Citations

Abstract Background: Indolent non-Hodgkin lymphoma (iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL), is typically responsive to initial chemoimmunotherapy, but relapse is expected. Single-agent rituximab is FDA approved and frequently administered for patients with relapsed/refractory (R/R) low-grade or follicular CD20-positive B-cell NHL. Lenalidomide is an immunomodulatory agent with preclinical and clinical antilymphoma activity alone and in combination with rituximab. We compared the efficacy and safety of lenalidomide plus rituximab (R2) to rituximab (plus placebo) in patients with R/R iNHL. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase III study of R2 vs rituximab/placebo (control) in patients with FL grade 1-3a or MZL who were previously treated with ≥ 1 prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab (refractory was defined as < partial response to rituximab or rituximab-chemotherapy OR disease progression < 6 months after last rituximab dose). Patients were stratified by prior rituximab treatment (yes vs no), time since last antilymphoma therapy (≤ 2 vs > 2 years), and histology (FL vs MZL), and then randomized 1:1 to R2 or control for up to 1 year. R2 patients received oral lenalidomide 20 mg/day (d), d1-21/28 for 12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2-5. Control patients received rituximab and placebo on the same schedule. Dose modifications were pre-specified in the protocol to manage toxicities. The primary endpoint was progression-free survival (PFS) per 2007 IWG criteria without PET as assessed by Independent Review Committee (IRC; central review). Secondary endpoints included overall response rate (ORR), complete response (CR), duration of response (DOR), time-to-next antilymphoma treatment (TTNLT), overall survival (OS), and safety. Results: A total of 358 patients were randomized (n = 178 R2; n = 180 control), median age was 63 years (range, 26 - 88), 34% FLIPI score ≥ 3, and histologies of 82% FL/18% MZL. Median number of prior systemic treatments was 1 (range, 1 - 12); 84% received prior rituximab and 51% had prior antilymphoma therapy within 2 years of enrollment. At median follow-up of 28.3 months, the study met its primary endpoint of PFS with HR = 0.46 (95% CI, 0.34 - 0.62; P < 0.0001) (Figure 1). Median PFS was 39.4 months for R2 vs 14.1 months for control. IRC-assessed ORR for R2 was 78% vs 53% for control (P < 0.0001). CR was 34% for R2 vs 18% for control (P = 0.001). Median DOR was 36.6 and 21.7 months for R2 and control arms, respectively. TTNLT was improved for R2 vs control with HR = 0.54 (95% CI, 0.38 - 0.78; P = 0.0007). OS data were not mature with 16 deaths reported in the R2 arm vs 26 deaths in control (HR = 0.61 [95% CI, 0.33 - 1.13]). Selected all-grade treatment-emergent adverse events (TEAEs) of interest more common in the R2 vs control arm (≥ 10% difference) were infections (63% vs 49%), cutaneous reactions (32% vs 12%), constipation (26% vs 14%), thrombocytopenia (15% vs 4%), and tumor flare reaction (11% vs 1%). Grade 3/4 TEAEs were reported in 69% R2 and 32% control patients. More frequent grade 3/4 TEAEs in the R2 vs control arm were primarily attributable to increased neutropenia (50% vs 13%) and leukopenia (7% vs 2%). Grade 5 TEAEs were reported in 2 patients in each arm. TEAEs leading to discontinuation of lenalidomide occurred in 9% of patients vs 5% for rituximab + placebo. Neutropenia was the only TEAE leading to discontinuation of lenalidomide in > 1 patient (n = 5). Seventy-one percent of R2 patients completed all 12 cycles of planned treatment vs 61% of control. Disease progression was the leading reason for discontinuation of lenalidomide/placebo (n = 21 R2, n = 54 control). Conclusions: R2 demonstrated superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of progression-free survival as well as secondary endpoints of ORR, CR, DOR, and TTNLT in patients with R/R FL grade 1-3a and MZL. At this early analysis, fewer deaths have been observed in the R2 arm. Despite additional hematologic toxicity, greater efficacy of the R2 regimen (and fewer early progressions) allowed more patients to complete the planned therapy and delayed the need for subsequent treatment. R2 represents an important new treatment option in patients with previously treated FL/MZL, with meaningful advantages over single-agent rituximab. Disclosures Leonard: Celgene: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; MEI Pharma: Consultancy; Juno: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Sutro: