Reduced Intensity Research Articles

Oral Proteasome Inhibitor Ixazomib for Switch-Maintenance Prophylaxis of Recurrent or Late Acute and Chronic Graft-versus-Host Disease after Day 100 in Allogeneic Stem Cell Transplantation

Graft-versus-host disease (GVHD) is a frequent complication in the first year after allogeneic stem cell transplantation (allo-HCT). Recipients of reduced-intensity (RI) or nonmyeloablative (NMA) conditioning combined with calcineurin inhibitor (CNI)-based GVHD prophylaxis frequently develop GVHD in the context of immunosuppression taper. Ixazomib is an oral proteasome inhibitor with a wide safety profile that has demonstrated immunomodulatory properties, inhibition of pro-inflammatory cytokines, and anti-tumor activity. We hypothesized that switch-maintenance GVHD prophylaxis using ixazomib would facilitate CNI taper without increased GVHD frequency and severity while maintaining graft-versus-tumor (GVT) effect and an acceptable safety profile. We conducted an open-label, prospective, single-center pilot study in patients with hematologic malignancies who received an RI or NMA conditioning and CNI-based GVHD prophylaxis that were within day 100 to 150 after HCT (n=18). Patients were treated with ixazomib once weekly on a 28-day cycle (3 weeks on, 1 week off). Treatment was safe; most adverse events were grade 1 or 2, with cytopenia and elevation in transaminases the most common. Five patients were removed from the study because of toxicity or side effects. Only 5 of 18 patients developed GVHD during the study, and its severity was driven by acute manifestations while chronic involvement was mild. The cumulative incidence of grade II-IV acute and chronic GVHD at 1-year after HCT was 33% (95% confidence interval [CI], 13-55). No patients died during the study, and only 1 had malignant relapse. An additional patient relapsed after completion of the study but within 1 year after HCT. The probability of progression-free survival and GVHD-free/relapse-free survival (composite endpoint) at 1 year were 89% (95% CI, 75-100) and 78% (95% CI, 61-100), respectively. Immune reconstitution analysis showed a rapid and sustained recovery in T-cell subpopulations and B cell reconstitution, and vaccine response in a subset of patients demonstrated continuing or de novo positive protective antibody titers. This study demonstrated low incidence of recurrent and late acute and chronic GVHD within 1 year after HCT possible associated with switch-maintenance GVHD prophylaxis using ixazomib. This approach allowed for CNI taper while preserving GVT effect, without aggravating GVHD. Our findings support further development of this approach and provide a proof-of-concept for switch-maintenance GVHD prophylaxis.

Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Influence of Conditioning Regimens with Total Body Irradiation (TBI) on Graft Versus Host Disease and Graft Versus Leukemia Effect Following Donor Lymphocyte Infusions (DLI)

Introduction In this study, our aim is to analyse the effect of conditioned with TBI on the outcome of DLI after allo-HSCT. Patients and Methods This retrospective study cohort included 152 patients treated with a total of 250 DLI for relapsed hematological malignancies after allo-HSCT from March 1991 through July 2018. Patients received myeloablative- (MA) (n=97 (63.8%)) or reduced-intensity (RI) (n=55 (36.2%)) conditioning regimens. TBI was administered at a total dose of 4 Gy/day for 3 days in MA regimens or 2 Gy/day for 1 day in RIC regimens. Results Thirty nine (25.7%) of 152 patients received TBI in conditioning regimen (Table 1). Median number of DLI was 1 (range, 1-5) in both groups. Seventy eight (20 (55.6%) and 58 (53.2%) in TBI and non-TBI group; p>0.1) patients developed acute grade II to IV GVHD. Chronic GVHD was occurred in 22 (51.2%; extensive in 4) and 52 (46%; extensive in 6) patients in TBI and non-TBI group (p=0.07). We could not demonstrate the lower doses of TBI associated with an increased risk of GVHD in TBI groups. Among all patients, 49 (32.2%) and 16 (10.5%) had relapse and/or progressive disease after DLI in non-TBI and TBI groups, respectively (p>0.1). The primary cause of death was relapse in both groups, whereas 5 (23.8%) and 11 (12.8%) patients died of TRM in TBI and non-TBI groups (p>0.1). The OS at 1 and 3 years were slightly higher in non-TBI group (Figure 1a). When analyzed according to the TBI doses, median OS is similar between two groups (Figure 1b). Discussion Irradiation is known to inhibit lymphocyte activity and consequently to reduce the incidence of GVHD in experimental models for allo-HSCT. In our study, acute and chronic GVHD incidence was similar in both groups but lower survival rate was seen in TBI group (p>0.1). Larger and prospective studies are warranted.

Allogeneic hematopoietic cell transplant (alloHCT) for hematologic malignancies in human immunodeficiency virus infected (HIV) patients (pts): Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0903)/AIDS Malignancy Consortium (AMC-080) trial.

7006 Background: AlloHCT has been regarded as risky in HIV pts, with concern about fatal infection. We set out to assess feasibility and safety of alloHCT in this first prospective multicenter trial. Methods: The primary endpoint was 100-day non-relapse mortality (NRM). Pts had drug-susceptible HIV; age ≥ 15 yr; adequate organ function; acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL), high risk myelodysplastic syndrome (MDS), or Hodgkin (HL) or non-Hodgkin lymphoma (NHL) beyond first CR; an 8/8 HLA-matched related or at least a 7/8 unrelated donor. Pts received myeloablative (MA) or reduced intensity (RI) regimens. HIV outgrowth assays (VOA) were performed with resting CD4+T-cells in pts who had clinically undetectable HIV plasma RNA at 1 yr. Results: Between 5/2012 and 12/2015, 17 pts underwent alloHCT. Pts were: male (17); white (11), African American (3), Other/Unknown (3); median age 47 yrs (25-64). Associated malignancies were AML (9), ALL (2), MDS (2), HL (1), NHL (3). Median CD4 was 224 (55-833). Conditioning was MA (8) and RI (9). At 100 days there was no NRM, 13 pts were in CR, 4 pts had relapsed/progressive disease; and 8 pts achieved complete chimerism. The cumulative incidence of Grades (Gr) II-IV acute Graft vs Host Disease (GvHD) was 41 % (95%CI: 18 %, 64%). At 6 mo, OS was 82 % (95% confidence interval [CI]: 55%, 94%); 9 pts achieved complete chimerism. At 1 year, OS was 57 % (CI: 31%, 77 %); 8 deaths were from relapsed/progressive disease (5), acute GvHD (1), adult respiratory distress syndrome (1) and liver failure (1). Infections were reported in 11 pts (3 Gr 2, 8 Gr 3). Infectious HIV was detected by VOA in 2 of 3 pts who were mixed chimeras but 0 of 2 who were 100% donor. Median follow up of survivors is 24 mo (7 to 27 ). Conclusions: HIV pts with heme malignancies underwent MA or RI alloHCT without any100-day NRM and there were no infectious deaths at 1 year. AlloHCT should be considered the standard of care for HIV pts who meet usual eligibility criteria. Clinical trial information: NCT01410344.

