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Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells.We studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells. The results in these patients were compared with those in 80 historical controls who received 2 units of unmanipulated cord blood.Coculture with mesenchymal stromal cells led to an expansion of total nucleated cells by a median factor of 12.2 and of CD34+ cells by a median factor of 30.1. With transplantation of 1 unit each of expanded and unmanipulated cord blood, patients received a median of 8.34×10(7) total nucleated cells per kilogram of body weight and 1.81×10(6) CD34+ cells per kilogram--doses higher than in our previous transplantations of 2 units of unmanipulated cord blood. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, as compared with 24 days in controls who received unmanipulated cord blood only (P0.001); the median time to platelet engraftment was 42 days and 49 days, respectively (P=0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion (P0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively (P0.001).Transplantation of cord-blood cells expanded with mesenchymal stromal cells appeared to be safe and effective. Expanded cord blood in combination with unmanipulated cord blood significantly improved engraftment, as compared with unmanipulated cord blood only. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00498316.).

Background: Fluid retention/overload (FO) is common during hospitalization for allogeneic stem cell transplantation (ASCT) and is associated with weight gain (WG), edema, and other symptoms such as shortness of breath. It is unknown if symptomatic FO impacts transplant outcomes. We hypothesized that FO is associated with non-relapse mortality (NRM) and worse survival after ASCT. Methods: FO was scored by an independent team using the following criteria: grade 1 - asymptomatic weight gain Results: We initially evaluated FO in a cohort of haploidentical transplant patients with hematologic malignancies (N=145) all treated with identical conditioning (melphalan-based) regimen, and received predominantly a bone marrow graft (94%). The median follow-up was 18 months. 43% of patients were in CR1/2. Median age for this group was 45 years (range 19-69), 58% were males. Median weight was 82 kg (37-180kgs) at study entry before starting the preparative regimen. The median creatinine was 0.75 with >1.0 mg/dl in 16% of the patients. Median DLCO was 70 and EF was normal (>40%) in all except 2 patients. Thirty patients (21%) developed ≥ grade 2 FO. Factors associated with Day100 NRM were ≥ grade 2 FO (HR 15, CI 4.2-55, p1 (HR 4.7, CI 1.6-14, p=0.005) and age>55 (HR 4.5, CI 1.5-13, p=0.008) by univariate analysis. In multivariate analysis (MVA) factors that retained significance were FO ≥ grade 2 (HR 13.1, CI 3.4-50, p1 at study entry (HR 3.5, CI 1.1-11, p=0.03). We verified the prognostic value of FO in a separate cohort of HLA matched transplants [N= 449, 190 matched related donor (MRD) and 259 matched unrelated donor (MUD)] with AML/MDS treated with fludarabine and busulfan conditioning. The median follow-up for this group was 23 months. The median age was 58 years (range 18-77). 42% were in CR1/2 at transplant. 68% had a peripheral blood graft. Median weight was 81kg (47-170). Median creatinine at transplant was 0.8, 19% had >1 mg/dl. Median DLCO was 71 and EF was normal (>40%) in all except 2 patients. Significant factors associated with Day100 NRM by univariate analysis, were FO ≥ grade 2 (HR 11, CI 4.5-25, p Conclusions: FO should be considered an important adverse event post ASCT. Grade 2 or greater FO is strongly associated with NRM and worse survival. FO is likely related to the rate of intravenous fluid administration and other factors (oncotic pressure, capillary leak and major organ dysfunction post-transplant). Caution is warranted to prevent excessive hydration and weight gain in the early post-transplant period. Other factors potentially associated with weight gain will be evaluated. Figure 1. (A) NRM and (B) OS in haploidenticaltransplants; (C) NRM and (D) OS in matched transplants. Figure 1. (A) NRM and (B) OS in haploidenticaltransplants; (C) NRM and (D) OS in matched transplants. Disclosures Alousi: Therakos, Inc: Research Funding.

