ALBERT

Description: Key Points Activating mutations in PLCG1 are a frequent finding in tumoral CTCL samples. This raises the possibility of targeted therapies against PLCG1 signaling pathway, using calcineurin inhibitors.

Description: Abstract 1947 Background: Thrombocytopenia requiring platelet transfusions is a constant in the hematopoietic transplantation (HT). In some situations, like the adult non-related donor and cord blood HT, the platelet engraftment is delayed for a long time. Hemorrhagic cystitis, venooclusive disease, graft-vs-host disease could to worse these procedures with a very high risk of bleeding and to increase the transplantation morbi-mortality. The agonists of thrombopoietin receptor (TRAs) have demonstrated to increase the platelet production in different pathological situations, like in the ITP and MDS patients. Thus, these new drugs could have a potential benefit in other clinical situations with low platelet production. Methods: We describe our experience in seven patients with Allogeneic HT using Romiplostim (NPlate®, Amgen Inc.), a parenteral TRA peptide, to accelerate the platelet engraftment or to increase the platelet level in the thrombocytopenia induced by HT conditioning or HT related complications. We have administrated Romiplostim in a compassionate basis (off-label). In all cases the drug was administered subcutaneously at a dose of 250 mcg. Most of the patients received only one dose, with the exception of patients #1 and 7, whom received two doses separated by seven days. The first case, a woman diagnosed as Acute Lymphoblastic Leukemia (ALL) with severe HLA platelet refractoriness acquired in the induction and consolidation chemotherapy treatments previous to HT, received two doses of 250 mcg of Romiplostim on days +4 and +12 after peripheral blood progenitor cells infusion from an HLA matched brother. Results: In the first case, a rapid and sustained platelet level increase was obtained, without platelet transfusional support. Encouraged by this successful result, we have used Romiplostim in six more patients with platelet refractoriness to platelet transfusions with or without bleeding. In all the patients the spleen was present. The patient #6, obtained a previous platelet engraftment that was loosed with the beginning of severe cGVHD. (see table) Conclusion: The use of Romiplostim could be very useful in HT complicated by severe platelet transfusions refractoriness. Our data encourages the realization of a randomized prospective study with this drug in HT. Graphic evolution of platelet count over time is depicted in the next figure: Days after Romiplostim administration. Number of platelets x109/L. Disclosures: Ojeda: Amgen Inc.: Consultancy, Honoraria. Off Label Use: Romiplostim (Nplate)is an agonist of thrombopoietin receptor (TRAs) that have demonstrated to increase the platelet production in different pathological situations, like in the ITP and MDS patients.

Description: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare and complex disease characterized by a severe prothrombotic state caused by a complement system mediated hemolysis. The introduction of the anti-C5 antibody, Eculizumab, has been conducted in many Hematology units worldwide to adopt new diagnostic tools to evaluate new and old PNH patients in order to consider the adequacy of the adoption of this new drug in each case. Magnetic Resonance Imaging (MRI) allows a more adequate and profitable approach in PNH that other radiology techniques used for this purpose. In the last four years Hematology and Radiology units in our Hospital have collaborate in the clinical evaluation of PNH patients performing MRI (cranioencephalic, thoracic and/or abdominal) in acute complications of PNH patients (9 patients) or as a programmed protocoled evaluation previous to consider Eculizumab treatment (14 patients). The protocoled evaluation consists in thoracic and abdominal MRI evaluations in all cases, and cranioencephalic MRI (with independence of the presence of neurological symptoms) in 9 cases. The PNH patients were examined with 1.5 Teslas magnet for cranioencephalic,thoracic and abdominal MRI and with 3.0 Teslas magnet for some cranioencephalic MRI (Achieva Magnets; Philips Healthcare, Best, The Netherlands). Different protocols designed for the study of this pathology, using morphological sequences with different empowerment, functional sequences and angiographic studies after administration of intravenous contrast (gadobutrol) have been used. In the abdominal explorations had been performed calculations of T2 * for the quantification of deposit of iron in liver and kidney. The first group of patients (incidental studies in acute/chronic situations) included Classical and with other bone marrow failure syndrome (BMFS) Parker’s types. The second group (protocoled studies previous consideration of Eculizumab therapy) consisted on 11 Classical Parker’s type patients with active hemolysis (LDH increased 3-13 times over normal levels) and elevated PNH clone (73-99% negative GPI granulocytes by FLAER cytometry); and 3 with BMFS Parker’s type patients (LDH increased 2-6 times over normal levels) with lower PNH clone (43-50% negative GPI granulocytes by FLAER cytometry). Thrombosis was found in