ALBERT

Description: Background: PTCL is a heterogeneous group of hematologic malignancies associated with a poor prognosis for most subtypes. In the relapsed setting, hematopoietic stem cell transplantation (HSCT) is the only potentially curative option for patients with PTCL. However, many patients are not able to achieve an adequate response to allow for HSCT. Belinostat (Beleodaq) is a potent pan-histone deacetylase inhibitor that was recently approved in the US for the treatment of patients with R/R PTCL. Approval was based on data from the pivotal Phase 2 BELIEF study that enrolled 129 patients with R/R PTCL (N = 120 evaluable), and demonstrated durable clinical benefit and tolerability. This analysis presents data for 12 of the enrolled patients (9 evaluable) who proceeded to HSCT following belinostat treatment. Methods: Patients with R/R PTCL received belinostat as a 1000 mg/m2IV infusion on Days 1-5 of a 21-day cycle. The primary endpoint of the study was Objective Response Rate (ORR; Complete Response [CR] + Partial Response [PR]) determined by an Independent Review Committee (IRC). We present efficacy and safety data for the subset of 12 patients who subsequently went on to HSCT. Results: Among 12 patients who subsequently proceeded to HSCT, 4 went on to receive an autologous HSCT and 8 received an allogeneic HSCT; 8 patients (67%) were female and 4 (33%) were male, and the median age was 54.5 (range 31-71) years. The median number of prior anticancer therapies was 2 (range 1-8), including 3 patients with prior autologous HSCT. The median number of belinostat treatment cycles was 2.5 (range 1-14) compared to the median of 2.0 (range 1-8) in the overall study population. Most patients in this subgroup had PTCL-Not Otherwise Specified (58.3%), angioimmunoblastic T-cell lymphoma (16.7%), or anaplastic large cell lymphoma (16.7%); 41.7% of patients had Stage IV disease. Three of the 12 patients were not evaluable for response due to insufficient histological material for confirmation by central pathologic analysis. The IRC-confirmed ORR for the 9 evaluable patients was 33.3% vs 25.8% in the study overall, and included 2 CRs, 1 PR, 2 patients with stable disease (SD) and 3 patients with progressive disease (PD). Duration of Response after transplant ranged from 41-261 days for the 3 belinostat responders. At last study contact, 2 patients had died from cardiac events (unrelated to belinostat) and 10 remained alive, with Overall Survival (OS) ranging from 8-23+ months. Most adverse events (AEs) were Grade 1-2, with two treatment-related Grade ≥3 AEs (neutropenia and prolonged QT interval); 3 serious AEs (arthralgia, lower limb fracture, and pyrexia) were reported in this subgroup. Conclusions: Belinostat was well tolerated in previously treated patients with R/R PTCL and enabled some patients to proceed to HSCT. Three patients responded and went on to HSCT following belinostat; the remaining patients had HSCT following SD (2), PD (4) or were not evaluable (3). OS was prolonged when compared to historical controls. Summary of Patients Treated with Belinostat Who Subsequently Went on to Hematopoietic Stem Cell Transplantation Sorted by Subtype and Response Table 1PatientSubtype(Stage)Prior RegimensECOGPSBelinostat CyclesIRC ResponseOS(months)DoR(days) Evaluable Patients931-003^PTCL-NOS (IIIB)3114CR11.56261907-006PTCL-NOS (IIA)5 + auto SCT02SD13.93-907-007^PTCL-NOS (IVA)402SD12.09-907-005^PTCL-NOS (IIIA)202PD13.63-140-002PTCL-NOS (IVA)817PD17.64-914-006PTCL-NOS (IIIA)4 + auto SCT02NE13.73-245-001AITL (UNK)106PR19.9141221-003ALCL ALK– (IA)2 + auto SCT011CR20.4173907-001ALCL ALK– (IVA)204PD22.87- Non-Evaluable Patients*914-002PTCL-NOS (IVB)102PD7.75-147-002^AITL (IIIB)221NE9.43-147-001Hepatosplenic TCL (IVA)103NE10.22- AITL = angioimmunoblastic T-cell lymphoma; ALCL = anaplastic large cell lymphoma; ALK = alkaline phosphatase; auto = autologous; CR = complete response; DoR = duration of response; ECOG = Eastern Cooperative Oncology Group; IRC = independent review committee; NE = not evaluable; NOS = not otherwise specified; OS = overall survival; PD = progressive disease; PR = partial response; PS = performance status; PTCL = peripheral T-cell lymphoma; SCT = stem cell transplantation; SD = stable disease; TCL = T-cell lymphoma *Lack of central pathologic confirmation resulted in exclusion from the evaluable population ^Autologous hematopoietic SCT Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Hsu:Spectrum Pharmaceuticals: Employment. Choi:Spectrum Pharmaceuticals: Employment. Allen:Spectrum Pharmaceuticals: Employment. Visser:Sanofi: Membership on an entity's Board of Directors or advisory committees. Horwitz:Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Infinity: Research Funding; Kiowa-Kirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Jannsen: Consultancy.