Consultancy; Biotest: Consultancy; United Therapeutics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy; BMS: Consultancy. Trněný:F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria. Izutsu:Otsuka: Honoraria; Bristol- Myers Squibb: Honoraria; Nihon Medi-Physics: Honoraria; Novartis: Honoraria; Mundhi: Honoraria; HUYA Bioscience International: Research Funding; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Gilead Sciences: Honoraria; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Zenyaku: Research Funding; Celltrion: Research Funding; MSD: Honoraria; Ono: Honoraria, Research Funding; Symbio: Research Funding; Celgene: Consultancy, Research Funding; Solasia: Research Funding; Sanofi: Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Zhu:Beijing Cancer Hospital (Peking University Cancer Hospital): Employment. Scheliga:INCA - Instituto Nacional Do Cancer, Brazil: Employment. Pinto:Servier: Consultancy; BMS: Honoraria, Research Funding; MSD: Honoraria; Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Gilead: Honoraria. Scheinberg:Novartis: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding; Pfizer: Speakers Bureau. Flinn:Trillium: Research Funding; Takeda: Research Funding; Calithera: Research Funding; Incyte: Research Funding; Verastem: Research Funding; ArQule: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Agios: Research Funding; BeiGene: Research Funding; Kite: Research Funding; Portola: Research Funding; Verastem: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Forma: Research Funding; Merck: Research Funding; Novartis: Research Funding; Constellation: Research Funding; Curis: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Moreira:Instituto Português de Oncologia do Porto FG, EPE, Porto, Portugal: Employment. Liu:Celgene: Employment, Equity Ownership. Kalambakas:Celgene: Employment, Equity Ownership. Fustier:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Gribben:Cancer Research UK: Research Funding; Unum: Equity Ownership; Novartis: Honoraria; Abbvie: Honoraria; Wellcome Trust: Research Funding; Acerta Pharma: Honoraria, Research Funding; Kite: Honoraria; NIH: Research Funding; Roche: Honoraria; Janssen: Honoraria, Research Funding; Medical Research Council: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics: Honoraria.

Abstract Introduction - Allogenic hematopoietic cell transplantation (HCT) remains potential curative treatment for hematologic malignancies. Anti-thymocyte globulin (ATG) is an immunoglobulin directed to human T lymphocytes, and may decrease the risk of chronic graft versus host disease (cGVHD). Use of ATG has been associated with higher incidence of disease relapse and infection. While the optimal dosing of ATG has not been well established, higher doses (≥ 7.5 mg/kg) have a stronger association with infection and disease relapse. Our institution utilizes low dose rabbit ATG at 2.5 mg/kg for in-vivo T-cell depletion. In this retrospective study we evaluated outcomes in patients receiving low dose ATG to those not undergoing in-vivo T-cell depletion with the hypothesis that low dose ATG protects against cGVHD without impacting infectious complications or relapse. Patients and Methods - We evaluated all patients with 8/8 HLA Matched unrelated Donors (MUD) undergoing HCT between 2007 and 2016. Patients were divided in to two cohorts, those receiving low dose ATG to those that did not. Both cohorts received standard GVHD prophylaxis with calcineurin inhibition plus methotrexate or mycophenolate. The primary outcome was overall survival (OS). Secondary outcomes included relapse free survival (RFS), EBV reactivation, CMV reactivation, CMV disease, invasive fungal infection, incidence of acute GVHD (aGVHD) grades III-IV, and moderate to severe cGVHD. A subset analysis was performed to assess relapse free survival (RFS) in patients with myeloid malignancies. Descriptive statistics were utilized for baseline characteristics; and a series of univariate and multivariant Cox proportional hazard regression models were conducted for outcomes of interest. A Kaplan-Meier (K-M) survival curve was used to depict probability of survival by ATG cohort. Results - We identified 209 patients, with 129 (62%) in ATG group and 80 (38%) in non-ATG group. At baseline, there were no differences in the age at transplant, sex, ABO incompatibility, or performance status. The ATG cohort had fewer low disease risk index (DRI) patients and more patients with intermediate or high DRI (2.4%, 64.6%, 28.3% vs 18.4%, 51.3%, 23.7% respectively), and