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Objectives Serum free light chain (sFLC) measurements have inherent analytical limitations impacting sFLC clinical interpretation. We evaluated analytical and diagnostic performance of three polyclonal sFLC assays on four analytical platforms. Methods sFLC concentration was measured using Diazyme FLC assays (Diazyme) on cobas c501/c503 analyzer (Roche); Freelite assays (The Binding Site) on Optilite analyzer (The Binding Site) and cobas c501 analyzer and Sebia FLC ELISA assays (Sebia) on AP22 ELITE analyzer (DAS). Imprecision, linearity, method comparison vs. Freelite/Optilite, antigen excess detection and reference value verification were assessed. Diagnostic performance was compared on 120 serum samples and on follow-up samples of five patients with κ and λ monoclonal gammopathy. Results Method comparison showed excellent correlation with Freelite/Optilite method for all assays. A large proportional negative bias was shown for both Sebia κ and λ ELISA and a significant positive proportional bias for λ in the low ( Conclusions Important analytical limitations remain for all sFLC applications. Differences in reference values and diagnostic performance hamper interchangeability of sFLC assays. Assay specific sFLC decision guidelines are warranted.

Supplemental table 1. Bone marrow BI-505 concentration and MM-cell ICAM-1 expression

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients.Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses.Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505′s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months.Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206). Clin Cancer Res; 21(12); 2730–6. ©2015 AACR.

Diffuse large B-cell lymphoma (DLBCL) masquerading as a recurrent inguinal hernia is rare. We report the case of a 73-year-old male patient who presented with a symptomatic bulge in his left groin. Medical history revealed bilateral preperitoneal inguinal hernia repair, osteoporosis and atrial fibrillation. The patient's further history was not significant.Sonography revealed recurrence of an indirect inguinal hernia (4.5 cm × 2.3 cm) on the left, with bilateral subcutaneous lymph nodes that were deemed unremarkable. We planned an elective left-sided anterior inguinal repair. Apixaban was stopped two days prior to surgery.During surgery we identified the bulge as a lump attached to the spermatic cord. No hernial sac was present. Together with the consulting urologist, we concluded a possible malignant etiology and performed an orchiectomy along with resection of the lump.Microscopic and immunohistochemical analysis revealed a DLBCL with non-germinal center phenotype and c-MYC rearrangement. Further staging confirmed stage IE disease with extranodal paratesticular involvement. The patient was subsequently treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, prednisone and showed complete metabolic remission after two cycles. This case illustrates the broad differential diagnosis of inguinal swelling and (para)testicular tumors.

We report the first documented case of hepatitis E virus-associated haemophagocytic lymphohistiocytosis. This case emphasizes the fact that infectious agents other than those classically described should be taken into consideration as a potential trigger of virus-associated haemophagocytic syndrome. Prompt recognition is crucial to start early treatment of the underlying infection and possibly improve the outcome of this frequently fatal syndrome.

Ruxolitinib was recently approved for the treatment of patients with polycythemia vera who are resistant/intolerant to hydroxyurea based on data from the RESPONSE studies. This phase 3b, Expanded Treatment Protocol study (NCT02292446) of ruxolitinib for hydroxyurea-resistant/intolerant patients with polycythemia vera (

Cardiac amyloidosis (CA) is often overlooked or misdiagnosed. Effects of growing disease awareness, diagnostic ameliorations and novel treatment options on CA diagnosis and management are scarcely reported. To report trends in diagnosis, referral routes, clinical presentation, early onset diagnostic red flags and outcome in de novo CA subjects. An unselected cohort of 139 de novo CA patients over an 8-year period in a tertiary referral hospital was recruited. Transthyretin (ATTR, 82%, n = 114) was the most common CA form; Light-chain (AL, 15%, n = 21) and secondary (AA, 3%, n = 4) are less prevalent. Increased awareness over time led to a marked ATTR diagnostic surge, steep non-invasive diagnostic approach increment and increased nuclear medicine and external cardiologist referrals (all p < 0.001). A total of 41% (n = 57/139) of patients were referred by non-cardiology specialist disciplines. Specific referral to rule out CA (24–36%) and diagnostic time lag from symptom onset (9 ± 12 to 8 ± 14 months), however, did not improve (all p > 0.050). Multiple early red flag events preceded CA diagnose several years in ATTR: Left ventricular hypertrophy (LVH, 60%, 4.9 ± 4.3 y), heart failure (54%, 2.5 ± 3.5 y), atrial fibrillation (47%, 5.9 ± 6.7 y), bilateral carpal tunnel syndrome (43%, 9.5 ± 5.7 y) and spinal stenosis (40%, 7.4 ± 6.5 y). LVH ≥ 12 mm was absent in 11% ATTR (n = 13/114) and 5% AL (n = 1/21) patients. Hypertension was common in both ATTR (n = 70/114, 62%) and AL (n = 10/21, 48%). 56% (n = 78/139) of CA presented with heart failure. Cumulative 1 and 5-year mortality of 10%/66%, 40%/52% and 75%/75% for ATTR, AL, and AA, respectively, remains high. Although CA diagnostic uptake and referral improve, specialist-specific disease and diagnostic red flag ignorance result in non-timely diagnosis and unfavourable outcome.

