Abstract: Acute lymphoblastic leukemia (ALL) is a heterogeneous disease and treatment guidelines are still evolving. Allogeneic stem cell transplantation (allo-SCT) offers a potentially curative option and is recommended in first relapse and for high-risk patients in first complete remission (CR). Survival after allo-SCT could be substantially improved due to better risk stratification, patient selection and adapted treatment protocols leading to reduced non-relapse mortality (NRM). Prognostic factors for survival after allo-SCT still need to be defined: pheno- and genotype, patients´ age, conditioning regimens and remission status prior to allo-SCT are under discussion. We analyzed the outcome of 180 consecutive ALL patients who received allo-SCT at the Freiburg University Medical Center between 1995 and 2018 with regard to treatment response, survival, adverse reactions, and performed subgroup analyses to identify prognostic factors. The median age in our cohort was 37 years (ys), 19% were older than 55 ys. 27% were diagnosed with Philadelphia (Ph)-positive ALL, 24% with T-ALL. 36% were treated with relapsed/refractory disease. 48% of allo-SCTs were conducted with a HLA-matched, 19% with a HLA-mismatched unrelated and 33% with a related donor. In 61% the conditioning regimen included total body irradiation (TBI). In 48% no minimal residual disease (MRD) was detected prior to allo-SCT, 20% were transplanted in MRD-positive CR. The overall response rate was 86%, with MRD-negativity in 78%. With a median follow up of 10 ys, we observed a median overall survival (OS) of 23 months and a median progression free survival (PFS) of 11 months. The 10ys-OS was 33%, the 10ys-PFS 31%. The cumulative incidence of relapse was 68% at 10 ys, the cumulative incidence of NRM 12%. Acute graft-versus-host disease (GvHD) III-IV° occurred in 17%, severe chronic GvHD in 9%. Survival was significantly better in patients reaching MRD-negative CR before allo-SCT (10ys-OS 48% vs. 19%, p 〈 0.0001; 10ys-PFS 46% vs. 17%, p 〈 0.001) and in thoses receiving TBI (10ys-OS 40% vs. 19%, p 〈 0.01; 10ys-PFS 37% vs. 19%, p 〈 0.001). There was no significant difference in survival between patients younger or older than 55 ys (10ys-OS 37% vs. 21%, p=0.183; 10ys-PFS 34% vs. 21%, p=0.208) and between those diagnosed with T-, Ph-positive or -negative B-ALL (10ys-OS 41% vs. 35% vs. 29%, p=0.298; 10ys-PFS 38% vs. 33%. vs. 27%, p=0.238). Due to lower NRM, survival improved depending on the year of allo-SCT (10ys-OS 1995-2000 22% vs. 2001-2010 32% vs. 2011-2018 n.r., p 〈 0.01; 10ys-PFS 20% vs. 30% vs. n.r., p 〈 0.01). With a very long follow-up and high rate of MRD-assessment, we observed a high response rate and a low rate of severe GvHD. Our data confirm that allo-SCT enables long-term survival in high-risk ALL, suggest that, in certain subgroups, survival may be best in patients transplanted in CR and receiving TBI for conditioning, including the relevant observation that allo-SCT can be performed in carefully selected elderly patients. Disclosures Finke: Medac: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Riemser: Honoraria, Other: research support, Speakers Bureau. Wäsch:Pfizer: Consultancy; Sanofi: Other: Travel, Research Funding; Celgene: Other: travel, Research Funding; Jazz: Other: travel, Research Funding; Amgen: Consultancy; Gilead: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Amgen: Other: travel, Research Funding; Gilead: Other: travel, Research Funding.

