Immunomodulation of Both Donors and Recipients with Atorvastatin As a Strategy for the Prevention of Acute Graft-Versus-Host Disease (aGVHD): Results of Two Parallel Prospective Trials in Recipients of Matched Sibling Allogeneic Hematopoietic Cell Transplantation (alloHCT)

Abstract Abstract 1942 Introduction: Acute GVHD is a leading cause of morbidity and mortality following alloHCT. Atorvastatin (a statin drug) is a potent immunomodulatory agent capable of suppressing T cell–dependent immune responses that holds promise as a novel and safe agent for the prophylaxis of aGVHD. In murine models atorvastatin administration to both donor and recipient mice (compared to prophylaxis in either donors or recipients alone), prevented aGVHD by inhibiting donor T-cell proliferation, inducing T-helper 2 polarization, and by inhibiting recipient antigen presenting cell function (Zeiser et al. Blood, 2007). Several retrospective studies also suggest statins as potential prophylactic agents for aGVHD. Methods: We report here the results of two parallel, ongoing, prospective, phase II trials (NCT01175148 & NCT01491958) evaluating the safety and efficacy of a ‘two-pronged’ strategy of atorvastatin administration as aGVHD prophylaxis, to both adult (age ≥18yrs) donors and recipients of matched sibling alloHCT. The approach was identical in both protocols. Subjects with a history of atorvastatin allergy/intolerance were not eligible. As GVHD prophylaxis, atorvastatin at 40mg/day orally was administered to sibling donors, starting 14–28 days before the anticipated 1st day of stem cell collection. In alloHCT recipients GVHD prophylaxis consisted of atorvastatin (40mg/day) administered from day -14 to day +180 (or until stopping immunosuppression, toxicity, development of grade [Gr] II-IV aGVHD, or severe chronic GVHD [cGVHD]). In addition all recipients received standard GVHD prophylaxis with tacrolimus and methotrexate. Ex vivo CD34+ cell selection or in vivo T-cell depletion was not permitted. Primary outcomes were rate of Gr II-IV aGVHD at day +100 and safety of atorvastatin administration to alloHCT donor/recipient pairs. Both trials tested the null hypothesis H0: p≥35%, vs. the alternate H1: p≤15%, where p is probability of Gr II-IV aGVHD at day 100. Secondary outcomes included rates of late-onset aGVHD, cGVHD, relapse, progression-free survival (PFS), and overall survival (OS). Results: Between September 2010 and June 2012, 34 donor/recipient pairs were enrolled at WVU (n=24) and OSU (n=10). Median donor age was 50.5 yrs (range 24–69). Median duration of atorvastatin prophylaxis in donors was 15 days (range 7–26). No atorvastatin related Gr 3–4 toxicities were seen in the healthy donors. Table 1 shows baseline patient (pt) characteristics. At transplantation 16 pts (47%) had high-risk disease, 12 (35%) were chemorefractory, 11 (32%) had HCT-CI of ≥3, 14 (41%) were female to male allografts, and 12 (35%) pts had ABO mismatched transplants. Median follow up of survivors is 158 days (range 31 – 658). Atorvastatin was well tolerated with no Gr 2–4 adverse events. All pts engrafted. The median time to ANC ≥500/μL was 18 days (range 5–25) and to platelets ≥20k/μL was 15 days (range 11–51). The median day 100 chimerism was 85.5% (55–100%) for T-cells and 100% (26–100%) for myeloid cells. Respective numbers at day 180 are 99.5% and 100%. Among 34 evaluable pts, the cumulative incidences (CI) of Gr II-IV and Gr III–IV aGVHD at day 100 were 6.0 ± 4.2% and 0% respectively. Respective CI rates at day 180 are 16.7 ± 8.3% and 10.2 ± 7%. CI of mild/moderate and severe cGVHD at 1 year are 15.8 ± 8.9% and 18.3 ± 10.2%, respectively. Infectious complications were infrequent, with no fungal infections or EBV reactivations and few CMV reactivations (n=3). Non-relapse mortality was 0% at day 100 and 4.5% at day 180. CI of relapse at day 180 was 27.6 ± 9.2%. One year PFS and OS estimates are 54% and 66%, respectively. Conclusions: A two-pronged immunomodulatory strategy of atorvastatin administration to alloHCT donors/recipients appears to be a feasible, safe and potentially effective modality for aGVHD prophylaxis. Final results of NCT01175148 & updated results of NCT01491958 will be presented at the meeting. Disclosures: Hamadani: Celgene Corp: Speakers Bureau; American Cancer Society 116837-IRG-09-061-01: Research Funding; ASBMT & Millennium New Investigator Award: Research Funding; Conquer Cancer Foundation of ASCO: Research Funding. Off Label Use: Off Label use of atorvastatin for GVHD prophylaxis. Efebera:(NIA) K12 CA1333250: Research Funding; Leukemia and Lymphoma Society: Research Funding.

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Gemcitabine, Dexamethasone, and Cisplatin (GDP) As Secondary Chemotherapy In Relapsed/Refractory Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood.v122.21.4345.4345 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4345-4345 ◽

Cited By ~ 1

Author(s):

Stephen Parkin ◽

Joseph M. Connors ◽

Laurie H. Sehn ◽

Diego Villa ◽

Richard Klasa ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Primary Therapy ◽

