ALBERT

Description: Abstract 3068 Advanced age is becoming less of a barrier to allogeneic hematopoietic cell transplantation (HCT) and transplantation has become an established standard of care for many older patients (pts) with hematologic malignancies. We previously reported superior quality of life (QOL) scores in pts age 60 and over undergoing high dose chemotherapy and autologous stem cell transplant compared with pts less than 60 (Dabney J et al, Blood 2008 112: Abstract 2381). These data prompted us to evaluate QOL assessments in pts≥60 undergoing allogeneic HCT compared to pts

Description: Allogeneic HCT is a potentially curative but high risk therapy for patients with hematologic malignancies. HCT recipients are typically followed closely by their transplant center within the first 100 days, and with advances in supportive care, day 100 survival has continued to improve significantly over time. Longer term survival, however, remains a challenge and the factors that predict for later mortality are not well understood. We thus undertook this retrospective analysis to identify prognostic factors for 1-and 2-year survival among day 100 survivors. Of 413 patients that underwent a first allogeneic HCT from 2006 to 2014, 355 survived 〉100 days post-transplant. Diagnoses included acute myeloid leukemia (N=163), myelodysplastic syndrome (N=89), acute lymphoblastic leukemia (N=62), chronic myeloid leukemia (N=34), or undifferentiated/biphenotypic leukemia (N=7). 34% of patients had high risk, 18% intermediate, and 48% low risk disease by American Society for Blood and Marrow Transplantation (ASBMT) RFI risk category. Median age at transplant was 50 years (range, 18-73). The majority of patients were Caucasian (89.6%). Median household income was $49,980 (range 13,316-112,530) and median distance from transplant center was 46 miles (range, 1-1055). 40% patients had a high HCT co-morbidity index, 32% intermediate and 28% low. 152 (43%) patients underwent a matched related donor, 148 (42%) matched unrelated donor, 36 (10%) umbilical cord blood (UCB), 13 (3%) haplo-identical, and 6 (2%) mismatched unrelated donor transplants. The majority of patients (75%) underwent a myeloablative transplant and bone marrow (BM) (53%) was the primary graft source. Cox proportional hazards was used to identify prognostic variables for 1- and 2-year mortality in the 355 surviving patients using baseline characteristics and factors evaluated at day 100. Baseline characteristics as described above included patient, disease, transplant, and socioeconomic/psychosocial factors. Additional variables evaluated at day 100 included number of readmissions, days hospitalized, GVHD rates, infections, relapse within the first 100 days of transplant, and QOL measures as assessed by the Functional Assessment of Cancer Therapy Bone Marrow Transplantation (FACT-BMT), scored at baseline and day 100. 1- and 2-year mortality was 71%, and 54%, respectively, compared to a day 100 mortality of 86%. Among day 100 survivors, the most common causes of death within the first 2 years were relapse (N=78, 54%), followed by infection (N=24, 17%), pulmonary or other organ failure (N=23, 16%), and GVHD (N=16, 11%). In multivariable analysis evaluating risk factors for mortality among the day 100 survivors, lower income (HR 1.25, P=0.013), high risk ASBMT RFI (HR 1.75, P=0.03), relapse (HR 7.84, P

Description: Introduction: Traditional prognostic factors for adult acute lymphocytic leukemia (ALL) include age, white blood count at diagnosis, and cytogenetic (CG) risk. We sought to identify a more detailed prognostic risk score for newly diagnosed adult patients (pts) based on these and other pre-treatment characteristics. Methods: 82 newly diagnosed ALL pts given induction chemotherapy (IC) at our institution between the years 2003-2011 were included, and data were obtained by chart review. Institutional review board approval was obtained. Variables examined included: gender, age, immunophenotype, CG risk, pre-IC body mass index (BMI), pre-IC and day 28 serum albumin, absolute