Abstract: Background: DNA demethylating azanucleoside drugs are known to upregulate HLA molecules and germline/Cancer Testis antigens on malignant cells. Thus these drugs may be considered a rational treatment option also for patients relapsed after allografting. Until now for these patients DLI is standard treatment, with only limited activity of additional low-dose cytarabine (LD-AraC). It has thus been hypothesized that azanucleosides, when given at low doses, may not act solely by cytotoxic effects like LD-AraC, but also via their ability to modulate the aberrant epigenotype of leukemic cells and thus reactivate silenced genes. We have piloted a 3-day schedule of 5-azacytidine (aza) at a total dose (TD) of 300 mg per course (thus substantially lower than the schedule established for treatment of MDS), followed by DLI, in pts with relapse of AML/MDS after allografting. Patients and Methods: Between 10/2006 und 4/2008, 22 patients (20 with AML, 2 with CMML) relapsed after allografting received a 3-day course of aza at 100 mg/day s. c., where feasible followed by DLI 1–2 weeks later. Median age at time of allografting was 62 years (range 28 – 75). 16/22 pts were male, 12 had de novo, 8 secondary (s)AML. 9/22 (41 %) had poor-risk cytogenetics. 20 pts had received Fludarabine-based reduced-toxicity conditioning regimens, 2 conventional myeloablative conditioning. At start of aza, 16, 4 and 1 pt were in 1st, 2nd or 3rd relapse, respectively, 1 pt had refractory sAML. Median number of days from transplant to first aza was 257 (range, 76 to 1492). Median % blasts in bone marrow and peripheral blood before aza was 57 and 5, respectively (ranges, 〈 5– 〉 95, 0–91), one patient had extramedullary relapse. Results: 22 pts received a total of 55 courses of aza (43 courses: 300 mg TD, 10 courses: 375 mg TD, 2 courses: 450 mg TD, 1 course: 540 mg TD), with a median of 2 courses (range, 1–10). In 16/22 pts (73 %), aza was followed by DLI, with a total of 42 courses of aza/DLI given. Treatment was repeated every 4 weeks. Only 1 pt. experienced Grade III aGvHD 2 mths after DLI, clinically relevant neutropenia was observed in 3 pts. 5 patients had disease control and stable mixed chimerism but no objective hematologic response. In 2 pts a stable conversion to complete donor chimerism occurred. 15 pts did not respond to this treatment. 9/22 pts proceeded to second allogeneic transplantation. 7/22 pts are alive at time of analysis. The median time from start of aza to death or last follow-up was 131 days (range 23–625). Conclusions: This low-dose outpatient regimen of aza followed by DLI is feasible, with a very low aGvHD rate. Objective responses including complete donor chimerism (10%) occurred also in pts with poor-risk cytogenetics, and notably also in pts having already received previous DLI monotherapy (suggesting that DLI activity might be enhanced by preceding aza treatment). A dose escalation based on this schedule appears warranted, incorporating translational studies aimed at dissecting whether the effect of aza is via a cytotoxic effect or modulation of gene expression in the malignant cells.

Abstract: The outcome of patients with T cell lymphoma treated with standard chemoterapeutic substances remain poor, making the search for new active substances a highly medical need in this hematologic neoplasia. Recent phase II clinical trials showed very promising activity of farnesyltransferaseinhibitors (FTI) in relapsed/refractory T-NHL patients (Witzig et al. 2011). Regarding the molecular mechanisms behind this therapeutic effect, conflicting data regarding Ras as the initially proposed intracellular target of FTI and the involvement of MAP kinases in cellular effects of FTI in T cells exist (Marks et al. 2007, Ding et al. 2011). Together with observations in breast and ovarian cancer cells suggesting the GTPase Rheb as target for inhibition of farnesylation (Basso et al. 2005), the targets of FTI might vary according to the examined cell type. Interestingly, in breast cancer cells FTI mediatied inhibition of Rheb action resulted in reduced mTOR signaling. Nevertheless, as a putative additional targeted treatment approach in T-NHL, incubation with mTOR inhibitors