four cases, one in the inferior cava and and three arterial (two cerebral and one in descendent aorta). In three patients this finding implied to initiate Eculizumab therapy. Minor ischemic brain changes were displayed by three patients. None of the eighteen patients explored with thoracic MRI, displayed pulmonary hypertension signs despite the elevation of pro-BNP in eight of them. Iron overload in the liver and/or kidneys were very frequent. The finding of a reversal of the normal cortical and medullary intensities on T1 and T2 weighted images of both kidneys was evident in the majority of patients with severe PNH types. Interestingly, one patient with a chronic PNH severe form displayed no renal iron cortical after two years on Eculizumab therapy. This finding was also evident in patients with active hemolysis in the past but with very low PNH clones and clinical remission of the disease. Many other incidental discoveries includes cholelithiasis, splenomegaly, kidney arterial vessel constriction, vascular anomalies, kidney and vesical stones, adrenal adenoma, atheromatosis at different levels, Tornwaldt cyst, hamartoma, hemangiomas and abnormal bone marrow signal. MRI is the best imaging technique to diagnose thrombosis in PNH patients and to control evolution. Moreover, in the cerebrovascular setting allows a more fine and precise diagnosis of the minor pathologic thrombotic changes. MRI is the only imaging technique that permits to evaluate the iron overload that in some PNH cases could be underestimated and needs quelation therapy. In our opinion all new patients with classical severe hemolytic PNH must be evaluated prospectively with MRI. The collaboration of the Radiology team with the Hematologist is fundamental to acquire expertise in this rare disease. Disclosures: Pastrana: Alexion Pharmaceuticals: Speakers Bureau. Ojeda:Alexion Pharmaceuticals: Consultancy, Speakers Bureau.

Description: Abstract 1382 The effectiveness of rituximab maintenance in the treatment of CLL has been investigated in a phase II clinical trial that includes two treatment parts. First, patients were given R-FCM up to 6 cycles as induction therapy, achieving an overall response rate of 93% and 46% of CR with negative minimal residual disease (MRD) (Bosch et al. JCO, etc). Second, three months after concluding R-FCM, patients having achieved CR or PR receive rituximab maintenance (375 mg/m2) every three months for two years (up to 8 cycles). We present here the preliminary results of the second part of the study, namely the efficacy of rituximab maintenance. Evaluation of response was performed three months after the last cycle of maintenance and included bone marrow (BM) examination, MRD assessment in peripheral blood and BM by four-color flow cytometry. Patients in whom rituximab maintenance was prematurely interrupted due to toxicity were considered as failures. Fifty-six patients (median age 60 years, 70% female) responding to R-FCM were evaluable for response to rituximab maintenance. Median number of cycles of maintenance given was 8 (range, 3 to 8), 77% of patients completed the entire planned treatment, whereas 91% received 6 or more cycles. Treatment was delayed due to insufficient hematological recovery in 12 cycles (2.7%). Toxicity was mainly hematological, with neutropenia being observed in 31.8% of cycles (Grade 3&4 in 8.9%), thrombocytopenia in 3.4% and anemia in 3.9%. Hypogammaglobulinemia occurred in 38% of patients (low levels of IgA in 50%, IgG in 34%, and IgM in 60%). Eight patients, three of them with hypogammaglobulinemia, experienced grade 3&4 infectious episodes (4 pneumonia, 2 gastrointestinal, 1 myositis, and 1 cerebral abscess). Herpes virus (I/VZ) reactivation was observed in 8 patients. Two patients died due to multifocal leukoencephalopathy and hemophagocytic syndrome, respectively. After rituximab maintenance, 44.6% of patients were in CR MRD negative, 41% in CR, 3.6% in PR, and 10.7% failed to treatment. Failures were due to disease progression (two patients), development of severe neutropenia (two patients), and death (two patients). Among 28 patients that were in CR MRD (-) at the onset of the maintenance part, 19 held the MRD negative status at the end of maintenance, 5 (18%) turned negative into positive MRD (probability of conversion, 40% at 30 months), whereas 4 failed to treatment (2 neutropenia, 1 progression, 1 death). Moreover, 5 of 24 patients (22%) in CR MRD(+) after R-FCM became MRD negative after rituximab maintenance, 17 maintained the CR, one patient achieved a PR, and one patient progressed under maintenance (Table 1). In conclusion, rituximab maintenance after chemoimmunotherapy seems to prolong duration of response and, in some cases, improves the quality of response towards a CR with negative MRD. Maintenance with rituximab had the major benefit in patients in CR with positive MRD. The exact role and the best dosage and treatment schedule of rituximab as maintenance therapy in CLL should be now investigated in randomized clinical trials. Disclosures: Bosch: Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is currently not approved as maintenance therapy for patients with chronic lymphocytic leukemia. Garcia-Marco:ROCHE: Consultancy, Honoraria, Research Funding.

