well-described and ongoing problem for patients with amyloidosis. These data suggest that definitive subtyping is still not routinely performed in the evaluation of amyloidosis. At our center, efforts to standardize the evaluation of Congo-red positive biopsies using definitive typing are underway. Disclosures Gopal: Seattle Genetics: Research Funding.

Description: Background: Standard chemotherapies for relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) are often unsuccessful. Pre-treatment ("priming") with hypomethylating agents such as decitabine has been shown to sensitize AML cells to chemotherapeutics, prompting a phase 1/2 study (NCT01729845) of MEC preceded by decitabine priming (d/MEC) in relapsed/refractory AML/MDS. Methods: Patients ≥18 years with relapsed/refractory AML or high-risk MDS (〉10% blasts) requiring first or subsequent salvage therapy were eligible if they had adequate organ function and a treatment-related mortality (TRM) score of

Description: Background Binding of E-selectin (E-sel) to sialyl Lex, the E-sel ligand, on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Higher expression of E-sel ligand is associated with relapse and poor survival. Uproleselan (GMI-1271), a novel E-selectin antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity such as mucositis with improved survival in vivo. Preclinical data support combination of uproleselan with chemotherapy improves response without additional toxicity. A phase 1/2 study (NCT02306291) of uproleselan added to chemotherapy (mitoxantrone, etoposide, cytarabine, MEC) in R/R AML showed promising outcomes at the recommended phase 2 dose (RP2D), including a CR/CRi rate of 41% and median OS of 8.8 m (95% CI 5.7-11.4). 11/16 (69%) evaluable patients were MRD negative (DeAngelo et al ASH 2018). Patients with sufficient expression of the appropriate E-selectin ligand (the target of the E-selectin inhibitor) exhibited higher CR/CRi rate and longer survival. Median OS for Leukemic blasts/E-sel ligand ≥10% vs leukemic blasts/E-sel ligand

Description: Background: The treatment of multiple myeloma (MM) is optimized by use of combination regimens consisting of agents with different mechanisms of action. Panobinostat is a pan-inhibitor of histone deacetylases types I,II, and IV. Panobinostat, bortezomib, dexamethasone was shown to be an effective regimen (San Miguel et al Lancet Hematol 2016; Richardson et al Blood 2016), leading to the FDA approval of panobinostat for patients with relapsed/refractory MM. Carfilzomib is a proteasome inhibitor that was FDA approved in relapsed/refractory MM with the advantage of minimal neuropathy. Panobinostat and carfilzomib has also been shown to be a highly active regimen in relapsed/refractory MM with an overall response rate of up to 75% (Berdeja et al, Haematologica, 2015). With the heterogeneity of MM, individual patients exhibit wide variability in responses to drug combinations. A test that could predict patient responses to specific agents might enable clinicians to optimize therapy for patients, improving outcomes. We developed an in vitro high throughput drug sensitivity assay with formal synergy testing to predict response. In this ongoing trial, Panobinostat with Carfilzomib and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Correlation with In Vitro Chemosensitivity Testing (NCT03256045), we will correlate individual patient in vitro sensitivity assay results with individual clinical response to the same triple drug regimen. Study Design and Methods: This study's objective is to directly demonstrate the utility of a high throughput drug sensitivity assay in determining biomarkers (e.g. individual IC50s, AUCs and/or synergy scores) to accurately predict response to combination therapy that was given prospectively to all enrolled patients. We are enrolling patients with relapsed/refractory MM by IMWG criteria with measurable disease defined by the detection of a quantifiable monoclonal protein in the urine or serum or an abnormal serum free light chain ratio. Additionally, patients must have adequate blood counts and organ function. Patients who have had prior autologous or allogeneic transplants or CAR-T cell therapy are eligible. The regimen consists of panobinostat 20 mg orally on days 1,3,5,15,17,19; carfilzomib 20 mg/m2/dose IV on days 1,2 of cycle 1, then dose escalation up to 45 mg/m2/dose days 8,9,15,16 and all days for subsequent cycles; and dexamethasone 20 mg orally on days of carfilzomib. Dose reductions of all three drugs are permitted per patient tolerance to allow continuation on study treatment. Up to 12 cycles of treatment are permitted. Patients are monitored by serial electrocardiograms and assessments of cardiac function. Safety parameters including adverse events are recorded. CD138+ plasma cells are procured from the patient bone marrow (aspiration and biopsy) and blood (when present) by magnetic bead separation. Cells are then added to 384-well plates and incubated overnight before the drugs are added. Cells are exposed to 8 concentrations (spanning 4 logs) of panobinostat, carfilzomib, or dexamethasone as singlet, doublet and triplet combinations for 72 hours. Cell viability is determined using CellTiter-Glo and IC50 and AUC values are are calculated by fitting data using least squares method to the standard four-parameter logistic model. Curve fitting is performed using IDBS XLFit software. The combination index is calculated by the method described by Chou and Talalay, Trends Pharmacol Sci 1983;4:450-4. Concentrations of Drug1 and Drug2 (that is, panobinostat and dexamethasone or panobinostat and carfilzomib) alone or in combinations are determined that give rise to 90% growth inhibition. At 90% Growth Inhibition, the Combination Index or CI = ([D1] in the combination / [D1] alone) + ([D2] in the combination / [D2] alone). All patients are treated with panobinostat, carfilzomib, and dexamethasone and evaluated for response using the IMWG response criteria. At the completion of enrollment at 35 patients, we plan to correlate the in vitro testing data with in vivo clinical response to determine appropriate biomarkers. This will be done by correlating the IC50s and AUCs for the individual drugs for responders vs. non-responders (including degree of response VGPR vs PR vs SD), as well as correlations of the synergy scores for each of the pairs of drugs in the responders vs. non-responders. Enrollment was initiated in April 2018. Disclosures Becker: Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; The France Foundation: Honoraria. Libby:Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy; Alnylam: Consultancy. Cowan:Juno: Research Funding; Abbvie: Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Cellectar: Consultancy; Celgene: Consultancy, Research Funding. Hammer:Glycomimetics: Consultancy.

