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An important paradigm in allogeneic hematopoietic cell transplantations (allo-HCTs) is the prevention of graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) activity of donor T cells. From an observational clinical study of adult allo-HCT recipients, we identified a CD4 + /CD8 + double-positive T cell (DPT) population, not present in starting grafts, whose presence was predictive of ≥ grade 2 GVHD. Using an established xenogeneic transplant model, we reveal that the DPT population develops from antigen-stimulated CD8 T cells, which become transcriptionally, metabolically, and phenotypically distinct from single-positive CD4 and CD8 T cells. Isolated DPTs were sufficient to mediate xeno-GVHD pathology when retransplanted into naïve mice but provided no survival benefit when mice were challenged with a human B-ALL cell line. Overall, this study reveals human DPTs as a T cell population directly involved with GVHD pathology.

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for blood or marrow transplantation (BMT). In this collaboration across North America, we retrospectively analyzed outcomes of first BMT using haploidentical donor and posttransplantation cyclophosphamide (PTCy) in MDS/MPN-overlap neoplasms (MDS/MPN), an otherwise incurable hematological neoplasm. We included 120 patients, 38% of non-White/Caucasian ethnicity, across 15 centers with median age at BMT 62.5 years. The median follow-up is 2.4 years. Graft failure was reported in 6% patients. At 3-years, nonrelapse mortality (NRM) was 25%, relapse 27%, grade 3-4 acute graft versus host disease (GVHD) 12%, chronic GVHD requiring systemic immunosuppression 14%, progression-free survival (PFS) 48% and overall survival (OS) 56%. On multivariable analysis, statistically significant associations included older age at BMT (per decade increment) with NRM (sdHR 3.28, 95%CI 1.30-8.25), PFS (HR 1.98, 95% 1.13-3.45) and OS (HR 2.01, 95% CI 1.11-3.63), presence of mutation in EZH2/RUNX1/SETBP1 with relapse (sdHR 2.61, 95%CI 1.06-6.44), and splenomegaly at BMT/prior splenectomy with OS (HR 2.20, 95%CI 1.04-4.65). Haploidentical donors are a viable option for BMT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Disease-related factors including splenomegaly and high-risk mutations dominate outcomes following BMT.

An important paradigm in allogeneic hematopoietic cell transplantations (allo-HCTs) is the prevention of graft-vs-host disease (GVHD) while preserving the graft-vs-leukemia (GVL) activity of donor T cells. From an observational clinical study of adult allo-HCT recipients, we identified a CD4+/CD8+ double positive T cell (DPT) population, not present in starting grafts, whose presence was predictive of ≥ grade 2 GVHD. Using an established xenogeneic transplant model, we reveal that the DPT population develop from antigen stimulated CD8 T cells which become transcriptionally, metabolically and phenotypically distinct from single-positive CD4 and CD8 T cells. Isolated DPTs were sufficient to mediate xeno-GVHD pathology when re-transplanted into naive mice but provided no survival benefit when mice were challenged with a human B-ALL cell line. Overall, this study reveals human DPTs as a T cell population directly involved with GVHD pathology.One Sentence SummaryHuman CD4+/CD8+ double positive T cells (DPTs) mediate xenogeneic GVHD but possess limited GVL activity.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for many hematologic conditions and is associated with considerable morbidity and mortality. Therefore, prognostic tools are essential to navigate the complex patient, disease, donor, and transplant characteristics that differentially influence outcomes. We developed a novel, comprehensive composite prognostic tool. Using a lasso-penalized Cox regression model (n = 273), performance status, HCT-CI, refined disease-risk index (rDRI), donor and recipient CMV status, and donor age were identified as predictors of disease-free survival (DFS). The results for overall survival (OS) were similar except for recipient CMV status not being included in the model. Models were validated in an external dataset (n = 378) and resulted in a c-statistic of 0.61 and 0.62 for DFS and OS, respectively. Importantly, this tool incorporates donor age as a variable, which has an important role in HSCT outcomes. This needs to be further studied in prospective models. An easy-to-use and a web-based nomogram can be accessed here: https://allohsctsurvivalcalc.iowa.uiowa.edu/.

Background primary myelofibrosis (PMF) is a myeloproliferative neoplasm which is associated with clonal molecular and cytogenetic abnormalities (CA) and varied clinical manifestations. While various CA have been previously described, t(15; 17) has not been reported in association with this condition. Case presentation A 69-year-old male presented with constitutional symptoms, cytopenias and bone marrow biopsy revealed immature blasts with fibrosis. Cytogenetic analysis showed a t(15;17) which initially suggested a diagnosis of acute promyelocytic leukemia (APL). However, flourescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) studies were negative for transcripts promyelocytic leukemia (PML) gene and retinoic acid receptor alpha (RARA) or PML-RARA fusion. Along with these results, a second review of bone marrow histology, flowcytometry and the detection of a calreticulin gene (CALR) mutation helped with the correct diagnosis of PMF. Patient was then treated with ruxolitinib, a JAK (Janus kinase) 1 and 2 inhibitor, and eventually proceeded to receive a matched unrelated reduced intensity conditioning (RIC) allogeneic stem cell transplantation (ASCT) and has been doing well at the 6-month follow up. Conclusions Our case highlights two points, that the t(15;17) is diagnostic of Acute Promyelocytic Leukemia (APL) in most cases, there are exceptions and it can be associated with other malignancies without causing any APL like features, as noted in this case. Also, that t(15; 17) by itself is never sufficient to diagnose APL without confirmation by other methods and relying solely on cytogenetics without timely confirmatory tests can lead to risks of delay in diagnosis and appropriate management.

We retrospectively reviewed the impact of impaired renal function (eGFR Stage 1: 100% IRF vs 37% NRF, p

Twenty-first-century anglophone literatures of the Global South are increasingly contending with the waning of the postcolonial welfare state and the rising hegemony of world markets. As a result, contemporary anglophone writing, predominantly from India, Nigeria, and Mexico, offers a re-descriptive matrix for postcolonial studies. Ranging from novels about neocolonial expansion to nonfiction about rising economies of scale, both diasporic and national anglophone literatures use the narrative conceit of entrepreneurship to diagnose the sheer reach of neoliberalism. Whether casting it as a mainly US-backed economic regime, the latest iteration of first-world developmentalism, or a post-1989 fallout of world economies toward a universalized market logic, neoliberalism has had a significant impact on the narrative forms and subjects produced within contemporary anglophone literatures. In the wake of the 2008 collapse, recession economics has precipitated varied reflections on the pernicious effects of hyper-valuation and its effects on the Global South by postcolonial and diasporic novelists like Aravind Adiga, Mohsin Hamid, and Teju Cole. Global Anglophone writing, broadly conceived, insistently calls attention to the material and psychic damage inflicted by the peripheralization of postcolonial nations in the production of a profitably global market imaginary. By tracking the formal centrality of the Bildungsroman, Indian, Nigerian, and Mexican writers demonstrate how they reject the universalism of Bildung as global development and instead gravitate toward a politics of compromise, failure, and refusal. They offer a grim counternarrative to the aspirational and upwardly mobile ethos that characterizes nonfiction from economically ascendant postcolonial nations. In modes of novelistic and nonfiction writing, a variety of figures, from murderous entrepreneurs to discontented psychiatrists to cynical bloggers, complicate the landscape of global neoliberalism. If the framework of the global troublingly obfuscates questions of labor and economic justice, then these diverse subjects self-consciously mediate between marginal cosmopolitanisms and precarious work regimes to reveal the stakes of transnational capital. In doing so, Global Anglophone literatures attest to an urgent need to rethink free market economics by finding new, egalitarian solutions to the problem of uneven development.