Off Label Use ◽

Peripheral T Cell Lymphoma ◽

Off Label ◽

Histologic Subtypes ◽

Label Use

Abstract Introduction The only known curative option for relapsed/refractory peripheral T-cell lymphoma (PTCL) is secondary chemotherapy followed by high dose chemotherapy and stem cell transplant (HDC/SCT), if chemosensitivity is demonstrated. The optimal choice of regimen in this setting, as well as in the transplant ineligible population is unknown. Gemcitabine, dexamethasone, and cisplatin (GDP) was developed as an alternative to DHAP with a favorable side effect profile and administration in the outpatient setting. Since 2002, it has been used as the preferred second-line regimen in patients (pts) with relapsed aggressive lymphoma at the BC Cancer Agency (BCCA), including those with PTCL intended for treatment with HDC/SCT, as well as for selected pts treated with palliative intent. Patients and Methods The BCCA Lymphoid Cancer database, provincial cancer pharmacy database, and the Leukemia/BMT Program of BC database were screened to identify all pts who received GDP for relapsed/refractory PTCL, excluding cutaneous ALCL. Clinical factors and whether transplant was planned at the time of relapse/progression were collected. Disease refractory to primary therapy was defined as progressive disease (PD) during primary treatment or relapse within 3 months (m) of treatment completion. All endpoints were calculated from the date of the first cycle of GDP unless stated otherwise. Results 51 pts were identified between 2002 and 2012 with either relapsed (n=31, 61%) or primary refractory (n=20, 39%) PTCL with the following histologic subtypes: PTCL-NOS, n=17 (33%); ALCL, n=16 (31%) [ALK-positive, n=4 (8%); ALK-negative, ALCL n=10 (20%); ALK status unknown, n=2 (4%)]; AILT, n=13 (25%); NK/T cell nasal type, n=4 (8%); hepatosplenic, n=1 (2%); subcutaneous panniculitis-like, n=2 (4%). First-line treatment consisted of a CHOP-like regimen in the majority of pts (n=48) and one patient with NK/TCL received SMILE. Two pts with NK/TCL received radiation alone. The median time to progression or relapse after initial diagnosis was 7.4 m (range 0.8-150.2). At relapse, the median age was 56 years (y) (range 17-86), 43% had an elevated LDH and most had advanced stage disease (stage III/IV, 88%), good performance status (PS 0-1, 69%) and a high or high-intermediate secondary IPI (sIPI >3, 57%). Pts received an average of 3 cycles of GDP (range 1-6). In total, 36 pts (71%) were planned for HDC/SCT, based on age and lack of significant comorbidities, following a response to GDP. Those planned for transplant were more likely to be younger (< 60 y) (p=.050) with a good PS (0-1) at relapse (p=0.049) but had a similar sIPI risk distribution (p=0.195). Of these, 26 ultimately underwent HDC/SCT (transplant rate 72%; auto, n=15; allo, n=11 [non-myeloablative n=2]). Pts who underwent alloSCT (vs autoSCT) were more likely to have disease that was refractory to primary therapy (p=.045). Of the 10 pts planned for SCT who did not undergo transplant, 8 were due to PD, 1 did not have a matched sibling donor, and 1 refused transplant. The overall response rate (ORR) to GDP for all 51 pts was 80% (CR 47%) and with a median follow-up of 10.4 m for living pts, the 2 y progression free survival (PFS) following GDP was 25% and the 2 y overall survival (OS) was 43% with no differences amongst the histologic subtypes. For pts planned for transplant, the ORR was 83% (CR 58%). The 2 y PFS and OS for this group intended for transplant were 30% and 50%, respectively, and those with relapsed disease (n=22) had a superior outcome to those with primary refractory disease (n=14) (2 y PFS 42.5% vs 9%, p=.0027). The 2 y post-transplant OS was 53% and there was no difference observed between the relapsed and refractory pts who were ultimately transplanted (p=.23). For all non-transplanted pts (n=25), the median PFS after GDP was 4.4 m and the median OS was 6.8 m. In responding pts, the median duration of response was 6.8 m. The small group of non-transplanted pts with a good PS (0-1) at the time of GDP, had an improved PFS (7.9 m vs 1.6 m, p=.044) and median OS (3.7 y vs 4.2 m) following GDP with 3 pts alive and without PD. Overall, GDP was well tolerated with no treatment related deaths. Conclusion Our results suggest that GDP is an effective secondary therapy for relapsed PTCL and can lead to long-term survival, especially in those pts who subsequently undergo HDC/SCT. Selected pts with good PS may have durable remissions in the palliative setting. Disclosures: Off Label Use: Off label use of gemcitabine in the treatment of PTCLs. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Savage:Eli-Lilly: Consultancy.

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The Role of In Vivo T-Cell Depletion On Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation From HLA-Identical Siblings in Patients with Follicular Lymphoma: An European Blood and Marrow Transplantation Study.

Blood ◽

10.1182/blood.v114.22.3375.3375 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3375-3375

Author(s):

Julio Delgado ◽

Carme Canals ◽

Michel Attal ◽

Kirsty Thomson ◽

Antonio Campos ◽

...

Keyword(s):

T Cell ◽

Follicular Lymphoma ◽

Research Funding ◽

Alkylating Agent ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Off Label ◽

Reduced Intensity

Abstract Abstract 3375 Poster Board III-263 Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (Allo-HCT) has become a feasible and effective therapeutic approach for younger patients with relapsed or refractory follicular lymphoma (FL). However, there is still much debate regarding the most appropriate conditioning regimen or whether the use of in vivo T-cell depletion (TCD) is beneficial or not for these patients. We analyzed the outcome of 164 patients with advanced FL reported to the EBMT from 1999 to 2007, who underwent RIC Allo-HCT conditioned with fludarabine plus an alkylating agent. Donors were HLA-matched siblings in all cases. Patients receiving transplants from alternative donors or conditioned with other agents were specifically excluded. The alkylating agent was melfalan in 48% of cases, busulfan in 32% and cyclophosphamide in 20%. Forty-six patients (28%) received anti-thymocyte globulin (ATG), 41 (25%) received alemtuzumab and 77 (47%) did not receive TCD in vivo. Median age at transplantation was 50 (range 29-64) years, and patients receiving alemtuzumab were significantly younger [45 (33-63)] than those receiving ATG [52 (29-64)] or no TCD [50 (32-64)], P = 0.05. There were no other differences among groups in terms of disease stage or presence of bulky masses at diagnosis, interval from diagnosis to HCT, number of prior therapies, or disease status at HCT. Engraftment was observed in 161 (98%) patients, with no significant differences among groups. Median follow-up was 43 (1–110) months for survivors. At three years, non-relapse mortality (NRM), relapse rate (RR), progression-free survival (PFS) and overall survival (OS) were 17% (95% CI 12-24%), 23% (17-31%), 60% (52-68%) and 75% (67-82%), respectively, for the entire cohort. The incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly higher for patients not receiving any TCD (31%) compared to TCD patients (18%), P = 0.05, and the incidence of chronic GVHD at one year was also significantly higher for the former compared to the latter group (68% vs. 25%, P < 0.001). There were no significant differences in NRM among groups, but there was a trend towards a higher RR in patients receiving alemtuzumab (40%) or ATG (24%) compared to patients receiving no TCD (16%) (P = 0.15), which translated into a trend towards a significantly shorter 3-year PFS for the alemtuzumab group (42% vs. 69%; P = 0.18). However, there were no differences in the 3-year OS among groups, which was 77% for patients receiving alemtuzumab, 73% for those receiving ATG and 77% for patients not receiving any TCD. In conclusion, results with RIC Allo-HCT from HLA-identical siblings were very promising for patients with advanced FL. Both alemtuzumab and ATG were effective in reducing acute and chronic GVHD, but had no significant impact on NRM. There was a trend towards a shorter PFS for patients receiving alemtuzumab, which did not translate into a significantly different OS. Disclosures: Delgado: Bayer Schering Pharma: Consultancy, Research Funding; Genzyme: Research Funding. Off Label Use: The use of alemtuzumab as a T-cell depleting agent in the context of hematopoietic transplantation is considered off-label.