Description: Plerixafor (PXF) is a bicyclam molecule, which acts as a reversible inhibitor of SDF-1 binding to CXCR4. A single injection results in immediate release of CD34+ cells into the peripheral blood. Sofar, PXF has been used for stem cell mobilization only in a limited number of allogeneic donors (Devine et al. Blood.2008;112(4):990) The currently ongoing randomized phase 2 Hovon -107 study of the Dutch hemato-oncology group HOVON (www.hovon.nl) aims to compare the feasibility of intravenous (iv) versus subcutaneous (sc) PXF (Genzyme Europe BV) 320 µg/kg subcutaneously (sc) 9 hours before the planned stem cell collection or intravenously (iv) 4 hours before stem cell collection in healthy adult matched sibling donors. Concurrently, all stem cell products are evaluated for the total number of CD45+; CD34+ cells and other hematopoietic stem cell subsets, including more primitive progenitor cells (MPP/CMP: CD34+/CD45RA-/CD90- and HSC :CD34+/CD45RA-/CD90+). Furthermore, the frequency and absolute numbers of CD3+, CD4+; CD8+;CD19+; CD 3-CD16/CD56+ (NK) cells and several T cell subsets, including Foxp3+, Th1, Th2 and Th17 cells, are assessed. Thereby, the HOVON-107 study enabled us to retrospectively compare lymphocyte and CD34+ HSPC subsets in grafts harvested in healthy donors (n=27) following PXF versus a similar evaluation of those subsets in grafts (n=10) harvested following G-CSF(Neupogen) (2 x 500 ug/kg (sc) for 5 days). Data are presented with respect to the composition of stemcell harvests, obtained after a single gift of PXF (13 iv and 14 sc) followed by 15 liters leucopheresis. For comparison of the stem cell products between the two groups the Mann-Whitney U test was applied. Results: Both groups are comparable with respect to age/sex. Mobilization with PFX resulted in similar WBC numbers as compared to G-CSF mobilization. The total number of CD34+ cells was significantly lower after PFX mobilization: median 200 x106; (range 40-560) vs 400 x106 (360-840) after G-CSF (p=0.000). However after PFX mobilization, the CD34+ cells contained a higher frequency of immature HSC and a lower frequency of MPP as compared to G-CSF mobilized grafts. The lower number of CD34+ HSPC and the higher frequency of HSC within CD34+ HSPC resulted in similar numbers of immature HSC in PXF mobilized grafts (PFX 50;1-218 x106 for G-CSF 90;11-200 x106 p=0.411).Although it is known that Plerixafor can mobilize a higher number of T-cells no data are available about the frequencies of distinct T cell subsets in the grafts. PFX mobilization resulted in higher numbers of CD3+T cells and CD19+B cells. The number of CD3-CD16/56+ NK-cells did not differ between both groups. Within the CD3+ T cell population, the CD4/CD8 ratio did not differ between both groups of mobilized grafts. While absolute numbers of T-cells were significantly increased, the frequencies of IFN-gamma+ Th1 cells, IL-4+ Th2 cells; IL-17+ Th17 cells and Foxp3+ regulatory T cells were not significantly different between both groups, resulting in increased Treg and Th1 after PFX (see Table below) In conclusion, allogeneic stem cell grafts harvested in healthy donors following a single dose of Plerixafor contain higher numbers of primitive progenitor cells, and higher numbers of both effector and regulatory T-cells as compared to grafts harvested following G-CSF. The impact of altered subset numbers on clinical endpoints including graft versus host, engraftment, and overall outcome remain to be established. Abstract 2451. TableCD3 (x 109)CD3/4 (x 109)CD3/8 (x 109)CD19 (x 109)CD3-CD16/56+ (x 109)Treg (x 109)Th1 (x 109)Th2 (x 109)Th17 (x 109)PFXMedian Range22.7 9.8-56,7 13.2 6.3-30.56.6 2.8-22.15.7 0.6-18.11.40.5-4.30.7 0.3-2.52.8 0.3-9.30.2 0.0-1.80.20.0-6.8G-CSFMedian Range12.8 7.6-217.5 4.3-15.43.8 2.0-6.03.1 1.9-4.51.30.5-2.90.4 0.2-1.20.9 0.4-2.70.20.1-0.40.1 0.0-0.5P-value0.0010.0050.0030.0020.7320.0220.0160.2890.129 Disclosures De Greef: Sanofi The Netherlands: Membership on an entity's Board of Directors or advisory committees. Petersen:Sanofi the Netherlands: Membership on an entity's Board of Directors or advisory committees. Visser:Sanofi the Netherlands: Membership on an entity's Board of Directors or advisory committees. Niederwieser:Novartis, Gentium, Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Abstract 3078 Introduction Adding rituximab to induction therapy has improved overall survival in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) after high dose chemotherapy followed by autologous stem cell transplantation (AuSCT) to 50–60%. However, there is still room for improvement. Addition of 90Yttrium ibritumomab tiuxetan prior to the BEAM conditioning regimen seems feasible and results in promising data with respect to