Description: We report results of single unit Cord Blood (CB) transplants and co-infusion of a low number of highly purified mobilized PB CD34+ (MPB) cells from a 3rd party donor in 22 consecutive adults with high risk leukemia, median age 29 (16–63) and weight 66 (53–85) Kg. Basic conditioning regimen was Fludarabine, TBI, CTX and ALG, with modifications in 6 patients because of circumstancial factors. The CB units had 2.3 (1.31–3.7) x107 TNC/Kg and 0.1 (0.049–0.37) x106 CD34+ cells/Kg and were 0–2 HLA mismatches to the recipient. The 3rd party donor was an HLA haploidentical relative for 18 (sibling 10; mother 4; father 2; son 1; nephew 1), a higher HLA mm relative for 3 and a fully HLA mm unrelated donor for 1; infused cells were 2.3 (1.05–2.54) x106 CD34+/Kg and 0.23 (0.05–0.98) x104 CD3+/Kg. Post-transplant all patients received CsA and low dose Prednisone for GVHD prophylaxis. G-CSF was started on day +1 in all but 1 on day +5 and continued as required for ANC〉1.5x109/L. For the 18 patients receiving MPB-SC from a non-maternal donor, median time to ANC〉0.5x109/L was 10 days (9–12 days for 16; 16 and 17 for the other 2, 1 with G-CSF started on day +5). Analysis of DNA polymorphisms showed initial predominance of the 3d party donor both in granulocytes and mononuclear cells and subsequent progressive replacement by CB cells. Final complete CB chimerism was achieved in 17 patients between days 23 and 96 (median 56); 1, transplanted with residual disease, died on day 56 because of CMV Pn with 95% CB cells. The 4 who received maternal cells had no significant engraftment of these, although 3 had exclusive CB chimerism, 2 of which reached full CB engraftment (days 20 and 36). This different behaviour was not related to the non-inherited maternal antigens. Current clinical data suggest that replacement of the 3rd party graft by the CB engraftment may be due to rejection by the CB derived immune system. Morbidity due to early bacterial or fungal infections was remarkably low. Severe GVHD (grade〉II) occurred in 2 patients resulting in death (1 did not receive ALG); another 8 had less severe GVHD that responded to treatment. Third party donor cells were not detected in biopsy material of GVHD skin lesions. Deaths were toxic in 2 (1 had received “full intensity” TBI conditioning) and primarily due to opportunistic infections in 4 (2 CMV and 2 Toxoplasmosis, on days 64, 72, 96 and 241). Regression analyses show number of CB-CD34+ cells/Kg as the main factor influencing time to CB engraftment, with no significant effect of number of 3rd party donor CD34+ infused cells. Five years OS and DFS are 57 % for all patients and 80% for those under 40 receiving non-maternal 3rd party cells. No relapses have been observed. Our data show that the strategy of single unit CB transplant supported by 3rd party donor highly purified MPB CD34+ cells results in a short period of post-transplant neutropenia (as a consequence of prompt and transient engraftment of the 3rd party donor cells), significant GVL effect and high rates of OS and DFS, which makes CB transplant a favorable option for almost any patient requiring a hematopoietic unrelated stem cell transplant.