showed not only substantial antiproliferative effects in normal T cells but also in malignant human T cell lymphoma lines in vitro (Huang et al. 2010). Since further clinical trials with both substances did not show severe side effects, adding everolimus as combination partner might even enhance clinical activity of FTI in T cell lymphomas. Therefore, in order to test this hypothesis and to analyse if both substances differ in their molecular mechanisms of action, FTI and everolimus were tested in vitro in T cell lymphoma lines (Karpas, Derl-2, Jurkat) to evaluate potential synergistic modes of action. Methods and Results Incubation of human T cell lymphoma lines Karpas and Derl-2 with the FTI SCH66336 (lonafarnib) or the mTOR inhibitor everolimus showed a reduction in proliferation in a dose dependent manner (EC50 for everolimus: 0.1nM, EC50 for lonafarnib: 0.5 µM). Combining both drugs resulted in synergistic inhibition of proliferation. This inhibitory effect correlated with increased p27KIP1 expression. In our experiments, Rheb appeared to be highly expressed in all examined T cell lymphoma lines with even additional increase of protein expression in Karpas cells after FTI incubation. Comparing FTI action to inhibition of mTOR by everolimus on a molecular level, in our experiments lonafarnib treatment of Karpas cells resulted in an unexpected reduction in AMPK-phosphorylation, implicating involvement of this metabolic pathway in FTI mediated inhibition of proliferation in malignant T cells. This effect could not be observed in everolimus treated Karpas cells. In contrast, naive human CD4+ T cells showed very little Rheb protein expression, which could be significantly increased after TCR stimulation by induction of Rheb mRNA transcription. While everolimus treatment of TCR-activated normal human CD4+ T cells resulted in AKT-hyperphosphorylation, FTI did not induce any changes in AKT. Contrary to the malignant T cells, FTI treatment had no impact of AMPK phosphorylation in activated T cells. Actually, naive T cells treated with FTI showed an hyperphosphorylated AMPK status. Conclusion Lonafarnib and everolimus show synergistic antiproliferative effects in T cell lymphoma lines, most likely by interfering with mTOR and AMPK signalling, making this combination therapy interesting for clinical trials. In contrast, FTI does not mediate AMPK in activated normal T cells. This observations are in accordance with a differential targeting of Rheb by FTI in malignant or normal human T cells. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background: Allogeneic hematopoietic cell transplantation is a potentially curative therapy for patients with hematological malignancies. However a fraction of patients will develop corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) which both cause a high mortality and impaired quality of life. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib by modification of T cells and dendritic cells. Methods: In this retrospective analysis, 19 stem cell transplant centers in Europe and the United States reported clinical outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGvHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGvHD (1-10). The median follow-up times were 26.5 (3-106) for SR-aGVHD and 22.4 (3-135) weeks for SR-cGVHD-patients. Results: The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). The median time to response was 1.5 (1-11) and 3 (1-25) weeks after initiation of ruxolitinib treatment in SR-aGVHD and SR-cGVHD, respectively. Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3%-90.7%,95% CI) and 97.4% (92.3%-100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Relapse of the underlying malignancy occurred in 9.3% (5/54) and 2.4% (1/41) of the patients with SR-aGVHD or SR-cGVHD, respectively. Conclusion: Ruxolitinib constitutes a promising new treatment option for SR-aGVHD and SR-cGVHD. Its activity in SR-aGVHD and SR-cGVHD should be validated in a prospective trials in both, SR-aGvHD and cGvHD. Disclosures Bertz: GILEAD Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bug:TEVA Oncology, Astellas: Other: Travel Grant; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis: Research Funding.