disease free and overall survival in high risk DLBCL patients even when treated with rituximab containing induction therapy. At the VU University Medical center, rituximab was added to (re-)induction therapy starting July 2001. From 2006 we started to add 90Yttrium ibritumomab tiuxetan (Zevalin®) to BEAM (Z-BEAM) in high risk DLBCL patients. In this retrospective analysis we compare outcome of Z-BEAM versus BEAM, both followed by AuSCT. Patients and methods All high risk DLBCL patients consolidated with high dose (radio-immuno) chemotherapy and AuSCT in CR or PR after rituximab-containing induction therapy were included. High-risk DLBCL was defined as either relapsed or refractory DLBCL or as histological transformation of indolent NHL. AuSCT was preceded by BEAM conditioning and 90Yttrium ibritumomab tiuxetan (0, 4 mCi/kg, max 32 mCi, starting 2006: Z-BEAM group) or by BEAM only (BEAM group). EFS and OS were estimated using the Kaplan-Meier method and compared using the log rank test. Results 43 patients received Z-BEAM and 42 patients received BEAM conditioning. Median age was 56 and 52 years respectively. No significant differences in disease characteristics were seen. Median follow up (range) was 15 months (6–54) and 39 months (0–112) respectively. Overall survival was significantly better in the Z-BEAM group compared with the BEAM group (p=0.02) with an estimated 2 year overall survival of 90% vs. 65%. (fig 1.) In the first 2 years of follow up 7 patients in the Z-BEAM group relapsed compared to 11 in the BEAM group, this did not reach significance (p=0.09). Median time to recovery of neutrophils and thrombocytes was not significantly different. Moreover, there was no significant difference in TRM (no TRM in the Z-BEAM group versus 2 patients in the BEAM group). Patients who relapsed, in both groups, were able to receive re-induction chemotherapy and, if indicated, allogeneic SCT without being compromised by decreased bone marrow reserve or non haematological toxicities. Conclusion Adding 90Yttrium ibritumomab tiuxetan to the BEAM conditioning regimen preceding AuSCT leads to a significant improvement in overall survival in high risk DLBCL patients, even if they have received rituximab during (re)induction. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3911 Poster Board III-847 Background Updated ICD-O and WHO classifications of Haematological Malignancies (HMs) take into account cell lineage, genotype, morphological aspects, immuno-histochemical and genetic characteristics, and clinical behaviour of the disease, dividing Lymphoid and Myeloid neoplasms in subcategories with possible similar aetiology or prognosis. Thus, good quality of morphological data on HMs is capital. The HAEMACARE project aimed to increase standardization and the availability of Cancer Registries (CRs) morphological data on HMs, in order to improve comparability of incidence, survival and prevalence across Europe. This study aims to present the HAEMACARE main results on survival of Myeloid Malignancies in Europe, by morphological subgroups, sex and geographical area. Materials and Methods We included 59,499 cases of Myeloid Malignancies occurred in the adult population (≥15 years old), both sexes, in 45 CRs from 16 European countries, over the period 1995-2002. CRs were grouped in 5 geographical areas: Northern Europe (Iceland, Norway, Sweden); Central Europe (Austria, France, Germany, The Netherlands, Switzerland); Southern Europe (Italy, Malta, Slovenia, Spain); Eastern Europe (Czech Republic, Poland); UK & Ireland. Morphological ICD-O-3 codes were grouped in 5 large categories: Acute Myeloid Leukaemia (AML); Myeloproliferative Neoplasms (MPN); Myelodysplastic Syndrome (MDS), Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) and NOS cases in which were grouped AL of ambiguous lineage (9805/3), Myeloid Leukemia (9860/3), Acute Leukemia (9801/3) and Leukemia (9800/3). Time trends of NOS cases incidence were computed in order to check the quality and completeness of data. Relative survival was calculated using the SEER free software. Results Among the 59,499 myeloid malignancies cases, they were 21,276 AML (38.4%), 20,049 MPN (35.5%), 8,480 MDS (14.2%) and 1,764 MDS/MPN (2.9%). 