Successful Salvage of High-Risk B-Cell Non-Hodgkin and Hodgkin Lymphoma with Double-Unit Cord Blood Transplantation Provides a Platform for Further Optimization

Introduction: Allogeneic transplantation using double-unit cord blood grafts (DCBT) is an alternative therapy for adult patients with high-risk lymphomas without a HLA-matched sibling or volunteer donor but the efficacy of DCBT in this setting is not established.Methods: We analyzed overall survival (OS) and progression-free survival (PFS) after 4-6/6 HLA-matched DCBT in adults with B-cell non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) who were transplanted 2/2006-5/2013.Results: Patient characteristics by diagnosis are shown in the Table. Overall, the 47 patients (median age 46 years, range 20-70) had a median number of prior treatment regimens of 4 (range 1-13), 22/47 (47%) patients had had a prior autologous transplant, and the median pre-transplant HCT-CI score was 2 (range 0-6). Twenty-eight (60%) were in complete remission (CR). Conditioning was reduced intensity (RI) but functionally myeloablative in 16 patients (8 Cy/Flu/Thio/TBI400, 8 Mel/Flu) and 31 patients received non-myeloablative conditioning (NMA, Cy/Flu/TBI200). CB units had a median infused TNC dose x 107/kg of 2.7 (range 1.5-4.3) for the larger unit and 1.9 (range 0.9-3.4) for the smaller unit and a median donor-recipient HLA-allele match of 5/8 (range 1-7). The cumulative incidence of donor-derived engraftment was 98% (95%CI:77-99) with a median 22 day (range 13-37) and 10 day (range 7-46) neutrophil recovery after RI and NMA conditioning, respectively. Day 100 grade II-IV acute GVHD (20 grade II, 7 grade III, 1 grade IV) and 1-year chronic GVHD were 61% (95%CI:45-74) and 17% (95%CI:8-29), respectively. Day 180 transplant-related mortality (TRM) was 17% (95%CI:8-29). To date, 11 patients have progressive disease (median 3.4 months, range 2.8-58.0). The 3-year cumulative incidence of progression was 22% (95%CI:11-34). With a median 60 month (range 15-101) follow-up of survivors, the 3-year KM estimate of OS and PFS are 56% (95%CI:44-73) and 44% (95%CI:31-61), respectively (Figure). Of 23 patients who have died, 7 died of progressive disease whereas 16 died of transplant complications (2 organ failure, 10 GVHD, 2 infection, 1 encephalopathy of unknown cause, and 1 donor leukemia). Best PFS was observed in patients with follicular NHL (3-year PFS 62%) followed by HL (3-year PFS 47%) whereas those with diffuse large B-cell lymphoma, for example, did poorly (Table). There was no differences in 3-year PFS according to recipient age, HCT-CI, or number of prior regimens (each split above versus below the median), or receipt of a prior autologous transplant (all p = NS). Similarly, patients in CR pre-CBT (n = 28) had a 3-year PFS of 42% as compared to a 46% PFS in the non-CR patients (n = 19), p = 0.568. Four of 11 patients who relapsed survive to date (range 29-81 months) after treatment with chemotherapy (n = 3) or subsequent CB-derived mobilized peripheral blood stem cell (PBSC) transplant (n = 1).Conclusions: PFS after DCBT in patients with follicular NHL and HL is similar to that of adult donor allograft series and warrants further investigation. However, DCBT in other histologies is not as favorable. The high TRM rates may be influenced by the extent/intensities of prior therapy. Future clinical trials with DCBT should focus on strategies to reduce TRM, especially related to GVHD. Post-transplant maintenance to prevent disease progression could also be beneficial. Finally,chemotherapy to treat post-CBT relapse and CB-derived PBSC transplant are potential therapeutic options in selected patients.TableDiseaseType(N)Median(range) ageMedian(range)HCT-CIRemission statusMedian (range) prior regimens /N prior autoRegimenintensityPFSFollicular(n = 13)52 yrs (29-63) 1 (0-4)5 CR, 5 PR, 3 SD4 (2-8) / 3/13 (23%)3 MA 10 NMA3-yr: 62% (95%CI: 40-95)Diffuse large cell(n = 13)53 yrs (35-64) 2 (0-6)8 CR, 4 PR, 1 SD4 (1-7) / 3/13 (23%)4 MA 9 NMA3-yr: 23% (95%CI: 9-62)Mantle cell(n = 5)57 yrs (37-71)2 (1-6)5 CR3 (2-4) / 4/5 (80%)5 NMA2 disease-free at 29-70 monthsHodgkins(n = 15)35 yrs (20-50)3 (0-5)10 CR, 3 PR, 1 SD, 1 PD4 (2-13) / 12/15 (80%)8 MA 7 NMA3-yr: 47% (95%CI: 27-80)T-cellrich B-cell NHL (n = 1)38 yrs2PR7 / No auto1 MADied at 1.5 months [Display omitted] DisclosuresMoskowitz:Merck: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding.

Favorable T Cell Reconstitution In Reduced Intensity Conditioned Allogeneic Stem Cell Transplantation with Low-Dose Rabbit Anti-Thymocyte Globulin and Total Body Irradiation