Description: Background and Objectives: Following cord blood transplants (CBT) there is a period of severe and often prolonged immune deficiency that results in long term susceptibility to infections. Immune reconstitution is an important factor for long term survival. We analyzed the immune reconstitution of adult recipients of a single unit CBTs supported by a low number of third party donor highly purified mobilized hematopoietic stem cells (dual CB/TPD transplants), as previously described (Magro et al. Haematologica2006;91:640–8). This strategy results in transient double chimerism of CB and TPD cells and early granulocyte recovery, initially of TPD predominance. Complete CB chimerism is regularly achieved within 100 days.The objective of this study is to evaluate immune reconstitution in this CBT. Patients and Methods: Data were obtained from 19 patients between July 2004 and July 2006. Data collection was initiated at different intervals (from day −7 to +720, quartiles Q1=35, Q2=90 and Q3=210). Samples were obtained on days +15, +35, +55, +90 and monthly thereafter up to two years. By four-color flow cytometric immunophenotyping we analyzed the subsets of peripheral blood lymphocytes: CD3+/CD4+ (T helper/inducer), CD3+/CD8+ (T suppressor/cytotoxic), NK cells (CD3−/CD56+/CD16+) and B cells, as well as cells with naïve, memory and effector T-cell immunophenotypes. TREC bearing cells were analyzed by quantitative PCR in sorted CD4+ and CD8+ T cells collected from 3 months post-transplant onwards. Results: CD56+ cells recovered early after transplantation, with median absolute number counts (ANC) of 69 (range 18–307), 170 (0–366) and 159 (32–531) cells/uL in days +15, +35 and +55 samples [normal controls 153 (71–438)], representing the largest subset within the first two months (decreasing proportions of 60%, 50% and 40%, respectively). ANC of CD4 and CD8 T cells remained low for several months, progressively increasing to reach normal ranges at different intervals. Naïve CD4 and CD8 cells (CD45RO−/CD27+) start to be detected by immunophenotyping after three months post-transplantation with median ANC of 17 (12–79) and 12 (5–103) cells/uL respectively and increasing thereafter [normal controls 860 (552–1072) and 331 (227–521)]. By the end of the first year values of T cell subsets were: CD4+, 823 (16–1123) cells/uL [normal controls 872 (470–1093)]; CD8 934 (56–1174) [normal controls 371 (208–808)], with persisting predominance of the naive phenotypes and proportions of memory phenotypes slowly increasing. B cells became detectable around day +90 with median ANC of 249 (0–1934) cells/uL, rapidly reaching values within the normal range [275 (133–684)]. Transient acute GVHD was developed by six of the 19 patients. All showed a transient drop in absolute numbers of NK, T and B cells. Chimerism analysis showed initial transient double chimerism of CB and TPD cells. Complete CB chimerism was achieved between days +15 and +94 (median, +35). Results of chimerism of lymphocyte subsets and TREC are not yet available. Conclusions: Following dual CB/TPD transplants we have observed early recovery of NK and B-cells and slow development of T cells subsets and of non-naive immunophenotypes.

Description: Introduction Temsirolimus (TEM) is an mTOR inhibitor EMA approved for the treatment of patients (pts) with relapsed or refractory (R/R) mantle cell lymphoma (MCL). In a phase III trial TEM 175mg weekly for 3 weeks followed by 75mg weekly significantly improved PFS (4.8 months)  and objective response rate (22%) compared with investigator’s choice (1.8 months, 2% respectively). TEM has also been tested in combination with rituximab (RTX) in a phase II trial with encouraging efficacy results (ORR 59%, median time to progression 9.7 months) even in rituximab-refractory pts. However, few data have been reported on the use of TEM in everyday clinical practice. Methods Sixteen Spanish centres participated in this retrospective, observational and multicenter study: Inclusion criteria were as follows: pts ≥18 at the time of treatment, confirmed diagnosis of R/R MCL treated with TEM between January 1st 2010 and  December 31st 2012. Endpoints were overall response (ORR), partial response (PR) and complete response (CR) rate, toxicity as CTCAE v3.0 of NCI scale and overall survival (OS) and progression free survival (PFS).This study was approved by the Ethic Committee of all participant sites (PFI-TEM-2010-01). Results A total of 24 patients were included, 15 pts treated with TEM in monotherapy (TEM 175mg weekly for 3 weeks followed by 75mg weekly) and 9 in combination with RTX (TEM 25mg/week plus RTX 375mg/m2 per week during the first cycle and a single dose of RTX every other 28-day cycle). 