lymphocyte (ALC) and neutrophil (ANC) counts, positive culture (blood or other) during IC, positive imaging suggestive of infection (during IC), and allogeneic hematopoietic cell transplant (AHCT). CG risk was ascribed by CALGB criteria (Blood 1999; 93: 3983). BMI was defined by: underweight (≤ 18.5), normal (〉 18.5-25.0), overweight (〉 25.0-30.0), moderately obese (〉 30.0-35.0), severely obese (〉 35.0-40.0), and very severely obese (〉 40.0). The primary endpoint was overall survival (OS) which was measured from IC to death or last follow-up. Proportional hazards models were used for univariable and multivariable analyses. In the multivariable analysis stepwise variable selection was used to identify independent predictors. Results were internally validated using a bootstrap algorithm. For convenience measured factors were discretized using a recursive partitioning algorithm. Prognostic groups were formed by assigning “points” to each factor that were based on the magnitude of the estimated regression coefficients of the final model, and then summing the total number of points present. Results: Median age at diagnosis was 43 yrs (range 18-78); 58% male. 71% of pts (58/82) had a B-cell immunophenotype. CG risk included: normal: 15 pts (18%), high: 41 pts (50%), miscellaneous: 9 pts (11%), and unknown: 17 pts (21%). Twenty-four pts (29%) were Ph+. The majority of pts (70%: 57/82) received the CALGB 19802 regimen (Cancer 2013; 119: 90) for IC +/- a tyrosine kinase inhibitor (if they were Ph+). 27% of pts (22/ 82) received AHCT in CR1. Estimated median OS is 41.5 months (95% CI: 15.5-N/A). In univariable analysis age, pre-induction BMI, Day 28 ALC, pre- and Day 28 albumin, Day 28 ANC, Day 28 platelet count, evidence of infection, and CG risk were all seen to impact outcome. In multivariable analysis pre-IC BMI and albumin, age, and Day 28 ALC were identified as independent predictors. Assigning 1 “points” each for age 〉50, albumin prior to IC ≤ 3.2 g/dL, or Day 28 ALC ≤ 50 /uL and 2 points for BMI ≥ 35, 3 prognostic groups were defined: favorable (0 points) 32% of pts (26/80): estimated 5-yr OS of 68% +/-11%; intermediate (1 points) (29% of pts, 23/80): estimated 5 yr OS of 39% +/-11%, and unfavorable (≥ 2 points) (39% of pts, 31/80) with estimated 5 yr OS of 17% +/- 7% (Figure 1). Conclusion: We have constructed a simple prognostic model for newly diagnosed adults with ALL. This model will need to be validated in a larger group of uniformly treated patients. Table 1 Prognostic Factors for OS in Univariable and Multivariable Analysis Factor Univariable (HR (95% C.I.)) Multivariable (HR (95% C.I.)) Age at dx (≤50 vs. 〉50) 3.29 (1.80-5.99), p=.0001 2.83 (1.45-5.53), p=.002 Pre-IC BMI (35) 2.95 (1.57-5.52), p=0.0008 3.88 (1.84-8.17), p=.0004 Pre-IC albumin (≥ 3.2 vs. 〈 3.2 g/dl) 2.61 (1.43-4.77), p=0.002 2.66 (1.33-5.30), p=.0006 Day 28 ALC (〉 50/uL vs. ≤50/uL) 3.57 (1.61-7.91), p=0.002 3.11 (1.33-7.28), p=.009 CG risk 2.03 (0.98-4.22); p=0.06 ------ Day 28 albumin (〉2.3 vs. ≤2.3 g/dl) 3.37 (1.66-6.83), p=0.0008 ------ Day 28 ANC (〉200/uL vs. ≤200/uL) 4.51 (1.94-10.51), p=.0005 ------ Day 28 platelets (〉75K/uL vs. ≤75K/uL) 2.44 (1.26-4.72), p=.008 ------ Any positive culture (no vs. yes) 2.19 (1.19-4.04), p=0.01 ------ Blood culture positive for bacteria (no vs. yes) 2.34 (1.28-4.30), p=0.006 ------ Positive imaging suggestive of infection (no vs. yes) 2.44 (1.34-4.46), p=0.004 ------ Positive blood culture and image (no vs. yes) 1.96 (1.07-3.57), p=0.03 ------ Figure 1 Prognostic Groups Figure 1. Prognostic Groups Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1261 LGL leukemia is a rare bone marrow failure disorder characterized by a clonal expansion of terminally differentiated T- or NK-cells with large cytoplasmic granules. Cytopenias of one or multiple lineages are the dominant phenotype, though lymphocytosis without cytopenias can also be present. Goals of therapy are minimizing cytopenias. Currently used immunosuppressive and chemotherapeutic agents have produced variable clinical responses. Predictors of response to