Fisher's Exact test showed that this difference between ATG groups was statistically significant, p = <0.001. The ATG cohort also had significantly different rates of myeloablative (MA) conditioning regimens from the non-ATG cohort with fewer receiving MA (31% vs 53% p < 0.01). No statistically significant differences in OS were observed between the two ATG cohorts at up to 5 years post-transplant (p=0.35; Fig. 1). The primary predictor of OS was DRI very high vs low [HR 6.0 (2-18) p < 0.01]. The ATG exposed cohort had significantly lower risk of cGVHD [HR 0.17 (0.08-0.37) p = <0.001]. There was no difference in risk of death from relapse, incidence of EBV or CMV reactivation, CMV disease, invasive fungal infection, or grade III-IV acute GVHD. Low dose ATG was not associated with inferior RFS, including in subset analysis of patients with myeloid malignancies [HR 0.85 (0.5-1.4) p = 0.549]. Conclusions - Our study shows no significant difference in survival or death from relapse for patients who receive ATG. Importantly, patients receiving ATG had a lower rate of cGVHD with no increased rates of infectious complications. Low dose ATG did not appear to increase the risk of relapse, even when considering only myeloid malignancies. These findings suggest that low dose ATG can improve cGVHD with no impact on survival, relapse, or infectious complications. Additional prospective trials using low dose ATG compared to no ATG are warranted. Disclosures Palmer: Novartis: Research Funding.

Abstract Background The prognosis for AML or MDS patients (pts) with monosomal karyotype (MK) is dismal. Although a benefit for allogeneic hematopoietic cell transplantation (allo-HCT) compared to chemotherapy or autologous HCT has been demonstrated in young (≤ 60) pts (Cornelissen, 2012), the curative potential of allo-HCT in older (≥ 60) pts with monosomal karyotype AML/MDS is not known. Patients and methods In this retrospective review, we analyzed outcomes for 69 AML (n = 49) or MDS (n = 20) pts ≥ 60 who underwent allo-HCT at Mayo Clinic Arizona between 2005 and 2013, based on cytogenetic grouping as follows: cytogenetically normal (CN, n = 23), cytogenetically abnormal but not MK (CA, n = 32), and MK (n = 14). Monosomal karyotype was defined (Breems, 2008) as a karyotype with at least two autosomal monosomies or a single autosomal monosomy in combination with at least one structural abnormality. Univariate and multivariate statistical analyses were performed to evaluate the impact of these 3 cytogenetic groupings on outcome (primary endpoint progression-free survival). The median age for all pts was 66 (60-76), and median follow-up for surviving pts was 22 months (range 70 days – 7.1 years). Thirty-seven pts had high-risk disease (MDS > 5% blasts or AML not in CR), while 32 were considered standard risk (MDS <5% blasts or AML in CR). The majority of pts had good performance status (KPS ≥ 90% in 66), but 34 pts (49%) had an HCT-CI score of ≥ 3. Conditioning was myeloablative (Bu-Cy) in 4, reduced toxicity FBM (Fludarabine, BCNU, Melphalan) in 36, and RIC/NMA in 29. Donors were matched related in 18, matched unrelated in 36, and mismatched unrelated in 15. GVHD prophylaxis included tacrolimus in all pts combined with mycophenolate mofetil (37) or methotrexate (32); 49 pts received in-vivo T-cell depletion with rabbit anti-thymocyte globulin (rATG, Thymoglobulin, Genzyme, Cambridge, MA). Results The Kaplan-Meier estimate of progression-free survival (PFS) at 2 yrs was 59% (CN), 39% (CA), and 1.5% (MK); P = 0.004 (Fig. 1). The cumulative incidence of relapse at 2 yrs (with death without relapse as a competing risk) was 34% (CN), 25% (CA), and 94% (MK); P= 0.009). In a Cox proportional hazards analysis adjusted for age (≤ 66 vs. > 66), risk status (standard vs. high), conditioning (myeloablative [Bu-Cy + FBM] vs. RIC/NMA), use of ATG (yes/no), donor type (unrelated vs. related), and HCT-CI (0-2 vs. ≥ 3), the only factor predictive for inferior PFS was cytogenetic status (MK vs. CN, HR 4.64 [95% CI, 1.7 – 13]; P = 0.003); (MK vs. CA, HR 2.4 [95% CI 0.97 – 5.9]; P = .057). Conclusions Standard allo-HCT in AML or MDS pts ≥ 60 with a monosomal karyotype appears to have limited curative potential. Although larger studies will be required to confirm our results, novel transplant approaches or post-transplant strategies to prevent relapse should be a focus of future studies in this incurable pt population. Disclosures: Reeder: Novartis: Research Funding; Celgene: Research Funding; Millennium: Research Funding.

