ALBERT

Description: Abstract 4860 Backgroud: Chronic lymphocytic leukemia (CLL) is one of the most frequent chronic lymphoproliferative disorders in Europe. It is characterized by persistent monoclonal lymphocitosis with localized or generalized lymphadenopathy. Despite the initial clinical presentation, it has a heterogeneous natural history, with the majority of patients living 10–12 years, but with some patients dying rapidly, within 2–3 years of diagnosis. Beside clinical prognostic factors, novel cytogenetic markers are recognized to be useful in predicting disease free and overall survival in CLL. AIMS: In a retrospective study throughout 10 years (1999-2009), we analyzed the clinical and biological presentation and compared the evolution and survival of patients with B-CLL using different cytogenetic markers. METHODS: We identified 112 cases (63 males and 49 females) of B-CLL with cytogenetic study by fluorescence in situ hybridization (FISH). RESULTS: Amongst 112 patients, the male to female (M/F) ratio was 1.3:1 and the median age was 70 (43-96) years. At diagnosis, the median lymphocyte count was 15.5 G/L (5.4-173). Fifty five patients (49%) had lymphadenopathies and seventeen (15%) had splenomegaly and/or hepatomegaly at presentation. By the revised Rai staging system seventy (63%) patients were included in low risk group, thirty (27%) in intermediate risk group and twelve (10%) in high risk group. The expression of ZAP-70 and CD38 by flow citometry was performed in 75 patients and revealed 13 (17%) patients CD38+ and 12 (16%) ZAP70+. The study of chromosomal aberrations with FISH showed thirty six patients (32%) with no abnormality, thirty six (32%) with isolated 13q deletion, fifteen (14%) with 12 trisomy, twelve (11%) with 11q deletion and thirteen (11%) with 17p deletion. Forty (36%) patients showed progressive disease in a median time of sixteen months (0-120), thirteen with 13qdel, seven with 17pdel and five with 12 trisomy. After treatment two patients showed progressive disease, six maintain a stable disease and thirty two obtain a remission, nine in complete remission. The Overall Survival (OS) at ten years was 70%. By the revised Rai staging system the OS at ten years was 80% for low risk, 70% for intermediate risk and all the high risk patients died during follow up. The OS at five years for the del13q-, 12 trisomy, del11q- and del17p- was 90%, 88%, 58% and 60%, respectively. SUMMARY: Chronic lymphocytic leukemia is currently considered a chronic disorder with a favourable outcome, but with a variable evolution to progressive disease. This retrospective study allowed the characterization of patient with CLL in our department and the acknowledgement that our results are quite similar to the published data. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1932 High dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). At present, G-CSF-mobilized peripheral blood stem cells (PBSCs) are the preferred stem cell source for autologous HSCT. Fludarabine and lenalidomide are essential drugs in the front line treatment of NHL and MM respectively. Data suggests that fludarabine and lenalidomide therapy may have a deleterious effect on stem cell mobilization. Prior to the drug approval in Europe, a plerixafor compassionate use program (CUP) was available from July 2008 to August 2010 to provide access to the drug for patients with MM or lymphoma who had previously failed a mobilization attempt, and who were not eligible for another specific plerixafor trial. In the European CUP, 48 patients (median age 57 years; range, 36–69), previously treated with fludarabine (median 5 cycles; range, 1–7 cycles) were given plerixafor plus G-CSF for remobilization following a primary mobilisation attempt. All 48 patients had a diagnosis of NHL. The overall median number of CD34+ cells collected was 2.3×106 /Kg (range, 0.3–13.4). The minimum required number of CD34+ cells (≥2.0×106 per kg) was collected from 58% of patients, while only 3 patients (6%) collected ≥5.0×106 CD34+ cells. The collection target of 2.0×106/Kg was reached in a median of 2 apheresis sessions (range, 1–3). Thirty-five patients (median age 57 years; range, 34–66), previously treated with lenalidomide (median 5 cycles; range, 1–10 cycles) were given plerixafor plus G-CSF for remobilization. All patients the 35 patients had MM. The overall median number of CD34+ cells collected was 3.4×106/Kg (range, 1.1–14.8). The minimum required number of CD34+ cells (≥2.0×106 per kg) was collected from 69% of patients, including 12 patients (34%) who were able to collect ≥5.0×106 cells/Kg. In the Len group, 7 patients (20%) had received a prior autologous HSCT before salvage mobilization with plerixafor. Both targets were reached with a median of 2 apheresis sessions (range, 1–4). In conclusion, salvage mobilization with plerixafor plus G-CSF is successful in the majority of patients