therapy and overall outcomes have not been well studied. We reviewed 92 LGL patients (pts, T-LGL=79, NK-LGL=13) seen at Cleveland Clinic from January 2000 to July 2012 treated with various therapeutic agents. Overall (OS) and Progression-Free (PFS) Survival and Time to Next Treatment (TTNT) were estimated using the Kaplan-Meier method. The first three treatments for LGL pts were evaluated with TTNT; observation was not considered a treatment for this analysis. Risk factors for PFS and OS after initial treatment (including those who were never treated) were identified using Cox proportional hazard analysis. Clinical factors evaluated at time of diagnosis include age, sex, neutropenia (absolute neutrophil count ≤1000 per μL), anemia (hemoglobin ≤10gm/dL or transfusion requirement), lymphocytosis (absolute lymphocyte count 〉4000 per μL), lymphopenia (absolute lymphocyte count ≤1000 per μL), thrombocytopenia (platelet count ≤100 per μL), transfusion dependence (any red-cell transfusion requirement around time of diagnosis), history of B-cell dyscrasia and history of an autoimmune disease. Clinicopathologic risk factors included type of LGL leukemia (T- vs. NK-cell), detection of a monoclonal protein, number of Vβ clones measured by flow cytometry, and T-cell clonality by T-cell receptor (TCR)-γ rearrangement. P values of ≤0.05 were considered statistically significant. The median age of the cohort was 63 years (range: 16–85). 61% were male. Treatments (n=129) included cyclophosphamide (n=31), cyclosporine (n=33), methotrexate (n=25), alemtuzumab (n=12), chemotherapy (n=7), others (n=21), and supportive care or observation (n=28). Median TTNT was 18 months (range

Description: AYAs with cancer have been designated as a vulnerable population by the National Cancer Institute. This group, defined by the ages of 16-39 years, has not enjoyed the same survival improvements over the past several decades as older and younger cohorts. The reasons for outcome disparities among AYA leukemia patients are not well understood. Recent studies have compared outcomes of AYA HCT recipients with younger and older cohorts and reported no lag in survival improvements over time. However, long-term survival after allogeneic HCT in this age group has not been well described. We analyzed outcomes for 226 AYA patients with acute and chronic leukemia, myelodysplastic syndromes, aplastic anemia and lymphoma who were transplanted at our institution from 1/2000-3/2013. The median age at HCT was 29 years (range 15-39) and their median follow up was 5 years (range,

Description: Background: While achieving complete remission (CR) is a major treatment milestone in acute myeloid leukemia (AML) patients (pts) undergoing induction chemotherapy (IC), it is the time to achieve CR (Tc) that has greater prognostic value in predicting subsequent survival. We are particularly interested in seeing whether trends in white blood cell (WBC) count elimination and recovery during induction phase can aid in prediction of Tc, thus enabling real-time prognostication. Methods: Adult pts diagnosed with AML (excluding acute promyelocytic leukemia) at the Cleveland Clinic from 10/08 - 11/12 who underwent IC with 7+3 (cytarabine and anthracycline) and achieved CR were included. Pretreatment variables including age, gender, race, smoking status, body mass index at dx, peripheral blood counts at diagnosis (dx), peripheral and marrow blasts at dx, disease classification and metaphase cytogenetics (per CALGB/Alliance 8461 criteria) were assessed. For mapping WBC elimination and recovery kinetics, we collected data on total WBC, absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) at several different time points after IC – day 1, day 7, day 14 (range, 13-17), day 21, day 35 (range 30-45) and the day CR was achieved. Time intervals selected for analysis included time taken for clearance of peripheral circulating blasts; time to reach nadirs for WBC, ANC and ALC; and time to ANC recovery (from ANC nadir to 〉 500/µL). Tc was assessed as a function of WBC, ANC and ALC measurements (at the above predefined time points); time intervals; and magnitude of drop and rise in WBC, ANC and ALC (log reductions and improvements in counts) using multivariable logistic and Cox proportional hazards models and stepwise regression using Akaike’s Information Criterion (AIC) for model selection. Due to multiple testing, parameters are reported as significant if p 500/µL was significantly associated with delayed Tc (p