Abstract Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHL) including the rare lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia (WM). Using whole exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). MYD88L265P was detected at lower frequencies in other indolent lymphomas including LPL (0%), MALT (4%), nodal MZL (5%) and splenic MZL (8%); all but one MYD88L265P was heterozygous. Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B cell survival, therapeutic targeting of MYD88 signaling pathways may be useful clinically. However, while the effects of MYD88L265P on the activity of IRAK1/4 and NF-κB are have been studied previously, we are lacking a thorough characterization of the role of intermediary signaling proteins such as TRAF6 and TAK1 on the biology of MYD88L265P-expressing B cells. A better understanding of the proteins involved in MYD88L265P signaling may lead to the development of more targeted and effective therapeutic approaches. In an attempt to identify MYD88L265P –specific therapeutic targets we first wanted to characterize the role of intermediary signaling proteins that facilitate the downstream activation of NF-κB. Upon activation of TLRs or IL-1b receptors, MYD88 forms a homodimer and recruits IRAK1/4 and TRAF6 into a complex resulting in association and phosphorylation of TAK1 followed by activation of NF-κB. We monitored the formation of a complex comprised of MYD88, IRAK1, IRAK4 and TRAF6 and immunoprecipitation of either endogenous IRAK4 or IRAK1 revealed constitutive association of IRAK with TRAF6 and MYD88L265P. To assess if the formation of a MYD88L265P/IRAK/TRAF6 complex results in downstream activation of TAK1, constitutive TAK1 phosphorylation was measured and detected in all three cell lines that express MYD88L265P. An association between TAK1 and TRAF6, another measure of TAK1 activation, was also detectable. When a similar analysis of TAK1 was performed in DLBCL cells expressing wild-type MYD88, no phosphorylation of TAK1 was detected, nor was TAK1 associated with TRAF6. IRAK1, IRAK4, TAK1, TRAF6, and MYD88 were expressed at similar levels in all cell lines studied and therefore did not contribute the differences in MYD88 complex formation observed between cell lines. These studies were further confirmed using HEK 293T cells that were transduced with either a vector control plasmid or HA-tagged MYD88WT or MYD88L265P expression plasmids. Together, these studies suggest that MYD88L265P forms a complex with IRAK and TRAF6 resulting in constitutive activation of TAK1 and NF-κB. To confirm the significance of TAK1-mediated MYD88L265P signaling on lymphoma cell growth, the effect of the selective TAK1 inhibitor, (5Z)-7-Oxozeaenol, on cell proliferation was tested. All MYD88L265P-expressing cell lines were sensitive to TAK1 inhibition in a dose-dependent manner (0-10 μM). In contrast, NHL cells expressing MYD88WT were found to be insensitive to TAK1 inhibition. We next tested the impact of the TAK1 inhibitor on a MYD88L265P positive WM patient sample. Similar to what was seen in the WM cell lines, the TAK1 inhibitor inhibited WM cell growth and survival in a dose dependent manner. Additionally, the TAK1 inhibitor significantly reduced the level of IL-10 secreted by each of the cell lines. Together, these data suggest that MYD88L265P drives cell proliferation and cytokine secretion through a TAK1-dependent mechanism. In conclusion, we are the first to validate by NGS in a large patient cohort the high prevalence and specificity of MYD88L265P in WM. Cells harboring the L265P mutation but not wild-type MYD88 exhibit constitutive signaling leading to the hyperactivation of NF-κB. We have established the role of TAK1 as an integral component of MYD88L265P signaling in both WM and DLBCL cell. Our data suggest that targeting TAK1 clinically may be an effective strategy for the treatment of WM and other lymphomas driven by MYD88L265P signaling. Disclosures: Fonseca: millennium: Consultancy; amgen: Consultancy; Binding site: Consultancy; onyx: Consultancy; medtronic: Consultancy; Genzyme: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; lilly: Consultancy; Onyx: Research Funding; cylene: Research Funding.