Abstract: Abstract 5101 Introduction: Enteropathy associated T-cell Lymphoma(EATL) is a distinctive clinicopathological entity but knowledge about potential prognostic factors in this disease is very limited. Aim: Clinicopathological and immunohistochemical analysis of single center EATL cohort focusing especially on stromal components, activation molecules and potential loss of TCR receptors. Methods: Detailed clinical analysis of a cohort of 21 patients from the southern-west Germany was performed. Additionally broad panel of immunohistochemical staining including MUM1IRF4, Blimp-1, FoxP3, TCR γ, TCRβ, CD11c was done. Univariate statistical analysis of survival was performed. Results: The study group comprised of 12 males and 9 females, aged 37–86, with the median survival time of 5 months after the initial diagnosis. Following clinical factors turned out to be connected with longer overall survival (OS): age ≤ 60years (p=0, 007), Ann Arbor Stadium I+II (p =0, 048), good general condition (p = 0, 0068), IPI 1–3 (p=0, 004), usage of anthracycline in the chemotherapy regimen (p=0, 0504). Longer event free survival(EFS) was connected with good general condition (p=0, 023) usage of anthracycline (p=0, 047). There was 17 Type I cases (81%) and 4 Type II (19%). EATL type, histological variants of neoplastic cells, perivascular and angiocentric growth pattern as well as tissue eosinophilia did not influence survival. There was a strikingly strong infiltration of the neoplastic infiltrate by CD11c+ dendritic cells in 9/21 cases, but it was prognostically irrelevant. MUM1/IRF4 expression was observed in 8/19(42, 1%), Blimp-1 in 5/14 (35, 7%) and FoxP3 in 7/20 (35%), but only FoxP3 positivity was connected with longer EFS. There was a trend toward worse OS (p=0, 18) and EFS (p=0, 12) in Blimp-1 positive cases. Expression of TCRβ was observed in 4/21(19%), of TCRγ in 3/21(14, 3%) while the majority of cases (14/21), showed loss of expression of both proteins. There was a trend toward longer OS (p=0, 19) and EFS (p=0, 16) in TCR β+ than in TCRγ+ and TCR γ-β- cases. TCRβ expression was statistically significant more frequent in patients that achieved complete remission (3/7) than in group that did not achieve CR (1/14, p=0, 049). Conclusions: In EATL several clinical factors can provide relevant prognostic information. Immunohistochemical expression of FoxP3, Blimp-1 and TCRβ seems also to be prognostically usefull. TCRβ is the only marker that can predict response to the chemotherapy in this very aggressive neoplasm. Disclosures: Finke: Fresenius Biotech GmbH: Honoraria, Research Funding.

Abstract: Abstract 1264 Tolerance induction together with sustained disease control remain to be critical for longterm survivors after allogeneic hematopoietic cell transplantation (HCT). Regulatory T cells (Tregs) are involved in the regulation of graft versus host disease (GvHD) and graft versus leukemia effect (GvL). Although calcineurin inhibitors are frequently being used for the prevention of GvHD, tolerance induction might be hampered in HCT patients due to deteriorated Treg function. Data from animal models of HCT suggest that inhibition of the mammalian target of rapamycin (mTOR) results not only in suppressed T cell alloreactivity but also in sustained Treg function. On the other hand severe reduction of T cell alloreactivity might result in diminished control of especially advanced malignant disease. To explore the clinical efficacy of a calcineurin-free GvHD prophylaxis regimen, we initiated a phase I/II monocenter trial using everolimus and mycophenolate-sodium (MMF-Na) as GvHD prophylaxis in patients undergoing allogeneic HCT with peripheral stem cell (PBSC) grafts after reduced toxicity and standard conditioning. 28 patients were included (median age: 49,2 years, range: 21–65). The diagnoses were: AML/MDS (n=16), ALL (n=3), CML/MPS (n=3), T-PLL (n=1), NHL/CLL (n=6). At the time of transplantation 22/28 (78%) patients were at high risk (not in CR1/CP, untreated) for early relapse. Conditioning included fludarabin based reduced intensity (n=24) or standard regimens containing busulfan (n=2) or clofarabine (n=2). Four CR1 patients received additional alemtuzumab (total 10mg) for GvHD prophylaxis. PBSC grafts were obtained from unrelated (n=20) and related (n=8) HLA-matched donors. No graft failure occurred. Engraftment kinetics for myeloid cells were normal, patients without alemtuzumab showed rapid reconstitution of the T cell compartment with median cell counts of 〉 200 CD4+ cells/μl at day +30 together with complete donor chimerism in 15/18 evaluable patients. No grade IV/V toxicities (according to CTC criteria) were observed due to the study medication. After a median follow up of 9 months, 3 relapses of 24 patients with CR after HCT (12,5%) occurred, of those one AML patient could be salvaged with withdrawal of immunosuppression. Nine patients have died. The causes were underlying malignant disease (n=2), GvHD (n=2), viral infections (n=3 with two cases of HHV6 associated encephalitis), post-surgery thrombembolism (n=1), and one unknown. Treatment related mortality after 100 days is 14,2%, after 1 year 21,4%. Due to the early recovery of T cell immunity mild forms of acute skin GvHD were common early after reconsitution, while acute GvHD Grade III-IV could be observed in 8/26 patients. Chronic GvHD occurred in 15/22 patients (68%) with moderate and severe forms in n=10 and n=3 patients, respectively. Cytomegalovirus (CMV) reactivation could be seen in 5/20 patients at risk, while no CMV disease developed. Importantly, in the first year after HCT no severe bacterial or fungal infections were observed even in cases with prolonged everolimus treatment. The whole cohort experienced a median overall survival of 20 months, median progression free survival was 19 months. In conclusion, GvHD prophylaxis with everolimus and MMF-Na is feasible but results in an increased frequency of moderate chronic GvHD without major bacterial and fungal infectious complications. Since this sustained alloreactivity might reduce the risk of relapse this regimen could be suited for patients undergoing HCT with advanced or uncontrolled malignant disease. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 2545 Steroid refractory Graft versus Host Disease (GvHD) is a serious complication following allogeneic haematopoietic stem cell transplantation (HCT). Recently, novel therapeutic strategies involving multipotent stromal cell (MSC) transfusions have shown promising clinical results. Nevertheless, little is known on the interaction between MSC and immunosuppressive agents currently used for GvHD treatment and prophylaxis. Here we investigated the effects of mammalian target of rapamycin (mTOR) and calcineurin inhibitors on MSC mediated allogeneic T cell suppression. Since both of these drugs inhibit protein translation and exert potent antiproliferative effects, we assumed that MSC immunomodulation would be abrogated following mTOR or calcineurin inhibitor treatment. In an experimental in vitro suppression assay human MSC were pre-incubated with either everolimus or cyclosporine at concentrations currently used in the clinical practice. After 3 hours, MSC were washed several times to remove any immunosuppressive drug in the supernatant and cultured with magnetically sorted allogeneic human CD4+ or CD8+ T cells at a ratio of 1 MSC to 10 T cells prior to T cell activation with anti-CD3/CD28 coated beads. Surprisingly, MSC treated with mTOR inhibitors exerted significantly enhanced suppression of allogeneic CD4+ T cell proliferation (76%+/−12%) as determined by thymidine incorporation in comparison to MSC pre-incubated with cyclosporine (59%+/ & minus;12%) or untreated MSC (39%+/ & minus;10%). Similar results were obtained when MSC were cultured with CD8+ T cells. High pressure liquid chromatography (HPLC) did confirm that no remaining immunosuppressive drug in the culture supernatant was responsible for this observation. Subsequently we investigated, whether regulatory T cells (Treg) expansion would account for this enhanced MSC mediated immunosuppression. When everolimus treated MSC were added to CD4+ T cells in the suppression assay, significantly more lymphocytes expressed a regulatory CD4+CD25high FOXP3high phenotype (22%) in short and long term cultures while cyclosporine pre-treatment of MSC induced a Treg population (10%) comparable to untreated MSC (7,3%). When neutralizing antibodies against transforming growth factor-beta (TGF-β) were added, lower numbers of Tregs were induced by mTOR treated MSC (15,7%), cyclosporine treated MSC (8,8%) and untreated MSC (7,3%). In addition, several reports proposed indoleamine 2,3-dioxygenase (IDO) as a potent mediator of MSC dependent immunosuppression, since IDO expression results in depletion of tryptophan that is essential for cell proliferation. In the presence of interferon-gamma (IFN-γ), MSC up-regulate IDO and exert enhanced suppression of alloreactive T cell proliferation. However, when MSC pre-treated with everolimus were stimulated with IFN-γ, IDO expression was reduced. In addition IFN-γ signalling abrogated Treg expansion induced by everolimus pre-treated MSC. Thus, combined effects of mTOR inhibitors and IFN-γ signalling reduced