ALBERT

Description: Background The epitome of cancer treatment personalization is N=1 segmentation where a custom therapy is designed for every patient. Because most cancer aberrations are not actionable mutations and tumors can have more than one actionable mutation, this one biomarker/one drug approach to cancer personalization has inherent limitations due to its over simplification. Personalization 2.0 methodology creates a patient simulation avatar incorporating a patient’s genomic profile information holistically. Methods Bone marrow samples from two myeloma patients (P1 and P2) refractory to most recent treatment was collected, and P1’s sample was sorted into CD138+ and CD138- cells. The patient cells were analyzed for chromosomal alterations using Comparative Genomic Hybridization (aCGH) arrays by GenPath Diagnostics and cytogenetic chromosome analysis by Washington University School of Medicine and New York University (NYU), respectively. Using this information, a predictive simulation avatar model of each patient was created by Cellworks based on genomic profile of patients. A digital functional library of over 80 FDA-approved drugs and agents currently in clinical trials were simulated individually and in combination using the two patient avatars to create a personalized treatment for each patient. The findings were prospectively validated using patient cells ex vivo as assessed by MTT assay at New York University. Results P1 aberrations included trisomy of CCND1 and deletion of TP53 along with single copy losses in different arms of chromosomes 1, 6, 8, 12, 13, 14, 16, 17 and 22 and gains in different arms and regions of chromosomes X, 1, 4, 7, 9, 17, 3, 5, 11, 15 and 19, indicating the presence of hyperdiploid clones. Using this information, 897 gene perturbations were included to model this patient simulation avatar. Simulation predicted high beta-catenin (CTNNB1) activity with increased hedgehog and NOTCH pathways that were inherent causes of Bortezomib resistance. Significant activation of STAT3 and STAT5 due to amplification of IL6 pathway, JAK2 and JAK3 was noted. Amplifications of MET, IGFR and FGFR converged at ERK and AKT signaling loops. Along with deletion of TP53, this profile had amplification of many anti-apoptotic genes including survivin, MCL1 and XIAP. Modeling predicted sensitivity to the JAK inhibitor Tofacitinib, a drug approved for rheumatoid arthritis. This was prospectively validated ex vivo, and the experimental data correlated with the prediction showing a reduction in viability. P2 aberrations include losses in chromosomes X and 9 and a chromosome 11:14 translocation that is a common occurrence in MM. This translocation results in an amplification of CCND1 expression. The genomic aberrations reported include knockdown of tumor suppressors RXRA, TGFBR1, TJP2 and TSC1. TSC1 regulates the mTOR pathway, and its deletion causes an aberrant activation of mTOR and its downstream targets. Reduced expression of RXRA and TJP2 both in different manners leads to increase in AP1 activation. NFkB is also activated due to RXRA reduction. TGFBR1 reduction decreases the expression of cell cycle inhibitors via SMAD2/3 down-regulation. In this patient avatar, modeling predicted sensitivity to a combination of Sirolimus and Trametinib. Ex vivo validation confirmed this prediction of additive synergy of these two drug agents in the context of this patient. Conclusions This study demonstrates and validates the personalization of treatment through two patient cases based on creating predictive simulation avatar models using genomic profile information. This modeling holistically incorporates all genomic aberration information and is not limited to associating drugs to actionable mutations. Disclosures Doudican: Cellworks: Research Funding. Vali:Cellworks: Employment. Basu:Cellworks: Employment. Kumar:cellworks: Employment. Singh:Cellworks: Employment. Sultana:Cellworks: Employment. Abbasi:Cellworks: Employment, Equity Ownership.