22 were male and the median age was 71 (range 53 to 84). Regarding histology grade, 17 (74%) pts had classic, 1 (4.3%) blastoid and 5 (21.7%) unknown. According to simplified MIPI prognostic score, 6 (26.1%) pts had low risk, 10 (43.5%) intermediate risk and 7 (30.4%) high risk. Five pts had 10-40% of Ki 67 index, 3 had 〉40% and 14 pts unknown. Median number of prior therapies in TEM monotherapy cohort was 2 (range 1 to 7) and 4 (range 2 to 8) in the combination cohort. Median duration of therapy was 3.07 months in the TEM monotherapy cohort and 2.03 months in the combination cohort. The overall response rate (ORR) with TEM in monotherapy was 60% (40% CR and 20% PR) and 6.7% of disease stabilization. For those patients treated with TEM plus RTX, the ORR was 78% (56% CR and 22% PR) and 20% of disease stabilization. Median PFS for patients who reached CR in TEM monotherapy cohort was 12.73 months (95%CI, 1.28 to 24.19) and 10.93 months (95%CI, 1.40 to 20.46) in the combination cohort. Overall the median PFS for all patients was 7.30 months (95%CI, 2.36 to 12.24). Two pts underwent allogeneic stem cell transplantation after successful TEM monotherapy treatment. In terms of tolerability, 13 pts of 15 developed at least one adverse event (AE) in the TEM monotherapy cohort and 5 pts of 9 in the combination cohort. Most common AE (all grades) were thrombocitopenia (75%) in both cohorts, rash (37%), diarrhea (12%), hyperglucemia  (12%), hyperlipemia (8%), mucositis (8%) and neumonitis (8%). Most common G3/4 adverse event was thrombocytopenia (33%). Conclusions Although this is a small sample size, TEM efficacy in this study seems to be higher compared to previous Phase II and III trials with an acceptable toxicity profile in pts with MCL. The median PFS in the combination therapy cohort was surprisingly lower than in the monotherapy cohort which may be explained by differences in clinical features between both groups. Disclosures: Off Label Use: Use of temsirolimus in combination with rituximab. Morán:Pfizer: Employment. Viqueira:Pfizer: Employment.

Description: Since 1964, a total of 56 patients with Paroxysmal Nocturnal Hemoglobinuria clone (PNH) were evaluated in our Hematology Unit. The PNH was evaluated with Ham’s and/or sucrose tests until 1993, when the firsts cytometric analysis of PNH were performed in our Laboratory with CD55 and CD59 markers on granulocytes mainly, and since 2011 also with the FLAER technique. According with PNH Parker´s Classification, most of the patients were Classical PNH type (28 patients), and the remaining included in the other subsets such as 21 PNH in the setting of another bone marrow failure syndrome (BMFS) and 7 PNH subclinical. Most of the patients (70%) displayed an Aplastic Anemia (AA) before or concomitantly with the diagnosis of PNH, and received immunosuppressant drugs (Steroids with/out antithymocyte globulin & Cyclosporine). In four patients an Allogeneic Hematopoietic Transplantation was performed due to a Severe Aplastic Anemia (2 patients), a Classical Severe PNH (before Eculizumab era) or a Myelodysplastic Syndrome. Another patient received a Liver Transplantation because of advanced Hepatitis C related liver failure. In our PNH series, an unexpected high incidence of cancer has appeared, with 8 patients (14,5%) displaying different hematological or non-hematological cancers in the lasts years:SexAge Diagnosis PNHParker’s ClassificationYear Diagnosis PNHYear Diagnosis CancerPrevious ImmunosuppressionCancerYear Death♂16Classical19692011YesLymphoma2011AA & Liver Tx♀30Classical19732003NonePancreatic2006♂38Classical19741995NoneGastric20122012Pulmonary♂26Classical19892013Yes, SteroidsCerebralAlive♀25Classical19942005YesLymphoma2006AA & Cord-Blood Tx♂40BMFS19951995Yes, SteroidsLiver1995♂75BMFS20112009NoneSeminoma2012*♂56Subclinical20101999Yes, SteroidsProstaticAlive*Dead because bone marrow failure. In our PNH series, cancer reports as one of the most frequent final cause of death, with thrombosis with similar incidence (11 patients of the 56 are dead, with 5 patients dead because thrombosis), although the high incidence and severity of thrombosis episodes in this cohort of patients (20 patients experienced thrombosis with a total of 40 events). As displayed supra, some of the cancers could be attributed to the therapy applied in particular patients: The two secondary lymphomas after organ transplantation could be explained by the immunosuppression employed in these procedures. Only three patients did not received immunosuppressant drugs before cancer diagnosis. This high mortality cancer rate precludes the indiscriminate use of steroids in PNH patients. This result, never reported before in PNH, merits an investigational survey of cancer incidence in PNH patients in the PNH International Registry. Disclosures: Ojeda: Alexion Pharmaceuticals: Consultancy, Speakers Bureau.