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Pre-Transplant Rituximab Is Associated with Reduced Rate of Acute GvHD After RIC-Allosct In Lymphoma Patients: Results From A Retrospective Monocenter Analysis.

Blood ◽

10.1182/blood.v116.21.1319.1319 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1319-1319

Author(s):

Roberto Crocchiolo ◽

Jean El Cheikh ◽

Luca Castagna ◽

Alix Helvig ◽

Sabine Furst ◽

...

Keyword(s):

Cumulative Dose ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Off Label Use ◽

Off Label ◽

Number Of Patients ◽

Grade 3 ◽

Reduced Rate ◽

Label Use

Abstract Abstract 1319 Introduction: both B and T cells are implicated in the pathophysiology of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (AlloSCT). Anti-thymocyte globulin (ATG) administered during conditioning has been shown to reduce both acute and chronic GvHD, while rituximab has been claimed to reduce incidence of GvHD: previous studies indicated a reduced incidence of acute and/or chronic GvHD, but sometimes with controversial results. Here we present results from a retrospective, monocenter analysis on a selected population of lymphoma patients undergoing reduced-intensity (RIC) AlloSCT, with or without ATG in the conditioning regimen. Methods: adult patients receiving RIC-AlloSCT from a HLA-identical sibling donor for relapsed CD20+ lymphoproliferative disease at our Institution were included in the analysis. Data on patients and donors, conditioning regimen, use of rituximab and cumulative dose during the six and three months before AlloSCT were collected. Rituximab was administered in association or not with chemotherapy, according to each patient's treatment strategy. Analysis was conducted separately on patients receiving ATG (ATG cohort) or not (non-ATG cohort). Correlation analysis between ATG, rituximab cumulative dose before AlloSCT and grade 2–4, grade 3–4 acute GvHD (aGvHD), or limited/extensive chronic GvHD (cGvHD) was performed. Results: a total of 57 patients transplanted between Avril 1999 and November 2009 were included in the study, 18 and 39 in the non-ATG and ATG group respectively. Of these 57 patients, 32 were treated with rituximab for a median (range) cumulative dose within 6 months before AlloSCT of 1500 (375-3375) mg/mq, ending at a median (range) of 43 (5-177) days prior to transplant. Details are shown in table 1. Median follow-up was 749 days (146-4051). No significant differences existed between patients receiving rituximab vs. those without rituximab, with the exception of a different number of patients with CLL or FCL. Among the 18 non-ATG patients, we observed a slightly reduced rate of severe (grade 3 or 4) aGvHD in those patients who received >= 375 mg/mq rituximab within three months before AlloSCT (n=13) compared to those receiving < 375 mg/mq or no rituximab (n=5): 2/13 vs. 2/5 (p=ns). In the ATG cohort, rituximab use at a dose >= 375 mg/mq (n=10) within three months was associated with a reduced rate of severe aGvHD compared with < 375 mg/mq or no rituximab (n=29): 0/10 vs. 7/29 (p=0.08). Reduction of grade 2–4 aGvHD rate was also observed: 1/10 vs. 14/29 (p=0.03). No effect on cGvHD appeared in the two cohorts. Discussion: present data suggest a role of rituximab administered before AlloSCT in reducing the incidence of aGvHD. This effect was more pronounced when concomitant administration of ATG was performed during conditioning regimen, indicating a possibly sinergistic effect of both T- and B-cell depletion in preventing GvHD. Although retrospective and small-sized, the present analysis, conducted on a quite homogeneous population of patients, confirms previous findings and enhances further investigations on larger number of patients. Disclosures: Off Label Use: Zevalin is off-label use in conditioning regimen in France.

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ATG Dose Correlates with Acute and Chronic GvHD In Patients Undergoing Reduced-Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation: A Large Retrospective Monocenter Analysis on 301 Patients.

Blood ◽

10.1182/blood.v116.21.3485.3485 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3485-3485

Author(s):

Roberto Crocchiolo ◽

Sabine Furst ◽

Luca Castagna ◽

Jean El Cheikh ◽

Catherine Faucher ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Chronic Gvhd ◽

