Atorvastatin administration to both the donors and recipients of matched related donor (MRD) allogeneic hematopoietic cell transplantation (allo-HCT) as acute graft-versus-host disease (GVHD) prophylaxis has been shown to be safe and effective. However, its efficacy as acute GVHD prophylaxis when given only to allo-HCT recipients is unknown. We conducted a phase II study to evaluate the safety and efficacy of atorvastatin-based acute GVHD prophylaxis given only to the recipients of MRD (n = 30) or matched unrelated donor (MUD) (n = 39) allo-HCT, enrolled in 2 separate cohorts. Atorvastatin (40 mg/day) was administered along with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. All patients were evaluable for acute GVHD. The cumulative incidences of grade II to IV acute GVHD at day +100 in the MRD and MUD cohorts were 9.9% (95% confidence interval [CI], 0 to 20%) and 29.6% (95% CI,15.6% to 43.6%), respectively. The cumulative incidences of grade III and IV acute GVHD at day +100 in the MRD and MUD cohorts were 3.4% (95% CI, 0 to 9.7%) and 18.3% (95% CI, 6.3% to 30.4%), respectively. The corresponding rates of moderate/severe chronic GVHD at 1 year were 28.1% (95% CI, 11% to 45.2%) and 38.9% (95% CI, 20.9% to 57%), respectively. In the MRD cohort, the 1-year nonrelapse mortality, relapse rate, progression-free survival, and overall survival were 6.7% (95% CI, 0 to 15.4%), 43.3% (95% CI, 24.9% to 61.7%), 50% (95% CI, 32.1% to 67.9%), and 66.7% (95% CI, 49.8% to 83.6%), respectively. The respective figures for the MUD cohort were 10.3% (95% CI, 8% to 19.7%), 20.5% (95% CI, 7.9% to 33.1%), 69.2% (95% CI, 54.7% to 83.7%), and 79.5% (95% CI, 66.8% to 92.2%), respectively. No grade 4 toxicities attributable to atorvastatin were seen. In conclusion, the addition of atorvastatin to standard GVHD prophylaxis in only the recipients of MRD and MUD allo-HCT appears to be feasible and safe. The preliminary efficacy seen here warrants confirmation in randomized trials.

Atorvastatin (ATOR) administration to both the donors and recipients of MRD alloHCT as aGVHD prophylaxis is safe and effective (JCO. 2013; 31:4416-23). The efficacy of ATOR as aGVHD prophylaxis when given toalloHCT recipients only is unknown. We conducted a multicenter, phase II study (NCT01665677) to evaluate the safety and efficacy of ATOR-based aGVHD prophylaxis given only to the recipients of MRD and MUD alloHCT, enrolled in two separate cohorts. Acute GVHD prophylaxis consisted of tacrolimus, micro-dose methotrexate and ATOR (40mg/day) from days -14 to +180. Ex vivo or in vivo T-cell depletion was not permitted. Primary outcomes were incidence of grade (Gr) 2-4 aGVHD at day 100 and safety of ATOR. The study was powered to detect a 20% reduction in day 100 Gr 2-4 aGVHD relative to historical rates (35% to 15% in MRD and 55% to 35% in MUD). From Sep 2012-March 2015, target enrollment of 30 MRD and 39 MUD patients (pts) was completed. Table 1 shows baseline pt characteristics. Only 1 MRD pt had Gr 3 ALT elevation. All pts engrafted (median of 16 days for MRD and 15 days for MUD grafts). Median day 100 CD33+ cell chimerism in both cohorts was 100%. The cumulative incidence (CI) of Gr 2-4 and Gr 3-4 aGVHD at day100 in the MRD cohort was 9.9% (95%CI: 0-20%) & 3.4% (95%CI: 0-9.7%) and in MUD cohort 29.8% (95%CI: 15.7-43.9%) & 18.3% (95%CI: 6.2-30.3%), respectively. CI of Gr 2-4 aGVHD at day180 were 16% and 34.9% in MRD and MUD, respectively. The respective figures for Gr 3-4 aGVHD at day180 were 3.4% and 21.4%. CI of moderate/severe chronic GVHD at 1 year for MRD and MUD were 35.6% (95%CI: 15.7-55.4%) and 43.5% (95%CI: 23.1-63.1%), respectively. At 1-year, the rates of non-relapse mortality were 3.3% and 9.4%; relapse 43% and 19%; progression-free survival 50% and 71%, and overall survival 65% and 76%, respectively for MRD and MUD cohorts. Addition of ATOR to standard GVHD prophylaxis in MRD and MUD HCT appears to be feasible, safe and effective.Table 1MRDN=30(range)MUDN=39 (range)Male pts1727Median age, yrs61 (19 –72)58 (23–74)Median days on ATOR183 (26–533)141 (22-202)Median KPS90 (70-100)90 (70-100)Median HCT-CI2 (0-7)2 (0-5)CIBMTR Disease Risk Low1222 Intermediate95 Advanced912Diagnosis Leukemia/MDS3620 Lymphoma38 Others-2 Chemorefractory912 Prior autograft53 10/10 HLA match3039Conditioning RIC1715 Myeloablative1324 PB graft3039 ABO mismatched725Median Follow-up of survivors, days378 (245-973)299 (176-720) Open table in a new tab