Description: Background: Pulmonary Hypertension (PH) is a well-known complication of the advanced phase of Myeloproliferative Diseases (MPD) such as Polycythemia Vera (PV), Essential Thrombocytopenia (ET) and Myelofibrosis (MF). Although initially attributed to increased pulmonary vascular resistance (group 1 PH of the WHO classification), this entity was classified in 2009 in group 5 PH (unknown mechanism and miscellaneous PH). Our aim was to describe the prevalence and possible causes of PH in a series of patients with MF. Methods: We studied a series of patients with Primary MF or Secondary MF to other MPD with cardiac ultrasound, right heart catheterization and scintigraphy after intraarterial infusion of Tc99-labeled albumin macroaggregates. Results: We studied 11 consecutive patients with MF (7 male, mean age 58 years, 4 with MF post-PV, 4 post-TE and 3 Primary MF) during the period 2009-2014. All of them had mutations of JAK-2 gene, fibrosis in bone marrow biopsy and visceromegaly (all with intermediate-2 or higher IPSS). Median NTproBNP levels were 4597 pg/ml (range 175-5700). Echocardiogram showed high systolic pulmonary pressure in most cases, with a mean of 54 ± 17 mmHg (range 35-80). Right heart catheterization showed high cardiac output (HCO) in all patients (table 1). After ruling out other causes of HCO, a scintigraphy was performed after administration of Tc99-labeled albumin macroaggregates in descending thoracic aorta. In every case, a percentage of the labeled macroaggregates (6.1 ± 2.0% of the radioactivity) were plugged in the pulmonary capillary bed, what is diagnostic of the presence of microfistulas in infradiaphragmatic territory. In two of these patients, scintigraphies were performed at diagnosis and after been treated with the anti-JAK drug Ruxolitinib (Novartis Pharma). A favourable impact of this drug was obtained in the two cases, probably due to a reduction of spleen volume. Conclusion: Most patients with MF show pulmonary hypertension associated with high cardiac output caused by microfistulas, without significant increase in pulmonary resistance. This finding has important clinical implications, because pulmonary vasodilators (once recommended) should be contraindicated, since they could cause worsening of the clinical picture. Ruxolitinib could resolve PH in MF and a prospective study in this sense could be indicated. Table 1. Patient 1 2 3 4 5 6 7 8 9 10 11 Pulmonary Artery Pres. (S/D/Mean) 58/38/ 42 69/41/ 50 48/29/ 40 84/26/ 45 57/17/ 30 22/17 / 19 51/16 / 28 22/9 / 13 25/8 / 14 71/23 / 39 30/7 / 15 Pulmonary wedge pres. 28 37 27 13 9 7 13 7 8 12 6 Cardiac output (l/min) 12.5 8.0 11 7.1 8 7.3 8.7 6.7 7.45 6 7.8 Cardiac index (l/m/m2) 5.5 4.0 6.6 3.6 5 4 4.8 4.0 4.5 3.9 5.1 Pulmonary vascular resistance (Wood U.) 1.2 1.4 1.2 4.5 2.6 3 1.7 0.9 0.8 4.5 1.1 Disclosures Ojeda: Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fores:Alexion Pharmaceuticals: Consultancy, Speakers Bureau.