with MM previously treated with lenalidomide. In fludarabine-exposed patients, only 58% of patients will achieve successful salvage mobilization with plerixafor plus G-CSF, suggesting the need for large prospective studies evaluating the efficacy of plerixafor for frontline mobilization in this subgroup of patients.Table 1.Study population characteristicsCharacteristic (%)Fludarabine (N=48)Lenalidomide (N=35)Patient age, median (range)57 (36–69)57 (34–66)Patient gender    Male26 (54)18 (51)    Female22 (46)17 (42)Fludarabine or Lenalidomide cycles, median (range)5 (1–7)5 (1–10)Diagnosis and disease statusIndolent NHL48 (100)0 (0)Multiple myeloma0 (0)35 (100)Previous chemotherapy: number of lines, median (range)3 (1–6)4 (1–9)Previous autograft    Yes07 (20)    No43 (90)20 (57)    Data missing5 (10)8 (23)Radiotherapy    Yes5 (10)3 (9)    No36 (75)24 (68)    Data missing7 (15)8 (23)Mobilization strategy with plerixafor    Steady-state GCSF mobilization38 (79)27 (77)    Chemotherapy+GCSF mobilization10 (21)8 (23)No. of patients collected44 (92)34 (97)CD34+ cells collected per Kg, median (range)2.3 (0.3–13.4)3.4 (1.1–14.8)No. of patients who reached ≥ 2.106 CD34+28 (58)24 (69)No. of apheresis days to reach ≥ 2.106 CD34+2 (1–3)2 (1–4)No. of patients who reached ≥ 5.106 CD34+3 (6)12 (34)No. of apheresis days to reach ≥ 5.106 CD34+2 (1–3)2 (1–3)NHL, non-Hodgkin lymphoma Disclosures: Mohty: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 4870 Background: Dendritic cells (DC) are a heterogeneous population of lineage-negative antigen-presenting cells derived from CD34+ hematopoietic progenitors, present in tissue, blood and bone marrow (BM), where plasmacytoid DC (pDC) are a normal finding, representing 0.2 ± 0.1% of cell populations (Matarraz et al, 2010). DC neoplasms include solid tumors (such as DC sarcomas) and an entity classified by the World Health Organization (2008) as an acute myeloid leukemia (AML)-related precursor neoplasm: blastic pDC neoplasm/leukemia, an aggressive disease with poor prognosis, with no clinical trials to orient consensus regarding the most effective treatment; it is usually chemo-resistant, although some cases respond to AML-like regimens and allogeneic hematopoietic stem cell transplant. It is not clear if the presence of an increased DC population in non-DC AML confers pDC neoplasm-like biological characteristics to the former. Aims: This study aims to evaluate whether an increase in the size of DC populations in newly-diagnosed non-DC AML affects the latter's biological behavior, as represented by the overall survival (OS) of patients with the disease. Methods: We reviewed all AML diagnosed in our Hospital between January 1st 2008 and December 31st 2010, identifying 146 patients. We excluded 9 patients who had no flow cytometry immunophenotyping (IP) performed, and 7 whose first IP was performed after treatment was instituted. In that time frame, we also diagnosed 4 pDC neoplasms. Of the 130 patients included, 91 had their presenting IP performed on BM aspirate, while the remaining 39 were phenotyped on blood samples. The size of the DC populations and blastic DC maturation were determined on these samples. Patients were classified into 2 groups according to the size of the DC component; one (the Non-DC Group) had a DC component of up to 0.3% (in practice, the highest value in this group was 0.2%); the other (DC Group) had a percentage over this limit (the lowest value being 1.0%). OS data was determined for both groups; special consideration was given to age strata, separating patients under 65 years of age (Under-65) from those 65 or older (Over-65) and etiology (distinguishing de novo AML from AML secondary to therapy, myelodysplasia or myeloproliferative diseases). The percentage of DC identified by IP did not influence nor alter the type of treatment instituted. Results: We found that the presence of a DC component above the normal BM interval (as determined by Matarraz et al) was associated with a significantly decreased OS, with patients with DC components over 0.3% presenting with a median OS of 2.4 months (mean: 6.4 ± 1.6) and those with a component under 0.3% with a median OS of 8.6 months (mean: 17.0 ± 1.9) (p = 0.033). In our series, patients Over-65 had a median OS of 2.9 months (mean = 6.9 ± 1.0) and those Under-65 a median of 21.3 months (mean = 22.5 ± 2.5), p 〈 0.001. The differences in OS according to DC component were attenuated in patients Over-65 (median = 1.8 vs. 3.9 months, p = NS), whereas in patients Under-65 the median survival was 2.7 months (mean: 8.7 ± 2.9) for the DC Group and 24.4 months (mean: 24.3 ± 2.7) for the non-DC Group (p = 0.035). The differences in OS were also significant for de novo AML (median = 2.4 vs. 16.0 months, mean = 4.7 ± 1.9 vs. 20.5 ± 2.6, p = 0.017), but not statistically relevant for secondary AML (median = 4.4 vs. 5.5 months, mean = 8.4 vs. 10.8, p = NS). Discussion: In this study, we found that an increase in the size of the DC component as determined by IP at diagnosis on newly-diagnosed AML had a negative impact on prognosis, with a significant decrease in median and mean OS in patients with a percentage of DC over the upper limit of the normal interval. We also determined that the decreased survival was primarily attributed to the better-prognosis groups (patients under 65 and with de novo AML), whereas the effect of the worsened prognosis was attenuated in those patients with a bad prognosis at the outset (patients over 65 and with secondary AML). If data from DC neoplasms could be extrapolated, we could suggest that AML with increased DC components are less chemo-sensitive, which would explain the OS differences found in the Under-65 group, as well as the no-difference found in the Over-65 Group, which is frequently undertreated due to comorbidities. Conclusion: Our study suggests that the size of the DC component at diagnosis as determined by IP is a new prognostic marker predictive of decreased survival. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Patients with multiple myeloma (MM) and severe renal impairment (SRI) have shorter survival and are often excluded from clinical trials. In these patients the use of Lenalidomide (Len) is based in pharmacokinetic models and because of the risk of increased toxicity, Len dose must be adjusted to renal function. Purpose To evaluate the outcomes of relapsed MM patients (RMM) with SRI (baseline creatinine clearance (CrCl)

Description: Background Melphalan, prednisone and thalidomide (MPT) is a standard therapy for NDMM recognized worldwide based on a statistically significant advantage in overall survival (OS) and progression-free survival (PFS) vs. MP (Facon Lancet 2007; Fayers Blood 2011; NCCN 2013). The combination of lenalidomide and low-dose dexamethasone (Rd) increased OS with fewer adverse events (AEs) than treatment with lenalidomide and high-dose dexamethasone in NDMM pts (ECOG E4A03) (Rajkumar Lancet Oncol 2010). The FIRST trial is a multicenter, open-label, phase III trial comparing the efficacy and safety of Rd versus MPT in transplant-ineligible NDMM pts. Methods NDMM pts either ≥ 65 years of age, or not candidates for SCT were randomized to one of three arms: Rd in 28-day cycles until disease progression (Arm A), Rd in 28-day cycles for 72 weeks (18 cycles, Arm B), or MPT in 42-day cycles for 72 weeks (12 cycles, Arm C). Assessments by International Myeloma Working Group criteria were done after each cycle. Pts with renal impairment were enrolled; however, pts on dialysis were excluded. Starting doses of lenalidomide and dexamethasone were adjusted based on renal function and age, respectively. Melphalan starting dose was adjusted based on age, absolute neutrophil count, platelet count, and renal function; and thalidomide was adjusted for age. Dose adjustments were permitted for AEs. All pts were required to receive anti-thrombotic prophylaxis. Stratification factors included age, International Stage System, and country. The primary endpoint was a comparison of PFS in Arm A vs. Arm C. Secondary endpoints included OS, overall response rate (ORR), time to response, duration of response (DOR), safety, and quality of life (QOL). A preplanned additional analysis included time from randomization to second progression event or death (PFS2). The final preplanned analysis of independently adjudicated progressive disease (PD) events in Arm A vs. Arm C conducted after 960 events of death or PD, and an interim of OS in 64% of survival events (574/896 events) are presented in this abstract. Comparisons of PFS and all secondary endpoints, including OS for all three arms, will be presented at the meeting. Results A total of 1,623 pts were randomized 1:1:1 in three arms. As of today, 121 pts continue to receive lenalidomide on study (Arm A). The median age was 73 (40.0–92.0) years; 35% pts were aged ≥ 75 years; and 41% of pts had ISS stage 3 disease. After a median follow-up of 37 months, the trial met its primary endpoint (PFS), demonstrating a 28% reduction in risk of progression or death (HR=0.72; p= 0.00006). The preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of Arm A vs. Arm C (HR=0.78, p=0.01685); however, the pre-specified boundary (p