Description: Molecular mutations are routinely incorporated into the risk stratification of newly diagnosed acute myeloid leukemia (AML) patients (pts). However, their prognostic impact in relapsed AML has not been well characterized. To better understand the landscape and prognostic impact of molecular mutations in relapsed AML, we retrospectively examined pts with AML in first relapse. Methods: We performed multi-amplicon targeted deep sequencing on samples from bone marrow and peripheral blood of pts diagnosed with AML in first relapse at our institution between the years 2002-2013. A multiple gene sequencing panel of 64 genes that have been described as recurrently mutated in myeloid malignancies was applied. Genes were analyzed individually and grouped based on their functional pathways: RNA splicing, RNA-helicase family, DNA methylation/epigenetic, transcription factors, signal transduction/ receptors, histone/ chromatin modification, cohesion complex. Cytogenetic (CG) risk was ascribed by CALGB/Alliance 8461 criteria. The primary endpoints were response to salvage therapy and overall survival from relapse (OS-R). Binary logistic and proportional hazards models were used for univariable and multivariable analyses. Multivariable analyses of individual genes and functional groups used a stepwise variable selection algorithm and were based on the genes and gene groups found to be significant in univariable analysis at p 〈 0.20. Results: Data from 74 pts were analyzed. The median age at diagnosis was 61 years (range 27-77). CG risk at diagnosis: good (17%), intermediate (42%), miscellaneous (15%), poor (26%). At the time of relapse, 68% of pts received intensive salvage chemotherapy [i.e. MEC (mitoxantrone, etoposide, cytarabine), high dose cytarabine], 14% supportive care, and 19% low dose therapy. Sixteen percent of pts received an allogeneic hematopoietic stem cell transplant. The most common mutations were found in NPM1 (16%), DNTM3A (15%), IDH2 (14%), and PHF6 (10%). Overall, 19 pts (26%) had no mutations, 25 (34%) had 1, 12 (16%) had 2, 11 (15%) had 3, and 7 (9%) had 〉 3 mutations. Fifty-two percent of pts achieved a complete remission (CR) or CR with incomplete count recovery (CRi) with salvage therapy (95% CI: 39-64%) and median OS-R was 5.2 months. In multivariable analyses, the number of mutations (0, 1, 〉1) in DNMT3A, TP53, NRAS, and ASXL1 (panel 1) was the only factor found to be independently associated with worse OS-R and response to salvage therapy (p〈 0.0001 and 0.03, respectively). Adjusting for age, CG risk, and treatment, the number of mutations in panel 1 remained a significant predictor of OS-R (p=0.003) but not of response to salvage therapy (p=0.23). Multivariable analyses of panel 1 and conventional CG risk suggested that both factors contained prognostic information (p 〈 0.0001 and 0.07, respectively); and that a modified CG risk classification system could be defined using a simple scoring algorithm that assigns points to each conventional CG risk group and the number of panel 1 mutations that are proportional to the corresponding regression coefficients from the model and then summing the number of points present (Table 1). Based on the scoring system, 3 prognostic groups can be defined (Figure 1). Table 1. Scoring Algorithm Factor Points CG Risk  Good 0  Intermediate 2  Miscellaneous 2  Poor 3 Number of mutations in panel 1  0 0  1 3  〉1 6 Conclusions: Molecular mutations are prognostic for OS-R and may help identify patients who would benefit from novel therapies at the time of relapse. Specific predictive mutations included genes related to DNA methylation and histone modification suggesting that targeting these specific factors may improve outcome. Figure 1. Prognostic Groups Figure 1. Prognostic Groups Disclosures Carew: Boehringer Ingelheim: Research Funding. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Description: Healthcare disparities, such as race/ethnicity and SES, can impact access to care and outcomes in cancer patients. ASCT is standard therapy for high-risk relapsed and refractory lymphoma, but is a highly specialized and resource-intensive procedure. The association of race and SES with outcomes in lymphoma patients undergoing ASCT has not been described previously. We conducted a retrospective cohort study of 687 consecutive ASCT recipients with Hodgkins (N=154, 22%) and non-Hodgkins (N=533, 78%) lymphoma transplanted between 2003 and 2013 at our institution. Zip code of residence was used to obtain median annual household income based on 2010 US Census data. Patients were categorized into low SES (1/KPS 1 year, however, mortality in the low SES group in primarily mediated through non-relapse causes. Our study highlights the need for active interventions to mitigate health care disparities in this high risk population. Table. 5-year outcomes after ASCT for lymphoma by SES Outcomes All patients, N=687 1-yr survivors, N=551 Low SES High SES P-value Low SES High SES P-value Relapse mortality 29% 25% 0.03 16% 18% 0.53 NRM 16% 12% 0.18 14% 9% 0.07 OS 55% 64% 0.004 70% 74% 0.07 PFS 41% 47% 0.01 57% 58% 0.25 Figure 1. OS for all patients and 1-year survivors Figure 1. OS for all patients and 1-year survivors Figure 2. Figure 2. Disclosures Hill: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Majhail:Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.

Description: Background: Aberrant epigenetic modifications, fundamental to the pathogenesis of MDS, provide rationale for the use of the so-called hypomethylating agents, decitabine (DAC) and azacitidine (AZA). As depletion of DNA methyltransferase 1 (DNMT1) by these agents is S-phase dependent, episodic dosing used in common practice (SD-DAC; 20 mg/m2 x 5 days, every 28 days, SD-AZA; 75 mg/m2 x 5-7 days, every 28 days) affects only a fraction of the malignant clones. Alternative dosing schedules of decitabine with lower doses given more frequently (LD-DAC; .1-.2 mg/kg SC once/twice weekly) may decrease toxicity and increase response rates by improved hematopoietic differentiation and DNMT1 depletion while avoiding cytotoxicity. Data comparing use of very low and standard-dose DAC or AZA are lacking. Methods: We compared response, survival, and toxicities of 242 MDS patients (pts) treated at our institution from 9/06-10/13 with LD-DAC (n=39), SD-DAC (n=17), or SD-AZA (n=186). Response was assessed per International Working Group 2006 (IWG) criteria, progression-free (PFS) from date of response, and overall survival (OS) from diagnosis. Results: There were no significant differences in baseline characteristics, including median age (70 vs. 74 years, P=.93), proportion of patients with ≥5% bone marrow blasts (27% vs. 35%, P=.54), high/very high cytogenetic risk by the Revised International Prognostic Scoring System (IPSS-R, 25% vs. 40%, P=.31), number of pts with comorbidities (44% vs. 29%, P=.38), median time from diagnosis to treatment (14.6 vs. 6.4 months, P=.25) or prior MDS treatment (AZA and/or lenalidomide, 46% vs. 53%, P=.17), between the LD-DAC and SD-DAC groups, respectively. Likewise, the LA-DAC and SD-AZA groups were similar with respect to median age (70 vs. 68 years, P=.15), proportion of patients with ≥5% bone marrow blasts (27% vs. 39%, P=.19), and high/very high cytogenetic risk by the IPSS-R (25% vs. 27%, P=.83). However, pts in the SD-AZA group had a shorter median time from diagnosis to treatment (2.9 vs. 14.6 months, P=.009) compared to LD-DAC. Median treatment duration was longer in LD-DAC pts compared to SD-DAC (9.1 vs. 3.1 months, P=.0008) with a median cumulative dose of 8.4 mg/kg (range 1.2-41.2) and 350 mg/m2 (range 175-975) for LD-DAC and SD-DAC, respectively. Compared to SD-DAC, the LD-DAC group