Severe graft versus host disease (GVHD) continues to compromise transplant outcomes following reduced intensity (RI) allogeneic stem cell transplantation (SCT). ATG reduces the risk of GVHD in unrelated donor (URD) stem cell transplant (SCT) recipients. Here we report the results of a randomized phase II clinical trial evaluating two doses of rabbit ATG (Thymoglobulin, Sanofi Aventis) 5.1 (ATG5) and 7.5 mg/kg (ATG7.5) administered along with 450 cGy total body irradiation (TBI). This study followed an earlier trial which examined the optimal schedule of ATG administration in this regimen (Toor et al, BMT 2008). ATG was administered from day -9 to day -7, and fractionated TBI on day -1 and 0. Tacrolimus and mycophenolate mofetil were administered for GVHD prophylaxis. Forty-one patients with advanced hematologic malignancies were randomized and conditioned with ATG-TBI, stratified according to donor type, HLA-matched related (MRD) or unrelated (URD) donor. ATG5 had 10/19 URD recipients compared to 12/22 ATG7.5. Median age of the patients was 57; 9 patients had MM, 15 NHL, 12 CLL/PLL and 6 MDS/AML. Twenty-six were in CR at SCT (11 ATG5, 15 ATG7.5), 13 were in PR/SD (7 and 6 in the two arms) and 2 (1 in each arm) were in untreated relapse. Median number of prior therapies was 4 in each arm; 6 (ATG5) and 9 (ATG7.5) patients had a prior autologous SCT. Myeloid engraftment occurred at a median of 12 days after stem cell infusion in both arms; median neutrophil chimerism at 4, 8, 12 and 24 weeks was 0% recipient in both arms. Persistent mixed T cell chimerism was observed more frequently in the ATG7.5 arm with a trend toward full donor chimerism over time in the ATG5 patients (Figure 1); mean T cell chimerism was 14% in ATG5 and 25% in ATG7.5 at 4 weeks; 8 and 26 (repeated measures ANOVA p=0.058) at 8 weeks; 9 and 31 (RMANOVA p=0.016) at 12 weeks; and 6 and 27 (p=0.029) at 24 weeks respectively. Mean donor derived T cell counts (ddCD3; product of absolute CD3+ cell count and donor T cell chimerism) were 182/microliter, 1080, 872, 876 in ATG5 and 182, 290, 296, 445 in ATG7.5 patients at the corresponding time points, being significantly larger in the ATG5 arm compared to ATG7.5 at 8 (p = 0.008) and 12 weeks (p = 0.052). The changes in ddCD3 between successive months were significantly larger in the ATG5 cohort between 1 and 2 months (p = 0.004). Further, 2 patients in the ATG7.5 arm developed secondary graft loss indicating more robust engraftment in the ATG5 cohort, likely due to superior immune reconstitution. There was no significant difference in the survival between arms (Log-Rank P = 0.8). The 2-year survival rates were 64% (95%CI: 61%, 67%) ATG5 and 54% (95%CI: 50%, 58%) ATG7.5. Day 100 TRM was 0% in both arms; classical onset grade III-IV acute GVHD was not observed in either arm, 2 patients in the ATG7.5 arm developed grade II acute GVHD. Delayed onset acute GVHD occurred in 5 patients in the ATG5 cohort, (3 Grade III-IV) and 4 ATG7.5 (2 Grade III-IV) following early tapering of immunosuppression. Chronic GVHD occurred in 2 patients in ATG5 (1 mild, 1 severe) compared to 7 in ATG7.5 cohort (2 mild, 1 moderate, 4 severe). Overlap syndrome occurred in 2 in ATG5 patients and none in ATG7.5 cohort. GVHD was observed more frequently in patients with higher ddCD3 counts at 8 weeks. Relapse occurred in 26% vs 27%, ATG5 and ATG7.5 (Grey's test P=0.9). Two patients in the ATG5 cohort needed donor lymphocyte infusions (DLI) compared to 8 in ATG7.5 (Grey's test P = 0.07); 6 of these patients received prophylactic DLI for declining donor chimerism (5 in the ATG 7.5 cohort). A composite index (relapse, DLI, non-relapse mortality) was not significantly different between the cohorts (Log Rank P = 0.9). High-dose valacyclovir was used for CMV prophylaxis; CMV reactivation (>1000 copies/microl) developed in 2 ATG5 patients and 3 in ATG7.5 arm; EBV reactivation (>10 copies/microl) developed in 1 and 2 patients respectively in the two cohorts. In summary our clinical trial demonstrates that ATG5 in combination with low dose TBI yields optimal T cell engraftment, with an excellent safety profile and good clinical outcomes, and may serve as a platform for adoptive immunotherapy. Phase III clinical trial comparing this regimen with more established regimens for RI-SCT is being planned. Disclosures: Toor: Sanofi Avnetis: Research Funding.

An Anti-Human Thymocyte Globulin-Based Reduced-Intensity Conditioning Regimen Is Associated with a Higher Quality of Life and Lower Organ Toxicity without Affecting Lymphocyte Reconstitution

Reduced-intensity (RIT) conditioning regimens are gaining increased attention as a result of their advantages and efficacy. However, no data are available regarding whether these regimens improve patient quality of life (QoL). In our study, health-related QoL (HRQoL) was retrospectively assessed in 111 patients with hematological malignancies. Analysis of the Quality of Life Questionnaire indicated that 35 of the RIT patients were able to perform their normal work and returned to their baseline levels of function 2 to 3 months after transplantation. In the myeloablative (MA) group, only 24 patients were able to resume work, and these patients returned to their baseline levels of function 6 to 8 months after transplantation (68.6% vs. 40.0%, P = 0.004). Grade III–IV organ toxicity occurred in 20% of the RIT patients and in 52% of the MA patients (P = 0.001), and the cumulative incidences of grades III–IV acute graft-versus-host disease (GVHD) were 13.7% and 35.0% in RIT and MA patients, respectively (P = 0.015). In conclusion, the RIT conditioning regimens were well tolerated by the patients, with a low incidence of transplant-related mortality (TRM) and serious acute GVHD. In addition, these regimens minimized procedure-related toxicity, improved QoL and did not influence lymphocyte reconstitution; however, OS was similar for both regimens because the relapse rate was relatively increased in the RIT groups.

Relevance and Factors Predicting for Early Lymphocyte Recovery After Allogeneic Bone Marrow Stem Cell Transplantation (BMT).

Abstract 3053Recovery of the immune system is critical for the success of allogeneic stem cell transplantation. Several groups, including ours, reported that faster lymphocyte recovery was associated with improved outcomes. There is limited information however, on factors affecting lymphocyte recovery and its influence on outcomes specifically after BMT.We retrospectively assessed 536 consecutive patients (pts) with acute leukemia (452 AML/MDS and 102 ALL) who underwent BMT (and engrafted) at our institution between 01/1999 and 12/2010 to determine 1) predictors of early lymphocyte recovery (ELR), and 2) influence on outcomes of ELR defined as achieving absolute lymphocyte count of 1000/μL (ALC1000) by day 100 after BMT. Characteristics of the study population including demographics, graft, disease, and transplant characteristics assessed are described in the Table. Conditioning regimens were classified as reduced intensity (RI), or high intensity (including TBI-, busulfan-, or melphalan-based) conditioning, as previously described. Cox’s proportional hazards regression analysis was used to assess predictors of ELR and NRM on univariate and multivariate (MV) analysis. Pts who developed grade II-IV acute GVHD (aGVHD), received a second graft infusion, or relapsed before achieving ALC1000 were censored at the time of these events for the assessment of predictors of ELR. Only pts who were alive progression-free, and had not developed grade II-IV aGVHD by day 100 were eligible for the assessment of predictors of outcomes in landmark analysis starting on day 100 after BMT. Outcomes were assessed at the median follow-up in surviving pts of 40 months.On multivariate analysis, significant predictors of lower rate of ELR included TBI- or melphalan-based ablative conditioning (HR=0.5, p 0.003) (compared to RI or busulfan-based), and a haploidentical donor (HR=0.4, p 0.05). Preliminary analyses assessing CMV reactivation and grade II-IV aGVHD as time dependent variables showed these factors to be associated with higher and lower ELR, respectively. MV analyses incorporating these factors in prognostic model are ongoing and final results will be presented at the meeting.Among the 246 pts eligible for the outcomes assessment, ELR (HR=0.2, P <0.001) and remission status (CR1/CR2) at transplant (HR=0.3, P 0.004) were the only significant predictors of the rate of NRM on MV. The lower NRM rate in pts with ELR translated into higher overall survival on univariate analysis, yet this association was only significant at 1 year (HR1year 0.5, p=0.02; HR40 mo 0.7, p=0.2) after transplant. There was no impact for ELR on the rate of disease relapse at either one of these time points after BMT.In conclusion, early lymphocyte recovery is an independent prognostic factor for NRM after BMT. Lymphocyte recovery was influenced by the conditioning regimen, the use of a haploidentical donor and the development of aGVHD but not by the infused CD34 cell numbers or disease status at transplant. Disclosures:No relevant conflicts of interest to declare.

What Is the Role of Transplantation for Indolent Lymphoma?