Introduction Allogeneic hematopoietic stem cell transplant (HCT) patients are at risk for having a low Vitamin D (VD) level. VD level has been correlated with cancer incidence, pulmonary disease and infection. VD also has immunomodulatory properties and reports suggest that a low VD level increases the incidence of chronic GVHD and may impact mortality in HCT. HCT morbidity and mortality is attributed to infection, organ system toxicity, GVHD and recurrent disease. Identifying a correctable factor that would reduce the occurrence or severity of these complications would be beneficial. It is possible that VD may have significant effect on outcome after HCT due to its described properties. Normal VD level may infer better outcome for HCT patients by improving response in or preventing infection, protecting organ function, decreasing risk of relapse and/or decrease incidence or severity of GVHD. We hypothesize that there is a relationship between VD level and morbidity and mortality after HCT. We therefore studied VD levels pre- and post-HCT to determine if there was an impact of VD level on these outcomes. Patients and Methods Two hundred and fifty patients underwent myeloblative or non-myeloablative HCT between 3/12/2009 and 10/29/2012 at our institution. Baseline demographic data, disease characteristics, transplant variables and outcomes data were obtained from the transplant database. These data were supplemented by retrospective chart review for VD levels prior to transplant, at day 100 and 1 year post-HCT. Data were collected through day 100 for occurrence of infection and admissions to the ICU. Categories for VD level included normal (≥30 ng/ml) or abnormal (<30 ng/ml). Patient characteristics were compared using the Chi-square test or Wilcoxon rank sum test. The logrank test was used to compare the survival curves between groups, and the Cox proportional hazard model was used to measure the association between outcomes (mortality, relapse, acute or chronic GVHD) and VD level. Results Of the 250 patients undergoing HCT VD level was performed on 180 (72%) patients pre-HCT, 149 (60%) patients at day 100 post-HCT and 81 (32%) patients at 1 year post-HCT. The rate of acute or chronic GVHD was not significantly associated with VD level pre or post-HCT. Overall infection risk was not significant pre or post-HCT but when sorted by type of infection bacterial infection (p=0.01), radiologic evidence of pulmonary nodules/consolidation (p=0.03), and ICU admissions (p=0.0313) within the first 100 days post-transplant were significantly increased in patients who had a low VD level at day 100 post -HCT. Pre-HCT and 1 year post-HCT VD level did not impact mortality or relapse but there was a significant increase in one year mortality (p=0.02, HR = 5.99) and relapse (p = 0.03, HR=9.47) in patients who had a low VD level at day 100 post-HCT. Discussion This study shows that VD may play a significant role in bacterial infection, pulmonary infection, ICU admission, mortality and relapse after HCT. Those patients with a low VD level at day 100 post-HCT had significantly worse outcomes for relapse and mortality. Those patients with a low VD level at day 100 post-HCT had a higher incidence of lung infection, bacterial infection and admission to the ICU. In contrast to previous studies, we found no correlation between VD level and incidence of acute or chronic GVHD. This study is one of the largest reported and the first to our knowledge that reports decreased risk of certain types of infection (bacterial and lung), mortality and relapse in those with an adequate VD level receiving HCT. It is possible that supplementation of VD to keep levels ≥30 would reduce these complications of HCT. Future prospective study of VD is warranted. Finding a low cost and easy to administer therapy (such as VD replacement) that would reduce morbidity, mortality and relapse in the HCT population is needed. Disclosures: Reeder: Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.