Description: Abstract 4620 Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by dyshematopoiesis and high susceptibility to acute myeloid leukemia. Deregulated epigenetic mechanisms are likely involved in the pathogenesis of MDS. Gene silencing through aberrant CpG island methylation is the most extensively analyzed epigenetic event in human tumorigenesis and has huge diagnostic and prognostic potential. Aberrant methylation of gene promoter region is responsible for inappropriate gene silencing, and it has been associated to initiation and progression of cancer. However, in the MDS disease process, more and more gene dysfunction has been related with the pathogenesis. FLT3 and c-KIT are important members of the receptor tyrosine kinase family that are overexpress or dysexpress in many malignant hematologic diseases. However, little is known about the distribution and the role of these proteins in MDS. The study is to investigate the role of receptor tyrosine kinase FLT3 and c-KIT expression in patients with myelodysplastic syndromes (MDS) and their clinical implication. We have at moment examined c-kit protein (CD117) expression by flow cytometry, in CD34 bone marrow cells collected at diagnosis of 12 patients with de novo MDS and 5 non-neoplastic patients (controls). FLT3 mutations, in particular Internal Tandem Duplications (ITD) and the D835 mutation were analysed by PCR-RFLP. The median age was 72 years (22–89), gender M/F=5/7, WHO subtypes: RCMD (n=6), RA (n=3), RARS (n=1), AREB-2 (n=1), CMML (n=1) and IPSS: low (n=6), intermediate-1 (n=5) and intermediate-2 (n=1). None of the patients evolved to acute leukemia, with a median follow up of 24 months (7–74). Our preliminary results show an increase in c-KIT expression in CD34 positive cells in MDS patients as compared with controls. However, the percentage of c-KIT protein expressing cells was also higher than in the controls in particular in CD34 negative cells. There was a correlation of the c-kIT protein expression with the CD34 antigen of the cells. Expression is correlated with the WHO MDS classification and with IPSS, being highest in RAEB-2 and INT2 MDS prognostic group. These results suggest that the elevated c-KIT expression could maintain the affected clone in MDS. Besides that we didn't find any FLT3 mutations in our population However further data and refinement of data analysis are needed to confirm our results and to predict clinical outcomes. The preliminary results suggest that c-KIT expression could be helpful to the pathogenesis and prognosis prediction of MDS patients. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2993 High-dose chemotherapy followed by autologous stem cell transplantation is an approved therapeutic intervention in relapsed Hodgkin-lymphoma (HL) and Non-Hodgkin lymphoma (NHL). In multiple myeloma (MM) it remains standard of care in first remission. Unfortunately, a significant portion of patients fail to mobilize and collect a sufficient amount of hematopoietic stem cells, being considered as “poor-mobilizers”. The effectiveness of the hematopoietic stem cell mobilizing agent plerixafor was evaluated in nationwide compassionate use programs in 13 European countries and reported to the European Consortium of Stem Cell Mobilization (ECOSM). Here we describe the mobilization success of 580 proven poor-mobilizers (304 male, 276 female) with NHL, HL and MM in Europe between May 2008 and August 2009. Furthermore, we analyzed the mobilization of stem cells in major NHL subgroups. All patients received plerixafor plus granulocyte colony-stimulating factor in standard doses with or without chemotherapy. Two-hundred seventy patients with NHL (138 male, 132 female) with a median age of 56 years (range 12 – 75 years) and a median of two prior chemotherapy regimens (range 0 – 10) were enrolled. Median cell yield was 2.56 × 10 ^6 CD34+ cells/kg BW (range 0 – 17.37). The general accepted minimum of 2.0 × 10 ^6 CD34+ cells / kg bodyweight (BW) for transplantation was reached by 175 patients (64.8%) in a median of two apheresis sessions (range 1 – 4). Thirty-four patients (12.6%) yielded more than 5.0 × 10 ^6 CD34+ cells/kg BW. There were no significant differences in in stem cell harvests regarding number of prior mobilization attempts or number of prior chemotherapeutic regimens, as well as in comparing patients with diffuse large B cell lymphoma (n=28), follicular lymphoma (n=15), and mantle cell lymphoma (n=24), respectively. Fifty-four HL patients (24 male, 30 female) with a median age of 36 years (range 19 – 76) and a median of three prior lines of therapy (range 1 – 5) were enrolled. Median cell yield was 3.14 × 10^6 CD34 cells/kg BW (range 0 – 32.6). Forty-four patients (81.5%) collected the minimum of 2.0 × 10^6 CD34+ cells/kg BW in a median of two apheresis sessions (range 1 – 4). Twelve patients (22.2%) collected more than 5.0 × 10 ^6 CD34+ cells/kg BW. A total of 256 patients (148 male, 108 female) with a median age of 60 years (range 28 – 76) diagnosed with MM were enrolled. Patients had received a median of two prior lines of treatment and collected a median of 3.60 × 10 ^6 CD34+ cells/kg BW (range 0 – 15.27) in a median of two apheresis sessions (range 1 – 5). The minimum of 2.0 × 10 ^6 CD34+ cells/kg BW was collected by 209 patients (81.6%). Eighty-two patients (32.0%) yielded more than 5.0 × 10 ^6 CD34+ cells/kg BW allowing tandem transplantation. Overall, the CD34+ cell yield was significantly higher in MM patients than in NHL patients (p