“The Global Program Era” traces the rise of the international writer from the global South in the North American master of fine arts (MFA) program and the resulting effects on the contemporary global anglophone novel. Extrapolating from Mark McGurl's The Program Era (2009), I suggest that the creative writing program not only was instrumental in shaping postwar American letters but also continues to be of great relevance for contemporary global South writing. The article argues that developing-world MFA novelists have redeployed a Cold War programmatic imperative to “find your voice” through the stylistic development of what I am calling “vernacular anglophone realism.” The turn to the non-anglophone vernacular continues the postwar tradition of ethnic ventriloquism for a mainly bourgeois Western audience but also supplements a new non-Western, middle-class audience. Vernacular anglophone realism cultivates a sense of natality without losing the author's linguistic and geopolitical security in the English language, therefore allowing the global South writer to address both Western and non-Western audiences. While this might seem like a welcome development—one that refines an Orientalist market logic diagnosed by Graham Huggan as “the postcolonial exotic”—the article argues that MFA programs have encouraged a style of writing that centralizes the primacy of a global bourgeois/middle-class reader. Subsequently, the global South writer has become firmly ensconced in a financialized American creative market. While global anglophone literature has emerged as a critical reference for persistent injury by British colonialism, the article shifts the conversation to the cultural development of the American anglophone novel to query whether turning to the vernacular evades the problem of U.S. exceptionalism.

Introduction Allogeneic HCT is a potentially curative strategy for SAA. In combination with fludaribine, anti-thymocyte globulin (ATG) or alemtuzumab, low-dose (2 Gy) total body irradiation (TBI) has been incorporated in the conditioning regimen for matched unrelated donors (MUD) for SAA, with the intention of reducing the cyclophosphamide dose and rate of graft failure. Progressive telomeric shortening in SAA can theoretically increase the risk of radiation injury in affected patients. Outcomes between TBI and non-TBI containing conditioning regimens in SAA have not been systematically compared. Methods After regulatory approval, clinical and outcomes data for patients with SAA treated with allogeneic HCT from 1998-2018 were collected, and compared between TBI and non-TBI groups. Results Fifty seven patients were included in the study, median age 25 (range: 1-63) years; 23 (40%) 12 months in 28 (49%) patients. Graft source was bone marrow (BM) in 48 (84%) patients, followed by peripheral blood in 8 (14%), and cord blood in 1 patient. Twenty-nine (51%) patients were transplanted with matched sibling donors (MSD), followed by 20 (35%) MUD, and 13 (23%) others (cord/mismatch/haplo). TBI-containing regimens were used in 30 (53%) patients [MUD-20 (67%), mismatch-5 (17%)], while non-TBI regimens were used in 27 (47%) patients [MSD-24 (89%), mismatch-3 (11%)]. Although the rate of RBC (P = 0.02) and platelet transfusion dependence (P = 0.04) was higher in the TBI group, presence of clinically significant HLA alloantibodies prior to transplant (MFI>1000) was not different (P = 0.07). At a median follow-up of 77 (95% CI 63-95) months, there were 11 (19%) deaths [TBI-8 (27%), non-TBI-3 (11%), p=0.1]. Median overall survival (OS) was lower in the TBI group among MSD donors (163 mo v/s median NR, P = 0.01), and MSD+MUD donors (93 mo v/s NR, P = 0.0002, figure 1). The two groups did not significantly differ in terms of rates of graft failure (P = 0.7), acute (P =0.2), and chronic GVHD (P =0.6), and documented infections (P =0.5). Based on prior knowledge of adverse prognostic factors in SAA and limited events, a Cox proportional hazard model was designed with three variables; age at transplant, donor source and TBI-use. Only TBI use was independently associated with poor OS (HR 6, 95% CI 1-33, P = 0.05). Conclusion In our limited series, low-dose TBI use as part of pre-transplant conditioning regimen for SAA was associated with poor overall survival, despite no significant differences in rates of post-transplant graft failure, GVHD, and infections. Prospective validation of this finding in larger cohorts is needed.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy (HM) resulting from uncontrolled proliferation of myeloid precursors. The inherent low neo-antigen burden and low immunogenici...

Background Treatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant. Methods Gene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group. Results CD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo. Conclusion Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.

Introduction There have been considerable advances in the understanding of molecular markers in acute myeloid leukemia(AML). It is widely accepted that internal tandem duplication (ITD) in the juxta membrane domain of the fms-like tyrosine kinase-3 (FLT3) gene in patients with AML is associated with an increased risk of relapse and reduced overall survival. In several studies, alloSCT performed in first complete remission (CR) from matched-related donors (MRDs) has been shown to result in an improved survival. There is also evidence that alloSCT improves OS in high allelic ratio FLT3-ITD AML and in patients with low allelic ratio FLT3-ITD AML and wild-type nucleophosmin (NPM1) but not in mutated NPM1 with low FLT3 ITD ratio. We wanted to validate these findings in our own cohort. Methods We retrospectively reviewed 723 consecutive patients (>18 years) with newly diagnosed AML treated at Mayo clinic between January 2007 and July 2016. Patients with intermediate-risk cytogenetics and known NPM1 and FLT3 molecular genetics were included in the study (n =198). Patients who had M3 AML, who were lost to follow up and without molecular data were excluded. We analyzed outcomes based on therapy and molecular mutations. Results Baseline characteristics are listed in Table 1. As expected patients receiving alloSCT were younger and a higher proportion received high intensity induction therapy. The majority of patients were transplanted in CR 1 (72%, n=55), Table 2. Median time to transplant was 4.6 months (range 2-64 months). Median follow up for the entire cohort was 62 months. At last follow up 117 (59%) of patients have died. Median OS for the whole cohort was 27 months. OS was longer in patients receiving alloSCT (median OS 87 months vs 16 months for No SCT, p=0.0001)(Figure 1A). This survival advantage remained significant amongst patients achieving CR1 (Figure 1B). Molecular mutations predicted survival based on FLT3 and NMP1 status primarily amongst the non-transplant cohort (Figure 1C). Patients receiving SCT had a similar survival irrespective of molecular mutation profile(Figure 1D). Amongst the FLT3+ cohort, data on subtype and ITD allelic ratio were available in 47 patients (FLT3 ITD low allelic ratio ( Conclusion In our cohort, patients with intermediate risk AML achieving CR1 benefited from alloSCT. The poor prognostic impact of FLT3 mutations in this cohort may be abrogated by alloSCT. The FLT3 mutation burden (allelic ratio) may help further prognosticate this category of patients with intermediate risk AML.