Adult Patients ◽

Off Label Use ◽

Off Label ◽

Grade 3 ◽

Label Use

Abstract Abstract 3485 Introduction: RIC associating Fludarabine-Busulfan-ATG (FBA) is quite popular as preparative for allogeneic hematopoietic stem cell transplantation (RIC-AlloSCT). However the best association us still a matter of debate. Busulfan is crucial for disease control but limited by a dose-dependent toxicity and ATG plays a pivotal role in the prevention of both acute and chronic GvHD but with a potential higher relapse rate. Here we retrospectively compared different FBA regimens among adult patients transplanted at our Institution for a hematological malignancy, with the aim of identifying whether some pre- or peri-transplant variables are predictive of outcome. Patients and methods: on 635 patients allografted between May 1998 and Feb 2010, a total of 301 patients affected by malignancy received FBA-based RIC-AlloSCT and were the object of the present analysis. Comparisons between baseline patient, donor and AlloSCT characteristics with transplant outcome were performed: univariate and multivariate Cox regression analysis were used to find any correlation between the above mentioned variables and OS, DFS, NRM, relapse incidence, acute (aGvHD) and chronic (cGvHD) GvHD. Variables with p<0.20 were included in multivariate analysis, and only variables with a p<0.05 were retained in the final model. Results: median (range) follow-up was 917 (71-4051) days. Two-year OS, DFS and NRM were 66%, 58% and 20% for the entire cohort. Relapse at two years was 26%. Cumulative incidence of grade 2–4, grade 3–4, overall and extensive cGvHD were: 29%, 12%, 58% and 40%. In multivariate analysis, patient's age was significantly associated with OS, NRM, grade 2–4 and 3–4 aGvHD; disease status at transplant significantly correlated with DFS and relapse incidence. ATG at a dose of 5 mg/kg compared to 2.5 mg/kg, was significantly associated with a reduced risk of developing grade 3–4 aGvHD (HR= 0.46, 95% CI: 0.22–0.99, p=0.05) and cGvHD (HR= 0.33, 95% CI: 0.20–0.54, p<0.0001), without affecting relapse (p=n.s.). Overtime we modified our standard RIC from F5B2A1 (Fludarabine over 5 d, oral Bu over 2 d and ATG for1d) (N=114) to F5BX2A2 (Fludarabine over 5 d, IV Bu over 2 d and ATG over 2 d) (N=84). Population was not similar and notably older (51 vs. 57 years, p<0.0001) in the latter group. Despite this we observed similar NRM (22% vs. 23%: p=n.s.) in patients older than 55 years; in patients younger than 55 F5BX2A2 was associated with better but not statistically significant OS (77% vs. 65% at two years, p=0.21) and reduced NRM (9% vs. 18% at two years, p=0.10). Conclusions: in this large monocenter series of adult patients undergoing FBA-based RIC-AlloSCT, the use of ATG at a dose of 5 mg/kg appeared to significantly reduce incidence and severity of cGvHD and grade 3–4 aGvHD compared to ATG 2.5 mg/kg without increasing disease relapse. Moreover, despite patients' disparity between the two cohorts, reduced NRM was observed in patients < 55 years old treated with F5BX2A2 regimen with respect to those receiving F5B2A1. Disclosures: Off Label Use: Zevalin is off-label use in conditioning regimen in France.

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Double-Unit Cord Blood Transplantation for Hematological Malignancies in Japan: Multicenter Phase II Study (C-SHOT 0507)

Blood ◽

10.1182/blood.v118.21.3071.3071 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3071-3071

Author(s):

Atsushi Wake ◽

Shunro Kai ◽

Masaya Okada ◽

Mio Kurata ◽

Yoshiko Atsuta ◽

...

Keyword(s):

Cord Blood ◽

Cumulative Incidence ◽

Cord Blood Transplantation ◽

Off Label Use ◽

Off Label ◽

Blood Transplantation ◽

Gvhd Prophylaxis ◽

Engraftment Failure ◽

Research Grant ◽

Label Use

Abstract Abstract 3071 Objective: Double-unit cord blood transplantation (dCBT) has been widely applied for patients with less dose single-unit cord blood (sCB) because of a higher engraftment failure. Although several reports have suggested that dCBT may have impact on increasing GVHD incidence and reducing disease relapse, pre-transplant conditioning and GVHD prophylaxis varied too much to read the results. We therefore conducted a prospective multi-center phase II study assessing safety and efficacy of dCBT by using relatively uniform myeloablative conditioning and GVHD prophylaxis in Japan. Methods: From Apr. 2006 to Jan. 2010, patients younger than 55 years with hematological malignancies who lack any adequate unrelated and related donors and without prior history of transplantation were prospectively enrolled. Thirty-nine centers participated following approval by each institutional review board (Trial identifier: UMIN :C000000359, C-SHOT0507). Patients were eligible when there is no single unit with total nucleated cell (TNC) dose of > 2.5 × 107 /kg available, and at least 2 units available that have combined TNC > 2.5 × 107 /kg, with one of each > 1.5 × 107 /kg and the other < 2 × 107 /kg. CB units mismatched at 0–2 antigen in HLA-A, -B, -DR between unit and patient were selected. Preparative regimens were 12 Gy of TBI, Ara-C (12 g/m2) combined with G-CSF, and 120 mg/kg of CY for myeloid diseases, while TBI + CY for lymphoid diseases (S.Takahashi, et al. Blood 109;1322, 2007). GVHD prophylaxis was short term MTX and CsA. Results: Seventy patients were enrolled and 61 patients (AML 29, ALL 17, CML 6, MDS 6, ML 3) received dCBT. Nine patients did not receive dCBT due to disease progression (n=7) and other SCT (n=2). Disease status at dCBT was 27 in standard (CR1, CP1) and 34 in advanced (beyond CR1 or CP1). The median age was 37 years (range; 10–54) and median weight was 70.5kg (50.1–129.8). Median total and CD34+ cell doses (both units combined) at cryopreservation were 3.52 × 107 /kg (2.25 – 4.43) and 1.04 × 105 /kg (0.39 – 2.67), respectively. Median TNCs of larger and smaller unit were 1.90 × 107 /kg (1.47 – 2.48) and 1.60 × 107 /kg (0.74 – 1.97), respectively. Cumulative incidence of neutrophil recovery (NR, >0.5 × 109/L) was 67%(53–77) at day28, and 85%(73–92) at day 50. The median time to NR was day 26 (18–50) and median time to transfusion-independent platelet recovery (>20 × 109/L) was day 53 (32–98). Four died early before day 30 (2 on day8, 1 each on day11 and day 29) and 6 received 2nd transplantation due to engraftment failure (on day30, 33, 37, 42, 50, 54). Among engrafted 51 patients, all 50 patients assessed for chimeric status showed single donor-derived engraftment; 27 were from larger unit and 23 from smaller dose of TNC. Number of TNC of engrafted smaller unit was ranged from 0.74 – 1.96 × 107 /kg, including 6 that were even less than 1.5 × 107 /kg. There is no correlation between unit dominance and the number of TNC, CD34+ cell dose, CFU-GM dose, degrees of HLA/sex/ABO mismatches between units and recipients, and graft viability. Acute GVHD progressed in 33 (65%) of 51 evaluable patients (29% grade II-IV), and chronic GVHD was observed in 18 (36%) of the 50 evaluable patients (18% extensive). Actual EFS, RFS and OS at 1y and 3y was 48%(37–58) and 46%(35–56), 49%(36–61) and 47%(34–59), 57%(44–69) and 54%(40–65), respectively. Median follow-up period of survivors (n=32) are 1226.5days (365–1721). EFS at 1y of standard and advanced status patients was 67%(46–81) and 32%(18–48), respectively (p=0.023). Dose of TNC, CD34 and HLA disparity did not significantly affect on survival. Cumulative incidence of day100-TRM was 26%, and relapse late at 3y was 16.3%. Cause of death were disease progression in 11 and TRM (infection and organ failures) in 18. Discussion: Myeloablative dCBT can be a safe and effective alternative option for those who only have insufficient sCB available (less than 2.5×107/kg of TNC). So far, parameters assessed, such as the engraftment kinetics, survival rate, cumulative incidence of GVHD and relapse in dCBT seem to be comparable to our historical data of sCBT. Determinants of engrafting units after dCBT are still unclear. Disclosures: Off Lavel Use: G-CSF at pre-conditioning for myeloid malignancies is an off-label use in Japan. This study was supported by a Research Grant for Tissue Engineering (H17-014) and a Research Grant for Allergic Disease and Immunology (H20-015) from the Japanese Ministry of Health, Labor and Welfare. Disclosures: Off Label Use: G-CSF at pre-conditioning for myeloid malignancies is an off-label use in Japan. Kato:Research Grant for Tissue Engineering (H17-014) and a Research Grant for Allergic Disease and Immunology (H20-015) from the Japanese Ministry of Health, Labor and Welfare.: Research Funding.