Introduction: T-cell acute lymphoblastic leukemia (T-ALL) represents approximately 20-25% of all cases of ALL diagnoses per year. Given the rarity of T-ALL, there are limited data to guide the treatment of these patients, particularly as it relates to allogeneic stem cell transplantation (allo-SCT). Early thymic-precursor (ETP) ALL is a rare variant of T-ALL which expresses both myeloid and lymphoid markers, and has been associated with increased relapse and worse overall survival in some series. Minimal residual disease (MRD) is established as a prognostic marker for increased relapse in B-ALL, but its effect on T-ALL, particularly as it relates to allo-SCT, is less clear. We conducted a multi-center analysis of patients with T-ALL to determine the effect of T-ALL subtype and MRD on transplant outcomes to better guide decisions regarding therapy for this aggressive disease. Methods: Data from MD Anderson Cancer Center (MDACC), the National University Cancer Institute of Singapore, and the Oregon Health & Science University were reviewed. All patients with a diagnosis of T-ALL who received a first allo-SCT after January 1, 2000 were included in the analysis. Flow cytometry data were reviewed centrally at MDACC to determine the T-ALL subtype. ETP was defined according to Coustan-Smith et al. (Lancet Oncol 2009;10:147-56). T-ALL subtype was determined using a similar system based upon Ludwig (Leuk Lymph 1994: 13:Suppl 1: 71-76) and Gassmann et al (Br J Haem 1997:97:372-82). MRD was evaluated by flow cytometry within one month prior to allo-SCT on bone marrow biopsy, and was detected with a sensitivity of 10-3. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method. Disease progression, acute GVHD (aGVHD), and chronic GVHD (cGVHD) were determined utilizing the cumulative incidence (CI) method to account for competing risks. Prognostic factors for OS were assessed using Cox Proportional Hazards regression analysis on univariate and multivariate analysis. Results: 103 patients received first allo-SCT, with a median age of 31 years (range 2-72 years), and median follow-up time of 2.2 years (3.4-7.3 years). Of these, 91 had an identifiable subtype. The 3-year OS, PFS, CI NRM and CI progression was 34%, 31%, 11%, and 58% for the whole cohort, respectively. The CI 100-day NRM was 5%, while the incidence of grade II-IV aGVHD was 48% and CI cGVHD was 29% at 3 years. There was no difference in OS or NRM amongst T-ALL subtypes, including ETP (p=0.8), (Table 1). Furthermore, there was no difference in the rate progression of ETP (HR 1.5 (0.6-3.3, p=0.4). Amongst patients transplanted after 2007, when flow cytometry for MRD was widely utilized, 66 patients had available data: 41 MRD negative, 17 MRD positive, and 8 with no CR defined by >5% marrow blasts. On univariate analysis for OS, there was no difference according to institution, age, disease status at transplant (CR1 vs CR2+), white blood count, presence of extra-medullary disease at diagnosis, presence of CNS involvement, stem cell source, TBI vs no TBI, cytogenetic risk (SWOG classification), or complex cytogenetics. No CR at transplant (HR 3.9, p=0.003) and MRD positivity (HR 2.5, p=0.015) were associated with worse OS. With a median follow-up time of 2 years, the OS rates for patients who were MRD negative, MRD positive, and no CR were 62%, 24%, and 12%, respectively (Figure 1), with CI of progression of 30%, 69%, and 87% respectively (Figure 2). On multivariate analysis, MRD positivity was strongly predictive of OS (HR 2.3, p=0.03) and PFS (HR 2.1, p=0.04). Conclusions: There is no difference in outcomes of patients with T-ALL according to disease subtype. In particular, patients with ETP-ALL who underwent allo-SCT had similar outcomes to other T-ALL subtypes, suggesting that allo-SCT may overcome this poor prognostic primary disease feature. MRD at transplant is the strongest predictor of disease progression and lower survival in patients with T-ALL, with outcomes comparable to those transplanted with active disease. Novel approaches pre-transplant and post-transplant are necessary to mitigate the poor prognostic impact of MRD in T-ALL. Table 1. Outcomes of Allogeneic Stem Cell Transplantation According to T-ALL Subtype Subtype n (%) OS HR p-value PFS HR Progression p-value Early 30 (33) 41% Ref 41% Ref Ref Cortical 28 (31) 26% 1.3 0.4 24% 0.8 1.8 0.1 Mature 17 (19) 31% 1.1 0.8 23% NE 2.4 0.04 ETP 16 (17) 29% 0.9 0.8 22% 0.9 1.5 0.4 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Brammer: Celgene: Research Funding.