Purpose Graft-versus-host disease (GVHD) is major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Atorvastatin is a potent immunomodulatory agent that holds promise as a novel and safe agent for acute GVHD prophylaxis.Patients and Methods We conducted a phase II trial to evaluate the safety and efficacy of atorvastatin administration for GVHD prophylaxis in both adult donors and recipients of matched sibling allogeneic HCT. Atorvastatin (40 mg per day orally) was administered to sibling donors, starting 14 to 28 days before the anticipated first day of stem-cell collection. In HCT recipients (n = 30), GVHD prophylaxis consisted of tacrolimus, short-course methotrexate, and atorvastatin (40 mg per day orally).Results Atorvastatin administration in healthy donors and recipients was not associated with any grade 3 to 4 adverse events. Cumulative incidence rates of grade 2 to 4 acute GVHD at days +100 and +180 were 3.3% (95% CI, 0.2% to 14.8%) and 11.1% (95% CI, 2.7% to 26.4%), respectively. One-year cumulative incidence of chronic GVHD was 52.3% (95% CI, 27.6% to 72.1%). Viral and fungal infections were infrequent. One-year cumulative incidences of nonrelapse mortality and relapse were 9.8% (95% CI, 1.4% to 28%) and 25.4% (95% CI, 10.9% to 42.9%), respectively. One-year overall survival and progression-free survival were 74% (95% CI, 58% to 96%) and 65% (95% CI, 48% to 87%), respectively. Compared with baseline, atorvastatin administration in sibling donors was associated with a trend toward increased mean plasma interleukin-10 concentrations (5.6 v 7.1 pg/mL; P = .06).Conclusion A novel two-pronged strategy of atorvastatin administration in both donors and recipients of matched sibling allogeneic HCT seems to be a feasible, safe, and potentially effective strategy to prevent acute GVHD.

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.

Abstract Abstract 4536 Introduction: Allogeneic hematopoietic cell transplant (AHCT) is a potentially curative modality for various benign and malignant hematological disorders. Despite advances in supportive care, graft-versus-host disease (GVHD) remains the leading cause of morbidity and mortality following AHCT. In vivo T-cell depletion (TCD) with alemtuzumab or anti-thymocyte globulin (ATG) is commonly employed to prevent graft rejection and GVHD following AHCT. Published (albeit controversial) data suggest possible benefit with TCD in setting of unrelated donor (URD), HLA-mismatched and peripheral blood AHCT. We report here AHCT outcomes for patients who received alemtuzumab or ATG with transplant conditioning (TCD group) and compare them with patients who received T-cell replete allografts (non-TCD group). Methods: The study cohort consists of 150 consecutive patients who underwent AHCT between January 2003 through December 2009. All patients received peripheral blood allografts from matched sibling or URDs. T-cell depletion consisted of alemtuzumab 40mg in two divided doses on days -4 and -1 (n=39) or Thymoglobulin at a total dose of 6 mg/kg for ablative and reduced intensity conditioning (RIC) transplants and 7.5 mg/kg total dose for non myeloablative allografts (n=51). 4 patients received Atgam at 30mg/kg on days -5 to -3. Results: Of the 150 patients, 62.7% (n=94) were males. Median age was 49yrs (range 17–69). Baseline diagnosis included acute leukemias/myelodysplastic syndrome (n=88; 58.6%), chronic myeloid leukemia (n=19; 12.7%), non-Hodgkin lymphoma (n=27; 18%) and others (10.7%). There were 95 patients (63.3%) in the TCD group and 55 (36.7%) in the non-TCD group. The baseline characteristics of the TCD group and non-TCD group where well matched except for significantly more patients in the TCD group who had high risk disease (86.3% vs. 61.8%, p < 0.05) and received AHCT from URD (62.1% vs. 29.1%, p<0.05). Median follow-up time of surviving patients is 3yrs. Median time to neutrophil engraftment was 15days (range 7–29 days) overall, with no significant difference between the two groups (p = 0.92). Similarly median time to platelet recovery was 18days (range 4–106), with no significant difference between the two groups (p = 0.85). The incidence of grades II-IV acute GVHD (aGVHD II-IV) in the TCD and non-TCD groups was 42.1% (n=40) and 50.9% (n=28) respectively (p = 0.32). For subgroup of patients undergoing matched sibling AHCT the incidence of aGVHD II-IV in TCD and non-TCD groups was 28.9% (n=11) and 50% (n=18) respectively (p= 0.06). For URD AHCT the corresponding rates of aGVHD II-IV were 48.3% (n=28) and 64.7% (n=11) respectively (p = 0.23). Rates of aGVHD II-IV for patients in TCD and non-TCD group receiving HLA mismatched allografts were also not significantly different (p = 0.59). 110 patients were evaluable for chronic GVHD (cGVHD). The incidence of cGVHD in the TCD and non-TCD groups was 41.1% (n=39) and 45.5% (n=25) respectively (p = 0.86). On subgroup analysis of patients undergoing matched sibling, URD and HLA-mismatched transplants no significant difference in rates of cGVHD between the TCD and non-TCD groups was seen (p>0.05). Relapse rate in the TCD group was 32.6% (n=31) and in the non-TCD group 40% (n=22) (p = 0.22). The overall survival at 3 years was 39.2% in the TCD group and 39.3% in the non-TCD group, (p = 0.93). The 3 year progression free survival in the TCD and non-TCD groups were 34.8% and 27.2% respectively (p=0.85). Non relapse mortality at 100 days similarly were 12.8% and 16% and at 3 years were 40% and 41% in the 2 groups (p>0.05). CONCLUSION: Our limited, single institution experience in a cohort of 150 consecutive patients (transplanted within the last decade) suggests no significant benefit with routine use of in vivo TCD with AHCT. These results highlight the need to develop novel and more effective strategies for preventing and treating GVHD and for improving transplantation outcomes. Disclosures: Abraham: Genentech: Membership on an entity's Board of Directors or advisory committees. Hamadani:Celgene corporation: Honoraria, Speakers Bureau; Otsuka Pharmaceutical: Research Funding, Speakers Bureau.

