ALBERT

Description: Several authors have reported ASCT as a feasible, safe and effective treatment in HIV associated lymphoma patients (pts) receiving Highly Active Antiretroviral Therapy (HAART), particularly when being autografted with chemosensitive disease. To gain a better understanding of the usefulness of ASCT in HIV+ Lymphoma pts a retrospective comparative study (HIV+ vs HIV- lymphoma pts with ASCT) has been performed using the EBMT-LWP Registry. Methodology: Registry-based, retrospective, individually matched case-control analysis. Within the participating centres one or two HIV- controls for each HIV+ pt were selected from the registry with the following inclusion criteria: Known HIV serological status at ASCT, lymphoma (HL or NHL), ASCT performed between 1999 and 2006 and pts over 18 years of age. Two cohorts (HIV+ vs HIV-) were matched for histology, IPI at diagnosis (NHL), stage at diagnosis, disease status at ASCT, age at ASCT, year and country of ASCT. Results: 40 HIV+ lymphoma pts undergoing an ASCT were matched with 46 HIV- pts. Pts and transplant features are shown in table 1. With a median follow up of 36 mo, the differences regarding OS and PFS were not significant: 62% for HIV+ vs 69% for controls, and 56.5 vs 58%, respectively. No differences were seen regarding HL and NHL pts. An overall TRM of 10% was observed in the HIV cohort, mainly related to infections, while no cases of TRM were seen within the control arm. Since survival rates between the HIV+ and the matched HIV- lymphoma populations remained comparable, the HIV condition should not preclude these pts from being treated according to the same criteria as the HIV negative lymphoma population. Nevertheless, infectious complications should be cautiously followed within the HIV+ lymphoma pts undergoing an ASCT. Patients and transplant features HIV+ HIV- n=40 % n=46 % Age [Median (range)] in years 41.4 (29.2–62.5) 44 (16–62.4) p= NS Male sex 35 87.5 25 54.3 p=0.001 Histology     DLBCL 24 60 25 54.3 p= NS     Burkitt lymphoma 2 5 2 4.3 p= NS     T-cell NHL 2 5 3 6.6 p= NS     HL 12 30 16 34.8 p= NS Disease status at ASCT     Complete remission (CR) 21 (12 in CR1) 52.5 (30 in CR1) 20 (11 in CR1) 43.5 (24 in CR1) p= NS     Chemosensitive disease 16 40 25 54.3 p= NS     Chemorefractory disease 3 7.5 1 2.2 p= NS CD34+ cells infused mill/kg [median (range)] 4.9 (1.6–21.2) 4.8 (0.9–21.2) p= NS     G-CSF prior to engraftment 36 90 21 46 p= 0.0001     Neutrophil engraftment 39 98% 46 100 p= NS Cause of Death     Relapse/progression 9 60% 10 84% p=0.08     Secondary malignancy 1 6.7% 1 8% p= NS     Transplant-related deaths 4 26.7% 0 0% p=0.06     Other 1 6.7% 1 8% p= NS

Description: All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 × 109/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 × 109/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 × 109/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

Description: Patients with aggressive forms of Mycosis Fungoides (MF), Sézary syndrome (SS) and other less common subtypes of primary CTCL have a dismal prognosis with conventional therapy. A potential role for alloSCT in these patients has been suggested by a number of case-reports and small series. We conducted a retrospective registry analysis of 64 recipients who received an alloSCT from HLA-identical donors (52 related, 12 unrelated) for advanced CTCL reported to EBMT between 1997 and 2006: 23 MF, 21 SS, 16 primary cutaneous anaplastic large cell lymphoma and 4 subcutaneous panniculitis-like T-cell lymphoma; 38 patients were male, 26 were female; median age was 46 years (5–65); median follow up of survivors was 28 months. AlloSCT was performed at a median of 22 (3–313) months from initial diagnosis, following a median of 3 (1–8) prior lines of therapy, the stem cell source was PB in 54 cases and BM in 10 cases, reduced-intensity conditioning (RIC) was used in 41 (64%) cases. Twenty-three percent of patients were in complete response (CR) and 26% in partial response (PR) at the time of alloSCT. All other patients were primary refractory (RE, 25%) or progressed after a previous response (PG, 26%). Non-relapse mortality was 24% at 3 years, and appeared higher in patients receiving myeloablative conditioning (MAC) than in those receiving RIC alloSCT (35% vs 16%; p=0.06). Acute graft versus host disease (GVHD) occurred in 37% of patients at risk, and chronic GVHD in 69% of patients alive at day +100. The cumulative incidence of disease relapse (36% at 3 years) was significantly higher in patients with advanced disease status at alloSCT (RE/PG 46% vs CR/PR 21%; p=0.01), but similar in patients with related and unrelated donors (p=0.39) and receiving MAC or RIC (p=0.6). Progression free survival (PFS) at 3 years was 41%, with a significant advantage for patients in CR/PR at alloSCT (58% vs 26%; p