[Background]: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. [Methods]: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m²) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. [Findings]: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. [Interpretation]: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma, This study was sponsored by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

In newly diagnosed multiple myeloma (MM), patients ineligible for front-line autologous stem cell transplantation (ASCT), melphalan and prednisone (MP) with thalidomide (MPT) or bortezomib (VMP) are standard first-line therapeutic options. Despite new treatment regimens incorporating bortezomib or lenalidomide, MM remains incurable. The FIRST study demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) for the combination of lenalidomide and low-dose dexamethasone (Rd) until progression vs. MPT in transplant-ineligible ndMM patients. However, to date no head-to-head randomized controlled trials (RCTs) have compared Rd or MPT versus VMP. We conducted a network meta-analysis using RCTs identified through a systematic literature review to evaluate the relative efficacy of Rd versus other regimens on survival endpoints in previously untreated MM patients ineligible for ASCT. In this analysis, Rd was associated with a significant PFS and survival advantage versus other first-line treatments (VMP, MPT, MP), challenging the role of alkylators in this setting.

Infections are a major cause of death in patients with multiple myeloma. A post hoc analysis of the phase 3 FIRST trial was conducted to characterize treatment-emergent (TE) infections and study risk factors for TE grade >= 3 infection. The number of TE infections/month was highest during the first 4 months of treatment (defined as early infection). Of 1613 treated patients, 340 (21.1%) experienced TE grade >= 3 infections in the first 18 months and 56.2% of these patients experienced their first grade >= 3 infection in the first 4 months. Risk of early infection was similar regardless of treatment. Based on the analyses of data in 1378 patients through multivariate logistic regression, a predictive model of first TE grade >= 3 infection in the first 4 months retained Eastern Cooperative Oncology Group performance status and serum beta(2)-microglobulin, lactate dehydrogenase, and hemoglobin levels to define high-and low-risk groups showing significantly different rates of infection (24.0% vs. 7.0%, respectively; P < 0.0001). The predictive model was validated with data from three clinical trials. This predictive model of early TE grade >= 3 infection may be applied in the clinical setting to guide infection monitoring and strategies for infection prevention.

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses. Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505′s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months. Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206). Clin Cancer Res; 21(12); 2730–6. ©2015 AACR.

Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.

BACKGROUND Few Tx options are available for pts with inadequately controlled PV. European LeukemiaNet defined resistance/intolerance was seen in ≈25% pts treated with HU (Alvarez-Larran et al, 2012). In the HU-resistant/intolerant PV pts evaluated in the pivotal RESPONSE study (week [wk] 208), RUX was well tolerated and superior to standard therapy in achieving durable hematocrit (HCT) control, hematologic response, and spleen size and symptom reductions. This Ph 3b ETP study was planned to provide RUX Tx to HU-resistant/intolerant PV pts, who have no alternative standard Tx, and are not eligible for any ongoing clinical studies. Results from wk 24 data cutoff of this study (Devos et al) were presented at ASH 2017. Here, we report consolidated findings from the ETP study at wk 96 data cutoff (Dec 29, 2017 [final database lock]) to further support the use of RUX in this pt population with an unmet medical need. METHODS RUX Tx was initiated at a starting dose of 10 mg bid (could be titrated to a maximum of 25 mg bid). Visits were scheduled every 4 wks until wk 24 and every 12 wks thereafter; final analysis was done when all pts had been followed for 30 days after discontinuation of Tx or completion of Tx per protocol (transitioned to commercial RUX or until Dec 31, 2017, whichever date occurred first). The primary endpoint was to assess the safety of RUX. Secondary endpoints included change in HCT level, change in spleen length, and pt-reported outcomes (change in MPN-SAF TSS score). HCT control at wk 24 was defined by absence of phlebotomy (PBT) eligibility starting at wk 8 and continuing through wk 24, with no more than 1 PBT eligibility occurring after first dose date and prior to wk 8. PBT eligibility was defined by confirmed HCT >45% (at least 3 percentage points higher than HCT at baseline [BL]), or confirmed HCT >48%. Blood count remission at wk 24 was defined by HCT control, and white blood cell count RESULTS At data cutoff, 161 pts with PV were enrolled (BL characteristics similar to that presented at ASH 2017). End of Tx was reported for all 161 pts: Tx duration completed per protocol (141 pts), adverse event (AE [12 pts]), consent withdrawal (3 pts), pt decision (2 pts), disease progression (2 pts), and death (due to accident [1 pt]). The median exposure was 25.1 wks (range, 0.4-104.7), and median dose intensity of RUX was 20.0 mg/day (range, 6.7-47.7). AEs (regardless of study drug relationship) led to dose adjustment/interruption in 37.9% pts and study drug discontinuation in 8.7% pts. The most common hematologic AEs (rate=number of events per 100 pt-year exposure [pt-year exposure=110.2]; all grades]) included anemia (31.8) and thrombocytosis (10.0), while headache (24.5), diarrhea (14.5), constipation (12.7), and fatigue (12.7) were the most frequent non-hematologic AEs. For all reported grade 3/4 AEs, exposure-adjusted rate was less than 3. Thromboembolic events (all grade; Standardized MedDRA Query) were reported in 3 pts. Disease progression was reported in 4 pts (myelofibrosis=3 pts; acute myeloid leukemia=1 pt). The incidence of other neoplasms (regardless of study drug relationship) was low (leiomyoma, malignant melanoma, marginal zone lymphoma, renal cancer [1 pt each]; squamous cell carcinoma [2 pts]; basal cell carcinoma [3 pts]). Infections (all grades) were reported in 57 pts (grade 3/4 in 5 pts). At wk 24, 73 pts (45.3% [95% CI, 37.5%-53.4%]) achieved HCT control; hematologic remission was seen in 29 pts (18% [95% CI 12.4%-24.8%]). Changes in blood count parameters over time are shown in Fig. 1. In evaluable pts (N=105), use of PBT decreased from BL (39 PBTs between screening and BL) to end of Tx (5 PBTs in 12 wks prior). Best spleen response from BL for each pt by wk 96 is shown in Fig. 2. At least 50% spleen length reduction was seen in 86.7% (78/90) of pts from BL at any time in the study. Overall, 33.8% (46/136) of pts had ≥50% reduction in MPN-SAF TSS from BL at the end of Tx. CONCLUSION The observed safety profile of RUX in the ETP study was consistent with that of the RESPONSE studies. Efficacy results were close to the observed values in the RESPONSE studies. RUX Tx resulted in HCT control, hematologic remission, spleen response, and symptom reduction in this HU-resistant/intolerant pt population in need of a viable Tx option. Safety and efficacy findings from this ETP study support the use of RUX for pts with inadequately controlled PV, an unmet medical need. Disclosures Foltz: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. de Almeida:Celgene: Speakers Bureau; Novartis: Speakers Bureau. Ranta:Novartis: Consultancy. Cartes:Novartis: Honoraria. Kiladjian:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chrit:Novartis: Employment, Equity Ownership. Yin:Novartis: Employment. Morando:Novartis: Employment, Equity Ownership. Devos:Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy.