Despite advances in chemoimmunotherapy, indolent B-cell non-Hodgkin lymphomas (B-NHLs) are generally not considered curable with this approach. Much attention has been paid to the prospect of hematopoietic cell transplantation (HCT) as a way to improve long-term outcomes for this group of diseases. Autologous (auto) HCT provides intensive conditioning therapy followed by rescue of hematopoiesis, and this has been shown in randomized studies to prolong survival compared with more standard chemotherapy, albeit with increased short-term toxicity and the potential for higher rates of secondary malignancies. Allogeneic (allo) HCT can provide anticancer effects beyond the conditioning therapy through the immune-mediated graft-versus-lymphoma (GVL) effect. It can be administered following myeloablative (MA) conditioning or reduced-intensity (RI) regimens aimed at sufficiently suppressing the patient's immune system to allow engraftment of donor hematopoiesis. However, this same potentially curative alloreactivity of the engrafted immune system can lead to graft-versus-host disease (GVHD), a significant cause of morbidity and mortality following allo HCT. This article will discuss the current role of both auto HCT and allo HCT in the management of indolent lymphoma as well as the relative risks and benefits of each approach such that the reader can place this in context of the multitude of options available for patients with indolent B-NHL.

Outcomes for Patients Aged 60 and Over Are Similar to Younger Patients Following Reduced-Intensity Allogeneic Stem Cell Transplant for CLL

Abstract 3100The advent of reduced intensity (RI) conditioning for allogeneic stem cell transplant (HSCT) has brought the question of safe application of this therapy (tx) to older patients. This is of particular importance in CLL where the median age at diagnosis (dx) is 65 yrs. This study compares outcome post RI HSCT in those aged 60 and older (older group, n=23 pts) to those less than age 60 (younger group, n=35 pts) who received RI HSCT at the Leukemia/BMT Program of BC 2001 - June 2011 (total group n=58). Forty-two of 58 (73%) were male. Racial origin was mostly white with only 2/58 (3%) Asian pts. Max stage (Rai) pre-HSCT was advanced (III + IV) in most (31/58, 53%); 13 pts (22%) had B symptoms. Characteristics of the entire group (n=58) include (med, range): interval from dx to HSCT 7.4 yrs (0.4–29); number of prior tx 4 (1–14) and % lymphocytes in pre-HSCT marrow 71 (3–98). 22% (13/58) had bulky nodes (>5cm). Six (10%) had Richter’s transformation. HSCT comorbidity index (Sorror) was 0 in 33 (57%), 1–2 in 18 (31%) and >= 3 in 7 pts (12%). Most received prior nucleoside analog (57/58, 99%) and rituxan (47/58, 81%) tx. Twenty-five (43%) were resistant (RES) to last tx given; 30 of 56 pts (54%) were fludarabine (flu) RES. The younger and older group were similar apart from age at dx and HSCT (med, range) which were 47 (26–57) vs 54 (36–55) yrs and 56 (42–59) vs 63 (60–68) yrs respectively. Med donor age was 46 yrs (19–76); 39 (67%) were male; 83% of female donors were parous; 27 (47%) were unrelated (UD); and 12 (21%) mismatched. Stem cells were peripheral blood. Conditioning was non-myeloablative (flu/cy) in 14 pts (24%), and reduced intensity (fludarabine/busulfan) in the remainder (44 pts, 76%). For UD HSCT campath was added to flu/bu in 19 and thymoglobulin in 8 pts. Gvhd prophylaxis was cyclosporine and methotrexate. Count recovery occurred in 97%; 2 pts did not recover (both <60yrs); 1 died (H1N1) and 1 is > 1 year post 2nd RI UD HSCT. Graft failure (GF) occurred in 8 pts (14%) predominantly related to campath; 1 pt died (H1N1), 1 is well with autologous recovery 3 yrs post GF and 6 of 8 required further HSCT (including 2 older pts who survive > 1 yr post 2nd HSCT). Acute graft vs host disease (gvhd) grades 2–4 occurred in 83% of pts and chronic gvhd in 54% and was neither more severe nor prevalent in older pts. CR post HSCT has occurred in 26 /58 pts (45%), a med (range) of +108 days (0 days -5.4 yrs). DLI was given to 11 pts (4 older pts). At median (range) follow up of 20 months (0.3–120) post HSCT and 10.1 yrs (0.7–37) post dx 44 / 58 pts (75%) survive in the whole group, including 25/35 pts (71%) younger group and 19/23 pts (83%) older group. Death in CR occurred in only 2/14(14%) deaths or 2/58 pts (3%), both of whom were younger pts. Time of death post HSCT was similar in the younger and older groups. Pre-HSCT FISH was performed in 52 /58 pts; results were abn in 47/52 pts (90%); 28/29 (97%) younger and 19/23 (83%) older group and included: del 17p in 15 pts (26%); del 11q in 15 (26%); trisomy 12 in 11 (19%); del 13q in 29 (50%) and bi-allelic del 13q in 11 (19%). Abn FISH normalized pre-HSCT in 8 /52 (15%) and post-HSCT in 18/40 pts (45%), leaving only 22/54 (40%) with currently abnormal FISH tests. Donor chimerism >=90% was achieved to date in 43/50 assessable pts (86%) and occurred with similar frequency in younger and older age groups. Survival analysis for the whole group demonstrated the following had a positive impact on OS (p value): achievement of donor chimerism > 90% (0.006); CR post HSCT (0.010) and normal FISH or clearance of previously abn FISH (0.007). Non-significant factors included FISH (Dohner ranking); 17p del; acute gvhd gr 2–4; cgvhd; and patient age. KM estimate for OS at 1, 2, and 5 years is: whole group 85%, 73%, 73%; younger 82%, 73%, 73; older 90%, 72%; 72%. There is no difference in OS for the younger vs older group (p= 0.7). In conclusion advances have now made it possible to safely and successfully perform RI HSCT for fit older pts with CLL and obtain similar outcome and overall survival to younger pts. This allows application of this potentially curative therapy to this important patient population. Disclosures:No relevant conflicts of interest to declare.

Post-Engraftment Persistent Leukocytosis May Be An Independent Poor Prognostic Factor in Allogeneic Stem Cell Transplant Patients