Description: Background: Over the past two decades, peripheral blood stem cells (PBSC) have surpassed bone marrow as the preferred graft source for adult allogeneic transplantation due to its more rapid engraftment and potentially better graft-vs-tumor effects, and because PBSC collection is much less invasive for the donor. The optimal CD34+ PBSC dose is ≥ 4.0x106cells/kg, but doses ≥ 8.0x106cells/kg are suggested by some for reduced-intensity conditioning and haploidentical transplants. There is no established minimum CD34+ PBSC dose, but doses below 2.0x106cells/kg have been associated with a higher risk of engraftment delay and failure. There is significant inter-donor variability in the ability to mobilize PBSCs. Several factors have been identified as predictors of PBSC mobilization in healthy donors including: gender, age, weight, body mass index (BMI), and blood counts before and after mobilization. The impact of the donor’s comorbidities on mobilization is currently unknown. Patients/Methods: We performed retrospective chart review of 488 consecutive adult patients who underwent apheresis for allogeneic stem cell donation at Washington University School of Medicine from 2006 through 2013. Patients who received any collection regimen other than 10mcg/kg of G-CSF daily with 20 liters (+/-10%) apheresis on Day 5 were excluded. Patients who had undergone a previous apheresis for stem cell donation were excluded. Univariate analysis was performed to identify predictors of CD34+ PBSC collection in a single apheresis. Variables analyzed were: gender; age; weight; BMI; donor-to-recipient weight ratio; pre and post-mobilization blood counts (white blood count [WBC], hematocrit, platelets, neutrophils, lymphocytes, and monocytes); pre-mobilization glucose and triglyceride levels; post-mobilization peripheral blood (PB) CD34+count; and medical history significant for hypertension, hyperlipidemia, or diabetes mellitus. Subsequently, a linear regression multivariate analysis was performed with all variables found to be significant in the univariate analysis. 2-tailed tests for significance were used throughout the analysis. Results: 304 patients met the eligibility criteria for analysis. The median age was 53 years (range 18-76), 90% were Caucasian, and 50% were male. The median number of CD34+ cells collected was 7.4 x106/kg (range 0.8-27.1). 97% (295) collected ≥ 2.0x106 CD34+cells/kg, 81% (247) collected ≥ 4.0x106 CD34+cells/kg, and 44% (134) collected ≥ 8.0x106 CD34+ cells/kg. Post-mobilization PB CD34+ count (r= 0.841, p

Description: Background: The need to repeat peripheral blood stem cell (PBSC) mobilization and collection arises infrequently in healthy donors, but may be required due to insufficient initial collection, graft failure, or relapse of the recipient’s disease. Currently no published data exists on the efficacy of remobilization of healthy PBSC donors. Studies of remobilization in patients undergoing autologous transplantation (ASCT) have largely focused on the use of alternative mobilization agents such as chemotherapy or plerixafor. Boeve et al (Bone Marrow Transplant, 2004) reported that remobilization with G-CSF in patients undergoing ASCT who failed initial mobilization with G-CSF, resulted in higher numbers of CD34+ cells collected than the initial collection, though this required a doubling of the dose of G-CSF. Patients/Methods: We performed retrospective chart review of 977 consecutive adult (〉18 yrs) donors who underwent apheresis for PBSC donation at Washington University School of