Introduction While melphalan 200 mg/m2 has been the standard preparative regimen for ASCT, studies are currently evaluating the role of including novel agents along with melphalan to improve outcomes. We have previously reported outcomes in patients younger than 65 years who received intensive conditioning, ASCT, followed by triple maintenance therapy. This current prospective study evaluates the tolerance of this therapy in elderly patients older than 65. Here we report preliminary responses and safety outcomes. Methods and patients A total of 41 eligible patients above the age 65 were prospectively enrolled in the IRB approved phase II trial beginning in June 2013. After induction chemotherapy and stem cell collection, ASCT was performed with a preparative chemotherapy consisting of VDT-Melphalan 200 mg/m2. Early after engraftment, patients were started on maintenance for 2 years with triple agent therapy consisting of either a proteasome inhibitor (PI) or an immunomodulatory drug (Imid), along with steroids. Primary end points include PFS, frequency of severe toxicities, ICU admissions, and percentage of patients able to complete the full course of maintenance. Results Thirty seven of the 41 patients enrolled received a single ASCT and were included in the analysis. Median age was 71 (range: 66 to 77). Twelve patients (59%) had standard risk cytogenetics and 15 patients (40%) had high risk cytogenetics by FISH. Median follow up was 26 months (range: 3 months – 5 years). Median time to neutrophil and platelet engraftment were both 11 days. There was one death within day 100 related to candida sepsis. Only 2 patients were re-hospitalized within 100 days but none required ICU admission. Median time to start post-transplant therapy was 73 days (range: 47 to 185 days). Best responses noted prior to initiation of maintenance were 17 sCR (47%), 3 CR (8%), 10 VGPR (28%) and 6 PR (17%). Thirty five patients (95%) were able to start on planned triple maintenance regimen. Twelve patients have completed 2 years of maintenance therapy at last follow up. A total of 3 patients died during maintenance phase due to progressive disease. Median PFS and OS were not reached and 3 year PFS and OS were 82 and 91%, respectively. Conclusions This is the first trial to prospectively evaluate the safety and efficacy of early ASCT in elderly MM patients using a novel agent conditioning regimen followed by a triple maintenance therapy consisting of either a PI or an Imid combination. These results indicate that the regimen is safe and well tolerated without any increased mortality, and results in a deep, sustained response rates. Longer follow up will determine the long term side effects of the regimen, disease responses and PFS in elderly patients.

Background Patients with immunoglobulin light chain (AL) amyloidosis often present with organ dysfunction secondary to the deposition and aggregation of the amyloidogenic light chain. Renal involvement typically presents as proteinuria, however renal dysfunction manifesting as reduced creatinine clearance (CrCL) may also be seen, often contributed to by other comorbidities and can complicate therapy for these patients. Patients and methods We retrospectively reviewed all patients receiving an autologous stem cell transplant (ASCT) for AL amyloidosis at the Mayo Clinic Rochester between 19th May 1999 and 30th of September 2017, to identify the impact of impaired renal function (CrCL Results Baseline characteristics for each cohort are summarized in Table 1. Median age and the proportion of males in each cohort were similar. Predictably renal amyloidosis was more common in the IRF group (90% IRF cohort vs 60% NRF cohort, p Conclusions ASCT is an effective therapy in patients with AL amyloidosis and impaired renal function. Although PFS and OS in this cohort are similar to those with normal renal function, the 100 day mortality and proportion of patients requiring dialysis post ASCT are higher and need to be considered prior to recommendation of this therapy for patients.

Many cancers, including multiple myeloma (MM), retain more cytosolic iron to promote tumor cell growth and drug resistance. Higher cytosolic iron promotes oxidative damage due to its interaction with reactive oxygen species generated by mitochondria. The variation of mitochondrial biogenesis in different stages of MM disease was evaluated using gene expression profiles in a large clinical dataset. Sixteen of 18mitochondrial biogenesis related gene sets, including mitochondrial biogenesis signature and oxidative phosphorylation, were increased in myeloma cells compared with normal plasma cells and high expression was associated with an inferior patient outcome. Relapsed and drug resistant myeloma samples had higher expression of mitochondrial biogenesis signatures than newly diagnosed patient samples. The expression of mitochondrial biogenesis genes was regulated by the cellular iron content, which showed a synergistic effect in patient outcome in MM. Pharmacological ascorbic acid induced myeloma cell death by inhibition of mitochondria oxidative phosphorylation in an in vivo model. Here, we identify that dysregulated mitochondrial biogenesis and iron homeostasis play a major role in myeloma progression and patient outcome and that pharmacological ascorbic acid, through cellular iron content and mitochondrial oxidative species, should be considered as a novel treatment in myeloma including drug-resistant and relapsed patients.