29,651 cases (52.6%) were diagnosed in male and 26,848 in female (47.4%). The geographical distribution of cases was not equivalent across Europe: 47.8% of the cases were from UK & Ireland, 14% from Central Europe, 2.4% from Eastern Europe, 17.4% from Northern Europe and 18.4% from Southern Europe. This figure was the same for all categories. They were 48.4% of AML and 49.6% of MPN up to 70 years-old instead of what this category represent 75.7% of MDS and 76.6% of MDS/MPN. Relative survival was evaluated by entity according to WHO classification, by area for main groups and morphology codes, by sex, by age and by period of time. Conclusion From Eurocare database, survival data are usually produced for large categories in which myeloid disease are not always identified. Within the HAEMACARE project we applied the WHO classification rules to identify cases and group them in a meaningful way. This allowed us to provided survival data from the largest series of myeloid malignancies from European countries. This study was presented on behalf the HAEMACARE working group; Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3092 Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal lymphoma that arises from intraepithelial lymphocytes. In Western countries EATL accounts for 5% of all gastrointestinal lymphomas and in 80–90% of all cases this lymphoma is associated with celiac disease (CD). Based on clinical presentation, EATL can be divided into two subtypes: primary and secondary EATL. Primary EATL develops without a preceding history of CD. The first presentation is often perforation or obstruction, which leads to diagnosis of both EATL and CD. Secondary EATL is diagnosed in patients with well-established CD or refractory CD. These patients deteriorate and eventually develop EATL. The current standard treatment for both types of EATL consists of surgery and chemotherapy, but overall survival (OS) is poor and new therapeutic strategies are urgently needed. For risk-based selection of patients for new therapies and clinical trials, prognostic models as the International Prognostic Index (IPI) are generally used. Since IPI is not predictive for EATL, we determined a prognostic model specifically for EATL, which can identify high-risk patients who need more aggressive therapy. Forty-one patients were diagnosed with EATL and retrospectively analyzed. Two- and 5-years OS were 18% and 10% respectively (range: 0 – 97 months). In multivariate analysis, 3 risk factors were predictive for survival: serum LDH 〉 normal (P 〈 0.001; RR 6.65; 95% CI 1.96 to 9.89), presence of B-symptoms (P 〈 0.001; RR 4.41; 95% CI 2.73 to 16.18) and subtype secondary EATL (P = 0.036; RR 2.33; 95% CI 1.06 to 5.13). A weighted point score was assigned to each of these 3 factors and a prognostic model was constructed. Four risk groups were identified (P 〈 0.0001). Group I showed most favorable outcome: 2- and 5-years OS were 55% and 30% respectively. Although survival rates in groups II, III and IV were significantly different, in none of these groups 2-years survival was achieved. Therefore, the model was simplified to a low risk and a high risk group (P 〈 0.0001, Figure 1). The low risk group represented patients with no risk factors, i.e. primary EATL with no B-symptoms and normal LDH. In the high risk group, patients had 1 or more of the risk factors elevated serum LDH, B-symptoms or subtype secondary EATL. The new prognostic model showed superior predictive capacity as compared to IPI. In conclusion, our new prognostic model clearly identifies a high and a low risk group. Patients with one or more of the risk factors serum LDH 〉 normal, B-symptoms or subtype secondary EATL are at high risk, and therefore new therapies for this group are urgently needed. Figure 1: Survival in EATL. Low risk group = no risk factors. High risk group = presence of 1 or more of the following risk factors: serum LDH 〉 normal, B-symptoms or subtype secondary EATL. Figure 1:. Survival in EATL. Low risk group = no risk factors. High risk group = presence of 1 or more of the following risk factors: serum LDH 〉 normal, B-symptoms or subtype secondary EATL. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3538 Poster Board III-475 Introduction Recently, Yttrium-90 labeled anti-CD20 (90Y-ibritumomab tiuxetan, Zevalin®) has been introduced as a new therapeutic option in relapsed malignant B cell lymphoma. The results of adding 90Y-ibritumomab tiuxetan to high-dose BEAM with autologous stem-cell transplantation(auSCT) are promising. However, the toxic impact of radioimmunotherapy to the haematopoietic microenvironment, and its effects on stem cell homing and engraftment are largely unknown. Stromal Derived Factor-1 (SDF-1α) is a key regulator of stem cell engraftment. SDF-1α has been found to co-localize with hyaluronan (HA) on human bone marrow sinusoidal endothelium and endosteum, supporting transendothelial migration of human progenitor cells and their final anchorage within specific niches of the BM. External irradiation influences levels of SDF-1α and HA. Therefore, we studied the effect of 90Y-ibritumomab tiuxetan on in vivo SDF-1α and HA levels. Patients and methods Patients with relapsed B cell NHL, treated with Zevalin-BEAM and autologous stem cell transplantation were