We evaluated the impact of busulfan dose intensity in patients undergoing reduced toxicity/intensity conditioning allogeneic transplantation in a multicenter retrospective study of 112 consecutive patients. Seventy-five patients were conditioned with busulfan (0.8mg/kg/dose IV x 8 doses), fludarabine (30mg/m2/day, days -7 to -3), and 6mg/kg of ATG [reduced intensity conditioning (RIC) group], while 37 patients received a more-intense conditioning with busulfan (130mg/m2/day IV, days -6 to -3), fludarabine (40mg/m2/day, days -6 to -3) and 6mg/kg of ATG [reduced toxicity conditioning (RTC) group]. At baseline both groups were matched for median age, unrelated donor allografts, and human leukocyte antigen-mismatched allografts. More patients in RIC group had high-risk disease, and higher median comorbidity index. There were no graft rejections. Median time to neutrophil (17 days vs. 15 days; p=0.003) and platelet engraftment (16 days vs. 11 days; p<0.001) was significantly longer in the RIC group. RTC group had significantly more bacterial (62.2% vs. 32%; p=0.004) and fungal infections (13.5% vs. 1.3% p=0.01). For RIC and RTC groups rates of grades IIIV acute GVHD (34% vs. 40%; p-value=0.54), and chronic GVHD (45% vs. 57%; p-value=0.30) were not significantly different. In similar order at 1 year the cumulative-incidence of non-relapse mortality (NRM; 12% vs. 21%; p-value=0.21) and relapse rates (38% vs. 39%; p=0.96) were not significantly different. Patients in RIC and RTC groups had similar 1-year overall survival (61% vs. 50%, p=0.11) and progression-free survival (50% vs. 36%, p-value=0.39). Our data suggest that the merits of higher busulfan dose intensity in the context of fludarabine/busulfan-based RTC may be offset by higher early morbidity. Copyright (C) 2011 John Wiley & Sons, Ltd.