Abstract 4574Leukocytosis has been documented as a risk factor for thrombotic events in various clinical conditions such as ischemic heart diseases, polycythemia vera, intensive chemotherapy and stem cell transplantation (SCT). Allogeneic (allo) SCT is characterized with a unique peri-engraftment phase simultaneously harboring T cell alloreactivity, endothelial damage, leukocyte elevation and an abundance of variable secreted cytokines. Whether leukocytes are a causative or surrogate marker for the underlying process is not concluded and whether leukocytosis is linked to the severity of acute graft-versus-host disease (aGVHD) has not been previously elucidated.The study included 59 consecutive patients undergoing matched related or unrelated allo SCT for hematological malignancies at the Rambam Medical Center, Haifa, Israel in 2010. Median age 45 years (21–66), 35 males and 24 females. Conditioning protocols were either myeloablative with busulfan/cyclophosphamide or reduced intensity (busulfan or melphalan based). Patients’ clinical course and blood counts were followed for 2 months and categorized into 3 groups according to their post-engraftment leukocyte counts and leukocytosis duration.The outcome is summarized in the following table:GroupLeukocyte countNo. patientsMedian days to engraftmentMedian days to leukocyte >10x103/μl120-day mortalityCause of death1< 10X103/μl16+154/162 respiratory failure,1 relapse, 1 septic shock2> 10x103/μl (< 7days)27+13+362/271 aGVHD (GI grade 4), 1 SOS*3> 10x103/μl (> 7 days)16+11+2510/164 aGVHD (GI grade 4), 4 thrombotic events**, 2 idiopathic pneumonia with end organ failure and infective complications*SOS- sinusoidal obstructive syndrome**2 SOS, 2 thrombotic thrombocytopenic purpura+120 days were chosen as the cutoff to include patients dying of the mentioned complication after day +60.The results summarized in the table suggest that patients with early and protracted leukocytosis post engraftment are at increased risk for severe and fatal complications (group 3). The 16 patients in this cohort included 9 in complete remission (CR); 7 with active disease; 5 sibling and 11 matched unrelated donor (MUD) SCTs; 6 myeloablative and 10 reduced intensity (RI) conditioning. This mix was similar to that of patients in groups 1 and 2. Leukocytosis occurring at a later phase (group 2) seems to have minimal or no impact on survival during the first 120 days post transplant. All deceased patients had documented platelet engraftment, although few did receive platelet concentrates as indicated clinically.In conclusion, protracted leukocytosis post engraftment in allo SCT patients may be an independent risk factor not only for fatal thrombotic events but also for aGVHD, mostly gastrointestinal, although larger studies are needed to confirm this. The peri-engraftment syndrome may have long-term prognostic and therapeutic implications, beyond the immediate clinical management. Given that such patients are still with endothelial dysfunction and within a rich milieu of cytokines, incorporation of anti-aggregating agents (such as anti p-selectin or GPIIb/IIIa) in the treatment protocol at this stage may have a role and should be investigated. Furthermore, mechanisms leading to such leukocytosis also need to be assessed. Disclosures:No relevant conflicts of interest to declare.

Poor FEV1 or DLco on Pre-Transplant PFT Does Not Compromise Outcomes In Patients Undergoing a Reduced-Intensity Allogeneic Progenitor Cell Transplant.

AbstractAbstract 1322 Background:Pre-transplant work-up prior to an allogeneic stem cell transplant (allo-SCT) generally includes pulmonary functions tests (PFT) with assessment of FEV1 and DLco. It has been previously published that patients with a DLco or FEV1 less than 60% of predicted have higher non-relapse mortality (NRM) when undergoing a myeloablative allo-SCT. However, the PFT criteria for selecting candidates for a reduced intensity (RI) allogeneic transplant allo-SCT remains poorly investigated. We performed a retrospective analysis to assess the impact of low FEV1 or DLco on NRM and overall survival (OS) in patients undergoing a RI allo-SCT. Methods:All patients who underwent a RI allo-SCT for hematological malignancies at MD Anderson Cancer Center from Jan 2000 to April 2009 were included. Using Cox's proportional hazards regression, we compared the rate of NRM and OS between patients who had a pre-transplant FEV1 or DLco > 50% (control group) prior to a RI allo-SCT and those with FEV1 and DLco < 50% (study group). The cumulative incidence of NRM was estimated considering disease progression as a competing risk. Actuarial OS was estimated by the Kaplan-Meier method. Results:Patient characteristics are presented in Table 1. There were no statistically significant differences between the study and control groups except for age and sex. A significantly higher proportion of patients were > 50 years in the control group (65%) compared with the low PFT group (45%, P=0.02) and there were more males in the control group (P=.001). The median FEV1 and DLco in the study group was 55% (28-111) and 47% (33-98) of predicted, respectively. On univariate analysis abnormal PFTs did not impact OS at 30 months (HR 1.1, 95% CI 0.7–1.8, P=0.7) or NRM at 1 year (HR 1.3, (95% CI 0.6–2.7, P=0.4). Active disease at SCT, and a diagnosis of CLL, NHL or HL were associated with significantly worse OS and NRM, whereas age >50 years was only associated with worse OS. Low PFT had no significant impact on OS and NRM when evaluated separately in patients older or younger than 50 years old. Conclusion:Our experience suggests that a low (<50% of predicted) FEV1 or a DLco on pre-transplant evaluation does not adversely impact NRM and OS after RI allo-SCT. These findings need to be validated in a multivariate analysis.Table 1:Patient CharacteristicsLow PFT (N, %)Control (N, %)p–valueNumber of patients33774Follow–up (Median, range) months33 (5–95)28 (1–116)Age, Median, years (range)48 (21–77)55 (20–77)0.06Sex, male12 (36%)497 (64%)0.001Active disease at RI allo-SCT24 (73%)555 (72%)0.9Donor:MRD19 (58%)332 (43%)0.09MUD13 (39%)373 (48%)Other1 (3%)69 (9%)Cell Source:Peripheral blood25 (76%)505(65%)0.2Bone marrow8 (24%)269 (35%)Diagnosis:AML/MDS/ALL/CML15 (48%)337 (43%)0.7CLL/NHL/HL12 (36%)337 (43%)MM/AA/Other5 (15%)100 (13%)Table 2:Cumulative incidence of Non-relapse mortality and ActuarialSurvivalLow PFTs (N=33)Control (N=774)p–value% NRM3 months12 (95% CI 5–30)10 (95% CI 8–13)0.812 months25 (95% CI 13–45)21 (95% CI 18–25)0.4% OS:3 months88 (95% CI 71–95)88 (95% CI 85–90)0.912 months53 (95% CI 34–68)62 (95% CI 58–65)0.3 Disclosures:No relevant conflicts of interest to declare.

Incidence, Risks, and Outcomes of Relapse Following Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Non-Hodgkin's Lymphoma.