MSC mediated T cell suppression. Collectively, these data suggest that MSC pre-treated with mTOR inhibitors induce enhanced immunosuppressive capacity towards allogeneic T cells due to induction and expansion of Tregs in a, at least partially, TGF-β dependent way. In contrast, mTOR inhibitors and IFN-γ enhance MSC immunomodulation by independent mechanisms. However, when combined they antagonize each others effects. In conclusion, our results support the combined use of mTOR inhibitors and MSC for the treatment of steroid refractory GvHD. This combination may induce Treg expansion that can treat GvHD without limiting graft versus tumor effects. Additionally, determination of IFN-γ serum levels may predict the outcome of this combined therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 670 Introduction: Relapsed/refractory B-precursor ALL in adults has a dismal prognosis with only 35–40% of patients reaching a hematological complete remission (CR) with a median overall survival of 4–6 months. An exploratory phase II trial was conducted in this patient population with blinatumomab, a bispecific T-cell engaging (BiTE®) antibody that directs cytotoxic T-cells to CD19 expressing target cells. Methods: The primary endpoint was hematological CR or CR with partial hematological recovery (CRh*) within 2 cycles of blinatumomab. Secondary endpoints included overall survival (OS) and safety. Blinatumomab was administered by continuous intravenous infusion for 28 days followed by a 14-day treatment-free interval. Responding patients had the option to receive 3 additional cycles of treatment or to proceed to allogeneic hematopoietic stem cell transplantation (HSCT). Three dosing regimens were explored (Table 1) to identify the optimal regimen with respect to efficacy and toxicity. Results: 36 patients were treated; 26 out of the 36 treated patients (72%) achieved a hematological CR/CRh*. Ten out of 26 (38%) responders had a CRh*. 24 out 26 (92%) responders achieved also a molecular response (minimal residual disease level below 10−4 as measured by PCR) within the first 2 cycles. Twenty out of 21 (95%) patients in first relapse responded whereas only 6 out of 15 (40%) of the remaining patients achieved a hematological CR/CRh*. Thirteen patients proceeded to allogeneic HSCT in CR/CRh* after blinatumomab treatment, and one of them developed a medullary CD19− relapse after allogeneic HSCT. The other 13 responders did not receive allogeneic HSCT. Eight of these 13 patients relapsed: 2 relapses were CD19− (1 medullary and 1 extramedullary); 3 were CD19+ (1 medullary and 2 extramedullary), and 3 were with pending CD19 status (all 3 medullary). The median survival for all 36 treated patients is 9.0 months with a median follow-up time for OS of 10.7 months. For patients who achieved a CR/CRh*, the median survival is 14.1 months whereas for patients who failed blinatumomab therapy the median survival is 6.6 months. Cytokine release syndrome (CRS) and CNS events were reported as medically important events. Two patients with high tumor burden and no cytoreductive prephase required treatment interruption or discontinuation. CRS syndrome could be either prevented or treated by adapting a dexamethasone regimen for patients resulting in no further treatment interruption due to CRS. Fully reversible adverse drug events of the CNS leading to treatment interruption were observed in 6 patients: 3 patients with seizures and 3 patients with encephalopathy. CNS symptoms fully resolved, and all 6 patients were able to resume treatment at a lower dose; however, 2 out of these 6 patients had a recurrent event and permanently discontinued. One patient stopped treatment due to fungal infection leading to death. As final dose and schedule, 5 μg/m2/day in week 1 and 15 μg/m2/day for the remaining treatment (as in cohorts 2a and 3) was selected for further investi-gation based on safety and efficacy considerations. In the extension cohort, cohort 3 (n=18), the most common treatment emergent adverse events (TEAE) were pyrexia (70%), headache (39%), tremor (30%) and fatigue (30%). Summary: The final dosing regimen of blinatumomab produced exceptionally high complete hematological and molecular remission rates and was well-tolerated. Updated follow-up information regarding duration of response and survival will be presented. A global phase II study to confirm these data is being conducted. Disclosures: Topp: Amgen: Consultancy; Affimed: Consultancy. Goekbuget:AMGEN: Consultancy, Honoraria, Research Funding. Zugmaier:Amgen: Employment. Mergen:Amgen Research Munich GmbH: Employment. Bargou:Amgen: Consultancy, Honoraria.