Medicine from 1995 through 2013. We identified 66 donors who had undergone more than one mobilization. Two cohorts of donors were identified for analysis: Group 1 included donors mobilized initially and again subsequently with G-CSF (10 ug/kg/day), or GM-CSF (5 ug/kg/day) + G-CSF (10 ug/kg/day). Group 2 consisted of donors mobilized with a CXCR4 antagonist, plerixafor (240-320 ug/kg) or POL6326 (1000-2500 ug/kg), and subsequently were remobilized with G-CSF (10 ug/kg/day). Statistical Analysis: Spearman correlations were performed to analyze the relationship between peak peripheral blood (PB) CD34+/uL level; the number of CD34+ cells collected per kg (recipient weight); and the number of CD34+ cells per L of apheresis collected during initial mobilization (MOB1) and remobilization (MOB2); and the interval (days) between MOB1 and MOB2. One-way ANOVA with repeated measures analyses were performed to determine the relationship of PB CD34+/uL, CD34+/kg and CD34+/L during MOB1 and MOB2. Results: Group 1 included 30 donors. The median age was 49 years (range 18-75) and 15 were male. The median number of days between MOB1 and MOB2 was 140 (range 26-2238). All 30 donors were remobilized due to graft failure or relapse of the recipient’s disease. PB CD34+/uL, CD34+/kg and CD34+/L all correlated between MOB1 and MOB2. The mean PB CD34/uL at MOB1 was 69 compared to 37 at MOB2 (p= 0.029); the mean CD34/kg collected at MOB1 was 5.6x106 compared to 3.3x106 at MOB2 (p= 0.002); and the mean CD34/L collected at MOB1 was 24.0x106 compared to 17.6x106at MOB2 (p= 0.023). The interval between MOB1 and MOB2 did not correlate with any of the MOB2 variables. Results from the analysis are summarized in Table 1. Group 2 included 32 donors. The median age was 51 years (range 21-67) and 18 were male. The median number of days between MOB1 and MOB2 was 20 (range 4-1123). 18 donors were remobilized due to mobilization failure, while 14 were remobilized due to graft failure or relapse of the recipient’s disease. The mean PB CD34/uL at MOB1 was 15 compared to 68 at MOB2 (p〈 0.001); the mean CD34/kg collected at MOB1 was 2.5x106 compared to 7.1x106 at MOB2 (p〈 0.001); and the mean CD34/L collected at MOB1 was 10.6x106 compared to 30.1x106at MOB2 (p〈 0.001). The interval between MOB1 and MOB2 did not correlate with any of the MOB2 variables. Results from the analysis are summarized in Table 2. Conclusion: Remobilization with G-CSF or GM-CSF and G-CSF after initial successful mobilization with the same regimen results in poorer mobilization while remobilization with G-CSF after initial mobilization with a CXCR4 antagonist results in dramatically improved mobilization. The reason for this remains unclear, but in this study the interval between collections was not associated with successful remobilization. Abstract 850. Table 1 Group 1 MOB 1 MOB 2 One-way ANOVA Spearman Correlation PB CD34/ul 69 (13-417) 37 (1-115) F(1.0, 29.0) = 5.26, p= 0.029 r= 0.615, p〈 0.001 CD34/kg (x106) 5.6 (0.8-13.8) 3.3 (0.3-10.6) F(1.0, 29.0) = 11.77, p= 0.002 r= 0.483, p= 0.007 CD34/L (x106) 24.0 (4.5-72.0) 17.6 (2.8-41.3) F(1.0, 29.0) = 5.74, p= 0.023 r= 0.566, p〈 0.001 Abstract 850. Table 2 Group 2 MOB 1 MOB 2 One-way ANOVA Spearman Correlation PB CD34/ul 15 (2-54) 68 (14-358) F(1.0, 31.0) = 23.16, p〈 0.001 r= 0.433, p= 0.013 CD34/kg (x106) 2.5 (0.2-19.7) 7.1 (1.7-42.4) F(1.0, 31.0) = 33.84, p〈 0.001 r= 0.769, p〈 0.001 CD34/L (x106) 10.6 (1.4-67.1) 30.1 (6.0-165.0) F(1.0, 31.0) = 34.70, p〈 0.001 r= 0.774, p〈 0.001 Disclosures No relevant conflicts of interest to declare.