Description: Background: Fludarabine phosphate (F)-based nonmyeloablative conditioning regimens are associated with reduced transplant-related toxicity and allow transplantation in patients (pts) above 55 y.o. Aims: We prospectively studied the role of ATG to control the development of graft-versus-host-disease (GVHD), accelerate donor engraftment and maintain GVT effects in pts not eligible for classical allogeneic transplant. The subgroup of pts with 60 yo or more was analysed and compared with the younger population. Population: A total of 113 pts were enrolled in the phase II study. Pts with lymphoid malignancies were conditioned with F (30 mg/m²/day for 4 days) plus cyclophosphamide (1g/m²/day for 3 days) or cytarabine (Ara-C, 2g/m²/day) for myeloid malignancies. All pts received cyclosporine (3–5 mg/kg IV, daily) and ATG (10 mg/kg/day for 4 days - [ATG-4, n= 36] or 2 days - [ATG-2, n=67] ). Chimerism analyses were performed on d30, 45, 60 and 90. Results: 29 pts had 60 y.o. or more.Diagnoses were as follows: 9 MM, 5 NHL, 3 CLL, 5 AML, 4 MDS, 2 CML, 1 WM. The median age was 63 (range 60–74) years. The median follow-up was 24 months. Prior to transplantation, 35% of pts were in complete remission. 65% had poor prognostic disease(PR, RR or PD). Engraftment rate was 100% of the evaluable pts. Treatment-related mortality was 48%,much higher than in the younger population (15%) and due primarily to infectious complications. Grade II-IV acute GVHD (aGVHD) at d90 were similar in both populations (35%). Chronic GVHD rates were similar in both groups (40%). At d90, 23 pts were evaluable for T-cell chimerism analysis. Full (〉90%) donor chimerism was achieved in 20/23 pts. Overall survival was higher in patients with good prognostic diseases (60% vs. 48%). No pts developed veno-occlusive disease. Conclusion: These results confirm the feasibility of F-based nonmyeloablative conditioning in elderly population but infectious complications remain a concern compared to younger population.

Description: Abstract 442 Background. ESAs are usually the first line tx of anemia in non del 5q lower risk MDS. However, not all pts respond to ESAs and median response duration is only about 2 years (Park, Blood 2008;111:574). Long-term outcome of pts who do not respond to or relapse after response to ESAs is incompletely known. We analyzed this outcome by updating a previously reported lower-risk MDS cohort of 403 pts treated with ESA in centers of the GFM (Blood 2008;111:574). Methods. We analyzed in that cohort low and int-1 (lower risk) IPSS pts with Hb75 was associated with shorter survival (median OS 31 mo vs. not reached for age 65 (P=0.03). 83 pts relapsed after an initial response (IWG 2000 major and minor in 60.2% and 39.8% pts, resp) of 16.5 mo median duration (range 3–74 mo). At tx onset, M/F was 1.35, median age 74.3, WHO classification RA, RCMD, RARS, RAEB-1 in 14%, 38%, 32%, 16% of cases, resp, karyotype fav, int in 92% and 8% pts, resp, IPSS low, int-1 in 51% and 49% of pts. Median serum ferritin was 695 ng/mL and median sEPO 64 IU/L. 45% of the pts were TD (median 2 RBC units/mo). Median OS and 3-y CI of AML after relapse were 53 mo and 9.7%, resp. Median OS after relapse was 26 mo in RAEB-1 and not reached in other WHO subtypes (P=0.06) and was not influenced by the presence of multilineage dysplasia. Pts who relapsed after 24 mo had a 4.1% 3-y CI of AML vs 12.8% in pts who relapsed before 24 mo (P=0.40). Median OS was not reached in pts who relapsed after 24 mo vs 53 mo in those relapsing before 24 mo (P=0.90). No pre-tx characteristic was predictive of relapse before or after 24 mo. 16% of the 83 pts were aged 65 (P=0.17), and their 3- CI of AML after relapse was 0% vs 12% in pts aged 〉65 (P=0.31). In the overall pt population (ie pts with primary resistance, pts with relapse and pts with sustained response), univariate competing risk modeling found CI of death from cardiovascular causes to be correlated with TD and older age at tx onset but not with response status, while only age remained significant in multivariate analysis (HR=1.12 [1.014-1.24], P=0.02). Both older age and early failure (ie primary failure or relapse