AbstractAbstract 3451Relapse is the major cause of treatment failure and death following reduced-intensity (RI) allogeneic hematopoietic stem cell transplantation (HSCT) for non-Hodgkin's lymphoma (NHL), yet there are no reports that focus specifically on the natural history of relapse in this patient population. We assessed relapse risks and outcomes on 120 consecutive patients (median age = 52 years; range, 28–71 years) with NHL (indolent = 43; aggressive = 77) who all received a T-cell replete allograft from HLA-matched siblings following a reduced-intensity conditioning regimen (fludarabine/cyclophosphamide). All patients were assessed for disease status at 1, 3, 6, 12, 18, 24 months post-transplant, and annually thereafter or as clinically indicated. Median event-free survival (EFS) from transplant date for all 120 patients was 11.3 months (range, 0.5–105.5+ months) with a 5-year EFS = 35%. Median EFS (months) was assessed for the following pre-transplant characteristics: chemo-resistant vs. chemo-sensitive = 3.3 vs. 39.1, p = 0.0001; pre-transplant disease status - CR vs. PR vs. SD vs. PD = not reached (NR) vs. NR vs. 11.2 vs. 1.7, p <0.0001; aggressive vs. indolent histology = 6.6 vs. 15.8, p = 0.13; number of disease sites: 0–1 vs. 2 vs. 3 vs. 4+ = 4.8 vs. 7.4 vs. 18.4 vs. 7.1, p = 0.85. Median overall survival (OS) from transplant date for all 120 patients was 71.1 months (range, 0.5–120+ months). We identified 55 patients (46%) who either relapsed or progressed post-transplant. Among those who have progressed/relapsed to date, median time to progression/relapse was 3 months (range, 0.5–46 months) with 72% of progressions/relapses occurring prior to 6 months post-transplant. The overall cumulative incidence (CI) probabilities for relapse/progression, adjusted for competing non-relapse mortality, at 3, 6, 12, 24 and 36 months were 0.169, 0.329, 0.394, 0.447, and 0.460, respectively. The association of 3-year relapse CI probabilities with pre-transplant characteristics were as follows: aggressive vs. indolent histology = 0.530 vs. 0.315; chemo-resistant vs. chemo-sensitive = 0.571 vs. 0.316; disease status prior to transplant – CR vs. PR vs. SD vs. PD = 0.210 vs. 0.217 vs. 0.597 and 0.627; number of prior treatments: 1–2 vs. 3 vs. 4 vs. 5+ = 0.375 vs. 0.418 vs. 0.613 vs. 0.450; sites of disease: 0–1 vs. 2 vs. 3 vs. 4+ = 0.458 vs. 0.516 vs. 0.331 vs. 0.579. Median OS from date of progression was 8.3 months (0.5 - 94+ months) with a 5-year OS = 32%. No patient who progressed/relapsed within 3 months post-transplant has survived beyond 12 months, with one patient still alive at 6 months. Median OS (months) from date of progression was assessed for the following characteristics: progression < 3 months vs. ≥ 3 months post-transplant = 2.6 vs. NR, p <0.0001; progression < 6 months vs. ≥ 6 months post-transplant = 5.3 vs. NR, p = 0.0002; aggressive vs. indolent histology = 7.8 vs. 18.3, p = 0.53; number of disease sites: 0–1 vs. 2 vs. 3 vs. 4+ = 5.8 vs. 13.8 vs. 4.9 vs. 12.9, p = 0.75; number of prior treatments: 1–2 vs. 3 vs. 4 vs. 5+ = 8.4 vs. NR vs. 11 vs. 5.6, p = 0.27; response vs. no response to relapse/progression treatment = NR vs. 4.7, p = 0.0087 (determined by a landmark method, beginning 30 days after progression to allow time for determination of response to relapse treatment). These data demonstrate that a significant minority of NHL patients, who relapse after RI allogeneic HSCT, can achieve long-term survival, including patients with aggressive histology. These analyses, which utilized standard clinical characteristics, identified NHL patients at higher risk for relapse and poorer outcomes once relapse occurred. In particular, disease progression/relapse occurring less than 3 months post-transplant was associated with an extremely poor prognosis; novel strategies and trials are needed for such patients. These results need to be confirmed by other groups, and these analyses need to be performed in other transplant settings (e.g. unrelated donors and myeloablative conditioning). The use of these patient characteristics, alone or in combination, may ultimately lead to a method of estimating the risk for relapse and the subsequent prognosis, if relapse should occur, in NHL patients undergoing RI allogeneic HSCT. Disclosures:No relevant conflicts of interest to declare.

Brain Natriuretic Peptide (BNP) Elevations In Allogeneic Stem Cell Transplant (ASCT) Recipients at the Time of WBC Engraftment. Correlation with Engraftment Syndrome and Cardiac Dysfunction.

AbstractAbstract 1309Engraftment syndrome (ES) may occur in ASCT recipients at the time of neutrophil recovery and is suspected to reflect increased capillary permeability due to increases in proinflammatory cytokines. Clinical features of ES may include fever, weight gain, rash, hypoxia and pulmonary infiltrates, which are by definition non-cardiogenic and non-infectious in origin. We have observed elevations in BNP in ASCT recipients at the time of WBC engraftment who appear to meet clinical criteria for ES and therefore chose to monitor BNP at the time of hospital admission, on day + 0, and at engraftment to further characterize the relationship between conditioning intensity, ES and cardiac dysfunction.A retrospective review was conducted of pretransplant cardiac features and transplant course in 139 patients undergoing ASCT between January, 2007 and April, 2010. Informative data was available for 122 transplants in 121 pts (74 males, 48 females). Median follow up of survivors was 266 days (minimum 100 days). Median age was 52 yrs (range 17–72). Transplant indication was AML 80 (66%), NHL 20 (16%), other 22 (18%). There were 58 (48%) matched related (MRD) and 64 (52%) unrelated donor (MUD) transplants. Graft source was PBSC (118) and BM (4). High dose (HD) therapy (Busulfan/Fludarabine or TBI/Cyclophosphamide [Cy]) was used in 61 transplants (50%), and reduced intensity (RI) conditioning (Busulfan/Fludarabine based or Pentostatin/TBI based) was used in 61 (50%). Tacrolimus and Mycophenolate were used for GVHD prophylaxis in 104 (85%), and Tacrolimus, Sirolimus, and Methotrexate were used in 18 (15%) mismatched transplants. Filgrastrim was routinely used from day +7 to engraftment. Forty pts (33%) had a history of HTN, CAD, CHF, or arrhythmias, 28 (25%) had received a high cumulative anthracycline dose (≥300 mg/m2 adriamycin equivalent), and 22 (18%) received HD Cy in the conditioning regimen. Results were analyzed according to a clinical diagnosis of ES noted in the medical record as well as by fulfillment of two or more diagnostic criteria (fever, rash, weight gain >2.5%, hypoxia/pulmonary infiltrate of noncardiac and noninfectious origin) present within 96 h of engraftment, as noted by Gorak et al. (BBMT 11:542, 2005).Median admission BNP (nl<100pg/ml) was 57 pg/ml (range 40–386, n=99). Median Day 0 BNP was 59.50 pg/ml (range 40–2580, n=120). Median engraftment BNP was 216 pg/ml (range 40–11200, n=122). Abnormal BNP at admission, on day 0, and at engraftment was seen in 24%, 45% and 76% of pts respectively, with engraftment BNP>400 in 37%. The incidence of ES was 11% by clinical impression and 25% by definition criteria. Ninety four percent of pts with ES had abnormal BNP at engraftment and 61% had BNP >400. Seventy percent of pts with no evidence of ES or overt cardiac complications were noted to have abnormal BNP at engraftment, and 53% had BNP >400. Weight gain occurred in 27% of all pts and of these 90% had elevation in BNP. Six pts experienced acute cardiac complications at the time of WBC engraftment with markedly elevated BNP. There were no primary cardiac deaths.A high cumulative anthracycline dose was associated with elevated BNP on day 0 and at WBC engraftment. High BNP on day 0 was also associated with reduced intensity conditioning but not with age. There was no correlation between cardiac history or HD Cy with elevations in BNP at any point. Elevated BNP at engraftment as well as presence of ES were significantly more common in MUD recipients. No correlation was observed between elevated engraftment BNP or presence of ES with acute GVHD or survival. One-year non relapse mortality was higher in pts with high anthracycline dose (28 vs. 18%%), high BNP at engraftment (22 vs. 7%), or MUD transplant (22 vs. 13%); High anthracycline dose was the only significant predictor of NRM in multivariate analysis. However, in the group of patients with normal BNP on day 0, a BNP >400 at engraftment was an independent predictor of both NRM and OS.Conclusions: Elevations in BNP following ASCT are common and are associated with anthracycline exposure and MUD source. Marked elevations were noted in patients with or without ES or evidence of cardiac compromise and are of uncertain etiology. The high frequency of abnormal BNP in pts with ES and the prognostic value of a de novo elevation in BNP at the time of engraftment suggest the physiologic stress of WBC engraftment following ASCT has important cardiac consequences which deserve further study. Disclosures:No relevant conflicts of interest to declare.