included after obtaining their informed consent. At 3 different time points, bone marrow aspirates and peripheral blood samples of 9 consecutive patients were analysed: day -22 (before Z-BEAM), day -8 (7 days after Zevalin (0.4 mCi/kg, max. 32 mCi (n=8) or 64 mCi (n=1) (before BEAM)) and day 0 (after BEAM and before auSCT). SDF-1α and HA protein levels were determined in bone marrow and peripheral blood plasma using ELISA. Also, SDF-1α mRNA expression was quantified by real time PCR. Quality of bone marrow stroma was determined by investigating CFU-F after 1 and 2 weeks and the percentage of confluency in cultures after 1, 2 and 3 weeks. Also, in 5 patients dosimetry of Zevalin was performed. Results In 5 patients dosimetry of Zevalin was performed, by using Zirconium-89 labelled Zevalin as surrogate for PET scanning at day 0, +3 and +6 after injection. Patients received 3.4.10 * 6/kg(mean, range 1,9-8,3) CD34+ cells, and all but one showed engraftment. ANC〉0.5 10*9/l was reached at 12,8 days (range 11-15, n=9), platelets〉50 10*9/l at 18 days (range 11-38, n=8) ), being comparable with retrospective data on BEAM transplantation. In the one patient not recovering, a second transplant did not result in platelet recovery. Zevalin alone did not affect bone marrow MNC count (23,3 vs 17,4 10*6/ml, p=0.40), CFU-F capacity (colonies 〉 50 cells: 2,4 vs 8,3, p=0.35) and stromal confluency (41,9 vs 62,1%, p=0.31). In addition, the levels of SDF-1α (4584 vs 5305 pg/ml, p=0.11) and HA (227 vs 247 mcg/ml, p=0.86) were not influenced. Following BEAM, production of SDF-1α (4584 vs 6166 pg/ml, p=0.01) and HA levels (227 vs 356 mcg/ml, p=0.03), significantly increased. A corresponding increase in SDF-1α mRNA copies was observed (0.16 vs 17.2 cps % GAPDH, p=0.02), indicating that induction of SDF-1α gene expression was involved. There was a trend in decreased quality of bone marrow stroma, as determined by MNC count, CFU-F capacity and confluency. Whereas Fibroblast Growth Factor increased the confluence of stromal culture before and after Zevalin, it didn't overcome the harmful effect of the BEAM chemotherapy. Conclusion 90Y-ibritumomab tiuxetan alone did not effect the bone marrow environment as measured by SDF-1α and HA. As expected, significant changes were found after high dose chemotherapy. Engraftment and repopulation after Z-BEAM and auSCT was similar to standard BEAM followed by auSCT. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Despite current ABO/RhD matching and strict antibody screening policies, still every year transfused patients experience life-threatening hemolytic reactions due to boostering of previously immunization to red blood cell (RBC) antigens. Prevention can be optimized by administering RBC units at least matched on the most immunogenic antigens to high risk patients. In this respect, we set out to assess the immunogenicity of RBC antigens. Methods We performed an incident new user cohort study among previously non-transfused, non-alloimmunized patients who received RBC transfusions between 2006 and 2013 in six Dutch hospitals. Patients developing alloantibodies were followed up until their first RBC alloantibody identification and all non-alloimmunized patients until the last negative screen. To compute dose-specific alloimmunization risks and thereby evaluate the immunogenicity of various RBC antigens, only antigen-positive units transfused to all patients lacking this antigen should be considered. Per definition, alloimmunized patients met this condition. RBC phenotypes of non-alloimmunized patients were however unknown since phenotyping is routinely limited to ABO and RhD antigens. For each RBC antigen we therefore randomly extracted a subgroup of non-immunized patients whose size was based on the known proportion of antigen-negative individuals in the Caucasian population. The given antigen-positive units transfused to these 'antigen-negative cohorts' functioned to estimate the number of antigen-positive units transfused to the true antigen-negative, non-alloimmunized individuals in the source population. Multiple imputation was used to complete the dataset regarding some missing donor antigen phenotypes. We then calculated cumulative immunization incidences for each RBC antigen according to the total number of mismatched (i.e. antigen-positive) units using Kaplan-Meier survival tables. Women under 45 years of age were analyzed separately as in the Netherlands they receive c, E and K matched blood. Results In 474 of 21,512 patients (2.0%), 537 first formed antibodies were detected, the majority against E and K antigens. Cumulative immunization incidences after 40 RBC units transfused increased to 7.6% (CI 4.8-11.2). Due to lower frequencies of Rh and K immunizations, women under 45 years, who received blood matched on these antigens, demonstrated significantly lower cumulative immunization incidences compared to the remainder of the study population (4.4% (CI 0.2-20.5) versus 7.6% (CI 4.8-11.2) after 40 units received, log-rank p 0.013). Anti-c was only formed by RhD-positive patients while the lack of RhD expression led to significantly less E immunizations (cumulative immunization incidences 1.7% (CI 0.0-32.0) and 3.7% (CI 1.4-7.9) after 40 RBC units received for RhD-negative and RhD-positive patients respectively (log-rank p