required more frequent dose reductions/delays (67% vs. 20%, P=.004) and experienced more hematologic toxicity (85% vs. 29%, P〈 .0001), respectively. While median time to best response was similar for LD-DAC and SD-DAC (3 vs. 4.1 months, P=.52) there was a trend for higher IWG response rates (30% vs. 18%, P=.06) and lower disease progression rates (18% vs. 41%, P=.06) for LD-DAC compared to SD-DAC. However, this did not translate into a difference in median PFS (11 vs. 7.6 months, P= .34) or OS (23.9 vs. 18.2 months, P=.64, Figure 1). Comparing these results to SD-AZA, while LD-DAC had a longer median treatment duration (9.1 vs. 5.1 months, P=.052) and shorter median time to best response (3 vs. 5.3 months, P=.005) than SD-AZA, response rates were similar (30% vs. 31%, P=.5) and there were no significant differences with respect to median PFS (11 vs. 7.1 months, P=.059) or OS (23.9 vs. 21.1 months, P=.5, Figure 1). Conclusion: Pts treated with the LD-DAC strategy have a response rate at least equivalent to SD-DAC and SD-AZA, though they required more dose adjustments and receive treatment for a longer time period. Survival was similar for all dosing strategies. Very low-dose DAC is an active treatment approach and will be compared to standard-dose DAC and AZA in an upcoming randomized, prospective trial conducted through the MDS Clinical Research Consortium. Figure 1 Figure 1. Disclosures Off Label Use: Subcutaneous administration of very low-dose decitabine in treatment of MDS .

Description: Background: Acute Myeloid Leukemia (AML) patients (pts) being screened for clinical trials are often excluded based on laboratory values outside the normal range because of concerns of early treatment-related toxicities that can lead to adverse outcomes including death or delayed time to complete remission (CR). It has been shown that the time to achieve CR (Tc) has greater prognostic value in predicting survival than achieving CR per se (Estey et al., Blood 2002). In this study we assessed correlations between pretreatment risk factors and early (within 30 days of induction) treatment-related non-hematologic toxicities (TNHT) following IC, and between these toxicities and Tc and the probability of achieving CR. Methods: Adult pts diagnosed with AML (excluding acute promyelocytic leukemia) at the Cleveland Clinic from 10/08 - 11/12 who underwent IC with 7+3 (cytarabine and anthracycline) and had complete toxicity data were included. Variables including demographics, AML disease characteristics, abnormal laboratory measurements at diagnosis and during treatment, treatment response, and ICU stay, were assessed. The outcome of interest were development of non-fatal early TNHT and its effect on CR and Tc. TNHT were mapped as linear distance beyond the normal laboratory range and were set to zero if within limits. This was done for serum sodium (Na), potassium (K), bicarbonate, liver enzymes (AST, ALT), total bilirubin, INR (international normalized ratio), serum creatinine and albumin. These metrics were analyzed as a function of covariates at diagnosis using standard linear regression. They were then treated as covariates in logistic regression models of CR and in linear models of Tc. Akaike’s Information Criterion (AIC) was used in stepwise logistic regression model selection. Due to multiple testing, parameters are reported as significant only if p40, 12%) and one was underweight. All patients developed TNHT following IC: 98% (n=89) had electrolyte abnormalities, 26% (n=24) had elevated serum creatinine levels and 99% (n=89) had abnormal liver function indicated by AST, ALT, bilirubin, albumin and INR. Overall, 68% pts achieved CR, 9% (n=8) had complete response with incomplete recovery of counts, 10% (n=9) had persistent disease and in 12, determination of CR was not done due to early death or severe debilitation. Of all pretreatment variables, advancing age correlated with worsening hypoalbuminemia (p=0.0076); higher WBC with worsening hyperkalemia (p=0.001); absolute neutrophil counts with high K (p=.0002); and LDH with high K levels (p