Description: Background: Because infections are a major cause of morbidity and mortality after AML induction chemotherapy, patients typically remain hospitalized for monitoring and rapid antimicrobial therapy until hematopoietic recovery. With declining early mortality and improved oral antimicrobials, interest in moving post-induction care to the outpatient setting has emerged. In the 5-year period since completing a prospective phase 2 trial evaluating an Early Hospital Discharge (EHD) strategy, EHD following AML-like induction chemotherapy has become routine at our institution. In recent retrospective analyses, we found 〉80% of EHD patients required hospital readmission, primarily for neutropenic fever. Still, the EHD strategy was safe and reduced healthcare resource utilization, and EHD patients spent 〉70% of their post-chemotherapy time as outpatients. Here, we investigated differences in the pattern of infectious complications between patients managed as outpatients following induction chemotherapy and those who remain hospitalized until hematopoietic recovery. Methods: We retrospectively identified all adults ≥18 years with untreated AML/high-grade myeloid neoplasms (≥10% blasts in blood/ bone marrow) who started intensive induction chemotherapy ("7+3" or a regimen of similar/higher intensity) at our institution from 8/1/2014-7/31/2018. Patients were considered "EHD" if they were discharged from the hospital

Description: Human tumors contain large numbers of clonal, subclonal and random mutations. Clonal mutations, present in 30% or more of the cells, are classified as either drivers that promote proliferation or passengers of unknown or to be determined function. Subclonal and random mutations that are present in a small subset of tumor cells, prior to chemotherapy, could serve as a reservoir for the emergence of drug resistance. Even in the presence of clinical complete remissions in AML, subclonal mutations could be present in a small number of cells that selectively expand during chemotherapy and result in relapse and death. Next-generation DNA sequencing now makes it feasible to monitor the frequency of different subclonal mutations in patients as tumors evolve over time, raising the possibility of personalizing treatment by anticipating the mutations that signal relapse in time to prevent clinical recurrence of AML. We have used Duplex DNA Sequencing (DS) to detect very low-frequency subclonal and random mutations in AML during relapse and prior to treatment. While whole genome sequencing (WGS) provides extensive data on the clonal distribution of mutations in AML, it lacks sufficient accuracy to identify subclonal mutations when they are present at frequencies less than 5%. In contrast, DS focuses on a limited number of target genes at the level of single DNA molecules. Mutations are scored only if they are present at the same position in both strands of the same DNA molecule and are complementary, resulting in sequencing accuracy that is more than 1000-fold greater than that of routine next-generation DNA sequencing. Using DNA from 12 treatment-naïve AML samples and 2 normal bone marrow samples, we first targeted the exons that encode the catalytic domains of the five major human replicative polymerases. We detected both synonymous and non-synonymous mutations in most of the targeted genes. Mutations in the two major human replicative DNA polymerases have been recently identified in adenocarcinomas of the colon, and mutations in the proof-reading domain of DNA polymerase epsilon result in the highest reported point mutation frequencies so far reported in any cancer. Until now, mutations in DNA polymerases have not been described in AML. Presumably a similar or higher subclonal mutation load exists in the coding regions of other genes in AML and in genes found in other tumors. In order to follow the course of mutation accumulation in AML after treatment and leading to relapse, we used capture hybridization that was designed to enrich for 15 genes previously reported to be mutated in AML. We identified multiple subclonal and random mutations in many of these genes. In one relapse sample, we identified a mutation in NRAS that was present in 32% of the cells. The same mutation was detected by DS in 1% of the cells from the same patient prior to treatment, which is well below the signal threshold of WGS. These initial studies demonstrate the feasibility of using DS to define the changes that occur during and after treatment, and suggest the use of DS to determine mutations that impart drug resistance. The findings from the DNA polymerase capture offers evidence that abundant non-synonymous mutations are present in treatment-naïve AML, implying that the seeds of treatment resistance may already have taken root by the time of diagnosis. Disclosures No relevant conflicts of interest to declare.