Description: Background: Bone lesions and extramedullary plasmacytomas, present in ~70% and ~15% of multiple myeloma (MM) patients at diagnosis, respectively, are a major source of morbidity. Extensive bone or extramedullary disease is often associated with severe pain, fracture, or spinal cord compression requiring immediate medical attention. Palliative radiation to the afflicted area(s) can provide relief or reduction of the associated symptoms. The presence of bone lesions or extramedullary plasmacytomas at MM diagnosis have been linked to poorer prognosis, but to date, the prognosis of patients with extensive bone or extramedullary disease requiring radiotherapy during front-line treatment is unclear. In a single institution retrospective study of 162 newly diagnosed MM patient’s, including 87 who received front-line radiotherapy, Yaneva, et al (J Buon, 2006) found no survival difference between patients who received radiotherapy during front-line treatment and those who did not. Methods: Using the SEERStat software, we extracted the case listings of 85,115 patients diagnosed with MM from 1973 through 2010 in Surveillance Epidemiology and End Results (SEER)-18 registries database based on the November 2012 submission. Children (under 18 years old) were excluded. Autopsy or death certificate only cases were excluded. As non-black minorities have been historically underrepresented in the SEER databases, patients identified as any race other than white or black were excluded. Patients were followed for OS through December 2011. Disease-specific-survival was defined as death from myeloma. Patients were classified as having radiotherapy during front-line treatment or not. Patients who refused radiotherapy (n = 184) or for whom radiotherapy status was unknown (n = 973) were excluded. Results: 77,714 patients were eligible for analysis. The median age at diagnosis was 70 years (range 18-85+); 54% were male; 19% were black. The median follow-up was 22 months (range 0-441). 25% (n = 19,295) of patients received radiotherapy during front-line treatment. Radiotherapy during front-line treatment was more common among patients under the age of 60 at diagnosis (30.9% vs 21.4%; p 〈 0.001), white patients (25.5% vs 21.8%; p 〈 0.001), and male patients (26.2% vs 23.2%; p 〈 0.001). The frequency of radiotherapy during front-line treatment decreased in the most recent decade (22.8% vs 27.3%; p 〈 0.001). Patients who received radiotherapy during front-line treatment had an estimated median disease-specific-survival of 38 months compared to 46 months for patients without (p 〈 0.001). In a multivariate cox regression model of age, race, sex, and radiotherapy during front-line treatment, all four variables were independently significant (Table 1). Radiotherapy was associated with a 17% (95% CI 15-20) increase in disease-specific mortality. The impact of radiotherapy was relatively stable over the time frame studied (Table 2). Conclusions: Radiotherapy during front-line treatment, a surrogate for extensive bone or extramedullary disease at MM diagnosis, is independently associated with increased disease-specific mortality. It has remained a relatively stable predictor of poorer prognosis throughout the timeframe tested, suggesting that MM treatment advances have not overcome the poor prognosis associated with extensive bone lesions or extramedullary disease at MM diagnosis. Table 1 Multivariate Overall Survival Analysis Overall Age HR1 (95% CI) p value

Description: Background: The use of autologous stem cell transplants (ASCT) for multiple myeloma (MM) has greatly improved overall survival (OS), however, not all patients have benefited equally. Several studies have indicated that patients over the age of 65 or 70 at diagnosis had no immediate improvement in OS following the use of ASCT for MM, which is intuitive as ASCT was not covered by Medicare until 2001 and today is still often reserved for patients under 70. In addition, Waxman, et al (Blood, 2010) reported that ASCT for MM, resulted in nearly a two-fold improvement in OS in white patients compared to black patients. This suggests that white patients had better access to ASCT as retrospective studies of MM patients who undergo ASCT have failed to show an OS difference between the two races. Disparities in the OS benefit of ASCT among patients of different socioeconomic groups have not been reported on to date. It is