BACKGROUND AND OBJECTIVESUnderstanding the effect of cellular graft composition on allogeneic hematopoietic cell transplantation (AHCT) outcomes is an area of great interest. The objective of the study was to analyze the correlation between transplant-related outcomes and administered CD34+, CD3+, CD4+ and CD8+ cell doses in patients who had undergone peripheral blood, AHCT and received either in vivo T-cell depleted or T-cell replete allografts.DESIGN AND SETTINGComparison of consecutive patients who underwent peripheral blood AHCT in our institution between January 2003 and December 2009.PATIENTS AND METHODSThe cohort of 149 patients was divided into two groups; non T-cell depleted (NTCD) (n=54) and T-cell depleted (TCD) (n=95). Study endpoints were overall survival (OS), progression free survival (PFS), engraftment kinetics (neutrophil and platelet recovery), incidence of acute graft versus host disease (acute GVHD), chronic GVHD, nonrelapse mortality (NRM) and disease relapse.RESULTSMultivariate analysis showed that higher infused CD34+ cell dose improved OS (relative risk 0.58, 95% CI 0.34-0.98, P=.04), PFS (relative risk 0.59, 95% CI 0.35-1.00, P=.05) and NRM (relative risk 0.49, 95% CI 0.24-0.99, P=.048) in the TCD group. By multivariate analysis, there was no difference in engraftment, grades II-IV acute GVHD, extensive chronic GVHD and relapse in the two groups relative to the infused cell doses. There was a trend towards improved OS (relative risk 0.54, 95% CI 0.29-1.01, P=.05) with higher CD3+ cell dose in the TCD group.CONCLUSIONOur findings suggest that higher CD34+ cell dose imparts survival benefit only to in vivo TCD peripheral blood AHCT recipients.

Peripheral blood progenitor cell mobilization with intermediate-dose cyclophosphamide (ID-CY) and granulocyte colony-stimulating factor (G-CSF) has been shown to be more efficacious, albeit more toxic, than low-dose cyclophosphamide (LD-CY) mobilization regimens in patients with multiple myeloma treated with conventional therapies. However, the relative importance of cyclophosphamide dose intensity in peripheral blood progenitor cell mobilization after novel induction regimens is not known. Here we report mobilization outcomes of 123 patients who underwent transplantation within 1 year of starting induction chemotherapy with novel agents. We compared consecutive patients undergoing mobilization with ID-CY/G-CSF (3-4 g/m(2)) at one institution (n = 55) with patients receiving LD-CY/G-CSF (1.5 g/m(2)) at a different transplantation center (n = 68). At baseline, the 2 groups were well balanced, except for more frequent previous lenalidomide use in the ID-CY group (P = .04). Compared with LD-CY, ID-CY use was associated with higher median peak PB CD34(+) cell count (35/mu L versus 160/mu L; P < .001), CD34(+) cell yield on day 1 of collection (2.6 x 10(6)/kg versus 11.7 x 10(6)/kg, P <=.001), and total CD34(+) cell yield (7.5 x 10(6)/kg versus 16.6 x 10(6)/kg; P <= .001). Six patients in the LD-CY group had mobilization failure, compared with no patients in the ID-CY group. A significantly higher proportion of patients in the LD-CY group (P < .001) were unable to collect >= 5 x 10(6)/kg and >= 10 x 10(6)/kg CD34(+) cells. Neutrophil and platelet engraftment were significantly faster in the ID-CY group, likely because of higher infused CD34(+) cell doses. In conclusion, compared with LD-CY, ID-CY produced a more robust peripheral blood progenitor cell mobilization and significantly reduced the rates of mobilization failure. These data caution against the use of LD-CY-containing mobilization strategies in patients with multiple myeloma undergoing stem cell collection after novel induction regimens. Biol Blood Marrow Transplant 18: 1128-1135 (2012) (C) 2012 American Society for Blood and Marrow Transplantation