Abstract: Background: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have limited treatment options, especially those receiving multiple prior therapies. Patients with MCL are mostly an elderly population with various comorbidities who receive multiple medications that may lead to an increased risk of toxicity from underlying disease, as well as drug interactions. These multiple, concomitant conditions introduce complexity into the evaluation of the risk-benefit ratio of available therapies. In the relapsed setting, there is increasing use of new treatment options, such as lenalidomide, which is an immunomodulatory agent with direct and immune-mediated mechanisms of action. Lenalidomide has shown efficacy and a tolerable safety profile in multiple studies of R/R MCL, including the randomized MCL-002 (SPRINT) study comparing lenalidomide vs. investigator's choice (IC) of monotherapy. The objective of this post hoc subgroup analysis from the MCL-002 study was to examine the effect and safety of lenalidomide in patients who are at risk of bleeding events because of multiple comorbidities or treatments (i.e., polymedication) denoted as LEN-CM compared with those not at risk (LEN), LEN-CM being a population with a limited choice of treatment options. Methods: The multicenter MCL-002 study randomized patients 2:1 to lenalidomide vs. single-agent IC of monotherapy (rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine; NCT00875667). Patients had 1-3 relapses or had failed prior therapy, and were ineligible for intensified chemotherapy or stem cell transplantation. Oral lenalidomide was initiated at 25 mg/day on days 1-21 of 28-day cycles until disease progression or as tolerated. Progression-free survival (PFS) was the primary endpoint (per modified 1999 IWG criteria); secondary endpoints included response rates, duration of response (DOR), overall survival (OS), and safety. The current analyses were based on investigator's assessment. Specific patient groups with or without increased bleeding risk due to comorbidities and/or treatment were identified for the subgroup analysis based on pre-existing characteristics at study initiation. Patients in the LEN-CM group included those with hemorrhages (or predispositions to such), concomitant anticoagulant therapy with vitamin K antagonists or nonsteroidal anti-inflammatory drugs, and/or current or preexisting atrial fibrillation requiring anticoagulants. Results: Of 170 patients originally randomized to lenalidomide treatment, there were 60 (35%) LEN-CM vs. 110 (65%) LEN patients included in this subanalysis. At baseline, patients in both groups generally had a similar baseline patient profile and prior treatment history, although there were some differences between groups: more patients in the LEN-CM group (vs. LEN) were 〉 =65 years of age (78% vs. 62%) and had more high-risk MIPI score at baseline (47% vs. 29%), whereas fewer had positive bone marrow (7% vs. 15%), high tumor burden (37% vs. 54%), or bulky disease (15% vs. 25%). Median PFS by investigator assessment was 10.7 months (95% CI, 4.3-14.0) for LEN-CM and 7.0 months (95% CI, 5.3-14.6) for LEN (Table 1). Overall response rates (ORR) in the LEN-CM vs. LEN patients were 29/60 (48%) and 49/110 (45%) with complete response (CR)/CR unconfirmed (CRu) rates of 6/60 (10%) and 13/110 (12%), respectively. Median DOR and OS were also similar in both groups of lenalidomide-treated patients. The safety profiles were similar for these subgroups, with similar rates of AEs leading to discontinuations and dose reductions/interruptions. Most common any grade treatment-emergent AEs ( 〉 =20%) for LEN-CM vs. LEN groups respectively were 48% vs. 52% neutropenia, 33% vs. 38% thrombocytopenia, 32% vs. 27% anemia, 25% vs. 19% fatigue, 23% vs. 22% diarrhea, and 5% vs. 23% pyrexia. Conclusions: For patients with R/R MCL, there is a high, unmet medical need for effectivetherapy with acceptable toxicity. Overall, the LEN-CM and LEN subgroups showed similar efficacy and safety outcomes. Results from this subgroup analysis of the MCL-002 study show that lenalidomide leads to clinically meaningful PFS and other efficacy outcomes irrespective of the presence or absence of bleeding risk due to comorbidities and/or treatment. Disclosures Walewski: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Novartis: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Belada:Seattle Genetics: Research Funding. Radford:Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; GSK: Equity Ownership; Astra-Zeneca: Equity Ownership; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jurczak:Morphosys: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celtron: Research Funding; Bayer: Research Funding; Takeda: Research Funding; Servier: Research Funding; Teva: Research Funding; Roche: Research Funding, Speakers Bureau; Sandoz-Novartis: Speakers Bureau. Morschhauser:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Kaplanov:State Budgetary Healthcare Institution "Volgograd Regional Clinical Oncology Dispensary #1: Employment. Thyss:Takeda: Research Funding; Millennium: Research Funding. Kuzmin:Republican Clinical Oncology Dispensary: Employment. Stelitano:Azienda Ospedaliera: Employment. Marks:Pfizer: Honoraria. Trümper:Roche: Research Funding; Mundipharma: Research Funding; Hexal: Membership on an entity's Board of Directors or advisory committees. Biyukov:Celgene: Employment, Equity Ownership. Barnett:Celgene Corporation: Employment, Equity Ownership. Casadebaig Bravo:Celgene: Employment, Equity Ownership. Arcaini:Sandoz: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding.