A Novel Reduced Intensity Conditioning Can Induce a High Incidence of Sustained Donor Engraftment After Double Unit Cord Blood Transplantation (CBT) without Anti-Thymocyte Globulin

AbstractAbstract 2351CBT can be curative for patients with high-risk hematologic malignancies. However, patients of older age, those with extensive prior therapy, or significant co-morbidities may not tolerate high-dose myeloablative conditioning. Reduced intensity (RI) or non-myeloablative (NMA) conditioning has been successfully used in CBT, especially in patients with lymphomas. However, patients with myeloid malignancies without extensive prior therapy have an increased risk of graft rejection following NMA CBT. Further, the addition of anti-thymocyte globulin (ATG) to enhance engraftment increases the risk of serious infections and Epstein-Barr virus post-transplant lymphoproliferative disease, and could increase the risk of relapse. Therefore, we investigated the efficacy and safety of a novel ATG-free RI conditioning prior to double unit CBT in patients with acute leukemias and myelodysplasia with the hypothesis that this regimen can induce a high incidence of sustained donor engraftment. Conditioning consisted of cyclophosphamide 50 mg/kg (day -6), fludarabine 30 mg/m2/day × 5 (days -6 to -2), thiotepa 5 mg/kg/day × 2 (days -5 and -4), and total body irradiation 200 cGy × 2 (days -2 and -1). All patients received cyclosporine-A and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Between 10/01/07-04/30/10, 20 patients were transplanted. The median age was 56 years (range 18–69). Thirteen (65%) had AML (9 CR1, 4 CR2), 4 (20%) had ALL (3 CR1, 1 CR3), and 3 (15%) had MDS (with one patient also having follicular lymphoma). The majority had high-risk disease. Indications for RI conditioning were the risk factors for transplant-related mortality (TRM) with high-dose conditioning of age ≥50 years, and/or extensive prior therapy, and/or significant co-morbidities. Thirteen patients had only 1 of these risk factors, whereas 7 had ≥2 risk factors. Units were predominantly 4–5/6 HLA-matched to the recipient (one 6/6, twenty-four 5/6, fifteen 4/6). The median infused cell doses of the larger units were 2.7 × 107 total nucleated cells/kg (range 1.46–5.56) and 0.95 × 105 CD34+ cells/kg (range 0.35–3.32), and 1.89 × 107/kg total nucleated cells/kg (range 1.42–2.47) and 0.59 × 105/kg CD34+ cells/kg (range 0.18–1.52) for the smaller units, respectively. The cumulative incidence of sustained donor engraftment at day 45 was 95% (95%CI: 81–100). The single patient with graft failure was 100% donor in the day 21 bone marrow, but died early post-transplant of multi-organ failure without count recovery. The median time to neutrophil recovery ≥0.5 × 109/l was 25 days (range 13–43). The median total donor chimerism in the day 21 bone marrow was 94% (both units combined, range 71–100), and sustained engraftment was accounted for by one unit in 18/19 engrafting patients. The incidence of grade II-IV acute GVHD at day 100 was 55% (95%CI: 32–78), and 46% (95%CI: 21–71) of patients have had late acute GVHD requiring ongoing therapy or chronic GVHD to date. The incidence of day 100 transplant-related mortality (TRM) was 20% (95%CI: 2–38). Notably, none of the 13 patients with only one risk factor died of transplant-related causes. By contrast, 5/7 (71%) patients with ≥2 risk factors died of TRM by day 100 (p=0.03, Table 1). Two additional patients died of relapse. With a median follow-up of 13 months (range 3–31), 1 year progression-free survival is 74% (95%CI: 55–94) (Figure 1). We demonstrate that this ATG-free RI conditioning is associated with a high incidence of sustained donor engraftment, and acceptable toxicities in older patients without other risk factors. While longer follow-up is needed, progression-free survival is encouraging provided multiple risk factors are not present. This conditioning combined with double unit grafts warrants further investigation, and may also be a promising alternative to high-dose conditioning in younger patients.Table 1Day 100 TRM according to number of risk factors (age ≥50 years, extensive prior therapy, significant co-morbidities).Risk FactorsDay 100 TRMP Value1 (N = 13)0/13 (0%)0.03≥2 (N = 7)5/7 (71%) [Display omitted] Disclosures:Giralt: Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

Extramedullary Relapse Following Reduced Intensity AlloHCT for Adult AML.

AbstractAbstract 3467 Background:In recent studies, the incidence of extramedullary (EM) relapse post full-intensity allogeneic hematopoietic cell transplantation (AlloHCT) for AML has been reported to be approximately 5–15%. However, the incidence and clinical significance of EM relapse following reduced-intensity (RI) AlloHCT has not been studied. To better understand the incidence and predictors of EM relapse following RI-AlloHCT for AML, a consecutive case-series of 246 adult AML patients who underwent RI-AlloHCT from (inception) February 2000 through December 2008 at City of Hope were identified and selected for analysis from a prospective observational research database. Patient Characteristics:The median patient age was 55 years (range: 19–71) with a fairly balanced gender distribution (male=125, 51%; female=121, 49%). There were 108 (44%) matched related donors and 138 (56%) matched unrelated donors. 221 (90%) of patients received peripheral blood stem cells. The median time from diagnosis to RI-AlloHCT was 6.4 months (range: 0.5–124.8). Disease status at HCT: 1CR/2CR=137(56%), induction failure=40 (16%), relapse=69 (28%). Nine percent (n=22) of patients had a history of EM relapse prior to RI-AlloHCT. Twenty-eight percent of patients (n=68) received a prior auto (n=50) or allo (n=18) HCT. The majority of patients received fludarabine/melphalan conditioning n=227, 92%. GVHD prophylaxis consisted of CSA/MMF=113, 46% or Tacro/Siro=135, 54%. A total of 205 patients were evaluable for cytogenetics. Based on SWOG criteria (2000), there were 10 (5%) favorable, 118 (57.5%) intermediate and 77 (37.5%) unfavorable cytogenetics. Results:Initial relapse occurred in the BM in 72 (29%) patients and EM sites in 16 (6.5%) patients. The sites were: brain/CSF 5, breast 3, multiple sites 2, spine 1, liver 1, ascites 1, soft tissue 1, testes 1, and bone 1. Three (1%) had concurrent bone marrow/EM relapse. In addition, 6 (2.4%) patients had a second relapse in an EM site. The sites of second or subsequent relapse were: CSF 2, multiple sites 2, spine 1, parietal mass 1. The two-year cumulative incidence of EM relapse was 10.4% (6.8%-15.7%). Treatment for EM relapse included: combined chemo-RT 11, RT and/or chemotherapy followed by second allo/DLI 4, chemotherapy 3, palliative care 3, and RT 1. Time from Allo-HCT to initial EM relapse was 12.2 months (range: 2.8–42.9) and time from HCT to initial BM relapse 6.5 months (range: 1.0–33.3). Overall survival after initial EM relapse was 68.8% (50.3% - 81.5%) at 1-year and 50.0% (37.3% - 61.5%) at 2 years. Risk Factors:Of the risk factors studied (prior EM disease, prior HCT, disease status, cytogenetic risk, and age (<55, >=55)), advanced disease status (IF/RL/>3CR) (HR: 2.8, p=0.04) and unfavorable cytogenetics (HR: 5.2, p<0.01) were found to be predictive of EM relapse. Conclusion:This is the first report to analyze specifically the incidence of EM relapse of AML post RI-AlloHCT. Our data show that the incidence of incidence EM relapse following RI-AlloHCT is similar to rates reported following ablative AlloHCT. By multivariable analysis, advanced disease and unfavorable cytogenetics were associated with increased risk for EM relapse, also similar to findings in the ablative setting. In conclusion, reduced-intensity conditioning does not appear to be associated with an increased risk of EM relapse. Furthermore, the median time to EM relapse exceeds median time to BM relapse and long-term survival is possible following EM relapse. Disclosures:No relevant conflicts of interest to declare.