NMA conditioning with TLI/ATG (TA) has shown remarkably low rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM). Randomized comparisons of TA with more intense conditioning regimens have not been performed. We report here a retrospective comparison of transplant outcome following NMA with TA or reduced "toxicity" conditioning with fludarabine, busulfan and ATG (FBA), in cohort of patients deemed not suitable for conventional myeloablative conditioning regimens. The study group consists of 48 consecutive patients who underwent ASCT after conditioning with FBA (n = 37) or TA (n = 11) because of advanced age or presence of co-morbidities. FBA regimen consisted of fludarabine 40mg/m2/day and busulfan 130mg/m2/day intravenously x4 doses starting day -6 and ATG 2mg/kg/day for 3 days, starting day -3. TA group received ATG 1.5mg/kg/day for 5 days and TLI dose of 800 cGy starting day -11. Baseline characteristics are in table 1.Table 1Patient CharacteristicsVariablesFBA (n=37)TA (n=11)p - valueSex : n (%)0.74Men21 (57)7 (64)Women16 (43)4 (36)Age: median (range)53 (17-65)58 (38-70)0.20Diagnosis: n (%)0.01Acute Leukemia/MDS24 (65)2 (18)Non-Hodgkin Lymphoma8 (22)8 (73)Chronic Leukemia3 (8)1 (9)Plasma Cell Disorder2 (5)0 (0)Remission Status: n (%)0.09Chemo-sensitive28 (76)11 (100)Chemo-refractory9 (24)0 (0)Risk group: n (%)0.25Standard risk12 (32)1 (9)High risk25 (68)10 (91)Prior autologous transplant: n (%)5 (13)1 (9)1.00Donor type: n (%)0.26Sibling9 (24)5 (45)Unrelated28 (76)6 (55)HLA mismatch: n (%)7 (19)1 (9)0.66CD 34+ dose: median (range) [x 10∗6/Kg body weight]7.2 (4-12.8)5.1 (2.6-9)0.03 Open table in a new tab The median follow up of surviving patients is 1 year. The rate of grade II-IV acute GVHD in the FBA and TA groups was 45.9%(n = 17) and 36.3% (n = 4) respectively (p = 0.73). Rate of Grade III-IV acute GVHD in the two groups was 8% (n = 3) and 36.3% (n = 4) respectively (p = 0.02). The rate of chronic GVHD in similar order was 37.8% and 36.8% (p = 1.0). Post transplant rates of proven bacterial, fungal and BK virus infections and CMV reactivation were similar between the two groups (p > 0.05). The cumulative incidence of disease relapse at 2years for FBA and TA groups was 46% and 10% respectively (p = 0.1). non-relapse mortality (NRM) for the FBA and TA cohorts at day 100 (2% vs.0%) and 2 years (31% vs.30%) was not significantly different (p = 0.3). Compared to FBA group, TA groups showed trends towards improved 2 year OS (40% vs.60%; p = 0.07) and significantly better 2year progression free survival (36% vs.60%; p = 0.036). Acknowledging the limitation of our study (including small sample size, retrospective nature, higher proportion of chemosensitive/low-risk patients in TA group), it is worth noting that NRM rates with TA are surprisingly identical to an ablative FBA conditioning. Rates of grade III-IV acute GVHD are also significanlty higher despite small patient numbers. The difference is PFS is likely due to low relapse rates in a standard-risk patient population. Our data highlight the need for prospective studies to define optimal conditioning regimens.

We evaluated the effects of busulfan's dose-intensity in patients undergoing RIC ASCT at two different transplant centers. Forty-three patients were conditioned with busulfan (0.8 mg/kg/dose IV × 8 doses), fludarabine (30 mg/m2/day, days -7 to -3), and 6 mg/kg of ATG (L-FBA), while 23 patients received a 'more-intense' RIC with busulfan (130 mg/m2/day IV, days -6 to -3), fludarabine (40 mg/m2/day, days -6 to -3), and 6 mg/kg of ATG (H-FBA). Median age was 55 years. 84% (N=56) had high-risk disease. 19 patients (29%) received mismatched allografts. 55 patients (83%) received grafts from unrelated donors. Baseline characteristics were well balanced between the two cohorts, except for higher proportion of unrelated donors in L-FBA group (p-value=0.02). All patients engrafted neutrophils and platelets (median 17 and 13 days, respectively). There were no graft rejections. Compared to patients receiving H-FBA, those receiving L-FBA had fewer CMV reactivations (48% vs. 30%; p-value=0.15), bacterial infections (69% vs. 43%; p-value=0.004) and slightly lower rates of 1-year non-relapse mortality (17% vs. 7%; p-value=0.19). Compared to L-FBA, H-FBA did not reduce relapse rates (34% vs. 43%; p-value=0.49). Rate of grade II-IV acute GVHD (30% vs. 52%; p-value=0.08) favored L-FBA, while incidence rate of chronic GVHD (40% vs. 40%; p-value=0.11) were similar. Median day +90 and +360 chimerism for both groups was 100%. 38 patients (58%) were in CR after ASCT. The median follow-up of surviving patients is 12 months. Compared to patients receiving H-FBA, ones receiving L-FBA showed a significantly superior 1-year overall survival (44% vs. 68% p-value=0.02) and trend toward improved 1-year progression free survival (33% vs. 60% p-value=0.07). Our preliminary, retrospective data suggests that L-FBA maintains acceptable rates of disease relapse, non-relapse mortality, full-donor cell chimerism and GVHD control compared to H-FBA, and may be associated with lower rates of infectious complications and improved survival.