Introduction: Allogeneic stem cell transplant (HCT) is the only potential curative option for patients with inherited marrow failure (iBMF) and myeloid germline predisposition syndromes (GPD). HCT outcomes are influenced by inherent disease specific-nuances such as alkylating agent and radio-sensitivity, immune deregulation, and higher risks for graft failure and GVHD; factors contributing to transplant related mortality (TRM) and morbidity. We carried out this retrospective study to assess survival outcomes and long term complications (LTC) in patients with IBMF and GPD that underwent HCT. Patients and methods: We queried our institutional database and identified patients with iBMF and GPD as defined by the 2016 WHO classification. These included Fanconi anemia (FA), short telomere syndromes (STS), Diamond-Blackfan anemia (DBA), GATA2 and RUNX1 haploinsufficiency, congenital amegakaryocytic thrombocytopenia (CAMT), deficiency of adenosine deaminase 2 (DADA2), among others. Patients with acquired causes of BMF were excluded. Statistical analyses were performed using SAS (JMP v14.1). Results: Twenty eight patients, median age 10 years (1 month-63 years), 46% males, were included in the study (table 1). Fanconi anemia Seven (25%) patients with FA underwent HCT, 5 (71%) without myeloid transformation and 2 after transformation to MDS/AML. Five (71%) patients received a RIC, 4 (57%) prior to transformation. At a median follow up (FU) of 126 m, the median OS was 194 m (95% CI 34m; NR) and 10 year survival was 64%. Grade 1 aGVHD was seen in four (57%) and 3 (42%) developed mild cGVHD, while 1 developed a donor derived AML (sibling not tested for FA). LTC included second primary malignancy (SPM) - squamous cell cancer (SCC) of skin and muscle invasive bladder cancer (MIBC) in 1(14%) and SCC of head/neck and anogenital region in 3 patients (43%), psychosocial complications (PS) in 6(85%), premature ovarian failure (POF) in 3(43%), and avascular necrosis (AVN) in 4(57%) patients. Short Telomere Syndromes (STS) Seven patients with STS underwent HCT, 2 (28%) after transformation to MDS. Five (71%) received RIC, including both the transformed patients. At a median FU of 67m, median OS was NR (95% CI 2m; NR) and 5 year survival was 47%. One (14%) patient developed grade 2 aGVHD and mild cGVHD of skin. Three (43%) developed SPM - skin cancers in 2 and MIBC in 1. PS was noted in 1(15%), and AVN in 3(43%). Three (43%) patients had concomitant mild IPF/restrictive lung disease. GATA2 haploinsufficiency : Seven patients with GATA2 haploinsufficiency underwent HCT; 2(28.5%) after transformation to MDS and 3(43%) to AML, of which 2(40%) received MAC. At a median FU of 57m, median OS was NR (95% CI 7m; NR) and 5 year survival was 71%. Three (50%) developed grade 2 aGVHD of skin and GI tract and 2(33%) developed mild cGVHD. LTC include PTLD, AVN and POF in 1 patient each. Ribosomopathies : One patient (13y) with DBA underwent RIC HCT and developed grade 2 aGVHD, secondary iron overload, and died at 10 months due to severe fungal infection. Others : Identical twins with CAMT underwent HCT (at 4y and 5y) from the same unrelated donor and at last FU (74m and 87m, respectively) remain 100% donor without GVHD. Two children with primary immunodeficiency and marrow failure underwent HCT (at 2y and 7y), one after transformation to MDS. The non-transformed patient is currently alive (120m), while the patient with transformation died 1month after HCT from disseminated cytomegalovirus infection. One patient with germline RUNX1 deletion developed CMML and underwent a RIC HCT and is alive at a FU of 4 months, with no GVHD. One patient with DADA2 (n=1) underwent RIC HCT without LTC. Due to the smaller cohort size, we compared OS in transformed and non-transformed patients for the IBMF and GATA2 patients only (n=24, 9 with transformation) (figure1). At a median FU of 74m, the median OS of transformed vs non-transformed patients was 108m(95% CI 1;108m) and 163m(95% CI 67m; NR), respectively (p=0.033). Conclusions: Our study demonstrates that HCT remains an important intervention for IBMF and GPD, with the maximum impact being gained prior to transformation. While only mild chronic GVHD was noted (37%), inherent syndromic issues resulted in a high rate of SPM (FA/STS) and organ failure (STS- IPF). Notably, one FA patient who received an MRD HCT developed donor derived AML, underlining the importance of genetic screening in asymptomatic related individuals. Disclosures Kenderian: Lentigen: Research Funding; Kite/Gilead: Research Funding; Morphosys: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Introduction: Patients who develop therapy-related myeloid neoplasms (t-MN) have dismal outcomes. Previous studies reported the incidence and risk factors associated with t-MN development. Lenalidomide, in the setting of oral, but not intravenous, melphalan is associated with a higher risk of t-MN (Palumbo et. al, Lancet Oncology, 2014). We carried out this study to evaluate the clinical and pathologic features of t-MN, therapies employed, and factors that predict long-term survival after diagnosis. Patients and methods: We identified patients who received the first ASCT 1998-2016 at our institution. t-MN was defined per the WHO 2016 classification. Median overall survival (OS) was calculated from the time of t-MN diagnosis to last follow-up or death. Statistical analyses were performed using SAS (JMP v14.1) or GraphPad Prism (v7). Results: Out of 2115 patients that underwent at least one ASCT, 53 (2.5%) developed t-MN. Thirty-five of 53 (66%) patients who developed t-MN had received lenalidomide. Among 2062 patients that did not develop t-MN, 916 (44.4%) patients received lenalidomide. Lenalidomide exposure was associated with development of t-MN (χ2 with Yate's correction 8.9, p=0.003). Ten patients were excluded from further analyses due to lack of follow up. Clinical characteristics are shown in Table 1a (N=43). Median age at t-MN diagnosis was 70 years (range 44-79). Median time from ASCT to t-MN was 5 years (range 1-15). After a median follow-up of 70 months (95% CI, 38-134), the median OS was 12 months (95% CI, 9-17, Figure). Primary causes of death were t-MN (71%), MM (12%), both (6%), and other including infection, GVHD, and unknown (12%). Seven (16%) had t-AML and 36(84%) had t-MDS. Three (42%) of 7 patients with t-AML had pure erythroid phenotype. At the time of last follow-up, 9 (21%) were alive. Seven (17%) underwent two ASCT, 16 (36%) received more than 2 years cumulative dose of lenalidomide. Median number of cycles of alkylator therapy including high-dose melphalan (HDM) used for ASCT was 2 (range 1-6). On univariate analysis, factors predicting OS from t-MN diagnosis were ≥ 2 alkylator vs. < 2 cycles (11 vs. 27 months, p=0.02), ≥10% vs. Eight (19%) patients proceeded to receive an autologous (n=4) or allogeneic (n=4) transplant for t-MN (Table 1b). There was no survival advantage for patients who underwent SCT for t-MN, compared to those who did not (17 vs. 10 months, p=0.3). Similarly, there was no survival advantage for patients who received allo SCT compared to auto SCT (21 vs. 16 months, p=0.7). Survival for t-MDS and t-AML was also not different (15 vs. 6 months, p=0.2). There is only one long-term survivor in the transplant group (s/p allogeneic SCT). Four of seven (57%) patients died of progressive t-MN, 1 died of progressive MM, progressive MM and t-MN, and TRM each. Conclusions: Lenalidomide, in the setting of HDM, is associated with an increased risk of t-MN. Increased exposure to alkylators, a higher tumor burden, and the presence of CK predict poor survival in t-MN. As HDM/ASCT followed by lenalidomide maintenance remains the standard of care for eligible patients, minimizing exposure to other alkylator regimens may be prudent. While considered the standard, only a minority undergo transplant; and post-transplant outcomes remain poor. Studies to identify prognostic genetic and epigenetic risk factors are ongoing. Disclosures Al-Kali: Astex Pharmaceuticals, Inc.: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Introduction: Allogeneic hematopoietic stem cell transplant is curative in several benign and malignant hematological disorders with predominant complications of graft versus host disease (GVHD) and infections. Antithymocyte globulin (ATG) has been shown in a number of prospective trials to be effective in decreasing acute and chronic GVHD. Recently, it has been suggested that recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration interacts with the dose of ATG administered and predicts transplantation outcomes. This interaction may depend on the preparative regimen and the dose of ATG used. We sought to determine if ALC at time of administration of ATG could impact clinical outcomes in a population treated with busulfan fludarabine myeloablative regimen and a fixed dose of 4mg/kg of ATG. Methods: Seventy consecutive pts who underwent a matched unrelated donor transplant with ATG at the University of Iowa were retrospectively analyzed. All pts received rabbit ATG (Thymoglobulin®) at 0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2 mg/kg on day -3 in addition to tacrolimus and methotrexate. All received a myeloablative preparative regimen with busulfan (130 mg/m2 days -6 to -3) and fludarabine (40 mg/m2 daily for 4 days). All but one pt received peripheral blood as graft source. The effect of patient, disease, and transplant characteristics on 2-year outcomes was evaluated using Cox and Fine and Gray regression models. For relapse, GVHD, and infections, death was considered a competing risk. Estimated effects of predictors are reported as hazard ratios (HR) along with 95% confidence intervals. Results: Median age was 59 years (range 20-68). Underlying diagnoses were AML (n=47), MDS (n=20) and CML (n=3). Disease Risk index showed 25 high risk, 24 intermediate risk and 21 low risk patients in this study. The median peripheral blood ALC on day -3 was 100 × 102/µL (range 0-1144 × 102/µL). Univariate analysis showed no significant impact of ALC (100+ vs Conclusion: Our single center experience using busulfan and fludarabine myeloablative regimen and rabbit ATG dosed at 4 mg/kg showed no interaction between the recipient peripheral blood ALC and ATG to predict GVHD, infections, overall and relapse free survival. Disclosures Farooq: Celgene: Honoraria; Kite Pharma: Research Funding.