TPS8057Background: DARA, a human CD38 monoclonal antibody, is approved for treatment of RRMM. DARA produces deep clinical responses in RRMM and induces T-cell expansion through reduction of immune ...

S88 Volume 29 Supplement C Hematologic and Hemato-Oncologic Aspects of Gaucher Disease Derralynn Hughes, MA, DPhil, MRCP, MRCPath1; Maria Domenica Cappellini, MD2; Marc Gabriel Berger, MD, PhD3; Jan Van Droogenbroeck, MD4; Maaike de Fost, MD5; Dragana Janic, MD, PhD6; Theodore Marinakis, MD, PhD7; Hanna Rosenbaum, MD8; Jesus Villarubia, MD, PhD9; Elena Zhukovskaya, MD10; and Carla Hollak, MD5 1Lysosomal Storage Diseases Unit, Department of Academic Haematology, Royal Free Hospital and University College Medical School, London, United Kingdom; 2Department of Internal Medicine, Policlinico Foundation IRCCS, University of Milan, Milan, Italy; 3Department of Hematology, CHU Hotel-Dieu, Clermont-Ferrand, France; 4Department of Hematology, AZ St. Jan AV, Brugge, Belgium; 5Department of Internal Medicine, Division of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 6University Children’s Hospital, University of Belgrade, Belgrade, Serbia; 7The Hellenic Collaborative Working Group of Hematologists on Gaucher Disease, Athens, Greece; 8Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center and Bruce Rappaport Faculty of Medicine, Haifa, Israel; 9Ramon and Cajal Hospital, Servicio de Hematologia, Madrid, Spain; and 10State Medical Academy, Chelyabinsk, Russia

The prevalence of monoclonal gammopathy of undetermined significance (MGUS) is generally estimated at 3.4% in the general population over 50 years, and its incidence increases with age. MGUS represents a preneoplastic entity that can transform into multiple myeloma or other lymphoproliferative disorders. The risk of malignant transformation is estimated at 1% per year and persists over time. Predictors of malignant transformation have been identified such as the heavy chain isotype, The level of monoclonal proteins, increasing levels of the monoclonal component during the first years off follow-up, the percentage of bone marrow plasmocytosis, the dosage of serum free light chains, the presence of immunophenotypically abnormal plasma cells, aneuploidy, and the presence of circulating plasma cells. Prognostic scores that combine certain of these factors have been proposed and allow the identification of high-risk patients. Their use could assist in tailoring the care for each patient, based on his/her risk profile.

TPS7079Background: MF is a Philadelphia chromosome negative myeloproliferative neoplasm, with a relatively poor prognosis. Ruxolitinib, a JAK1/JAK2 inhibitor, is the only approved therapy for MF, a...