Description: Background: Bortezomib was originally incorporated into DT-PACE (thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) as an intensive induction regimen (VTD-PACE) prior to high-dose melphalan and autologous transplant for multiple myeloma (MM). This regimen is effective in the induction setting, and also for patients with relapsed disease (Barlogie British Journal of Haematology 2007, Singh ASCO 2013). At our center, we examined the outcomes of MM patients undergoing chemomobilization with a regimen that substituted carfilzomib and lenalidomide for bortezomib and thalidomide (CarRD-PACE). Methods: Twenty MM patients with measureable disease received CarRD-PACE for chemomobilization. We excluded in this report patients with plasma cell leukemia, renal insufficiency, heart failure, or those patients who were refractory to carfilzomib. Results: The median age was 61.5 years (range, 35- 69). Nine of these patients were women (45%). The median left ventricular ejection fraction pre-treatment was 62% (range, 50 - 77%). Of patients with initial staging information, 8 were ISS stage I (47%), 5 patients ISS II (29%), and 4 were ISS III (24%). High risk cytogenetics, defined as presence of deletion 17p, t(4;14), t(14;16), were present in 5 patients at time of chemomobilization (25%). Fourteen patients (82%) had bulky disease (defined as having 〉 3 lesions, or having a single lesion 〉 3 cm on PET-CT or MRI) prior to treatment, assessed by MRI (n=12) or PET-CT (n= 2). The median time from diagnosis to mobilization was 9.5 months (range, 4- 44). Patients had previously received a median of 2 regimens of therapy (range, 1- 5). Fifteen patients received 1 cycle of CarRD-PACE, and 5 patients received 2 cycles. Eighteen patients response evaluable; in these patients, the overall CR/PR response rate after completion of treatment was 25% (4 PR, 1 CR), with fifteen patients (75%) having SD. A total of 18 patients (90%) collected stem cells after mobilization, requiring a median of 1 day of collection (range, 1-2), and collected a median of 18.3 x 10^6 CD34+ cells/kg (range, 4.8 - 69.88). Grade 3-4 toxicities occurred in 6 patients (30%), most common was neutropenic fever (n=4) (20%). No patients experienced a cardiac toxicity. Hospital readmission following treatment occurred in 4 patients (20%) for a median of 6.5 days (range, 3 - 15). Eighteen patients (90%) underwent a single autologous transplant, and 2 (10%) received tandem autologous-allogeneic transplant. Following autologous transplant, the median time to neutrophil engraftment was 18 days (range, 14 - 29 days), and the median time to platelet engraftment was 13 days (range, 7 - 19 days). The PFS at 6 months was 63% (95% CI, 0.382 - 1), and the OS at 6 months was 91% (95% CI, 0.754 - 1) (Figure). Discussion: CarRD-PACE is a well-tolerated and effective therapy in heavily treated multiple myeloma patients with substantial disease burden at the time of autologous transplant, and can successfully mobilize autologous PBSC. Despite the theoretical concern regarding the combination of 2 agents with cardiac toxicity (carfilzomib and doxorubicin), we did not observe any cardiac toxicities of any grade during treatment. This approach may be particularly useful in individuals with bortezomib associated neuropathy and or those with bortezomib refractory disease. Figure Kaplan-meier plots for progression free and overall survival. Figure. Kaplan-meier plots for progression free and overall survival. Disclosures Becker: GlycoMimetics: Research Funding. Shadman:Pharmacyclics: Honoraria, Research Funding; Acerta: Research Funding; Gilead: Honoraria, Research Funding; Emergent: Research Funding. Gopal:Seattle Genetics: Research Funding.