Kalyan Nadiminti,1,2 Kamal Kant Singh Abbi,2,3 Sarah L Mott,2 Lindsay Dozeman,2 Annick Tricot,2 Allyson Schultz,2 Sonya Behrends,2,3 Fenghuang Zhan,2,3 Guido Tricot2,3 1Division of Hematology/Oncology, 2Holden Comprehensive Cancer Center, 3Department of Internal Medicine, Blood and Marrow Transplantation, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Abstract: The addition of cytotoxic drugs to high-dose melphalan as a preparative regimen for autologous stem cell transplantation in multiple myeloma has not resulted in superior activity. Although novel agents have significantly improved outcome in multiple myeloma, their role in preparative regimens remains largely unknown. We have evaluated the toxicity and efficacy of combining bortezomib, thalidomide, and dexamethasone with high-dose melphalan. An institutional review board-approved retrospective analysis was performed on 100 consecutive patients receiving 153 transplants; 53 had tandem transplants; 64 patients received early transplants; and 36 had salvage transplantation. Endpoints were treatment-related toxicity and mortality, and quality of response post-transplantation with assessment of stringent complete remission (sCR) and minimal residual disease (MRD) status. Median age was 61 years, and median follow-up was 16.2 months. At 6 months, sCR was attained in 56% of patients and CR in 20%. An MRD status, assessed by sensitive (10-4) multiparameter flow cytometry, was achieved in 85%. The 100-day mortality rate was 2.6% (4/153); 1.8% for early transplants and 4.5% for salvage transplants. Grade 3–5 non-hematologic toxicities were mainly related to metabolism/nutrition; gastrointestinal and infectious problems. Median time to absolute neutrophil count of >500/µL was 12 days for both early and salvage transplantations. No significant differences in quality of response were observed between early and salvage transplantation or between single and tandem autologous stem cell transplantation. Since both sCR and MRD are excellent early surrogate markers for progression-free and overall survival, this regimen will likely be superior to melphalan alone, but it needs to be formally assessed in a randomized study. Keywords: multiple myeloma, autologous transplantation, response, toxicity, mortality, minimal residual disease&nbsp

We report the case of a 38-year-old woman who was initially diagnosed with stage II oestrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) negative infiltrating ductal carcinoma of the breast, in 2013. Breast MRI at that time showed multifocal disease in the right breast. The patient underwent a right mastectomy and axillary lymph node dissection, which revealed pT2 N1a breast cancer. Following this, she received four cycles of docetaxel and cyclophosphamide and adjuvant radiation. At that time, she had declined tamoxifen due to her history of lattice degeneration and concerns of retinal detachment. She was also offered letrozole with goserelin but declined due to their side effect profile and risk for retinal complications. The patient did well on routine follow-up until July 2015, when she presented to emergency department with symptoms of dizziness. Workup showed hypercalcaemia. Imaging studies including bone scan and CT scan showed multiple bone metastases, …

In the Victorian Literature and Culture (September 2010) issue dedicated to ‘Victorian Cosmopolitanisms’, Tanya Agathocleous and Jason R. Rudy call for the necessity to resituate the evolving new c...

Background; Major progress in the treatment of B cell tumors has been made in the past decades. Nevertheless, relapses and refractoriness to currently available chemotherapy and even to high dose therapy with stem cell transplantation still cause significant mortality. NEK2, NEver in Mitosis Gene A (NIMA)-Related Kinase 2, is a serine/threonine kinase. High expression of NEK2 increases cell survival and drug resistance, resulting in poor clinical outcome in multiple cancers including multiple myeloma and lymphoma. In this study, we used genetic mouse models to evaluate whether NEK2 is a druggable target in the treatment of B cell tumors including myeloma and diffuse large B-cell lymphoma (DLBCL). Materials and Methods: We have generated Nek2 knockout mice and crossed these with Eµ-Myc mice. RNA-sequencing was performed to determine signaling pathways related to Nek2 inhibition. Both NEK2 and USP7 (a protein interacting with NEK2) inhibitors were applied to treat myeloma and DLBCL in vitro and in vivo. Results: Mouse studies showed that Nek2 played a critical role in B cell tumor development and progression. Specifically, in genetic Eμ-MYC transgenic mice, which spontaneously develop DLBCL and Burkitt lymphoma, knockout of Nek2 prevented B cell tumor development and significantly extended mouse survival. Further, immunohistochemistry analyses showed that Nek2 was highly detected in biopsies from aggressive Burkitt lymphoma patients. Our data also indicate that both NEK2 and USP7 inhibitors significantly inhibited myeloma cell and lymphoma cell growth in vitro and in vivo models and without apparent toxicity to normal tissues. Intriguingly, the combination of USP7 inhibitor P5091 with doxorubicin blocked B cell lymphoma development and extended lymphoma mouse survival. Conclusions: Our studies demonstrate the importance of Nek2 function in tumorigenesis and progression in B cell lineage malignancies. Both NEK2 and USP7 inhibitors showed excellent efficacy in the treatment of myeloma and B-cell lymphoma. Disclosures No relevant conflicts of interest to declare.