Abstract 475FN2 Background: An IMiDs® immunomodulatory agent, Len has a dual mechanism of action: its tumoricidal effect directly leads to tumor cell death, and its immunomodulatory effect may keep the tumor in remission. A phase 3, randomized, placebo (Pbo)-controlled trial, MM-015 compares MPR-R with fixed-duration MPR and MP induction in transplant-ineligible NDMM pts. Interim results showed unprecedented reduction in disease progression risk with MPR-R (Palumbo et al, IMW 2011); this analysis focuses on pts aged 65–75 yrs in whom the greatest benefit was observed. Methods: A total of 459 pts aged ≥ 65 yrs with NDMM were enrolled. Induction consisted of nine 28-day cycles of melphalan 0.18 mg/kg (D1-4), prednisone 2 mg/kg (D1-4), and Len 10 mg (D1-21) (MPR-R and MPR) or melphalan and prednisone with Pbo (MP). After induction, MPR-R pts received Len 10 mg (D1-21) maintenance until progression; MPR and MP pts received Pbo. Pts with progressive disease (PD) could enroll in an open-label extension phase to receive Len 25 mg (D1-21) ± dexamethasone 40 mg (D1-4, 9–12, and 17–20). This analysis includes data up to Feb 28, 2011 (median follow-up, 30 mos). Results: There were 116/152 (76%), 116/153 (76%), and 116/154 (75%) of MPR-R, MPR, and MP pts, respectively, aged 65–75 yrs. Nearly 50% had ISS stage III disease, > 40% had β2-microglobulin > 5.5 mg/L, and 40% had CrCL < 60 mL/min. With a median follow-up of 30 mos, MPR-R reduced progression risk by 70% and significantly prolonged median PFS (31 mos) vs MP (12 mos; hazard ratio [HR]: 0.30 [95% CI, 0.20–0.45]; P MPR-R significantly extended median PFS vs MPR (31 vs 15 mos; HR: 0.44 [95% CI, 0.30–0.66]; P 75 years old. Response rates and quality were similar. MPR induction alone provided a significant PFS benefit vs MP (15 vs 12 mos; HR: 0.64 [95% CI, 0.45–0.90]; P =.009). MPR induction had an acceptable safety profile, allowing the majority of pts to reach maintenance. During induction, discontinuation due to adverse events (AEs) occurred in 13% of MPR and 4% of MP pts. The most common induction grade (Gr) 4 hematologic AEs for MPR-R, MPR, and MP were neutropenia (39%, 29%, and 7%) and thrombocytopenia (33%, 12%, and 4%). Febrile neutropenia was low for all arms (1%, 1%, and 0%). The most frequent Gr 3/4 nonhematologic AE was bone pain (3%, 3%, and 4%). Len maintenance was generally well tolerated, with no evidence of cumulative toxicities. Only 5% of Len maintenance pts discontinued due to AEs. The most frequent Gr 4 hematologic AEs were thrombocytopenia (5%), neutropenia (4%), and anemia (3%); and Gr 3/4 nonhematologic AEs included bone pain (5%) and diarrhea (5%). Hematologic second primary malignancies (SPMs) during induction and maintenance were 3 (2 AML, 1 ALL), 1 (MDS), and 0 in the MPR-R, MPR, and MP arms, respectively. These corresponded to incidence rates (IRs) per 100 pt-yrs of 1.8, 0.7, and 0. Solid tumor SPMs occurred in 2 pts per arm, were heterogeneous and balanced across arms; IRs were 1.2, 1.4, and 1.6, respectively. Conclusions: Continuous Len treatment with MPR-R significantly reduced disease progression risk compared with MP and MPR in pts aged 65–75 yrs. MPR induction significantly extended PFS vs MP. To date, MPR-R has provided one of the longest median PFS (31 mos) among other available regimens (bortezomib, melphalan, prednisone: 24–27 mos; melphalan, prednisone, thalidomide: 28 mos; bortezomib, melphalan, prednisone, thalidomide: 37 mos). The PFS benefit in the landmark analysis supports continuous treatment to suppress disease in all patient age groups. Management of toxicities is essential to allow pts to continue therapy and receive full benefits. Although hematologic SPMs were imbalanced, the risk of PD/death clearly outweighs the risk of SPMs. MPR-R should be considered a standard of care in transplant-ineligible NDMM pts aged 65–75 yrs. Disclosures: Palumbo: Merck: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Off Label Use: Lenalidomide in newly diagnosed patients with multiple myeloma. Catalano:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gisslinger:Celgene: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; AOP-Orphan: Speakers Bureau. Wiktor-Jedrzejczak:Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria, Research Funding. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Weisel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Droogenbroeck:Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Janssen Cilag: Consultancy. Cavo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Beksac:Celgene: Honoraria, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau. Spicka:Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Honoraria, Speakers Bureau; Novartis: Honoraria. Yu:Celgene Corporation: Employment. Herbein:Celgene Corporation: Employment. Mei:Celgene Corporation: Employment. Jacques:Celgene Corporation: Employment. Dimopoulos:Celgene: Consultancy, Honoraria.