Abstract Abstract 1272 Introduction: Allogeneic hematopoietic cell transplant (HCT) remains a potentially curative modality for various hematological disorders. The cellular composition of the infused allograft has important ramifications for transplantation outcomes, for example higher infused CD34+ cell doses have previously been shown to be is associated with early engraftment, improved survival and possibly increased acute graft-versus-host disease (GVHD) following HCT. The influence of cellular composition of infused allograft on transplant outcomes has been the subject of many previous studies. There is paucity of data on the impact of cellular composition of allograft on transplant outcomes of patients undergoing HCT with in vivo T-cell depletion (TCD) compared to patients receiving T-cell replete allografts. We report here a comparative analysis of the impact of CD34+, CD3+, CD4+ and CD8+ cell doses and survival outcomes of allogeneic, peripheral blood HCT patients receiving in vivo T-cell depletion with alemtuzumab or anti thymocyte globulin (TCD group) versus patients who underwent T-cell replete HCT (non-TCD group). Methods: The study cohort includes 150 consecutive patients who underwent allogeneic HCT between January 2003 through December 2009. All patients received peripheral blood allografts from matched sibling or unrelated donors (URD). In vivo T-cell depletion consisted of alemtuzumab 40mg in two divided doses on days -4 and -1 (n=39) or Thymoglobulin at a total dose of 6 mg/kg for ablative and reduced intensity conditioning (RIC) transplants and 7.5 mg/kg total dose for non myeloablative allografts (n=51). 4 patients received Atgam at 30mg/kg on days -5, -4 and -3. Impact of CD34+, CD3+, CD4+ and CD8+ cell doses divided into two groups; >/= 50th and < 50th percentile on overall survival (OS), progression free survival (PFS) and non relapse mortality (NRM) was initially measured by univariate analysis. Multivariate logistic regression analysis was constructed for variables showing significance on univariate analysis (p<0.1). Cellular components of allografts was done by standard flow cytometric techniques. Results: Of the 150 patients, 94 (62.7%) were males. Median age was 49 (range 17–69). Baseline diagnosis included acute leukemia and myelodysplastic syndrome (n=88; 58.6%), chronic myeloid leukemia (n=19; 12.7%), non-Hodgkin lymphoma (n=27; 18%) and others (10.7%). There were 95 patients (63.3%) in the TCD group and 55 (36.7%) in the non-TCD group. The baseline characteristics of the TCD group and non-TCD group were well matched except that significantly more patients in the TCD group had high risk disease (86.3% vs. 61.8%, p = 0.0005) and received allografts from unrelated donors (62.1% vs. 29.1%, p < 0.001). Median doses of the infused cellular components in the allograft were; CD 34+ = 5.8 × 106/Kg (range 1.2 – 16), CD3+ = 30.8 × 107 (4.5 – 100.8), CD4+ = 18.6 × 107 (1.9 – 63) and CD8+ = 11.3 × 107 (0.8 – 52.4). Median follow-up time for surviving patients was 3 years. In the TCD group, multivariate analysis showed that CD34+ cell doses >/= 5.8 × 106 was associated with improved OS (p=0.0085; CI 0.28–0.83), PFS (p=0.03; CI 0.31–0.93) and NRM (p=0.02; CI 0.21–0.89). Multivariate analysis also showed that CD3+ cell dose >/= 30.8×107 improved OS (p=0.03; CI 0.25–0.92), but not PFS (p=0.14; CI 0.16–1.31) and NRM (p=0.15; CI 0.23–1.26). No association was noted between CD4+ and CD8+ cell doses and OS, PFS and NRM (p>0.05), in the TCD group. In the non-TCD group, univariate analysis of CD34+, CD3+, CD4+ and CD8+ cell doses failed to show any statistical significance for NRM, OS and PFS (p>0.1). Conclusion: Our limited, retrospective analysis of 150 peripheral blood allogeneic HCT shows improved OS, PFS and NRM in patients receiving CD34+ cell dose >/= 5.8×106/Kg and improved OS with CD3+ dose >/= 30.8×107/Kg, limited only to the TCD group. No such association was seen in the non-TCD group. We hypothesize that higher CD34+ in TCD transplants probably improved survival by rapid engraftment and by robust immune reconstitution thereby reducing infectious complication otherwise associated with TCD. Disclosures: Abraham: Genentech: Membership on an entity's Board of Directors or advisory committees. Hamadani:Celgene: Honoraria, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau.