Introduction : Melphalan 200mg/m2 has been the standard conditioning regimen for ASCT for multiple myeloma. Novel agents in combination with high dose melphan are being evaluated in clinical trials to improve outcomes. We previously reported results of early ASCT ( < 12 months from diagnosis) using VDT (Bortezomib, Thalidomide, Dexamethasone) plus Melphalan 200mg/m2 conditioning chemotherapy followed by combination maintenance therapy in younger MM patients (Age Methods and patients: A total of 41 eligible patients with newly diagnosed multiple myeloma age ≥ 65 were prospectively enrolled in the IRB approved phase II trial beginning in June 2013. After an induction chemotherapy and stem cell collection, ASCT was performed with a preparative chemotherapy consisting of VDT-Melphalan 200mg/m2. The patients were considered to have high risk cytogenetics if they had 17p deletion, t(14;16), amp 1q, or t(4;14) by FISH on CD-138 sorted plasma cells. After engraftment and recovery, patients were started on maintenance therapy for 2 years. Planned regimen for the first year was a combination of VDT as 28 day cycles and year 2 therapy consisted of bortezomib, cyclophosphamide and dexamethasone( VCD) as 28 day cycles. Alternate regimens were used in case of toxicities. Primary end points include PFS, frequency of severe toxicities, ICU admissions, and percentage of patients able to complete the full course of maintenance. Responses were evaluated according to IMWG consensus criteria and adverse events were recorded according to CTCAE v 4.03. Results: 37 of the 41 patients enrolled received single ASCT between 2013 to 2016 of which 35 patients went to receive triple maintenance therapy and were included in this analysis. Median age was 68 (range: 65 to 75y). 12 (59%) and 15(40%) had standard risk and high risk cytogenetics by FISH, respectively. Median follow up was 27 months (3 months - 5 years). Major non-hematologic toxicities ≥ grade 3 were related to infections (25%), diarrhea (16%) and mucositis (11%). Median time to ANC and platelet engraftment was 11 and 17 days, respectively. There was one death within day 100 related to candida sepsis. Only 2 patients were re-hospitalized within 100 days but none required ICU admission. Median time to start post-transplant therapy was 73 days (range: 47 to 185 days). Best responses noted prior to initiation of maintenance were 17 sCR(47.2%), 3CR(8%), 10 VGPR(27%) and 6 PR(17%). 18 patients completed 2 years of maintenance therapy thus far and responses at the time of this analysis include sCR in 16 and CR in 2 patients. A total of 3 patients died during maintenance phase due to progressive disease. Median PFS and OS were not reached and 3 year PFS and OS were around 82 and 90%, respectively. Conclusions: This is the first trial to prospectively evaluate the safety and efficacy of early ASCT in elderly MM patients using a novel agent conditioning regimen followed by an intensive 2 year maintenance therapy. These results from the median follow up of 27 months indicate that the regimen is safe and tolerated without any increased mortality, and results in higher rates of deep and sustained responses. Major non hematologic toxicities included infections and GI related. No increased hospitalizations or ICU admissions were noted. Further follow up will determine the long term effects of the combination maintenance regimen, disease responses and survival in this group of elderly MM patients. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Introduction The role of early intensive treatment of multiple myeloma, including tandem autologous stem cell transplantation( ASCT) with bortezomib, thalidomide, dexamethasone( VDT) and melphalan 200mg/m2 as a preparative regimen, followed by 2 years of combination agent maintenance therapy, is being studied. We sought to analyze a cohort of patients who received early intensive treatment at the University of Iowa between 2012 and 2016. Patients and Methods All consecutive patients who received early( < 12 months since diagnosis) tandem ASCT and have completed at least 2 years of maintenance therapy between 2012 and 2016 were included for analysis. Planned maintenance therapy consisted of a combination of VDT in 28 day cycles for year 1 and bortezomib, cyclophosphamide and dexamethasone(VCD) in 28 day cycles for year 2. Alternate regimen were used in case of toxicities. The patients were considered to have high risk cytogenetics if they had 17p deletion, t(14;16), amp 1q, or t(4;14) by FISH. Event-free (EFS) and overall survival (OS) probabilities were estimated and plotted using the Kaplan-Meier method. For EFS, time was calculated from date of first transplant to relapse or death due to any cause. Treatment-related mortality was defined as death during transplant phase or maintenance phase due to causes other than disease relapse.The effect of clinical characteristics on outcomes was evaluated using Cox regression models. Estimated effects of predictors are reported as hazard ratios (HR) along with 95% confidence intervals. All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Responses were measured using IMWG consensus criteria. Results A total of 135 patients met the criteria for inclusion. Key patient characteristics are shown in table 1. The median age at first transplant was 58 years. HCT-CI was high in 68% of patients. 36% of the patients were ISS stage III, and high risk cytogenetics were present in 56%. Preparative regimen was VTD-Mel 200 in 88.9% of patients. Following the first transplant, 59% of patients had achieved CR, and following the second transplant 94.4% of patients achieved CR. At the time of median follow up, 27.4% of patients had died. The cause of death was infection (25%), organ failure (11%), relapsing myeloma (28%) or other (36%). Univariable analysis identified a statistically significant association only for age with risk of progression or death. Kaplan-Meier curves for progression free survival and overall survival in patients with high risk or low risk cytogenetics are shown in Figures 1 and 2 respectively. The hazard ratio for progression free survival and overall survival in patients with high risk vs low risk cytogenetics was 0.86 (95% confidence interval 0.45 - 1.64, p=0.65), and 0.88 (95% confidence interval 0.45 - 1.73, p=0.71), respectively. The 3 year EFS and OS of patients who received early tandem ASCT followed by 2 years of maintenance were 73% and 72%, respectively. Following the 2nd autologous transplant, 128 of 135( 94%) patients were started on maintenance therapy. VTD ( 74%) and VRD (6%) were the most common regimens used. Fifty six patients completed maintenance therapy for 1 year without regimen change, and 60 required regimen change due to toxicities. VRD (20), VPomD (9) and VRMp (8) were the most commonly used alternative regimens in the case of toxicities. Following year 1 of maintenance, 96 patients (75%) started a second year of maintenance. VCD (30%) or RD (23%) were the most common regimens. 63(43%) patients completed 2 years of combination maintenance therapy. Grade III-V non-hematologic toxicities during the combined maintenance phase were infection (56%) and peripheral neuropathy (23%) and hematologic toxicities were thrombocytopenia (13%), neutropenia (12%) and anemia (8%). Conclusion According to our results, patients with high risk cytogenetics did not have an inferior PFS and OS. These results suggest that in newly diagnosed MM patients, upfront treatment using novel conditioning regimen and tandem ASCT followed by intensive maintenance therapy can result in a very high CR rates, particularly in patients with high risk cytogenetics. Infections and peripheral neuropathies were the most common non-hematologic toxicities during maintenance. Longer follow up will determine further impact of maintenance therapy. Disclosures No relevant conflicts of interest to declare.

Response to treatment in patients with a plasma cell disorder is typically measured by evaluating the bone marrow and myeloma markers, including monoclonal protein spike and immunofixation (IFE) in blood and urine, and serum free light chains (sFLCs). Stringent complete response criteria for Multiple Myeloma (MM) patients require a normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. We performed a retrospective chart review to further evaluate these criteria. A total of 142 patient charts were analysed. Of these, 17 patients were found to have an abnormal sFLC ratio, but no other evidence of disease, including normal flow cytometry and normal fluorescence in situ hybridization (FISH) analysis on highly selected plasma cells. In all patients, the abnormal sFLC ratio was caused by abnormalities in the serum kappa light chains. These results suggest that current definitions may need to be revised to take aberrancies related to abnormal immune recovery into account.