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Low Dose Azacitidine (AZA) Reduces the Incidence of Chronic Graft-Versus-Host Disease (cGVHD) After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Blood ◽

10.1182/blood.v120.21.742.742 ◽

2012 ◽

Vol 120 (21) ◽

pp. 742-742 ◽

Cited By ~ 1

Author(s):

Marcos de Lima ◽

Simrit Parmar ◽

Julianne J Chen ◽

Sergio A Giralt ◽

Gabriela Rondon ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Research Funding ◽

Low Dose ◽

Control Group ◽

Cell Transplant ◽

Off Label Use ◽

Landmark Analysis ◽

Off Label ◽

Label Use

Abstract Abstract 742 AZA has immunomodulatory properties that may affect donor lymphocytes favorably, potentially leading to less GVHD after HSCT. We have been investigating low-dose AZA (32 mg/m2 daily for 5 days) to prevent AML/MDS relapse after HSCT. Interestingly, in our dose finding phase I study (Cancer, 2010) there was a suggestion of less cGVHD with longer AZA treatments. We then hypothesized that this approach leads to less cGVHD, and performed a comparison of patients that received AZA to prevent relapse versus historic controls that did not receive the drug. Major objective of this analysis is to determine the cumulative incidence of cGVHD with versus without AZA. Methods. Patients received AZA based on high risk of relapse disease, starting at a median of 45 days from transplant (range, 17–149). AZA effect on aGVHD was not studied since the drug was started after most cases of aGVHD had already occurred or/and had resolved or improved. Patients with active acute GVHD (aGVHD) were not eligible to receive AZA. Median dose was 32 mg/m2 (range, 8–40). Median number of AZA cycles was 3 (range, 1–54), and median time on AZA for patients that received >3 cycles (n=37) was 144 days (range, 93–1329). Using a computer algorithm, we randomly selected from our departmental database a control group consisting of patients who had received HSCT within the same time period, and had similar GVHD prophylaxis, stem cell source, and comparable low risk of grade II-IV aGVHD (Table). Two hundred and thirty patients were identified fulfilling these criteria. The rate of cGVHD was compared between the AZA group (grouped as 1–3 cycles and >3 cycles) and the control group, in a landmark analysis starting at 6 months after HSCT. Leukemia relapse or death in remission before cGVHD onset were considered as competing risks in this analysis. Results. Median follow-up was 25 months (range, 1–99) in the AZA group, and 31 months (range, 1.5–117) in the control group. 29, 24, and 115 patients in the >3 AZA cycles, 1–3 AZA cycles, and the control group were evaluable for the 6-month landmark analysis, respectively. The numbers of patients developing cGVHD and the HR at 2 years in this analysis were as follows: 53 of 115 controls (reference group), 11 of 24 patients who received 1–3 AZA cycles (HR at 2 years, 0.9; P=NS), and 6 of 29 patients who received >3 AZA cycles (HR at 2 years, 0.4; 95% confidence interval (CI), 0.1–0.8; P=0.02) developed cGVHD. Similarly, in a landmark analysis, the cumulative incidence of cGVHD was significantly lower in the subgroup that received >3 AZA cycles (figure). Conclusion. Low-dose AZA appears to reduce the likelihood of developing cGVHD. We are investigating if this effect is associated with preservation or improvement of the graft-versus-leukemia effect in an ongoing, randomized study. Disclosures: de Lima: Celgene: Research Funding. Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML. garcia Manero:celgene: Research Funding.

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The Addition Of Interleukin-6 Inhibition To Standard Gvhd Prophylaxis Prevents Acute Gvhd: Interim Results Of a Phase I/II Clinical Study

Blood ◽

10.1182/blood.v122.21.908.908 ◽

2013 ◽

Vol 122 (21) ◽

pp. 908-908 ◽

Cited By ~ 1

Author(s):

Glen A Kennedy ◽

Antiopi Varelias ◽

Slavica Vuckovic ◽

Ping Zhang ◽

Kelli PA MacDonald ◽

...

Keyword(s):