Abstract: Despite treatment of diffuse large B cell lymphoma has improved the last decade by incorporating rituximab to CHOP therapy, outcome in young high risk patients (aaIPI 2-3) remains poor with a substantial percentage of pts achieving only a short EFS and OS. In recent years primary autologous transplantation seemed to improve results. We designed an upfront treatment schedule consisting of 6 cycles CHOP-14 as backbone, incorporating dose dense rituximab as suggested by data from Pfreundschuh at al. and high dose MTX as CNS directed approach and compared results with own controls using primary autologous transplantation. All pts aged 〈 65 y presenting with high risk DLBCL at Freiburg University Medical Center since 2012 were treated with 6 cycles CHOP-14 and dose dense rituximab (375 mg/m²) on days 0, 1, 4, 8, 15, 22, 29, 47, 61 and 75. HD MTX (3.0 g/m²) was administered on days 30 and 76 right before standard CHOP. We reviewed all pts treated according to the protocol in an intention to treat analysis identifying 18 patients meeting the criteria. 3 pts presenting with the diagnosis of DLBCL were not treated according to the protocol. 1 pt with a double hit lymphoma was primarily intensified with HD chemotherapy and subsequent ASCT. 1 pt with a prior history of kidney transplantation received 6 cycles R-CHOP and 1 pt was however primarily intensified. Response was evaluated using PET-CT according to revised criteria for response assessment by Cheson et al. 2014. Of 18 pts, histology included DLBCL (n=17, 95 %) and follicular lymphoma grade IIIb (n=1, 5 %). Median age at diagnosis was 52 y (range 23-68 y), with 50 % female. Stage I/II vs. III/IV: 22 % vs. 78 %; Of stage I/II pts, 2 had a bulky disease, 1 pt had a testicular lymphoma and 1 pt had orbital involvement; B-symptoms: 44 %; LDH was elevated in all pts; ECOG 〉 1: 33 %; Extranodal site ≥ 2: 61 %; According to IPI and aaIPI 16 pts (89 %) had an intermediate high and high risk score. Median follow-up was 15.6 month (range 0.4 - 35.9). 16 pts (89 %) completed the protocol. No treatment related deaths were observed. Toxicities were as expected and manageable; one pt could not receive 6th cycle CHOP due to severe infection. One early death was observed 4 days after 1st R-CHOP due to lymphoma infiltration of the heart and consecutive arrhythmia. All pts responded, 13 pts achieving a CR (72 %) and 4 pts a PR (22 %). Of 4 pts in PR by PET criteria 3 pts underwent second biopsy. 2 pts were lymphoma negative and 1 pt positive. The lymphoma positive pt underwent radiation of residual lymphoma masses, achieving a CR. The other pts did not receive any further treatment and are retrospectively in CR with a prior false positive PET-CT Scan. For all pts estimated 18m-OS was 94.5% and 2y-PFS was 94.5%. No CNS events occurred. This data compared favourable to own historic controls using an R-CHOP based induction followed by R-VCPE intensification and autologous transpplantation after BEAM in 133 high-risk patients with 3y-OS of 68%. Dose intensification with rituximab, CHOP and MTX is feasible for high risk DLBCL pts 〈 65 y, showing promising results regarding ORR, progression-free and overall survival. In our cohort no CNS relapse was yet observed. Longer follow-up and larger cohort is required to confirm our results. Disclosures No relevant conflicts of interest to declare.