Multiple myeloma constitutes about 1% of all malignancies. It has complex cytogenetic and heterogeneous clinical presentations. Recent advances in molecular diagnostic methods have shed light into the chromosomal and molecular changes underlying the pathogenesis of plasma cell dyscrasias, such as Monoclonal Gammopathy of Unknown Significance (MGUS), Smoldering Myeloma (SMM), Multiple Myeloma (MM), and plasma cell leukemia. It is now well established that majority of hypodiploid and hypotetraploid karyotypes, otherwise known as non-hypodiploid karyotypes, harbor chromosomal changes that are considered high risk and have an aggressive disease course. The hyperdiploid category consists of trisomies of uneven chromosomes, and majority of the patients have a good prognosis, although a minority of patients have aggressive disease with up-regulation of proliferative genes. Risk stratification with gene expressions profiling and aCGH studies have helped classify patients into high risk, intermediate risk and good risk categories which are helpful in guiding therapy. While t(4;14) and del(17p) are considered to be the most deleterious cytogenetic abnormalities, del(13) by FISH analysis is considered an intermediate risk and t(11;14) is considered as a good risk marker. The worst outcomes are observed in the high risk category, and even the most intensive treatments cannot fully overcome the negative impact of genetic findings. Although some novel agents are showing promise in changing the outcomes of t(4;14), del(17p) remains a challenging disease. While many targeted therapies are under development, more work needs to be done in establishing and integrating routine testing of these cytogenetic markers into clinical practice to individualize treatment although within specific genetic subgroups there remains a high degree of variability in outcome determined by other factors, mainly the extent of the disease.

Background: Therapeutic options for patients with Multiple myeloma (MM) whose disease has relapsed after a prior autologous stem cell transplant (SCT) include an expanding armamentarium of novel agents, often combined with traditional chemotherapy, or a second SCT, with no clear standard of care. Upfront tandem transplantation has been shown to improve both progression free survival and overall survival. But currently, there is little data regarding the application of tandem SCT in relapsed multiple myeloma patients. Methods: We retrospectively analyzed the outcomes of patients who underwent salvage melphalan-based tandem SCT for relapsed MM at University of Iowa Hospitals and clinics. Progression free survival (PFS) was defined as the time from date of the first salvage SCT to disease progression or death, whereas overall survival (OS) was defined from the date of the first salvage SCT to the date of death from any cause. Results: Between 2012 and 2015, 12 patients with MM received tandem autograft (total 24 transplants) for relapsed disease at our center. Conditioning was with VDT-melphalan 200mg/m2 (21/24), VDT-MEL 140mg/m2 (2/24) and Velcade, gemcitabine, BCNU, melphalan and dexamethasone (1/24). The median age at the salvage SCT was 48 years (range 37-58); 7 patients were female. 17% had high risk cytogenetics (including t(4;14), +1q, p53 loss) at the time of salvage SCT. Median time between previous transplant and progression of disease was 34 months (range 8-108). Of the 7 patients, who received re-induction therapy, 71% had chemotherapy refractory disease prior to salvage SCT. Response was assessed at 2-3 months post-SCT. Overall response rate was 92%. 7/12 (58%) patients achieved stringent complete remission, one patient achieved CR, one patient achieved near CR, 2/12 patients achieved VGPR and 1/12 had stable disease (SD). Following salvage tandem SCT, all patients received consolidation therapy with three drug combination, intended to be given for two years. Three patients have shown progressive disease at the time of analysis. The median PFS was 390 days (range 265- 1085) (Table-1); the median OS was 517 days (range 338-1085) (Table-2). Rate of progression free survival in the 10 evaluable patients at one year was 80%. There was no transplant related mortality. One patient died of progressive disease. Conclusions: Salvage tandem SCT is an effective strategy for relapsed MM and is especially effective in patients who had received less intensive therapy initially (single transplant and no maintenance therapy). Incorporation of novel agents (monoclonal antibodies and high doses of carfilzomib) into maintenance strategies may further improve outcomes. Figure 1. Progression free survival for all the patients Figure 1. Progression free survival for all the patients Figure 2. Overall survival for all the patients Figure 2. Overall survival for all the patients Disclosures Farooq: Kite Pharma: Research Funding.