Abstract 4523 Introduction Bortezomib (VELCADE) is a proteasome inhibitor for treatment of MM. The eVOBS (electronic VELCADE Observational Study) evaluates treatment and clinical outcome with bortezomib in daily practice in the relapsed setting. Enrollment in the study started in Oct 06 and is still continuing, with 3 y follow-up for every enrolled patient. This report concerns preliminary efficacy and Quality of Life (QoL) results of 136 Belgian patients included in the latest interim analysis from June 2009. Patients and Methods Adults were eligible for study if they were scheduled to initiate bortezomib within the approved indication. All bortezomib dosages and concomitant treatments were permitted, except investigational therapies. Due to the non-interventional nature of the study, no predefined response criteria were mandated; response criteria included M-protein, EBMT, SWOG, or others as defined by the investigator. QoL assessment was conducted in Belgium only, using the EORTC Quality of Life Core Questionnaire (QLQ-C30). The EORTC QLQ-C30 comprises a global health status (GHS) scale, five functional scales and six symptom scales. The questionnaire was administered at baseline and at the start of each treatment cycle. Evolution of mean scores was determined in correlation with baseline characteristics and response. Results were also analyzed for all patients and responders (partial response (PR) or better) vs. non-responders. For this, a mixed model was used comparable to that described by Lee et al. [BJH (2008) 143, 511-519], with missing data due to death being assigned the lowest possible score (model A) vs. being treated as missing (model B). Predictive value of baseline QoL scores for Overall Survival (OS) and Progression Free Survival (PFS) was assessed. Results One hundred thirty six patients (57% male) are included in this analysis, with median age of 65y, and mean time since MM diagnosis of 2.9 years. Prior number of therapies received was 1 in 56%, 2 in 27%, and 3 or more in 11%. Five % received bortezomib in first line and for 1% data were missing. 97% of patients started bortezomib at 1.3 mg/m2 on the standard schedule. Median treatment duration was 5 cycles. Of the 97 patients that were evaluated for response so far, overall response rate was 69%, with 57% PR and 12% CR/nCR. 14% and 9% of patients reached MR and SD, respectively. 78% of all enrolled patients experienced AEs of any grade, which led to discontinuation of treatment in 30%, comparable with the 37% in the APEX trial (Richardson, NEJM 2005). For QOL assessment 103 patients completed the EORTC QLQ C-30 at baseline, with this number decreasing substantially in subsequent cycles (n=42 by cycle 4). Using model A (death = worst possible outcome), a small but significant decline in QoL was seen for physical, role, emotional, cognitive and social functioning, and for symptom scales of nausea and vomiting and financial impact. Of these, only the decline in cognitive functioning remained significant when applying model B (death = missing). In the APEX trial as well there was a decline in GHS as well as in 8 of the EORTC scale scores (Lee et al BJH 2008). No significant differences were seen according to baseline data (gender, age, line of therapy, lab values). Using model A, the evolution of QoL scores was significantly worse for non-responders vs. responders on the scales of physical, cognitive and emotional functioning, nausea and vomiting, sleep disturbance, diarrhea and financial impact. When using model B, no significant differences in QOL between responder and non-responder groups were detected. Worse baseline scores for nausea and vomiting and dyspnoea were predictive for worse PFS, but only dyspnoea was predictive for worse OS. Conclusion Overall in this study a slight decline was seen for some QoL parameters over the course of treatment, consistent with findings from the APEX trial (Lee et al. BJH 2008), which included patients similar to those in the eVOBS trial (Zervas IMW 2009). Using the model that assigns “worst possible outcomes” to data missing because of death, better QoL was seen in responders vs. non-responders, suggesting better QoL is at least partly linked to response. Interpretation should be done with caution due to the number of patients and the decreasing number of returned questionnaires over time. Disclosures: Delforge: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Van Droogenbroeck:Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Janssen-Cilag: Consultancy. Kuijten-Celzo:Johnson & Johnson: Employment. Diels:Johnson & Johnson: Employment. Ganguly:Johnson & Johnson: Employment, Equity Ownership. Dhawan:Johnson and Johnson Research Pharmaceuticals: Employment.

Current knowledge of the haematological and onco-haematological complications of type 1 Gaucher disease has been reviewed with the aim of identifying best clinical practice for treatment and disease management. It was concluded that: (i) Awareness of typical patterns of cytopenia can help clinicians distinguish haematological co-morbidities. (ii) Red blood cell studies and complete iron metabolism evaluation at baseline are recommended. (iii) Haemoglobin levels defining anaemia should be raised and used in Gaucher disease treatment and monitoring. (iv) Surgeons should be aware of potential bleeding complications during surgery in Gaucher patients. The higher incidence of multiple myeloma in Gaucher disease suggests that Gaucher patients should have their immunoglobulin profile determined at diagnosis and monitored every 2 years (patients 50 years). If monoclonal gammopathy of undetermined significance (MGUS) is found, general MGUS guidelines should be followed. Future studies should focus on the utility of early treatment to prevent immunoglobulin abnormalities and multiple myeloma

Intravascular large B-cell lymphoma or intravascular lymphomatosis (IVL) is an extremely rare form of non-Hodgkin's lymphoma. The most common clinical sign is fever of unknown origin (FUO). Histologically, there is proliferation of malignant lymphoid cells within vascular lumina. Cytologically, the cells have features similar to those found in classical large cell lymphoma. Examination of pulmonary artery blood showed the presence of this abnormal population in our patient; to the best of our knowledge there are only four other reports of detection of circulating tumor cells in IVL. The outcome is very poor. The diagnosis is most frequently made after biopsy of skin or brain but is often established post mortem. We present what is – to our knowledge – the first reported case of IVL diagnosed after biopsy of a testicle. In the event of FUO and suspicion of a malignancy, IVL – although very rare – should be one of the differential diagnoses.