Description: Introduction Autologous stem cell transplantation (AuSCT) is widely used in patients with histologic transformation of indolent lymphoma. Although probably superior to standard chemotherapy, there is still room for improvement. We are currently studying the effect of the addition of 90Yttrium ibritumomab tiuxetan (Zevalin) to BEAM conditioning followed by an AuSCT on survival in a prospective phase 2 trial. It is known that, after rituximab-BEAM-AuSCT, recovery of T cells occurs after 4 months and of B cells after 9 months, with normal levels only being reached after 1 and 2 years, respectively. (1,2) It is however unclear if, in patients uniformly pre-treated with rituximab-chemotherapy, followed by BEAM and AuSCT, the addition of Zevalin further hampers immune reconstitution. Materials and methods Patients (n=14) with histologically proven transformed lymphoma were included in this prospective phase 2 trial when conditioning for AuSCT was started. AuSCT was planned when CR or PR was reached after (re)induction containing a minimum of 6 courses of rituximab (375 mg/m2) and chemotherapy. Patients subsequently received pre-doses of rituximab on day -15 and -8 (250 mg/m2), Zevalin on day -8 (0.4 mCi/kg) and BEAM conditioning on day -7 to -1, followed by AuSCT at day 0. Blood samples were taken before the first predose of rituximab (day -15,t=0) and 3-6, 12-18 and 24-30 months after AuSCT. Absolute neutrophils were counted and samples were analyzed for NK-, B- and T-cell subsets using multicolor flowcytometry. T cells were defined using CD3 combined with either CD4 or CD8. NK cells were defined as CD45+, CD3-, CD56+ and/or CD16+, B cells as CD45+, CD3-, CD19+, memory B cells CD19+,CD27+. Recovery was defined as: Neutrophils 〉 0.5 x 109/l, CD19+ B cells 〉0,07 x 109/l (CD27+ B cells 〉0,03 x 109/l) CD4〉0,4 x 109/l,CD8〉0,13 x 109/l, NK cell 〉 0,08 x 109/l. (1,2) All infections after neutrophil recovery following AuSCT were registered. IgG levels were measured at baseline and after 2 years. Results A median of 3 (range 1-4) measurements were obtained depending on length of follow up. The median follow up was 26 months (range 3-30 months). Median time to neutrophil recovery was 22 days after AuSCT (range 17-29 days). As expected, patients were already severely B-cell depleted at start of consolidation (t=0, figure 1).B cells started to appear after nine months and reached (low) normal values after 12-18 months. T cell and NK cell recovery started after 3 months and took one year to normalize. (figure 1) All patients had IgG levels 〉5 g/l after AuSCT, without support. Only three infectious episodes were reported in 14 patients. In one patient an episode of herpes simplex virus infection with diarrhea was reported two months after AuSCT. In another patient a pneumonia was diagnosed two months after recovery from AuSCT (cultures stayed negative). Both had enough neutrophils but B cells and CD4 cells were not yet recovered. Both patients recovered completely after antiviral and empirical antibiotic and antimycotic therapy, respectively. One patient developed a herpes zoster virus infection at 2 years after AuSCT, recovering completely after antiviral therapy. Conclusion Compared to figures reported in literature (1,2), the addition of Zevalin to consolidation with BEAM and AuSCT after (re)induction with R-chemotherapy does not seem to lead to an increase of infectious complications or delayed immune-reconstitution as analyzed by T cell, B cell and NK cell recovery. References Kasamon YL, Jones RJ, Brodsky RA, Fuchs EJ, Matsui W, Luznik L, Powell D, Blackford AL, Goodrich A, Gocke CD, Abrams RA, Amvinder RF, Flinn IW. Immunologic recovery following autologous stem-cell transplantation with pre-and posttransplantation rituximab for low-grade or mantle cell lymphoma. Ann Oncol 2009: 1-8 van der Velden AMT, Claessen AME, van Velzen-Blad H, de Groot MR, Kramer MHH, Biesma DH, Rijkers GT. Vaccination responses and lymphocyte subsets after autologous stem cell transplantation.Vaccine 2007:8512-8517 Figure 1 Figure 1. Disclosures Wondergem: spectrum pharmaceuticals: Research Funding. Visser:spectrum pharmaceuticals: Research Funding.