Background Steroid-refractory (SR) acute graft-versus host disease (aGVHD) is a serious complication of allogeneic HCT, for which there is no established standard treatment. Both ECP and cytokine inhibitors such as Infliximab have apparent single agent activity in the therapy of SR aGVHD, but there are no published data that address the efficacy of combination anticytokine therapy and ECP in this setting. We report here results in 18 adult patients (pts) with grade III or IV SR aGVHD who were treated with concurrent Infliximab and ECP. Patients All pts underwent allogeneic HCT (first transplant, n=15, second transplant, n=3) for a hematologic malignancy at Mayo Clinic Arizona between March 2012 and May 2013. The median age was 61 (range 22-70), and the median follow-up of 6 surviving pts is 263 days (range 79-433). Donors were related in 3, matched unrelated in 8, and mismatched unrelated in 7. GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil in 13 pts and tacrolimus/methotrexate in 5; in addition, 17 pts received in vivo T-cell depletion with Thymoglobulin 2.5 – 7.5 mg/kg. All pts developed grades III-IV aGVHD at a median day 27 post-transplant (range 10-107) and failed to respond to a course of high-dose corticosteroids (methylprednisolone or equivalent 2 mg/kg daily) for at least 5 days. Treatment Regimen At diagnosis of SR aGVHD, pts were scheduled to receive weekly Infliximab 10 mg/kg (maximum 4 doses), concurrent with ECP performed twice or thrice weekly for one month, followed by a pre-specified taper schedule (anticipated total treatment duration of 6-9 months). To minimize infectious risk and morbidity, corticosteroids were tapered rapidly after the start of Infliximab/ECP therapy. Results Thirteen pts (72%) responded to the Infliximab/ECP combination; complete response (CR; resolution of all GVHD symptoms for at least 30 days and able to discontinue corticosteroids) was observed in 6 pts (33%), and partial response (PR; improvement in GVHD symptoms, partial taper of corticosteroids, and no additional agent for at least 30 days) in 7 pts (39%). At the time of this report, 6 pts are alive, and the Kaplan-Meier estimate of one-year survival is 22.5 % (95% CI, 8.8%-47%). Only pts who achieved CR had good outcomes (5/6 surviving and clinically well); among 13 pts with PR (7) or no response/progression (6) to Infliximab/ECP, 12 have died and one is day 79 post transplant and remains on ECP and low-dose prednisone. Eleven of the 12 deaths were related to GVHD or complications of its treatment (infection, multi-organ failure). Conclusions In this retrospective study of adult pts with severe (grade III/IV) SR aGVHD, treatment with 4 doses of weekly Infliximab and concurrent ECP resulted in an overall response rate of 72%, with one-third of pts achieving CR; the regimen was well-tolerated and facilitated early taper and rapid discontinuance of corticosteroids. Unfortunately, the overall survival of 22.5% at one year does not appear superior to other single agent or combination therapies reported in the literature, or to historical data from our program. Although a small percentage of pts appear to be long-term survivors, the majority of pts succumb to complications of progressive GVHD or infection. Given poor results with available therapies, and the dismal prognosis of pts with SR aGVHD, future research should focus on better preventative strategies for this devastating complication of allogeneic HCT. Disclosures: No relevant conflicts of interest to declare.

Abstract A favorable prognosis and a low rate of leukemic transformation has been attributed to the 5q- syndrome, a myelodysplastic syndrome (MDS) characterized by macrocytic anemia, hypolobulated micromegakaryocytic hyperplasia, and an interstitial deletion of chromosome 5. We examined the characteristics and outcome of 43 consecutive patients in our institution strictly defined by morphologic criteria and a solitary 5q- cytogenetic defect. The median age at diagnosis was 68 years, with a clear female predominance (7:3). Eighty percent of the patients were red blood cell transfusion-dependent at diagnosis and all untransfused patients had macrocytic indexes. In contrast, significant neutropenia or thrombocytopenia was rare. The French-American-British (FAB) class distributions were RA (72%), RARS (7%), RAEB (16%), and RAEB-IT (5%). At a median follow-up of 31 months, 56% of the patients survive, with a projected median survival of 63 months. The incidence of acute leukemia was 16% and was uniformly fatal. Clinical hemosiderosis occurred in 28% of the patients, resulting in two deaths. Neither survival nor the risk of leukemic transformation was predictable from initial clinical parameters, including FAB classification, Bournemouth score, and degree of aneuploidy. The lack of significant neutropenia and thrombocytopenia seemed to account for a very low incidence of infection and bleeding resulting in a prognosis equal or superior to historical patients with MDS. Therapeutic endeavors, including the use of corticosteroids, androgens, cis-retinoic acid, pyridoxine, and danazol, were largely unsuccessful.