Phase I ◽

Interleukin 6 ◽

Immune Reconstitution ◽

Acute Gvhd ◽

Off Label Use ◽

Control Cohort ◽

Off Label ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Grade Ii

Abstract We and others have demonstrated the dysregulation of interleukin-6 (IL-6) early after experimental bone marrow transplantation (BMT) and protection from acute GVHD following the administration of an anti-IL-6 receptor (IL-6R) antibody. In these models, where GVHD prophylaxis is not administered, systemic IL-6, IFNγ and TNF levels peak 7 days after BMT before returning to baseline by the third week. We have determined cytokine dysregulation in a large clinical cohort of allogeneic stem cell transplant (SCT) recipients conditioned with myeloablative Cy/TBI (12 Gy, n = 25) or reduced intensity Flu/Mel (120mg/m2, n = 25) receiving standard GVHD prophylaxis with cyclosporine and MTX (d 1 at 15mg/m2, d 3, 6, 11 at 10mg/m2). IL-6 levels rose from pre-transplant levels of 6.4 ± 0.7 pg/ml to a peak of 58.8 ± 8.8 pg/ml at day 7 (P < 0.0001) with a fall at day 14 to 39.0 ± 12.5 pg/ml (P < 0.0001) and return to baseline by day 30 (6.2 ± 0.9 pg/ml), consistent with the preclinical data. IL-6 dysregulation was not different in recipients of matched sibling or unrelated donor grafts but was proportional to the intensity of conditioning (day 7 levels after Cy/TBI vs. Flu/Mel: 83.3 ± 12.2 pg/ml vs. 31.0 ± 10.1 pg/ml, P< 0.0001). In contrast to preclinical mouse data, no systemic increases were seen in any other cytokine including IFNγ, TNF, IL-17, IL-4, IL-13 and IL-10. We thus initiated a phase I/II study whereby a human neutralizing monoclonal antibody (mAb) against the IL-6R was administered on day -1 to patients receiving Cy/TBI or Flu/Mel conditioned allogeneic SCT from HLA (10/10)–matched sibling or unrelated donors with standard cyclosporine/MTX GVHD prophylaxis. There was no T cell depletion. The primary endpoint was the incidence of grade II-IV acute GVHD and the study has achieved its planned enrollment (n = 48). There was no toxicity attributable to IL-6R antibody administration. Pharmacokinetic analysis confirmed high levels of IL-6R Ab at day 3 (mean 64.7 ug/ml) which persisted in all patients 3 weeks after BMT (mean = 9.8 ug/ml) and remained above the level of detection (0.1ug/ml) in 75% of patients at day 30 (mean = 1.9 ug/ml). IL-6 levels were dramatically increased (relative to baseline) in patients receiving antibody due to the inability to excrete the inactive IL-6 – soluble IL-6R antibody complex (peak IL-6 levels at day 7 = 773.6 ± 207.9 pg/ml; P < 0.0001) and remained increased at day 30 (60.9 ± 24.4 pg/ml; P < 0.0001), returning to baseline by day 60 (9.5 ± 1.7 pg/ml), consistent with antibody clearance. Soluble IL-6R levels also rose over the first month of SCT and levels at day 30 correlated with residual antibody levels (r2 = 0.72, P = 0.02). Neutrophil (> 0.5x109/L) and platelet (> 20x109/L) recovery was normal relative to a matched untreated control cohort at a median of 16 and 18 days respectively. Donor chimerism and immune reconstitution (conventional T, regulatory T and B cells) was equivalent at day 30 in recipients of IL-6R inhibition versus the control cohort. In contrast, changes in innate immunity were seen in patients receiving IL-6R inhibition with increases in plasmacytoid DC (P = 0.002), CD1c+ conventional DC (P = 0.04) NKT cells (P =0.03) and marked reductions in inflammatory (CD14+CD16+) monocytes (P < 0.0001). Transcriptional profiling of T cell subsets is underway. With 36 patients evaluable (beyond day 100, median follow up of 297 days), the incidence of grade II-IV GVHD is 11.1% in recipients of IL-6R inhibition versus 39.6% in the matched (n = 53) control cohort (P = 0.004). The incidence of grade III/IV acute GVHD is 5.6% in recipients of IL-6R inhibition versus 20.8% in the control cohort (P = 0.045). Protection from grade II-IV acute GVHD was noted in patients receiving both Cy/TBI (7.7% vs. 40.7%, P=0.045) and Flu/Mel conditioning (13.0% vs. 38.5%, P = 0.044). Rates of CMV reactivation were very low in the IL-6R neutralized patients (16.7% vs. 35.8% in controls, P = 0.04), likely due to the prevention of acute GVHD and its’ consequent therapy. At one year, the relapse incidence and disease free survival in patients receiving IL-6R inhibition versus the control cohort is 21.2% vs. 30.0% (P = 0.28) and 73.1% vs. 62.4% (P = 0.14) respectively. IL-6 is thus the principal inflammatory cytokine dysregulated after clinical allogeneic SCT and its inhibition appears to offer profound protection from acute GVHD despite robust immune reconstitution, without compromise of the GVL effect. Disclosures: Off Label Use: The use of Tocilizumab to prevent GVHD is experimental and an off label use.

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Randomized Phase II Trial of Pentostatin, Cyclophosphamide, and Rituximab with or without Concurrent Avastin for Previously Untreated B-Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v124.21.4673.4673 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4673-4673

Author(s):

Tait D. Shanafelt ◽

Betsy R. LaPlant ◽

Timothy G Call ◽

Daniel Nikcevich ◽

Jose F. Leis ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Response Evaluation ◽