Description: Earlier evaluation of therapy effect in patients with CML would assist in optimal use of available tyrosine kinase inhibitors (TKI). Single cell analysis by mass cytometry has enabled the quantification of up to 46 antibody epitopes, making it ideally suited for exhaustive immunophenotyping of the haematological hierarchy, and evaluation of associated dynamic signal transduction events, in a clinical setting. By integrating time resolved single cell signalling data with clinical parameters, we searched for prognostic and efficacy-response mass cytometry biomarkers within a month of TKI therapy. We report data from experiments used to validate the custom panels of antibodies, highlighting the power of mass cytometry in the analysis of primary patient material obtained on clinical studies. Peripheral Blood (PB) samples were collected before, 3 hours, 7 days and 28 days, after start of nilotinib (300 mg BID) treatment in a subset of patients (n=55) enrolled in the ENEST1st trial. PB cells were stained with two panels of antibodies, allowing a comprehensive immunophenotyping of numerous cellular subsets, and also the evaluation of intracellular phosphorylation status of several epitopes. Moreover, using a straightforward barcoding scheme, the time-resolved samples from each individual patient were pooled after barcoding and stained with the antibody panels to minimize sample variation. In a pilot study, 7 and 10 cell subsets were identified in PB samples from 4 untreated healthy donors and 2 complete sets of 4 patients enrolled in this sub study, respectively. Furthermore, a robust signal was measured for pCrkL, pStat5, pStat3, pCreb, pAbl Y412 and pAbl Y245. The two sets of samples from study patients showed substantial changes in activation status over the course of therapy. Some changes, such as pStat3 alterations are only detectable in neutrophils and monocytes, while the activity of others i.e. pCreb was found to be ubiquitous. CD34+ cells indicated decreased phosphorylation of CrkL, Stat5, and Abl Y412/245. To increase the immunophenotyping resolution of the myeloid lineage, 3 additional cell surface markers were incorporated into the cell surface panel. In 1 healthy donor, and in diagnostic samples from three patients enrolled in this sub study, this allowed the identification of 13 cell subsets: CD3+, CD4+, and CD8+ T cells, regulatory T cells (Tregs), monocytes, dendritic cells (DCs), plasmacytoid dendritic cells (pDC's), neutrophils, basophils, B cells, hematopoietic stem cells (Lin- CD34+ CD38-) and progenitor cells (Lin- CD34+ CD38-) (Figure 1 A,B). With respect to the relative number of cells identified for each cell type, the three diagnosis samples differed from the single healthy control. In the patients, we observed an expansion of the granulocytic compartment, as well as the emergence of CD34+ progenitor and stem cells in the peripheral blood. In conclusion, the here presented developed assay is able to resolve most of the cell subpopulations found in the hematopoietic tree, and also robustly measure the activity of central signalling substrates known to be involved in CML pathogenesis. With the addition of new phospho-specific antibodies, the methodology may facilitate the detailed characterization of CML in an immunological context, and may shed new light on both the disease and therapeutic mechanism. Analysis of variation in signal responses and immune profile are now in progress in the subset of patients (n=55) in the ENEST1st trial. Figure 1. Manually annotated SPADE tree from healthy donor and patient (3581_0002). With the incorporation of additional cell surface markers, the protocol was able to identify 13 cellular subsets in healthy donors (A) and a typical CML patient (B): CD3+, CD4+, and CD8+ T cells, regulatory T cells (Tregs), monocytes, dendritic cells (DCs), plasmacytoid dendritic cells (pDC's), neutrophils, basophils, B cells, hematopoietic stem cells (Lin- CD34+ CD38-) and progenitor cells (Lin- CD34+ CD38-). Figure 1. Manually annotated SPADE tree from healthy donor and patient (3581_0002). With the incorporation of additional cell surface markers, the protocol was able to identify 13 cellular subsets in healthy donors (A) and a typical CML patient (B): CD3+, CD4+, and CD8+ T cells, regulatory T cells (Tregs), monocytes, dendritic cells (DCs), plasmacytoid dendritic cells (pDC's), neutrophils, basophils, B cells, hematopoietic stem cells (Lin- CD34+ CD38-) and progenitor cells (Lin- CD34+ CD38-). Disclosures Thaler: AOP Orphan: Research Funding. Lang:Celgene: Consultancy. Hjorth-Hansen:Bristol-Myers Squibb: Research Funding; Ariad: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding. Hellmann:Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding, Speakers Bureau; BMS: Consultancy, Other: funding of travel, accomodations or expenses, Speakers Bureau. Giles:Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Janssen:ARIAD: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Porkka:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Ossenkoppele:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Mustjoki:Signe and Ane Gyllenberg Foundation: Research Funding; Finnish Cancer Institute: Research Funding; Sigrid Juselius Foundation: Research Funding; Pfizer: Honoraria, Research Funding; the Finnish Cancer Societies: Research Funding; Academy of Finland: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Gjertsen:Bergen University Hospital: Research Funding.