Imatinib and dasatinib modulate immune responses in vitro and in vivo . Immunological surveillance in the MRD-situation might be of particular relevance for long-term control or even elimination of CML-repopulating stem cells. Little is known about potential immune-modulatory effects of nilotinib in vivo . The ENEST1st study ([NCT01061177][1]) is focused on examining the role of firstline nilotinib therapy in CML-CP - this ENEST1st substudy involves a comprehensive immunological monitoring program. To evaluate and characterize the immunomodulatory effects of nilotinib therapy in newly diagnosed CML-CP patients. Peripheral blood was taken prior to treatment initiation and after 6 and12 months (mo) from 50 patients treated on the ENEST1st study. Samples were analyzed by nine color flow cytometry employing six panels of antibodies to determine various leukocyte populations including lymphocyte subsets (e.g. T cell subpopulations including Treg and NKT cells, NK cells, B cells), myeloid populations (e.g. monocytes, MDSC) and dendritic cell subsets (e.g. mDC, pDC), respectively. Changes in immune cell parameters were correlated to clinical endpoints and PK data. 55% of the patients included into this substudy achieved MMR at 6mo, 75% at 12mo and 79% at 12mo of therapy. MR4 was achieved by 21%, 31%, 50% of patients at 6, 12 and 24 mo of therapy, respectively. A high proportion of CD14+ monocytes with aberrant expression of CD56, present at baseline, dropped to undetectable levels at 6 and 12 mo of treatment. The most prominent immunological change from baseline to 12 mo was a dramatic increase of CD19+ B cells. The abundance of CD19+ B cells at baseline was negatively correlated with SOKAL score. Among T-cell subpopulations, the proportion of CD56+ NKT-cells decreased. Similarly, the proportion of CD8+ T cells significantly decreased concomitant with increasing CD4+ T cells during therapy. In parallel to a decrease of CD45RA+ expressing T cells among both CD8+ and CD4+ T cell subsets, the proportion of CD45R0+ memory cells increased. This increase was mainly due to an increase of the CD95+CD28+ central memory population. In contrast to our expectation, CD25high FoxP3+ Treg cells were even increased transiently 6 months after treatment initiation but at 12 months dropped back to levels seen at diagnosis. None of the immunological changes were associated with plasma levels of nilotinib or response to therapy. Various immunological changes were detected during nilotinib therapy. However, most changes after therapy are most likely due to normalization of the peripheral blood compartment. Correlation of a specific immunological signature with response to nilotinib could not be identified. However the increased proportion of memory T cells during therapy suggests a potential contribution of the cellular immune response to the eradication of malignant cells. Molecular analyses of NKT-cells will show whether the increased proportion before therapy is due to aberrant expression of CD56 as in monocytes or a specific expansion of this subset. Mustjoki: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Greil: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Thaler: Roche: Honoraria, Research Funding. Richter: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Verhoef: MedImmune: Research Funding. Mark: Novartis: Employment. Haenig: Novarts: Employment. Jurjonas: Novartis: Employment. Gastl: Novartis: Honoraria, Research Funding. Giles: Novartis: Consultancy, Research Funding. Hochhaus: Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Ossenkoppele: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Porkka: BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Wolf: Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Bristol-Meyers Squibb: Honoraria. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01061177&atom=%2Fbloodjournal%2F122%2F21%2F2731.atom

Experience with haploidentical stem cell transplantation in elderly patients after non TBI (total body irradiation) containing regimens is limited. We report a single centre experience with haploidentical stem cell transplantation in 16 patients with poor prognosis myeloid and lymphoid malignancies refractory to conventional therapy or relapsing after autologous stem cell transplantation. For none of these patients a HLA matched related or unrelated donor was available. All patients were transplanted between April 2004 and May 2007. Age was between 16 and 71 yrs (median 57 yrs), 11 of 16 were more than 50 yrs old. Of the 16 patients 3 had lymphoid malignancies (1 Hodgkin, 1 myeloma, 1 Phi+ ALL) and 13 had high risk MDS (myelodysplasia) or primary or secondary AML. All patients had relapsed after or were refractory to conventional chemotherapy (11 patients) or had relapsed after autologous stem cell transplantation (5 patients). All patients were prepared with a conditioning regimen consisting of Thiotepa 2 × 5 mg/kg on day −8, ATG Fresenius 5 mg/kg on days −7 to −3, Fludarabine 40 mg/m2 on days −7 to −3, Melphalan 100–140 mg/m2 on days −2. CD34 selection was by Clinimacs without postgrafting GVHD prophylaxis. Grafts contained a median of 9,8 × 106 CD34/kg (range 3,3–16,6 × 106/kg) and a median of 0,11 × 105 CD3/kg (range 0,04–0,3 × 105/kg). All donors were haploidentical family members. 13 of 16 donor-recipient pairs had at least one KIR ligand mismatch in the GVH (graft versus host) direction. Graft rejection occurred in 2 of 16 transplants, 1 patient was rescued with a second transplant from another haploidentical donor. All surviving patients are full chimeras (> 95% donor chimerism). Median time to ANC > 0.5 x10 9/l was 12,5 days (range 7–18 days) and median time to platelets > 50 × 109/l was 21,5 days (range 14–199 days). 5 of 16 patients died before they achieved a platelet count > 50 × 109/l. Non relapse mortality occurred in 4 of 16 (25%) patients within 1 year after transplantation. Causes of death were: aspergillosis 1, VOD 1, CNS bleeding 1, cGVHD 1. Acute GVHD grade II-IV occurred in 3 patients and was manageable with steroids and/or ATG. Chronic GVHD was observed in 3 patients (after DLI in 2 of them). Infections were the most important complication: aspergillosis in 7 patients, CMV in 4 patients, listeria meningitis in 1 patient. EBV-associated lymphoproliferative disease was seen in 2 patients, both responded to rituximab and DLI (donor lymphocyte infusions). Disease progression and relapse occurred in 6 patients within 1 year after transplantation (myeloma 1, AML 5). None of the relapsing patients responded to escalating doses of DLI. At the time of this report 8 of 16 patients are surviving, 6 of them without evidence of disease between 159 and 1214 days (median 425 days) after transplantation. Of the 6 disease free survivors 4 are older than 50 yrs and 5 have a KIR ligand mismatch in the GVH direction. Kaplan Meier estimate for overall survival and disease free survival is 43% at 2 yrs and 39% at 2 yrs respectively. We conclude that transplantation from natural killer (NK) alloreactive haploidentical family donors offers potential cure to about one third of elderly patients with advanced leukemia or MDS considered incurable by other therapies. TBI does not seem to be required to benefit from this treatment approach. Relapse rate and infectious morbidity remain major obstacles.