Off Label Use ◽

Advisory Committees ◽

Free Survival ◽

Off Label ◽

Grade 3 ◽

Label Use

Abstract BACKGROUND: Although chemoimmunotherapy (CIT) has improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 40-50% of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays. Interactions with nurturing environments can enhance CLL B-cell resistance to apoptosis. These interactions include cytokine mediated prosurvival signals by angiogenic molecules, such as VEGF and bFGF that nurture CLL B-cells in an autocrine fashion and promote CLL cell survival partly through up regulation of anti-apoptotic proteins. These findings provide a strong rationale for testing anti-VEGF therapy in combination with a purine nucleoside analogue CIT regimen for upfront treatment. We conducted a randomized phase 2 CIT trial using pentostatin, cyclophosphamide, and rituximab with (PCR-B) or without (PCR) bevacizumab (B), an anti-VEGF monoclonal anti-body. METHODS: Eligible patients were previously untreated and had CLL in need of treatment by NCI-WG criteria (Blood 111:5446). Patients were randomized using a dynamic allocation procedure stratifying for stage (0-II vs. III-IV) and FISH (17p or 11q deletion vs. other) to receive either 6 cycles of rituximab (100 mg on day 1 of cycle 1; 375 mg/m2on day 2 of cycle 1 and day 1 of cycles 2-6) followed by pentostatin (2 mg/m2) and cyclophosphamide (600 mg/m2) (PCR) administered every 21 days. Patients in the PCR-B cohort also received bevacizumab 15mg/kg on day 1 of cycles 1-5 and days 1, 22, & 43 of cycle 6. All patients underwent complete response evaluation 3 months after day 1 of cycle 6 (or last cycle of treatment for those completing < 6 cycles). MRD was assessed using 6-color flow cytometry (Leukemia 21:956) at the completion of treatment. RESULTS: 68 patients were enrolled through the Mayo Clinic Cancer Research Consortium between 1/2009 and 1/2013. Three patients were excluded from analysis: 1 patient canceled prior to treatment, 1 was dosed incorrectly, and 1 was ineligible due to immunophenotyping inconsistent with CLL. Median age of eligible patients was 63 years (range 43-81) and 43 (66%) were men. With respect to disease stage, 3 (5%), 38 (58%), and 24 (37%) had low, intermediate and high Rai stage disease. Eleven (17%) patients had deletion 17p or 11q & 29 (45%) had unmutated IGHV. No statistically significant differences were observed in these variables by treatment arm. All 65 evaluable patients have completed active treatment, with 54 (83.1%) completing the intended 6 cycles (PCR group 27/32 [84.4%] and PCR-B 27/33 [81.8%]). Hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 10 (31.3%) patients on PCR and 12 (36.4%) on PCR-B (p=0.79). Non-hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 9 (28.1%) patients on PCR and 18 (54.4%) on PCR-B (p=0.04). The most common such events were hypertension (PCR: 3.1% vs. PCR-B: 21.2%), proteinuria (0% vs. 6.1%) and creatinine increase (3.1% vs. 6.1%). Across both arms, 64/65 (98.5%) patients achieved a response including 31/32 (96.9%) treated with PCR and 33/33 (100%) treated with PCR-B (p=0.49). CR/CRi was achieved in 10/32 (31.3%) patients treated with PCR & 18/33 (54.5%) treated with PCR-B (p=0.08). Of the 28 who achieved a CR/CRi, MRD analysis was completed on 26, of whom 12 (46%) were MRD negative. With respect to treatment arm, 5/32 (16%) patients on PCR and 7/33 (21%) on PCR-B achieved an MRD negative CR. Median time to retreatment for all 65 patients was 44.8 (95% CI: 34.6 – NA) months. Median overall survival has not yet been reached. With current follow-up no differences between treatment-free survival (p=0.38), progression-free survival (p=0.23), or overall survival (p=0.45) are observed by treatment arm. Plasma levels of angiogenic cytokines VEGF, bFGF, thrombospondin (TSP) and the chemokines CCL3 and CCL4 were measured prior to treatment and at the time of the post treatment response evaluation. Correlations of these cytokines with clinical outcome will be presented. CONCLUSION: The addition of bevacizumab to purine analogue-based CIT was generally well-tolerated and may increase complete remission rates in patients with CLL. No clear improvement in treatment free survival has been observed to date. Disclosures Shanafelt: Hospiria: Research Funding; Pharmacyclics/Jannsen: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; glaxoSmithKline: Research Funding; Genetech: Research Funding; Polyphenon E Int'l: Research Funding. Off Label Use: Off label use of pentostatin for treatment of CLL. Off label use of bevacizumab for treatment of CLL. . Kay:Genetech: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

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Prognostic Impact of CD20 and CD25 Expression in Patients with Philadelphia-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL).

Blood ◽

10.1182/blood.v114.22.984.984 ◽

2009 ◽

Vol 114 (22) ◽

pp. 984-984 ◽

Cited By ~ 1

Author(s):

Fabio P.S. Santos ◽

Susan O'Brien ◽

Deborah A. Thomas ◽

Jorge Cortes ◽

Stefan Faderl ◽

...

Keyword(s):

Research Funding ◽

Adult Patients ◽

Lower Percentage ◽

Prognostic Impact ◽

Off Label Use ◽

Conventional Chemotherapy ◽

Off Label ◽

Cd25 Expression ◽

Significant Difference ◽

Label Use

Abstract Abstract 984 Poster Board I-6 Background: The Ph chromosome is the most common cytogenetic abnormality in adult patients with ALL and is associated with a higher risk of relapse and death. With the introduction of tyrosine kinase inhibitors (TKI; imatinib, dasatinib), the treatment of patients with Ph+ ALL has evolved. Regimens combining conventional chemotherapy with TKI have lead to significant improvements in the outcome of these patients. However, there is still a high incidence of relapse, and the determination of prognostic factors in these patients might lead to the development of risk-adapted therapy. CD20 is a cell surface marker expressed in 40% of adult patients with ALL, and it is associated with worse survival (Thomas D et al, Blood 2009; 113: 6330-6337). CD25 is the a-chain of the IL-2 receptor and has been reported to be associated with adverse outcomes in Ph+ ALL (Paietta E et al, Blood 2008; 112:Abstract 1500). Aims: To determine the prognostic impact of CD20 and CD25 expression in patients with Ph+ ALL. Methods: We retrospectively reviewed data of patients with Ph+ ALL treated at our institution with conventional chemotherapeutic protocols (Hyper-CVAD) alone or combined with TKI (Hyper-CVAD + imatinib and Hyper-CVAD + dasatinib). None of the patients received therapy with Rituximab. CD20 and CD25 expression were assessed by flow cytometry, and the cut-off for positivity was 20%. Survival was estimated by Kaplan-Meier method and compared by log-rank test. Results: We analyzed 126 patients with Ph+-ALL treated at our institution from November, 1992, until February, 2009. Patients received Hyper-CVAD alone (N=44), Hyper-CVAD + Imatinib (N=47) and Hyper-CVAD + Dasatinib (N=35). Median age of the whole cohort was 49 years (range 16-84). CD20 was positive in 69 of 124 (57%) evaluable patients. CD25 was positive in 63 of 112 (56%) evaluable patients. Patients that were CD20-positive had a higher incidence of peripheral lymphadenopathy (21% vs. 7%, p=0.04). Patients that were CD25-positive had lower lactate dehydrogenase (LDH) levels (median 1006 IU/L vs. 1433 IU/L; p=0.01), lower percentage of bone marrow blasts (median 86% vs. 90%, p=0.02), higher platelet counts (median 50×109/L vs. 32×109/L, p=0.01) and a higher incidence of CNS disease at diagnosis (21% vs. 4%, p=0.01). The complete response rate of the whole cohort was 91%. There was no impact of CD20 or CD25 positivity on disease-free survival (DFS) and overall survival (OS) of patients treated with Hyper-CVAD alone. In patients treated with Hyper-CVAD + dasatinib, CD20 positivity was associated with improved DFS (Figure 1) (median – not reached [NR] vs. 48 weeks [wks], p=0.01) and OS (median NR vs. 65 wks, p=0.06). Patients treated with Hyper-CVAD + imatinib who were CD20-positive had better DFS (median 91 vs. 57 wks, p=0.77) and OS (median 118 vs. 73 wks, p=0.98), but this did not reach statistical significance. There was a trend for worse survival in patients treated with Hyper-CVAD + dasatinib that were CD25 positive, but without a statistically significant difference (median DFS 55 wks vs. NR, p=0.10; median OS 85 wks vs. NR, p=0.11). We repeated the analysis combining Hyper-CVAD + dasatinib and Hyper-CVAD + imatinib (Hyper-CVAD + TKI). There was no significant difference in DFS and OS by CD20 expression (median DFS 130 wks vs. 53 wks, p=0.11; median OS 124 wks vs. 74 wks, p=0.11) or CD25 expression (median DFS 63 wks vs. 86 wks, p=0.33; median OS 100 wks vs. 117 wks, p=0.39). Conclusion: In patients with Ph+-ALL treated with regimens combining conventional chemotherapy and TKI, expression of CD20 may be associated with better survival outcomes. CD25 did not influence survival in our patients. More studies are needed to better determine the prognostic value of these markers and implement risk-adapted strategies treatment. Disclosures: Off Label Use: Off label use of imatinib and dasatinib in combination with cytotoxic chemotherapy. Cortes:Novartis: Research Funding; Bristol Myers Squibb: Research Funding. Kantarjian:Novartis: Research Funding; Bristol Myers Squibb: Research Funding.