also unclear if these disproportional improvements in outcomes have continued following the approvals of bortezomib and lenalidomide. Methods: Using the SEERStat software, we extracted the case listings of 85,115 patients diagnosed with MM from 1973 through 2010 in Surveillance Epidemiology and End Results (SEER)-18 registries database based on the November 2012 submission. Children (under 18 years old) were excluded. Autopsy or death certificate only cases were excluded. Patients identified as any race other than white or black were excluded. Patients were followed for OS through December 2011. Patients were divided into three cohorts based on the year of diagnosis, era 1 those diagnosed from 1973 to 1994, era 2 those diagnosed from 1995-2002 (to coincide with ASCT), and era 3 those diagnosed from 2003-2010 (to coincide with bortezomib’s approval). Socioeconomic status (SES) was approximated by median household income (MHI) of each patient’s county of residence from the 1990 US census; patients were divided into tertiles within their era of diagnosis based on MHI and classified as low-SES, middle-SES, or high-SES. Results: 78,681 patients were eligible for analysis. The median age at diagnosis was 70 years (range 18-85+); 54% were male; 18% were black. The median follow-up was 22 months (range 0-441). The OS of white patients increased from 23 months in the era 1 to 27 months in era 2, to 36 months in the era 3 (p

Description: Background: Despite improvements in overall survival (OS) and progression free survival (PFS), the prognosis of patients with relapsed/refractory multiple myeloma (RRMM) remains poor. Carfilzomib (CFZ), a second generation proteasome inhibitor, is active as a single-agent or in combination with lenalidomide and/or dexamethasone (DEX) in RRMM. Pegylated liposomal doxorubicin (PLD) combined with bortezomib has been shown to prolong PFS and OS and is FDA approved as combination therapy in MM. We investigated the combination of CFZ with PLD in RRMM in a Phase I study. Objective: To determine the maximum tolerated dose (MTD) of CFZ combined with PLD. Patient/Methods: Patients with RRMM after ≥ 1 lines of therapy, with measureable disease, and good performance status, organ function and hematological reserve were eligible. Prior CFZ or PLD/doxorubicin exposure was not exclusionary. CFZ was given on days 1, 2, 8, 9, 15 and 16 at escalating doses of 27-56mg/m2 and PLD was given on day 8 in 28 day cycles at a dose of 30mg/m2. All dose levels included a lead-in dose of 20mg/m2 of CFZ on days 1 and 2 of cycle 1. Following 6 cycles of combination therapy, PLD was discontinued and patients were treated with maintenance CFZ (once weekly). Dose escalation was performed using a 3+3 design; MTD was defined as the highest dose level where dose limiting toxicity (DLT) occurred in less than 2 of 6 patients. Disease response was determined using International Myeloma Working Group (IMWG) criteria. Results: 16 patients were enrolled from May 2012-March 2014. Median age was 66 years (range 53-79) and 11 were female. Seven patients were ISS stage 3, 9 were stage 1. 3 patients had 〉 50% plasma cells present on bone marrow aspirate, 8 had 〈 20%. By mSMART criteria, 2 patients were high-risk, 2 were intermediate-risk, and 12 were standard-risk. Most patients were IgG Kappa subtype (12); while 3 patients had Kappa light chain subtype, and 1 had IgG Lambda subtype. Median number of prior therapies was 3 (range 1-12). Median time from diagnosis to start of protocol was 42 months (range 9-236). 100% had prior exposure to lenalidomide; 87.5% had prior exposure to bortezomib; 75% had undergone autologous transplantation; 6% had prior PLD or doxorubicin exposure; and 6% had prior CFZ exposure. No DLTs were observed in any cohort. Two patients were unable to complete the first cycle of treatment due to early progressive disease, and were replaced. Grade 3/4 non-hematologic adverse events were rare, but included: UTIs (3), sepsis (2), pneumonitis (2), dyspnea (2), syncope (1), pleural effusion (1). Grade 3/4 hematologic AEs were limited to: anemia (7), thrombocytopenia (4), neutropenia (5), lymphopenia (4), and hemolysis (2). Most of the neutropenia (60%) and thrombocytopenia (75%) occurred in the 56mg/m2 cohort. The median number of cycles completed was 3.5 (range