A favorable prognosis and a low rate of leukemic transformation has been attributed to the 5q- syndrome, a myelodysplastic syndrome (MDS) characterized by macrocytic anemia, hypolobulated micromegakaryocytic hyperplasia, and an interstitial deletion of chromosome 5. We examined the characteristics and outcome of 43 consecutive patients in our institution strictly defined by morphologic criteria and a solitary 5q- cytogenetic defect. The median age at diagnosis was 68 years, with a clear female predominance (7:3). Eighty percent of the patients were red blood cell transfusion-dependent at diagnosis and all untransfused patients had macrocytic indexes. In contrast, significant neutropenia or thrombocytopenia was rare. The French-American-British (FAB) class distributions were RA (72%), RARS (7%), RAEB (16%), and RAEB-IT (5%). At a median follow-up of 31 months, 56% of the patients survive, with a projected median survival of 63 months. The incidence of acute leukemia was 16% and was uniformly fatal. Clinical hemosiderosis occurred in 28% of the patients, resulting in two deaths. Neither survival nor the risk of leukemic transformation was predictable from initial clinical parameters, including FAB classification, Bournemouth score, and degree of aneuploidy. The lack of significant neutropenia and thrombocytopenia seemed to account for a very low incidence of infection and bleeding resulting in a prognosis equal or superior to historical patients with MDS. Therapeutic endeavors, including the use of corticosteroids, androgens, cis-retinoic acid, pyridoxine, and danazol, were largely unsuccessful.

Abstract Introduction Although allogeneic hematopoietic cell transplantation (HCT) is an expensive modality of treatment for hematological disorders, very little is known about the financial burden for the patients themselves. We analyzed factors associated with financial burden and its impact on health behaviors of allogeneic HCT recipients. Patients and Methods A questionnaire was mailed to adult patients who were alive after allogeneic HCT performed between 1/06 to 6/12 at Mayo Clinic to collect information regarding financial concerns, household income, employment status, insurance, out-of-pocket expenses and health and functional status. A multivariable logistic regression analysis was performed to determine socio-demographic and clinical factors associated with financial hardship. Results Of 482 patients, 268 responded (response rate 56%). Respondents were more likely to be older and Non-Hispanic Whites. No significant differences were seen in disease or transplant characteristics between the two groups except that respondents were more likely to have received reduced intensity conditioning. Median follow-up after HCT was 2.3 years (range 0.7-6.7 years). All the patients for whom the insurance information was available (missing n=13) were insured. Median physical and mental component score, as derived from the SF-12, were 36.8 [Interquartile range (IQR) 29.3-49.0] and 53.1 (IQR 42.1-57.1) respectively, where the general population score is 50, and lower scores indicate worse functioning. The proportion of patients that reported being on medical disability increased from 8% prior to HCT to 29% after HCT. 73% of the respondents reported that being sick had hurt them financially. 54% experienced adverse financial consequences such as decrease in household income by &gt;50% due to the HCT, need to sell/mortgage home, withdraw money from retirement accounts or having to pay more for medical care than they could afford. 3% declared bankruptcy. 12% had out-of pocket costs for the past 3 months that were&gt; $5000. Median monthly medication copayments were $100 (range $ 0-3000). 36% patients felt that their insurance coverage was poor which was strongly correlated with adverse financial consequences (p=0.0013). Other risk factors for financial burden were poor physical functioning reflected by the physical component score &lt;40 (OR 3.2; p=0.005), lower household income (OR 3.08; p=0.006) and lack of commercial/private insurance (OR 4.2; p&lt;0.001) while adjusting for patient and transplant related characteristics. Time from transplant was a significant predictor (OR 1.2; p=0.03) in the univariate analysis, but lost its significance in the multivariate analysis. 