Abstract Abstract 1347 Introduction: High dose therapy and autologous hematopoietic cell transplantation (AHCT) is a standard therapy option for at least young (<65 years) and otherwise transplant eligible multiple myeloma (MM) patients. While outcomes of AHCT in Hodgkin's and non-Hodgkin lymphoma patients showing evidence of chemo-sensitive disease pre-transplant are clearly superior, the prognostic significance of pre-AHCT remission status in MM is controversial. Failure to achieve at least a partial remission (PR) in response to induction chemotherapy before AHCT has not been shown to negatively impact transplant outcomes, at least in the pre-thalidomide (Thal)/lenalidomide (Len)/bortezomib (Bor) era (Kumar S, BMT 2004 & Singhal S, BMT 2002). Whether this paradigm holds true for novel agent-containing induction therapies is not known. Recently <50% reduction in ‘serum M-protein’ following induction with Thal or Len based induction therapy has retrospectively been shown to predict poor outcome after AHSCT (Gertz M, Blood 2010). However, data evaluating transplant outcomes relative to pre-transplant remission status assessed by strict IMWG criteria, and data in Bor-based regimens is still scant. We report here the impact pre-transplant remission status on outcomes of AHCT after chemotherapy with novel agents. Methods: The study involves 63 consecutive patients who underwent a planned, single AHCT within 1-year of starting induction chemotherapy with regimens containing Thal, Len, or Bor, between 2000–2009. All patients with normal renal function received uniform conditioning with Mel200 (MEL140 if serum creatinine was >2 mg/dl). The disease response pre- and post transplant was determined by using the IMWG criteria. SPSS version 16.0 was used for statistical analysis. Kaplan-Meier method was used to calculate overall survival (OS) and progression free survival (PFS). Outcomes of patients achieving at least a PR (P-group; n=54) before AHCT were compared with one not achieving at least a PR (NO-P-group; n=9). As an exploratory analysis outcomes of patient achieving at least a very good partial response (VGPR) (V-group; n=40) with ones not achieving at least a VGPR (NO-V-group) was also performed (no-V group; n=23). Results: The mean age of the patients at transplant was 53yrs (range 44 –72yrs). 68 % (n=43) of patients were male. At diagnosis 42 patients (66%) had Salmon-Durie stage III disease, while 21 (34%) had stage I/II disease. Median Karnofsky performance status was 90. At the time of AHCT, the median HCT-CI score was 0. 33 % (n=21) of the patients received radiation therapy prior to transplant. At a median follow-up of 36 months, the 3 year OS of patients in P-group and NO-P-group was 58% vs. 60% (p=0.93) respectively. The 3 year PFS in similar order was 22% vs. 31% (p=0.74). The 3 year OS of patients in V-group and NO-V-group (44% vs. 62%) was also not significantly different (p=0.53). Respective figures of 3 year PFS are 22% vs. 24% (p=0.72) respectively. 3yr non relapse mortality was 5% for the whole cohort. Of the 31 patients that entered an AHCT with a PR, 15 improved to a CR post transplant, 2 improved their status to a VGPR whereas 14 remained in a PR. A total of 9 patients entered an AHCT with a stable disease (SD) of which 5 advanced to a CR, 3 a PR and one remained in SD. On the other hand of the 6 patients who entered an AHCT with a VGPR, 2 improved to a CR whereas the rest maintained their status. Finally, all the 17 patients entering an AHCT with a CR maintained their status. Conclusion: Our limited, retrospective data suggest acceptable AHCT outcomes in MM patients who do not achieve at least a PR in response to novel induction chemotherapies pre-transplantation. Failure to achieve a PR following novel induction therapies should not ‘routinely’ preclude consideration for high-dose therapy and AHCT. Disclosures: Abraham: Genentech: Membership on an entity's Board of Directors or advisory committees. Craig:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamadani:celgene: Honoraria, Speakers Bureau; otsuka: Research Funding, Speakers Bureau.

Background: The administration of alemtuzumab (Campath 1H) as part of the conditioning regimen prior to allogeneic stem cell transplantation has been associated with a low incidence of acute and chronic GVHD. Initial studies employing doses of 100 mg have reported a high incidence of viral infections. Lower alemtuzumab doses combined with standard GVHD prophylaxis regimens (calcineurin inhibitor + MTX) have also resulted in a low incidence of acute GVHD in patients with CD52-positive malignancies. We investigated the effect of low-dose (40 mg) alemtuzumab on engraftment (VNTR chimerism studies), the incidence of acute and chronic GVHD, CMV reactivation, survival, and immune reconstitution (examined by TREC content at various time points after transplant). Patient and Transplant characteristics: Twenty-seven patients underwent a matched (n=24) or 1-antigen mismatched (n=3) related (n=13) or unrelated (n=14) allogeneic stem cell transplantation for various hematologic malignancies. Median age was 41 years (19–59). Disease stage at transplant was early for 48%, intermediate for 11% and late for 41%. Three patients received bone marrow and 24 received PBSC grafts. Conditioning regimen consisted of TBI 10 Gy with partial lung shielding, Thiotepa 500 mg/m 2 , and Alemtuzumab 20 mg IV on day -4 and day -1. GVHD prophylaxis was with cyclosporine (n=13) or tacrolimus (n=14) and full-dose MTX. High-dose viral prophylaxis with valacyclovir 2000 mg QID was given to all recipients from a CMV seropositive recipient/donor pair starting at patient #9, due to a high incidence of CMV reactivation amongst the first 8 patients. Three patients received DLI for disease relapse. Median follow-up for survivors is 13 months (6–26). Results: Of eighteen evaluable patients (3 relapsed, 5 expired, 1 not done) at day 100, 15 had ≥ 95% donor chimerism, and 3 had 90–94% donor chimerism. The cumulative incidence of acute GVHD grade II-IV at day 100 was 4% (95% CI 1–16%), and the cumulative incidence of chronic GVHD at 1 year was 31% (12–52%). Cumulative incidence of non-relapse mortality at day 100 was 18% (7–35%), and at 1 year 31% (14–49%). Cumulative incidence of relapse at 1 year was 28%, resulting in a projected 1-year disease-free survival of 41% (22–60%), and overall survival of 54% (33–71%). Amongst the first eight patients, all (5/5) at-risk recipients developed CMV reactivation. After initiation of prophylaxis with high-dose valacyclovir, 4/11 at-risk recipients developed CMV reactivation. No patient died from CMV disease. TREC analysis in a limited number of patients showed rapid increase in TREC between day 0 and day 180, but no further increment between day 180 and day 365. Conclusions: The use of low-dose alemtuzumab results in low incidences of acute and chronic GVHD. CMV reactivation is common, and can be partially prevented by use of high-dose valacyclovir. Immune reconstitution data on a small subset of patients show limited output of thymic emigrant T cells after 6 months.