Description: BACKGROUND: Azacitidine and decitabine are indicated for the first line treatment of intermediate and high risk MDS. About 40% to 47% of patients respond to 1st line hypomethylating agents. The median duration of response is 13 months. There are no effective therapies for patients who fail to respond to or progress on hypomethylating agents. A phase II trial of high dose lenalidomide (50mg/day) induction therapy followed by low dose (10mg/day) maintenance therapy in elderly patients with AML had demonstrated a high CR/CRi of 30%. CR was restricted to patients with presenting WBC counts

Description: Background: The outcome for patients with relapsed or refractory acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) remains extremely poor; new chemotherapy agents with activity against these leukemias are urgently needed. Proteasome inhibition is a promising therapeutic target in acute leukemias with established efficacy in several other hematologic malignancies. Several published studies have demonstrated the potent in vitro anti-leukemic activity of the selective proteasome inhibitor carfilzomib (CFZ) in leukemia cell lines as well as in primary human AML and ALL blasts. Given the favorable toxicity profile of CFZ, there was a strong rationale to begin the clinical study of this agent in the treatment of acute leukemias. We performed a phase I, single arm, single center, open label study of CFZ in adult patients with relapsed or refractory AML and ALL. Objectives: The primary objective was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of CFZ in adult patients with relapsed/refractory AML and ALL. Secondary objectives included: determination of disease response, time to response, remission duration, progression-free survival, event-free survival, and overall survival. The study was designed to determine the safety and tolerability of carfilzomib in this patient population. Patients/Methods: Patients with relapsed or refractory AML or ALL after ³ 1 line of therapy, with good performance status and organ function were eligible. CFZ was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in a 28-day cycle at escalating doses of 36, 45, and 56mg/m2. All dose levels included lead-in doses on days 1, 2, 8 and 9. Up to 6 cycles of treatment were allowed. Dose escalation was performed using a 3+3 design; MTD was defined as the highest dose level where DLT occurred in less than 1 of 3 or 2 of 6 patients. Disease response was determined using International Working Group (IWG) criteria for AML. Results: 18 patients were enrolled from Dec 2010-July 2014. Eight patients discontinued prior to completion of cycle 1 for reasons other than study-related toxicity and were replaced.The median age was 70 years (range 32-78). 12 of the 18 patients were male. 17 patients had AML while 1 patient had ALL. The median number of prior therapies was 2 (range 1-4). 2 patients had undergone prior allogeneic stem cell transplantation. The median time from diagnosis to start of protocol was 9.7 months (range 1.4-102.0). Median white blood cell (WBC) count at study start was 3.2x109/L (range 0.6-42.2), with median peripheral blood blasts of 18% (range 0-62), and bone marrow blasts 45.5% (range 11-92). 7 of the 17 patients with AML had complex cytogenetics. 10 of the 18 patients were evaluable for disease response. Of the 10 evaluable patients, 2 patients achieved a partial response (PR), and 4 additional patients had stable disease (SD). The median duration on study was 21.5 days (range 1-64), with median overall survival (OS) of 1.9 months. CFZ was generally well tolerated; no DLTs were observed in any cohort. The most common grade 3/4 non-hematologic toxicities regardless of attribution were: dyspnea (17%), activated partial thromboplastin time prolongation (17%), intracranial hemorrhage or hematoma (11%), infection (11%), CHF exacerbation (11%), and hypophosphatemia (11%). Conclusions: Administration of CFZ was well tolerated, and a MTD was not established. The recommended dosage for further studies is 56mg/m2. In this limited phase 1 study of heavily pre-treated patients, we observed modest anti-leukemic activity. However, additional clinical trials incorporating CFZ in combination with other chemotherapeutic agents are now needed to assess the potential efficacy of CFZ in the treatment of AML and ALL. Abstract 5292. Table 1 ID Dose Level Diagnosis # of Prior Lines of Therapy Prior SCT # of Cycles Best Response 1 1 (36mg/m2) AML 1 N 3 SD 2 1 (36mg/m2) AML 3 Y