18 to 27% patients reported deleterious health behaviors due to financial constraints such as not taking prescribed medications, not using a recommended medical service or not making physician appointments. Conclusions A significant proportion of allogeneic HCT survivors experience adverse financial consequences with a few reporting severe outcomes like bankruptcy, despite having health insurance coverage. Future research should investigate potential interventions such as early financial counseling and connecting with sources of financial support to help at-risk patients and prevent long-term adverse financial outcomes after this life-saving procedure. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3513 To identify targets for rational combination therapies with 5-Azacytidine (5-Aza) in myeloid malignancies, we utilized high-throughput RNA-interference (RNAi) viability screening. A siRNA library targeting 572 kinases and a custom collection of 289 putative cancer targets, including cell cycle and apoptosis regulatory genes, were screened alone and in combination with 5-Aza in TF-1 and ML-2 myeloid leukemia cell lines to identify synergistic interactions in reducing cell viability. Of the 572 kinases that were individually silenced, less than 1% significantly increased sensitivity to 5-Aza. The kinase library was also screened in combination with 5-Aza in a third myeloid cell line, THP-1, confirming that few kinases sensitize to 5-Aza when inhibited. While few kinases sensitized to 5-Aza, the anti-apoptotic Bcl-2 family of genes emerged as potent sensitizers to 5-Aza from RNAi screens. Therefore, silencing by siRNA of BCL-XL, BCL-2, BCL-W, MCL-1 and BFL-1 was evaluated in combination with 5-Aza treatment in an expanded panel of myeloid cell lines including TF-1, HEL, THP-1, ML-2 and MDS-L. BCL-XL validated as a vulnerability and potent sensitizer to 5-Aza in erythroid leukemia cell lines TF-1 and HEL, whereas MCL-1 was a strong vulnerability in the monocytic leukemia cell line THP-1 and also a moderate sensitizer to 5-Aza in ML-2, THP-1, TF-1 and HEL. Published proteomics data from our group indicate that M6 and M7 leukemias exhibit higher levels of BCL-XL, while additional unpublished data suggest elevated levels of MCL-1 in M4 and M5 leukemias, supporting our functional observations. Additionally, data from the public database Oncomine suggest that BCL-XL expression is elevated in M6 and M7 leukemias while MCL-1 shows a trend towards elevation in M4 and M5 leukemias. Based on RNAi screening results, siRNA validation experiments and proteomic/mRNA expression data, we evaluated the BCL-2/BCL-XL/BCL-W inhibitor ABT-737 in combination with 5-Aza. ABT-737 resulted in dose-dependent sensitization to 5-Aza in all AML-derived cell lines examined (including M7, M6, M5, M4 and M2 FAB subtypes) and in the MDS cell line MDS-L; however, no sensitization was observed in the CML cell line K562. In extensive ex vivo experiments with 17 primary specimens, potent synergy between 5-Aza and ABT-737 was observed in AML, MDS and MPN samples, but not in most CML samples examined. Calculations with CalcuSyn software demonstrate synergy, with combination index values as low as 0.2, between 5-Aza and ABT-737 both ex vivo and in vitro. The combination of 5-Aza with ABT-737 resulted in substantial induction of apoptosis, measured by the induction of cleaved caspase 3 in TF-1 and HL-60 cells, as compared to either compound alone. Interestingly, although siRNA silencing of MCL-1 in combination with 5-Aza was potent across several cell lines, and silencing of BCL-XL preferentially in an erythroid differentiation background, ABT-737 with 5-Aza sensitized across a variety of cell lines and all myeloid primary specimens ex vivo. We suggest that inhibition of anti-apoptotic Bcl-2 family members is a most promising rational combination strategy with 5-Aza for the treatment of leukemias. Our results also highlight the potential utility of more specific anti-apoptotic Bcl-2 family inhibitors in the lineage-specific treatment of myeloid malignancies. Disclosures: Off Label Use: AraC in AML. Experimental Agent MK1775. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.