Description: Background Chronic myelomonocytic leukemia (CMML) is a rare hematological malignancy with features of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms. Most data on CMML arrive from the few available clinical and epidemiological studies where CMML was often combined with MDS. So far, phase 3 clinical trials and large population-based studies specifically addressing CMML are lacking. We conducted a large nationwide population-based study to assess trends in incidence, primary treatment and survival among CMML patients in the Netherlands from 1989-2012. Methods We selected all patients diagnosed with CMML in 1989-2012 (N = 1,359; median age 75 years; age range 22-95 years; 63% males) from the nationwide population-based Netherlands Cancer Registry (NCR). Patients with juvenile myelomonocytic leukemia were excluded. Despite changes in classification, separate morphology codes for CMML were available in all editions of the International Classification of Diseases for Oncology (ICD-O; 9893, 9868 and 9945 in the first, second and third edition, respectively) and could therefore be identified in the NCR throughout the whole study period. The ICD-O does not have separate codes for CMML-1 or 2. Data on primary treatment, that is, no therapy or only supportive care (NT/SC), chemotherapy (CT) and CT followed by a stem cell transplantation (CT + SCT), were retrieved from the NCR. Patients were categorized into three calendar periods (1989-2000, 2001-2006 and 2007-2012) and four age groups (18-59, 60-69, 70-79 and ≥80 years), unless otherwise stated. Incidence rates were age-standardized to the European standard population and calculated per 100,000 person-years. Relative survival rates (RSRs) were computed as a measure of disease-specific survival. Results The overall age-standardized incidence rate (ASR) of CMML increased from 0.23 per 100,000 in 1989-2000, 0.31 in 2001-2006 to 0.38 in 2007-2012. The annual ASR became stable at around 0.4 per 100,000 since 2008 (Fig 1A). The proportion of patients diagnosed in individuals aged ≥70 years was 70%. The incidence of CMML was higher in men than in women, which was ascribed to the higher incidence among the 70-year-old men compared with the equivalent female group (Fig 1B). The primary treatment of CMML patients remained unchanged during the entire study period. In the overall series, 975 (72%), 365 (27%) and 19 (1%) CMML patients received NT/SC, CT and CT + SCT, respectively. The use of CT + SCT was mainly restricted to patients 18-59 (n = 13) and 60-69 (n = 6) years of age. Survival of CMML patients was poor and did not improve over time as the 5-year RSRs (with 95% confidence interval) were 16% (12%-20%), 20% (15%-25%) and 20% (15%-25%) in the three calendar periods, respectively. As shown in Figure 2, the overall 5-year RSRs for patients in the four age groups were 21% (13%-29%), 23% (18%-29%), 20% (16%-24%) and 12% (7%-18%), respectively. With the limitation of small numbers (n = 19), the overall 5- and 10-year RSRs were 29% (10%-52%) and 30% (10%-53%) for patients undergoing CT + SCT as primary treatment. In other words, the RSR reached a plateau after 5 years since diagnosis. In the most recent period, the 5-year RSR was 73% (25%-95%) for patients undergoing CT + SCT (n = 7). Conclusions In this first large population-based study including almost 1400 CMML patients, we found that the incidence of CMML increased over time until the year 2007. This rise is probably explained by improved case ascertainment and augmented disease awareness, rather than by changes in etiologic factors. Primary treatment remained conservative throughout the study period as treatment options for CMML, which primarily affects the elderly, are very limited. As a consequence, relative survival remained poor and essentially unchanged in both younger and older patients over the past two decades. Therefore, CMML-specific prognostic models should be applied in the diagnostic work-up to evaluate prognosis and plan risk-adapted treatment, and assist in designing clinical trials that specifically assess therapeutic options in CMML patients in order to improve their survival. Disclosures No relevant conflicts of interest to declare.