Description: Background: CD37 is a tetraspanin protein expressed on the surface of normal and transformed B cells across a wide range of maturational stages that mediates death signaling via SHP1. Otlertuzumab is a CD37-specific therapeutic protein built on the ADAPTIRTM (modular protein technology) platform that has shown significantly greater direct killing of CLL cells than rituximab and higher levels of Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. Preclinical in vitro and in vivo models showed significant activity of otlertuzumab with bendamustine (benda). In phase 1 of this study involving 12 relapsed and/or refractory CLL patients (pts), otlertuzumab plus benda was well tolerated and showed activity. This phase 2 trial was conducted to investigate the activity of this combination compared to benda alone. Methods: Pts with relapsed-refractory CLL who had 1-3 prior treatments, adequate organ function, ECOG performance status ≤2, ANC ≥1200/μL and CrCl 〉40 mL/min were eligible. Pts were stratified at randomization (1:1) based on Cumulative Illness Rating Score (CIRS), CrCl, and deletion or mutation of 17p13.1. Pts in the study drug arm received otlertuzumab(20 mg/kg) weekly (1st dose split over 2 days) by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles. In both arms, benda (70 mg/m2) was administered IV on Days 1 and 2 of each cycle for up to six 28-day cycles. Safety was evaluated using CTCAE, v4.03 and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 1996 NCI and 2008 IWCLL Criteria. Results: 65 pts were treated; 32 with otlertuzumab plus benda and 33 with benda alone. Pt characteristics, response, and adverse events (AEs) are shown in the table. All but 4 patients have been followed for 2 years. Overall response rate was higher in the otlertuzumab+benda arm compared to benda alone (69% vs 39%, p=0.025) and median progression-free survival (PFS) was longer (14 m vs 10 m, p=0.016) in the otlertuzumab+benda arm. The frequency of all AEs was similar between treatment arms with hematologic and infection AEs being the most frequent. The imbalance in serious AEs appeared to be driven by CLL-related events in the benda alone arm. The half-life of otlertuzumab is 10 days and there were no pts with detectable antidrug antibody in the 14 pts tested to date. Pts were followed for 18 months. Conclusions: The combination ofotlertuzumab and bendamustine was well tolerated and significantly prolonged response rate and PFS over single agent bendamustine. The overall incidence of AEs was similar between the 2 treatment cohorts, but there was a higher incidence of pyrexia, neutropenia, and thrombocytopenia with the combination. However, the addition of otlertuzumab did not appear to increase the number of serious adverse events. The activity and safety profile of otlertuzumab warrants continued development. A trial in combination with obinutuzumab is underway and a trial in combination with a pi3k inhibitor is slated to start shortly. TableOtlertuzumab + Benda (n=32)Benda (n=33)Baseline CharacteristicsAge, median (range)65 (44-82)60 (48-79)CIRS 〉619%18%CrCl 〈 60 mL/min19%15%FIT75%67%Bulky disease*25%18%Prior rituximab81%64%Refractory16%12%≥ 2 Prior regimens63%39%del(17p13.1)13%18%TP53 mutation16%27%del(11q)47%30%Mutated IGVH25%21%Rai III/IV28%36%Efficacy IWCLL ORR**69%39%IWCLL CR9%3%IWCLL CRi3%0DOR, months (80% CI)13 (11-18)8 (7-10)PFS, months (80% CI)***14 (14-19)10 (9-11)%, All Adverse Events/All / ≥ Grade 3 Adverse EventsAny Event91/66100/76 Events in ≥5 patients in either armNeutropenia59/5639/39Any Infection59/1361/27Thrombocytopenia34/1927/15Pyrexia34/312/0Anaemia28/1333/15Nausea19/030/0Diarrhea16/321/0Fatigue16/015/3Pruritus16/03/0Upper respiratory tract infection16/09/0Cough13/021/0Bronchitis13/021/9Vomiting13/015/3Pneumonia9/615/12Headache6/015/0Constipation6/024/0Febrile neutropenia0/06/6%, Serious Adverse Events in ≥2 patientsAll serious events3146Pneumonia912Pyrexia99Febrile neutropenia06Bronchitis09 *nodes ≥7 cm or 3 adjacent/confluent nodes ≥3 cm **p=0.025 ***p=0.016 FIT = CIRS ≤6 and CrCL ≥60 mL/min, ORR = overall response rate, CR = complete response rate, Cri = CR with incomplete bone marrow recovery, PFS = median progression free survival, DOR = median duration of response Disclosures Robak: Emergent Product Development: Research Funding. Mato:Emegent Product Development: Honoraria. Byrd:Emergent Product Development: Research Funding. Awan:Lymphoma Research Foundation: Research Funding; Boehringer Ingelheim: Consultancy. Hill:Emergent Product Development: Research Funding. Stromatt:Emergent Product Development: Employment.