Relapse of hematologic malignancies after allogeneic stem cell transplantation remains a common problem, in particular for patients who have advanced disease at the time of transplantation. Thiotepa has excellent antileukemic and immunosuppressive activity, and could therefore be a useful drug in the conditioning regimen for patients with advanced hematologic neoplasms. We retrospectively analyzed toxicity, engraftment and survival data of 41 patients who received a conditioning regimen of thiotepa (600 mg/m2) and hyperfractionated TBI (10 Gy) prior to matched related (n=25) or matched unrelated (n=16) allogeneic stem cell transplantation. The mean age at transplantation was 37.8 years (range 20–59), all but five patients had advanced hematologic malignancies at the time of transplantation. GVHD prophylaxis was with standard cyclosporine and methotrexate. Engraftment was excellent, but the regimen was associated with a high incidence of grade III renal (41%) and hepatic (15%) toxicity, and high transplant-related mortality (44% at day +90). The 3-year event-free survival was 13% and overall survival 14%. We conclude that this regimen requires modification to reduce toxicity.

We evaluated the results of high-dose therapy (HDT) and autologous hematopoietic stem cell transplantation (ASCT) in patients with relapsed or primary refractory Hodgkin’s disease (HD), using a previously reported prognostic model based on the presence of three poor prognostic factors at the start of salvage therapy/preparative regimen: B symptoms, extranodal disease and the duration of last complete response of less than 1 year. Based on this model, the patients were divided into low-risk and high-risk groups. Between 1993 and 2001, 24 patients with HD were treated with HDT and ASCT. Eighteen of the 24 patients had 0–1 risk factors (low-risk group) and 6 patients had 2–3 risk factors (high-risk group). Using Kaplan-Meier analysis, after a median follow-up of 40.5 months, the progression-free survival (PFS) was 48%, and the overall survival (OS) was 55%. PFS in the low-risk group was 56%, and in the high-risk group 17% (p < 0.001). OS in the low-risk group was 68% and in the high-risk group it was 18% (p < 0.001). The 100-day transplant-related mortality for the entire group was 16%. Our results are comparable to those reported in previous clinical trials for patients with refractory and relapsed HD treated with HDT and ASCT. The use of a prognostic model appears useful for predicting the outcome of HDT and ASCT for HD patients, and may play an important role in choosing the appropriate therapy for these patients.

Allogeneic stem cell transplantation (SCT) is the treatment of choice for selected patients with chronic myeloid leukemia (CML). However, it is associated with a high risk of treatment-related mortality (TRM) and morbidity. To assist in decision making about transplantation, a simple scoring system to assess the risk is needed. We analyzed the utility of a scoring system, first reported by the European Group for Blood and Marrow Transplantation (EBMT). We analyzed the data from 31 patients who underwent allogeneic transplantation at our institution, using the EBMT scoring system. It was based on five pretransplant risk factors: donor type, stage of disease at time of transplantation, age of recipient, sex of donor and recipient, and interval between diagnosis and transplant. Seventeen patients had a risk score of 0–2, and 14 patients had a score of 3–7. Using Kaplan-Meier analysis, the estimated 4-year leukemia-free (LFS) and overall survival (OS) for patients with a score of 0–2 were 47 and 53%, respectively. In contrast, the estimated 4-year LFS and OS for patients with a score of 3–7 were 10.5 and 10.5%, respectively. Four-year TRM was 47% for the low-risk group (0–2), and 85% for the high-risk group (3– 7). This simple scoring system may play an important role in predicting the outcome of allogeneic SCT, and in choosing the appropriate therapy for patients with CML.