Heterogeneous Subsurface Scattering Using the Finite Element Method

Materials with visually important heterogeneous subsurface scattering, including marble, skin, leaves, and minerals are common in the real world. However, general, accurate, and efficient rendering of these materials is an open problem. In this paper, we describe a finite element (FE) solution of the heterogeneous diffusion equation (DE) that solves this problem. Our algorithm is the first to use the FE method to solve the difficult problem of heterogeneous subsurface rendering. To create our algorithm, we make two contributions. First, we correct previous work and derive an accurate and complete heterogeneous diffusion formulation with two key elements: the diffusive source boundary condition (DSBC)-an accurate model of the reduced intensity (RI) source-and its associated render query function. Second, we solve this formulation accurately and efficiently using the FE method. With these contributions, we can render subsurface scattering with a simple four step algorithm. To demonstrate that our algorithm is simultaneously general, accurate, and efficient, we test its performance on a series of difficult scenes. For a wide range of materials and geometry, it produces, in minutes, images that match path traced references, that required hours.

HLA-matched allo-SCT after reduced intensity conditioning with fludarabine/CY in patients with metastatic breast cancer

Fifteen patients with chemosensitive metastatic breast cancer (MBC) underwent reduced intensity (RIST) allo-SCT between 1999 and 2006. The purpose of this single-center study was to evaluate the feasibility, safety and efficacy of this therapeutic approach. The pretransplant conditioning regimen consisted of fludarabine (25 mg/m(2) at days -5 to -1) and CY (60 mg/kg at days -2, -1). Stem cells were from HLA-matched sibling donors. The treatment-related mortality was 2/15 (13%). Median PFS and OS were 144 days (43-509 days) and 303 days (122-1376 days), respectively. The 1-year PFS was 20%, and the 1-year and 2-year OS was 40 and 20%, respectively. No objective tumor responses were observed, but the relatively long PFS does suggest a graft-vs-tumor effect. Although RIST using this CY/fludarabine regimen is feasible, the efficacy in this set of patients was limited. Future clinical trials should be performed to improve the knowledge of mechanisms of antitumor effects in breast cancer.

Early Central Nervous Complications after Umbilical Cord Blood Transplantation for Adults

Early central nervous complications (CNS) are significant after allogeneic stem cell transplantation; however, the clinical characteristics of early CNS complications have not yet been well described. The medical record of 77 patients who underwent cord blood transplantation (CBT) between March 2001 and November 2005, at 8 centers of the Nagoya Blood and Marrow Transplantation Group were retrospectively reviewed. The preparative regimen included myeloablative CBT (n = 31) or reduced-intensity (RI)-CBT (n = 46). Of the 77 patients, 10 (13%) developed early CNS complications. Causes included Cyclosporine encephalopathy (n = 5), tacrolimus encephalopathy (n = 2), thrombocytic microangiopathy (n = 1), and unknown (n = 3). The median time of onset was 19 days (range: 2-58 days). All of the 10 patients developed impaired consciousness. Seizures developed in 6 patients. Early CNS complications spontaneously subsided in 3 patients. Three patients responded to cyclosporine or tacrolimus discontinuation. The remaining 4 patients died within 30 days of developing of early CNS complications. No relationship was detected between the preparative regimen and the onset of early CNS complications, while an HLA disparity showed borderline significance (hazard ratio, 3.24; 95% confidential interval, 0.94-11.20; P = .06). Early CNS complications are a significant problem after CBT, and the clinician has to be aware of the possibility of these complications.

Bronchoscopic Evaluation of Pulmonary Complications in Patients Undergoing Reduced-Intensity Versus Full-Intensity Transplants.

Pulmonary complications are common following hematopoietic stem cell transplantation (HSCT). The role of fiberoptic bronchoscopy with broncho-alveolar lavage (BAL) in recipients of reduced-intensity (RI) and full intensity (FI) transplants is now reported. Between January 2001-May 2008, 803 allogeneic transplants (212 RI, 591 FI) were performed on 784 patients at the University of Michigan Medical Center. Pulmonary complications, defined as eitherhypoxia > 24 hours, orclinical/radiographic features of pneumonitis, were identified in 313 (39.9%) patients post-transplant.Bronchoscopy was performed on 265 (84.7%) patients with pulmonary complications, including 69 patients undergoing RI transplants (median age 56 yrs, 10–68 yrs) and 196 patients undergoing FI transplants (median age 41 yrs, 1–64 yrs). The time to BAL was similar for recipients of RI when compared to recipients of FI transplant [median: 89 days (0–1854 days) vs. 104 days (7–1533 days)]. Pathogenic organisms were identified in 31.8% (RI) and 25.2% (FI) of BAL procedures. Invasive fungi were the most commonly identified organisms, identified on 48.1% (RI) and 45.2% (FI) of BALs in which pathogens were noted. The incidence of bacterial, viral (including CMV), and mycobacterial pulmonary infections were similar in recipients of RI and FI transplants. The frequency with which pathogens were identified varied with the timing of the bronchoscopy (see Table), with non-infectious pulmonary complications twice as likely to occur in the first 100 days post-transplant in FI than RI transplant recipients (p < 0.05). The BAL led to a change in medical management in 54.1% (RI) and 59.3% (FI) of cases respectively, with modifications in antimicrobial therapy in 38.8% (RI) and 42.1% (FI). The bronchoscopy led to modifications in immunosuppressive therapy in 27.1% (RI) and 27.6% (FI) of cases. BAL procedural related complications were rare in both groups, with pulmonary hemorrhage and transient hypoxemia occurring in < 2.5% of all patients undergoing a BAL.Conclusion: The incidence of pulmonary complications, as evaluated by bronchoscopy post HSCT, was similar for recipients of RI and FI conditioning regimen. Within the first 100 days post-transplant, non-infectious etiologies for pulmonary dysfunction were significantly more common in FI than RI patients. There were no other significant differences in the timing of pulmonary complications or the type of pathogenic organisms identified following a FI or RI transplant. Broncho-alveolar lavage is a safe procedure in patients following allogeneic transplants, altering medical management in over 50% of cases. Time post-transplant and % BAL with a pathogenic organism identifiedDay 0–100 *Day > 100TotalRI32.4%31.3%31.8%FI15.8%31.8%25.2%