Description: Background: Patients with MYC rearrangement positive large B cell lymphoma other than Burkitt lymphoma (MYC+ LBCL), have a dismal prognosis following standard first line therapy with R-CHOP. Retrospective studies report complete remission rates 〈 50% and 2-year overall survival (OS) of approximately 35%. Lenalidomide is an immunomodulatory drug and is able to down-regulate MYC and its target genes and proteins in B cells that harbor a MYC rearrangement. We report data of a prospective phase II study evaluating the efficacy of lenalidomide in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients. Methods: A national screening program for MYC rearrangement by fluorescence in situ hybridization (FISH) was performed in newly diagnosed LBCL patients. Patients with a proven MYC rearrangement, ≥ 18 year, Ann Arbor stage II-IV, were offered participation in a single arm phase II study. Treatment consisted of 6 cycles R-CHOP21 plus lenalidomide 15 mg on day 1-14, followed by two additional rituximab administrations. Use of G-CSF was mandatory. All patients received intrathecal methotrexate prophylaxis. 18F-FDG PET-CT (PET-CT) scans were performed at baseline, midterm (after 3 cycles) and end-of-treatment (EOT). Diagnostic lymphoma samples were centrally reviewed including immunohistochemical (IHC) work-up and complementary BCL2 and BCL6 FISH analysis. Cell of origin classification was determined by IHC (Hans) and by gene expression profiling (Lymph2Cx). The primary endpoint was complete metabolic response rate (CMR) on EOT PET-CT scan, according to the Deauville criteria and assessed by 2 independent nuclear medicine physicians performing central review. In case of discordance, a third adjudicator reviewed. Confirmation of bone marrow (BM) negativity at EOT for patients with positive BM at diagnosis was not required for CMR. Secondary endpoints included disease free survival (DFS), progression free survival (PFS), OS and predictive value of midterm PET-CT for EOT PET-CT scan. Data cut-off was July 4th 2018. Results: From April 2015 to February 2018, 85 patients were included at 20 hospitals. Planned interim analysis (after 26 consecutive patients completed treatment) revealed no safety concerns. At data cut-off, central data management, pathology and imaging review processes were completed for the first 60 patients. The remaining patients (60 to 85) are still on treatment or have recently finished treatment. Among the first 60 patients, 2 were declared ineligible, leaving 58 patients for this analysis (demographics and disease characteristics in table 1). Central pathology review confirmed diagnosis of MYC+ LBCL in all patients. Additional FISH analysis revealed that 41/58 patients (71%) had MYC and BCL2 and/or BCL6 rearrangements (double hit or triple hit), 11/58 (19%) had a single MYC rearrangement, 6/58 (10%) had a MYC rearrangement but no information on BCL2 and BCL6. At EOT PET-CT scan (primary endpoint), 36/58 patients (62%) were in CMR (95% confidence interval (CI) 50%-71%). 2/58 patients (3%) reached a partial metabolic response (PMR), and 20/58 patients (34%) had progressive disease (PD). At midterm PET-CT, 39/58 patients (67%) were in CMR; of these 29 were still in CMR and 10 showed PD at EOT PET-CT. 18/58 patients (31%) were in PMR at midterm; 7 of them converted to CMR, 2 remained in PMR, 9 showed PD at EOT. One patient went off protocol after two cycles due to progression. With a median follow-up of 17.2 months, 1-year estimates for OS were 79% (CI 66%-88%), for DFS 74% (CI 59%-85%), and for PFS 60% (CI 47%-72%). Grade 3 and 4 adverse events (AE) were seen in 26 (43%) respectively 9 patients (15%). Most common grade 3-4 AEs were gastrointestinal disorders, infections, and neutropenia. 55 serious AEs were reported in 27 patients (all hospitalization). 1 patient went off protocol due to grade 3 diarrhea. Univariate regression analyses revealed no significant prognostic factors for achieving CMR or prolonged survival yet. Conclusion: These data represent the first prospective trial worldwide for newly diagnosed MYC rearrangement positive LBCL patients. Treatment with R2CHOP demonstrates acceptable toxicity and promising efficacy with 62% CMR on centrally reviewed PET-CT scan and a 1-year OS rate of 79%. In December 2018, all 85 registered patients will have finished treatment and complete analysis of the primary endpoint and additional biological studies will be available. Disclosures Chamuleau: Gilead: Research Funding; celgene: Research Funding; Genmab: Research Funding; BMS: Research Funding. Mous:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; JANSSEN CILAG: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; sandoz: Membership on an entity's Board of Directors or advisory committees. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Kersten:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.