KIRs (Killer cell Immunoglobulin-like Receptors) are expressed on NK (Natural Killer) cells and a subpopulation of T lymphocytes namely memory CD8+ T cells. The distribution of KIR genes varies among individuals and populations. These genes are encoded on chromosome 19 (19q13.4). Till now 17 KIR genes and pseudogenes have been identified. KIRs recognise groups of HLA class I alleles. NK activity is partially controlled through the interaction between KIRs and their HLA ligands. Several studies report that KIRs may affect the outcome of Hematopoietic Stem-Cell Transplantations. We performed KIR typing of 17 genes and pseudogenes in 100 healthy Belgian unrelated individuals in “West-Vlaanderen” from Caucasoid origin using a PCR-SSP method. Three genes (KIR3DL3, 2DL4 and 3DL2), named frame-work genes, and the pseudogene 3DP1 were found in all individuals. KIR2DL1 and 2DP1 genes were present in a frequency of 99%. In addition, KIR3DL1 and 2DS4 genes represented a frequency of 97. The KIR2DL3 was found in 90% and the frequencies of other genes varied between 56% and 24%. The individual KIR gene content ranged from 8 to 17 genes. A total of 19 KIR locus profiles was observed. The most common KIR locus profile (32%) consisted of a combination of genes characterising A haplotypes (KIR2DL1 and 2DL3) without the presence of genes characteristic of B haplotypes (KIR2DL2 and 2DS2). The second most common KIR locus profile, accounting for 20% contained a combination of genes characteristics for both A and B haplotypes. The allele KIR2DS4*003 was found in 89% and KIR2DS4*00101/00102/002 only in 41%. KIR3DP1*00301/00302 was present in all individuals and KIR3DP1*001/002 only in 35%. Our results show that frequencies of most KIR loci in our Belgian population were comparable to literature data of other Caucasian populations. Only KIR2DS1 was lower (27% vs 47.7% with a p-value of 0.0002). In the future, KIR typing of donor and patient before a Hematopoietic Stem-cell Transplantation may be necessary, due to the diversity in KIR genotypes.

In recent reports, granulocyte PRV-1 mRNA has been shown to be over-expressed in the majority of polycythemia vera (PV) patients and with a variable frequency in essential thrombocythemia (ET) patients. Here we evaluate PRV-1 mRNA quantification in the diagnosis of PV and ET. Following patients were included in the study: 23 PV patients; 5 secondary erythrocytosis (SE) cases, 4 by lung disease and 1 by a hemoglobinopathy (Hb San Diego); 4 relative erythrocytosis (RE) cases; and 13 ET patients. PV and ET diagnosis was made according to the WHO criteria. At time of sampling 43% of PV patients and 54% of ET patients were receiving myelosuppressive therapy. To establish a cut-off value 28 healthy persons (15 female, 13 male) were also analysed. RNA was extracted from whole-blood leucocytes and quantified by real-time TaqMan PCR. ABL was used to control the mRNA quality (Ct ABL < 27.0 – mean 24.7) and to normalise the PRV-1 values. PRV-1 primer and probe sequences originated from Brohée D et al, Blood, 2002, 100:3146a and ABL primer and probe sequences from Beillard E et al, Leukemia, 2003, 17:2474. The results were expressed as a ratio PRV-1/ABL which could be calculated using the ΔΔCt method as the efficiencies of both PCR reactions were almost equal (for PRV-1 93% and ABL 94%). Within-run and between-run reproducibility of a normal sample had a CV of 10.1 % and 28.6% and of a highly expressing sample a CV of 9.5% and 21.6%. The values of the healthy controls had a normal distribution and a mean of 0.28 with a SD of 0.35. A cut-off level was determined as the upper 95% percentile and was 0.98. Results of the different patient groups are summarised in the table. The differences between PV vs healthy controls, PV vs SE/RE and ET vs healthy controls were significant with a p-value of respectively PRV-1/ABL mRNA ratio in healthy controls, PV, SE/RE and ET Normal PV SE/RE ET Median/mean 0.28 21.3 0.18 0.62 Range