Description: Chromosomal translocations have recently emerged as an important prognostic indicator in B-CLL (Mayr et al, Blood 2006). Until now however, their value had neither been determined in patients undergoing homogeneous treatment, nor compared to that of IgVH mutational status, another major prognostic factor in B-CLL. Sixty-five B-CLL pts treated with cladribine-containing regimens were included in the present analysis. All had been investigated by conventional cytogenetic analysis using TPA as a mitogen, interphase FISH (tested loci: 11q/ATM, 12cen, 17p/P53, 13q/RB1&/D13S319), IgVH mutational status and P53 mutational screening prior to inclusion. Translocations (n= 45) were detected in 42 % of the pts, and included both balanced (n=12) and unbalanced (n=33) types. Pts with translocations were more heavily pretreated (P=.05) and presented with significantly higher incidence of complex aberrations (P

Description: Following the widespread use of Highly Active Antiretroviral Therapy (HAART), ASCT has been reported as a feasible and effective treatment in the setting of HIV-Ly patients (pts). Nevertheless just series including up to 20 patients have been published so far. We present a preliminary analysis of the outcomes regarding the experience within the EBMT-LWP. Methodology: A retrospective analysis including HIV-Ly patients undergoing peripheral blood ASCT from 1999 to 2005 and reported to the EBMT was performed. Main endpoints: OS, EFS and TRM. Results: 44 pts from 14 institutions/7 countries were included: 39 males, median age 43 (29–62) years old. One pt underwent more than 1 ASCT (follow up censored at time of 2nd ASCT). In addition to HIV infection, 11 pts were co-infected by HBV, 8/43 by HCV and 16/36 pt met AIDS criteria (other than lymphoma) at the time of lymphoma diagnosis. Histology: 34 NHL (20 DLBCL; 7 Burkitt/Burkitt-like; 4 plasmablastic; 3 other), 59% of them with IPI〉2 at diagnosis; 10 HL (50% with Ann-Arbor stage〉IIB at diagnosis). Patients received a median of 2 (1–5) treatment lines pre-ASCT. Status at ASCT: 22 CR (13 in CR1); 18 in PR/chemo-sensitive relapse and 4 in primary induction failure/chemo-resistant relapse. Conditioning: 41 pts received BEAM/variants and 3 TBI-based regimens. Post-ASCT anti-tumour pre-emptive treatment was used in 10 pts (8 radiotherapy; 2 Rituximab). The median count of T-CD4+ cells/μl was 162 (8–702) at the time of ASCT; 26/38 had undetectable HIV viral loads. HAART was given in 39/42 pts during conditioning but was withdrawn in 9 of them. The median number of CD34+ cells infused was 5 (1,6–21,2) x106/kg. G-CSF was used until engraftment in 39/43 pt during a median of 8 (2–29) days. All pts but one who died on day +15 reached neutrophils〉500/μl at a median time of 11 (8–36) days. Platelet count 〉20.000/μl was reached in 39/44 pt at a median time of 14 (6–455) days. The pt engrafting platelets on day +455 was transfusion independent since day +49. Three new post-ASCT malignancies were reported: in situ epitelioma and myelodysplasia (+4 years) in 1 pt, and kidney adenocarcinoma (+3 years) in another one. Relapse occurred in 13 (29,5%) pts which status at SCT was CR in 4, PR/chemosensitive relapse in 5 and chemo-resistant disease in 4. The median time to relapse/progression was 5,2 (0,6–32,1) mo. Seventeen pts died (38,6%): disease relapse/progression (n=11), ASCT-related complication (n=4) -bacterial infection (n=3), secondary myelodysplasia (n=1)-, 1 pt died from an HIV-related complication and 1 pt died on day +15 of multi-organ failure within the context of a bacterial sepsis and pre-transplant renal dysfunction. With a median follow up time of 36,3 (3,2–72,3) mo, the OS and DFS probability at this point were 60,2% (67,5% when chemo-resistant pts were excluded from analysis) and 55% respectively. For those pts in CR1 at ASCT, OS at 36,3 mo was 85% vs 60% for those in CR〉1/PR/chemosensitive relapse. Conclusion: The results from the EBMT-LWP experience, the largest reported so far, show that ASCT remains a useful treatment in terms of TRM, long-term OS, and DFS for high risk HIV-Ly patients. These outcomes are comparable to those observed in HIV negative lymphoma patients.