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Subcutaneous Alemtuzumab Combined with Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allo-SCT In CLL with 17p- or Refractory to Fludarabine – Interim Analysis of the CLL2O Trial of the GCLLSG and FCGCLL/MW

Blood ◽

10.1182/blood.v116.21.920.920 ◽

2010 ◽

Vol 116 (21) ◽

pp. 920-920 ◽

Cited By ~ 12

Author(s):

Stephan Stilgenbauer ◽

Florence Cymbalista ◽

Véronique Leblond ◽

Alain Delmer ◽

Thorsten Zenz ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Remission Rate ◽

High Dose ◽

Off Label Use ◽

Advisory Committees ◽

Off Label ◽

Oral Dexamethasone ◽

Label Use

Abstract Abstract 920 CLL refractory to purine analogues (e.g. fludarabine, F) or with 17p- is associated with very poor prognosis. Alemtuzumab is active in F-refractory CLL, and has proven efficacy in patients (pts) with 17p-. However, outcome of F-refractory CLL is still poor in terms of remission rate and duration of remission. The multinational, multicenter CLL2O trial aims at achieving a higher remission rate by adding high-dose dexamethasone to alemtuzumab, and prolongation of remission duration and survival by alemtuzumab maintenance or allogeneic stem-cell transplantation (allo-SCT). Pts with CLL refractory (no PR/CR or PR/CR < 6 months) to F-based (e.g. FR, FC, FCR) or similar chemotherapy (i.e. pentostatin, cladribine, bendamustine), or exhibiting 17p- (untreated or at relapse) were eligible if they had “active disease”. Treatment was with subcutaneous alemtuzumab 30 mg weekly × 3 for 28 days, combined with oral dexamethasone 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or alemtuzumab maintenance with 30mg weekly every 14 days for up to 2 years (yrs). Decision for one of the two consolidation options was at discretion of patient and physician. From January 2008 to July 2010, 80 pts were enrolled at 22 centers and 79 were eligible; F-refractory (n=31), 17p- without prior therapy (n=31), and 17p- in relapse (n=17). Median age was 65 yrs in the F-refractory (range 38–76) and 17p- 1st-line group (36-76), and 60 yrs for the 17p- relapse group (54-73) with male predominance (F-refractory 74%, 17p- 1st-line 71%, 17p- relapse 82%). In the 17p- 1st-line and relapse groups, 52% and 50% were stage Binet C and exhibit reduced performance status (ECOG 1–2), compared to 81% Binet C and 60% ECOG 1–2 for the F-refractory cohort. Pretreated pts had received a median of 2 prior lines (F-refractory 1–6; 17p- relapse 1–5), and 5 pts had received prior SCT. In the F-refractory group, 16% of pts had 11q- and 52% had 17p-. IGHV was unmutated in 64% of 17p- groups and 72% in the F-refractory group. The median levels of ß2-MG / TK were 4.35 / 35.40 in the 17p- groups and 4.12 / 22.65 in the F-refractory group. Treatment data are currently available for 50 pts who completed induction therapy; F-refractory (n=19),17p- 1st-line (n=22), 17p- relapse (n=9). Full treatment duration (12 weeks) could be achieved in 47% F-refractory, 67% 17p- relapsed and 82% 17p- 1st-line pts. In the latter cohort, early stop of therapy was mainly correlated with CR, while in the F-refractory cohort with disease progression (n=2) and infections (n=5, 4 with no documented response). Response rates (ORR / CR) were 47% / 0% in the F-refractory cohort, 78% / 0% in the 17p- relapsed, and 100% / 23% in the 17p- 1st-line cohorts (as compared to this, ORR / CR was 71.4% / 4.8% with FCR in the 17p- 1st-line group of CLL8). Adverse events during treatment were mostly grade 1/2 apart from hematotoxicity. Grade 3/4 non-CMV infection occurred in 35% of F-refractory, 12% of 17p- relapsed, and 16% of 17p- 1st-line pts. CMV reactivation was observed in 32 % of the 17p- 1st-line pts, and less for the pretreated groups (F-refractory 16%, 17p- relapsed 18%). All CMV episodes were successfully treated, and there was no CMV-related death. Among 18 pts documented to receive alemtuzumab maintenance treatment, so far 3 SAEs have been reported: ITP (n=1, twice in the same pt), and fever / diarrhea / thyroiditis (n=1). At a median follow-up of 41.9 weeks (maintenance 54.7 weeks, allo-SCT 29 weeks), there were 7 (37%) deaths in the in the F-refractory cohort, 2 due to disease progression, and 5 due to infection. For the 17p- relapsed group, 3 progressions and 3 deaths were reported, with one case in each treatment option (SCT/maintenance), and one pt in salvage therapy. In the 17p- 1st-line cohort, 4 progressions occurred, 2 pts died, both in maintenance therapy. At 12 months, estimated overall survival was 54%, 66% and 100% in the F-refractory, 17p- relapse, and 17p- 1st-line cohorts, respectively. Accrual is currently ongoing with a target enrolment of 122 pts and updated results will be presented at the meeting. Disclosures: Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Off Label Use: off-label use of diagnostic tests and therapeutic agents. Leblond:ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria. Choquet:ROCHE : Consultancy. Hallek:Roche: Honoraria, Research Funding. Döhner:Pfizer: Research Funding.

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