Background: Melphalan 200mg/m2 is the standard preparative regimen in MM and addition of other cytotoxic drugs has not been found to result in superior activity. The novel agents have improved outcome in MM significantly, but data on their role in preparative regimens are scarce. The purpose of this study was to understand the toxicity and efficacy of triple therapy with VDT in combination with high-dose melphalan. Methods: An IRB approved retrospective analysis was performed on all patients who received an ASCT with the VDT-Mel during 2012-2014. Mel: 100 mg/m2 was given on days -4 and -1; V: 1 mg/m2 on days -4, -1, +2 and +5; T: 100 mg daily from -5 to +5; and D: 20 mg/day from -4 to -1 and +2 to +5. End points were treatment-related toxicity during the first 100 days and quality of response at 6 months post-transplant; 98 patients had follow-up ≥ 6 months. Patients in sCR were also minimal residual disease negative (MRD-) by 10-color flow cytometry with a sensitivity of 10-4. Results: 100 patients received 153 transplants; 47 patients underwent single and 53 had tandem transplants (TT); 64 patients received early (≤ 12 months of induction therapy) and 36 salvage transplantation. Median age was 61 y; median followup was 16.2 months. Only 1patient had achieved a sCR and 11 a CR prior to transplantation. Best responses at 6 months were 53% sCR (and MRD-), 24% CR, and 9% VGPR. The sCR rate after single transplant was 47% (overall) and 54% (early transplant) vs 59% and 60% after TT. Grade 3-5 non-hematologic toxicities were almost entirely related to infections (38% and 53% in single and TT, respectively); the 100-day mortality rate was 2.6% (4/153), 1.8% for early transplants and 4.5% for salvage transplants. Median time to ANC recovery > 500/µL was 12 days in both early and salvage transplantation. Conclusion: VDT-Mel is well-tolerated and resulted in minimal additional toxicity and a similar mortality rate when compared to historic data of MEL alone. Importantly, the sCR rate with MRD- by flow cytometry at 6 months in our study was very high compared to published reports. The ultimate sCR rate will be higher as at this time an additional 13 patients attained a sCR during further follow up past 6 months for a total of 66% sCR. Since both sCR and MRD- are proven early surrogate markers for progression-free and overall survival, it appears highly likely that this regimen will be superior to Mel alone and should become the new standard for ASCT in myeloma. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Background The serum free light chain (FLC test) allows measurement of low concentrations of FLC. Post-transplantation, especially after tandem autologous transplants and consolidation therapy, the immune system is often extremely suppressed and its recovery is disorganized. Patients and Methods This study was limited to patients with multiple myeloma, plasma cell leukemia and amyloidosis, who received autologous transplantation and consolidation therapy at the University of Iowa Hospitals and clinics. Most of these patients had already received some form of induction therapy with IMIDs or proteasome inhibitors or in combination. They then proceeded with a cycle of D-PACE followed by one or two autologous transplants. The preparative regimen for virtually all patients was VDT-MEL. Post-transplantation, most of the patients received consolidation therapy with VTD the first year and either VCD or Revlimid/dexamethasone for second year. Thereafter, all myeloma therapy was halted. Serum free light chains were measured with polyclonal FLC antisera according to Freelite, Binding site, UK. The kappa/ lambda ratio was calculated. Results In total 142 patients were evaluated; 12 % (17/142) of patients were found to have abnormal light chains ratio but no other evidence of active disease, including negative serum M-protein, serum IFE, urine M-protein and urine IFE. In addition, bone marrows showed no evidence of clonal plasma cells by both 10-color flow cytometry and FISH analysis of CD138 selected plasma cells; both methods have a sensitivity of ≥ 10-4. The κ/λ ratio was abnormal due to increase/decrease in the same light chain as the M- protein in 11/17 patients; 6/17 patients had abnormal κ/λ ratio due to increase in the opposite light chain as the M- protein (Table 1) Table 1. Patient with abnormal light chains due changes in Involved light chain levels Age Gender M protein/Light chain Transplant M protein Abnormal light chain Immunofixation Elevated or decreased Duration of abnormal ratio 64 Male IgG Kappa Tandem 0.0 Kappa Negative Elevated 2 weeks 58 Female IgA Kappa Tandem 0.0 Kappa Negative Elevated 4 weeks 46 Female Kappa Tandem 0.0 Kappa Negative Elevated 4 weeks 58 Male IgG Kappa Tandem 0.0 Kappa Negative Elevated 20 weeks 55 Male IgG Kappa Tandem 0.0 Kappa Negative Elevated 4 weeks 60 Male IgG Kappa Tandem 0.0 Kappa Negative Elevated One week 60 Female IgA Kappa Single 0.0 Kappa Negative Elevated 8 weeks 68 Female IgG Kappa Single 0.0 Kappa Negative Elevated 26 weeks 42 Male kappa Tandem 0.0 Kappa Negative Elevated One week 67 Male Kappa Single 0.0 Kappa Negative Decreased 3 weeks 68 Male IgG Kappa Single 0.0 Kappa Negative Elevated 8 weeks Patient with abnormal light chain ratio due to changes in the opposite light chain levels 53 Female IgG Lambda Tandem 0.0 Kappa Negative Elevated 2 weeks 62 Female IgA lambda Tandem 0.0 Kappa Negative Elevated 6 weeks 50 Male Lambda Single 0.0 Kappa Negative Elevated One week 60 Male IgG Lambda Tandem 0.0 Kappa Negative Elevated 100 weeks 68 Female IgA Lambda Single 0.0 Kappa Negative Elevated 8 weeks 68 Male lambda Single 0.0 Kappa Negative Elevated 4 weeks Conclusions According to the IMWG uniform response criteria, patients achieving CR for whom the involved FLC reduced sufficiently to normalize the FLC ratio (range, 0.26 to 1.65) in the absence of monoclonal BMPCs as assessed by immunohistochemistry or immunofluorescence are considered to have achieved stringent CR. However, patients can be in stringent complete remission with abnormal k/l ratios if 1) the ratio is abnormal because the non-involved free light chain is elevated while the involved free light chain is normal; 2) the ratio is abnormal because involved light chain is elevated, with no other evidence of disease, including multicolor flow cytometry and FISH analysis on selected plasma cells of the bone marrow and imaging by MRI and/or PET-CT scan. This occurred in > 10% of patients. It should be noted that the FLC causing the abnormal k/l ratio was always kappa. The IMWG criteria should be adjusted these potential pitfalls. Disclosures No relevant conflicts of interest to declare.

e19537 Background: DLBCL is a heterogenous disease in terms of outcome. Cell of origin is felt to be one of the most important predictors of outcome to therapy, with better outcome in germinal center B-cell-like (GCB) subtypes compared to non-GCB. Gene expression profiling (GEP) is the gold standard for determining cell of origin, however this is not widely available. Therefore, IHC algorithms have been developed as a surrogate to GEP in determining cell of origin. Several IHC algorithms have been reported, first by Hans et al. Later, refined by Choi, the algorithm incorporated new IHC markers such as GCET1. We report the use of a modified algorithm developed at our institution (UIHC), using IRF8 in place of GCET1, to predict overall survival (OS) and event free survival (EFS). Methods: A subset of UIHC pts (n=52) with DLBCL prospectively enrolled between 11/14/02 and 10/31/07 in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource were evaluated. Tissue sections were stained with anti...

9090 Background: With an increasing aging population and a growing number of people with organ transplant on immune suppression, patients presenting with locally advanced, unresectable and metastatic SCCS are on the rise. Options of therapy are limited to platinum or taxane doublets but the tolerability of these regimens is poor. Data regarding use of cetuximab in advanced SCCS is scarce and consists of a few case series and one phase II trial. The purpose of this study is to evaluate the use of cetuximab alone or in combination with chemotherapy in patients with SCCS treated at the University of Iowa Hospitals (UIHC). Methods: Patient data was compiled through medical record review of all patients diagnosed with locally recurrent, unresectable or metastatic SCCS seen at UIHC and treated with cetuximab alone or in combination with chemotherapy. Pathology was centrally reviewed. Results: A total of nine patients with SCCS received cetuximab as part of a definitive or palliative therapy with a loading dose of 400 mg/m2 followed by weekly 250mg /m2.Median age of patients is 64. Four patients had locally recurrent or unresectable disease, and five had distant metastases. Three patients had prior history of organ transplant. Chemotherapy included carboplatin AUC 5 with 5 fluorouracil 1000mg/m2/day for four days in two patients and weekly paclitaxel 80mg/m2 in four patients. One patient received concurrent definitive radiation with 6600 cGy. In total, six patients completed at least 6 weeks of cetuximab. All these patients showed clinical improvement in pain, tumor ulcer and bleeding as compared to pretreatment. Median time to disease progression after stopping treatment was 3 months. Three patients could not complete 6 weeks of cetuximab due to disease progression. The most common side effect was skin rash and hypomagnesemia. Conclusions: Cetuximab alone or in combination with chemotherapy is well tolerated and does show promise in treatment of patients with unresectable or metastatic SCCS. Most common side effect was skin rash. A larger trial with longer follow up is warranted to establish the role of cetuximab and an optimal combination therapy in improving quality of life in this patient population.

forms available from CIBMTR, as well as to enter new data while simultaneously reporting within FormsNet3. Dynamic queries were built for all commonly requested subsets of data, such as transplant volumes, mortality, engraftment, GVHD, etc. Conclusion: Compiling data for clinician requests and re-certifications, which used to take days, now takes only minutes. Patient-specific reports were built that allow users to instantly fax a request for information to external providers with one click of a button, which decreased the time spent on this activity alone by more than 75%. Our BMT program has found Access to be a dynamic, cost-effective and resourceful solution to meeting current program quality improvement (QI) data needs and fulfilling federal reporting requirements.