Description: Background: Optimal treatment for medically less fit adults with acute myeloid leukemia (AML) remains uncertain. Retrospective data suggest intensive therapy may lead to better outcomes in these patients. However, these findings must be interpreted cautiously because of the possibility of selection bias and other confounders. Ideally, the optimal treatment intensity is defined via randomized trial but whether patients and their physicians are amenable to such a study is unknown. We therefore designed a trial (NCT03012672) to 1) evaluate the feasibility of randomization between intensive and non-intensive therapy in this population and 2) examine the impact of treatment intensity on response rate and survival. We used CLAG-M as high-dose cytarabine-based intensive induction therapy. Rather than selecting different classes of drugs in the 2 treatment arms- which may have different modes of action and therefore confound the question of treatment intensity - we used reduced-dose ("mini") CLAG-M as the non-intensive comparator. Methods: Adults ≥18 years were eligible if they had untreated AML or high-grade myeloid neoplasms (≥10% blasts in blood or marrow) and were medically less fit as defined by having a "treatment related mortality" (TRM) score of ≥13.1, corresponding to a 〉10-15% 28-day mortality with intensive chemotherapy. Left ventricular ejection fraction ≤45% was the only organ function exclusion. Patient-physician pairs were first asked if they were amenable to randomized treatment allocation. If so, they were randomized 1:1 to mini- vs. regular-dose CLAG-M. If not, in order to evaluate our secondary endpoints, the patient or physician could choose the treatment arm and still enroll on study. Patients and physicians then completed surveys elucidating their decision-making processes. Up to 2 induction courses were given with mini- vs. regular-dose CLAG-M: cladribine 2 or 5 mg/m2/day (days 1-5), cytarabine 100 or 2,000 mg/m2/day (days 1-5), G-CSF 300 or 480µcg/day for weight

Description: Introduction: Survival rates continue to improve after allogeneic HCT (Gooley et al, NEJM, 2013). Population-based studies also indicate overall improvement in survival of older (60-80 years old) AML patients (pts) (Bower, Blood Cancer Journal, 2016). Yet, only a small minority (6%-8%) of them receive HCT (Medeiros, Ann Hematol. 2015). Given these potentially incongruent findings and the changing face of survival in AML, we designed the first prospective multi-center longitudinal study dating from first presentation of adults with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We compared survival according to whether or not pts received HCT at later time points. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including activities of daily living (ADL); frailty; geriatric assessment including cognition; QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale, ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. We used time-dependent Cox regression analyses to identify baseline and time-dependent risk factors associated with mortality in the overall population. The factors identified as significantly associated with mortality (p

Description: Introduction: Many patients with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with 10-19% blasts (MDS-EB2) do not enter complete remission (CR) following initial induction chemotherapy. At an academic referral center, such patients often stay to receive additional treatment, or return to their home communities for further care. For patients and providers alike, the decision about whether to stay or go after initial treatment failure is often fraught. To better inform such decision-making, in this retrospective single-center analysis, we compared covariate-adjusted survival for patients who elected to stay for further treatment at our center and those who returned to their home communities for subsequent care. Methods: We included adults ≥ age 18 years of age with newly-diagnosed AML or MDS-EB2 treated at our institution between January 2012 and May 2018 who failed to enter CR (〈 5% morphologic bone marrow blasts) or CR with incomplete hematologic recovery (CRi) after their first cycle of induction chemotherapy. We excluded patients who died before they could begin re-induction therapy. Patients who stayed at our institution for additional treatment are referred to as the "stay" group (n=86); patients who left are considered the "go" group (n=35). Multivariable Cox regression analysis was used to account for other measured covariates possibly influencing survival. Results: The go group was older and had a higher median treatment-related mortality (TRM) score (Table 1), the latter predictive of the probability of death within the first 28 days of initial induction therapy. Forty-seven percent of stay patients received high-intensity re-induction (containing cytarabine at individual doses ≥1g/m2) while 50% received low-intensity treatment (e.g. azacitidine, decitabine, or low-dose cytarabine). Twenty-nine percent of go patients received treatment (mostly low-intensity) in the community setting, while 63% received supportive care only. The stay patients had a median of 2 subsequent hospitalizations (range 0-12) and spent a median of 27 days hospitalized after initial treatment failure (range 0-124). Survival was longer in the stay group compared to the go group (median 8.3 vs. 1.8 months, p