Few studies have reported on the efficacy of donor lymphocyte infusions (DLI) for myelodysplastic syndromes (MDS) relapsing after T-cell depleted allogeneic stem cell transplantation. Since 1996 we have treated 11 patients with DLI as a single therapeutic modality (without chemotherapy) for a relapse of MDS after allogeneic stem cell transplantation. Median age of the patients was 56 years (range 23 to 73 years). Initial diagnosis was RAEB (4 patients), RAEBt (3 patients), secondary AML(3 patients) and MDS with fibrosis (1 patient). Conditioning was myeloablative in 10 patients ( TBI -Cyclophosphamide, Busulfan-Cyclophosphamide or Busulfan-Melphalan) and non-myeloablative in 1 patient (Busulfan-Fludarabine-ATG). Source of stem cells was peripheral blood in all patients. Donors were HLA-identical siblings in 10 patients and HLA-matched unrelated in 1 patient. Allografts were T-cell depleted with Campath 1H in the bag in 8 of 11 patients. GVHD prophylaxis was cyclosporin in all patients combined with methotrexate in the 3 patients receiving unmodified stem cells. Relapse of MDS occurred at a median of 123 days (54 to 373 days) after allograft. At the time of DLI the percentage of blast cells in the bone marrow ranged from 3 % to 50 % (median 6 %); donor chimerism ranged from 14 % to 91 % (median 72%). The total dose of CD3 lymphocytes ranged from 0.1 to 30 x 10 7 /kg (median 0.6 x 10 7/kg) and was administered in 1 to 4 infusions (median 1). Time interval between first and second DLI varied between 7 and 180 days.Three of the 11 patients achieved a durable complete remission with 100 % donor chimerism after DLI. These 3 patients are currently disease free at 20, 30 and 40 months from the first DLI. All durable responses were associated with limited chronic GVHD requiring temporary immunosuppressive therapy. Time interval between the first DLI and the achievement of complete donor chimerism varied between 6 weeks and 9 months. One of the 11 patients achieved a short state of complete chimerism for 4 weeks and died from relapse 146 days after DLI. Five of the 11 patients progressed after DLI and 4 of them died from disease progression at 29 to 112 days after first DLI. Two patients died at 26 and 97 days after the first DLI from acute GVHD grade IV after having received only 1 x 10 6 CD3 lymphocytes /kg from HLA-identical sibling donors. None of the 6 patients with a complex karyotype responded to DLI while 3 of 3 patients with a single chromosomal abnormality ( t(1,14), t(1,17), t(1,3)) had a durable response (p-value = 0.01). We conclude that DLI is a powerful therapy for about 30 % of MDS patients relapsing after T-cell depleted allogeneic stem cell transplantation. DLI may result in durable remissions particularly in patients with non-complex cytogenetic abnormalities. However, even low doses of donor T lymphocytes may cause mortality from severe GVHD.

Introduction Tyrosine kinase inhibitor (TKI) trough plasma level testing and pharmacodynamic evaluation (i.e. quantification of phosphorylated BCR-ABL downstream targets) may help to optimize patient-tailored dosing in CML-CP. For 2nd generation TKIs the clinical value of TKI plasma level and protein phosphorylation quantification remains unclear. The ENEST1st study (NCT01061177) is focused on examining the role of first-line nilotinib therapy in CML-CP. This ENEST1st substudy addresses the value of plasma-level testing and protein single cell phosphorylation pharmacodynamics as predictors of response and long-term outcomes. Methods Nilotinib levels were centrally quantified by means of mass spectrometry (HPLC-MS/MS) in 54 patients at 3 hours after first drug intake at day (d) 1 (Cmax) and at d7, d28 as well as at months (mo) 3, 6, 12 prior to morning drug intake (Cmin=trough level). Single cell quantification of intracellular protein phosphorylation was performed by flow cytometry (phosphoflow) in the myelocyte cell population after full blood fixation/cell permeabilization/erythrocyte lysis and analyzed 3 hours after first drug intake at d1 and on d7 and d28. Primary endpoint of the study was MR4 (BCR-ABL Results Our initial analysis focuses on correlation of drug levels with molecular response by correlating PK data to early molecular response, i.e. ≤10% BCR-ABL (IS) reduction at 3 mo as well as 0.1% IS (MMR), MR4 and MR5. At 3, 6, 12 and 18 mo, 24%, 56%, 74% and 77 % of the here investigated patients achieved MMR; 2%, 22%, 34% and 44% achieved MR4 and MR5 was detected in 0%, 5%, 15% and 14% of patients at the respective time points. Only 1 patient at 3mo had >IS 10% BCR-ABL. On d1 at 3 hours after intake of the first tablet the median peak plasma levels reached 408 ng/ml increasing to a median trough level of 834 ng/ml at d7, 888 ng/ml at d28, 919 ng/ml at 3mo, 1122 ng/ml at 6m and 1003 ng/ml at 12mo. Initial Cmax-levels at d1 significantly correlated with steady state levels thereafter (e.g. with trough levels at 12mo: r=0.56, p=0.004). Three mo drug levels were significantly negatively associated with lower BCR-ABL mRNA burden at 12m and 24m (r=-0.44, p=0.011 for m12 and r=-0.35, p=0.014 for m24). When median steady state drug levels were compared in different response categories (yes/no: MR4, MR5, MMR, >IS 10% at 3mo), significantly higher nilotinib trough levels at day 90 and mean trough level (day 28-180) were seen in patients achieving the primary endpoint of the study (MR4 at 18mo). Similarly, 3mo and mean through levels were also significantly higher in patients achieving MR5 at 12 or 18mo. As only one patient did not reach Conclusions Single cell myelocyte phosphoprotein detection allowed monitoring of the BCR-ABL signalling network. Inter-individual plasma levels show a relatively wide variability and Cmax levels upon first drug exposure correlate with later trough levels pointing out to a potential individual pharmacogenetic background regulating drug availability. PK-based optimizing of nilotinib-dosing may help to further improve response depth (i.e. reaching MR4 or MR5), which is assumed to be a prerequisite for treatment discontinuation. Disclosures: Wolf: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Mustjoki:Novartis: Honoraria, Research Funding. Greil:Novartis: Honoraria, Research Funding. Hjorth-Hansen:Pfizer, BMS: Honoraria, Travel expenses Other. Verhoef:Novartis: Research Funding. Mark:Novartis: Employment. Haenig:Novartis: Employment. Jurjonas:Novartis: Employment. Giles:Novartis: Consultancy, Research Funding. Hochhaus:Novartis: Research Funding. Porkka:Novartis: Honoraria, Research Funding. Ossenkoppele:Novartis: Consultancy, Research Funding; BMS: Consultancy. Gjertsen:Novartis: Honoraria, Research Funding.