Patients with steroid-refractory acute graft versus host disease (aGVHD) have dismal outcomes. Historically, anti-thymocyte globulin has been used in this setting with prior reports demonstrating that even when patients respond, long-term survival occurs in only 5% of patients (Arai et al, 2012). Unfortunately, no therapy has been shown to improve outcomes for this high-risk group. Pentostatin, a potent adenosine deaminase inhibitor, was previously tested in a phase 1/ 2 study in steroid-refractory aGVHD and demonstrated an overall survival (OS) of 25% with a median follow-up of < 3 months (m). We performed a retrospective review of patients receiving pentostatin for steroid-refractory aGVHD with the goal of characterizing long-term outcomes. Methods: All patients transplanted at MD Anderson Cancer Center from January, 2006 to December, 2014 who received at least one dose of pentostatin for steroid-refractory aGVHD were included in this analysis. Pentostatin was dosed at 1.5 mg/m2 on days 1-3 and repeated every two weeks as indicated. Patients who received the drug as GVHD prophylaxis, upfront therapy, beyond third-line, for classic chronic GVHD or following relapse were excluded. Primary endpoints included day 28 response and OS. Results: A total of 60 patients received pentostatin as second (n=22) or third line (n=38) treatment for steroid-refractory aGVHD. The median age was 52 years (range, 2-70). First dose of pentostatin was administered at a median 69 days post-transplant (27-595) with a median of 3 doses provided (range, 1-9). A majority of patients had steroid-refractory lower GI (78%) and/or liver (43%) GVHD. Baseline characteristics described in table 1. The median time from initiation of steroids to pentostatin was 15 days (range, 4-172). OS at 18 m after pentostatin initiation was 21%, with median follow-up of 19 m (range, 7-77).A total of 22 (37%) patients died before day 28 and were considered non-responders. Day 28 response rate was 33% with 20 patients achieving a complete (n=11) or partial response (n=9). Pentostatin administration 60 (HR 1.9, 95% CI 0.99-3.6, p=0.05). Within our analysis, patients destined for early mortality within 30 days of pentostatin exhibited all these features: liver GVHD, receipt of pentostatin >100 days from transplant, and age >60, with an OS of 35% at 30 days compared to 72% in the absence of these features (p=0.001). Conclusions: Patients with steroid refractory aGVHD have dismal outcomes. However, long-term survival does occur, especially when additional therapy is administered promptly. Novel strategies to identify patients who are destined to fail upfront therapies are likely to improve outcomes. We identified that earlier dosing of pentostatin after recognition of steroid refractoriness improved response rates. Further, patients without liver GVHD and who were ≤60 had better OS, identifying those who will benefit most from this therapy. Conversely, pentostatin should be avoided in patients >60 with liver GVHD as these patients had extremely high mortality with two-thirds dying by day 30. Table 1. Baseline characteristics at pentostatin initiation. Variable Patients (N=60) Preparative Regimen Intensity Non-myeloablative (%) 22 (37) Ablative (%) 38 (63) Overall GVHD Grade 2 (%) 11 (18) 3 (%) 21 (35) 4 (%) 28 (47) Skin GVHD Stage 0 (%) 48 (80) 1 (%) 4 (7) 2 (%) 5 (8) 3 (%) 3 (5) Lower GI GVHD Stage 0 (%) 12 (20) 1 (%) 10 (17) 2 (%) 6 (10) 3 (%) 11 (18) 4 (%) 20 (33) Unknown (%) 1 (2) Liver GVHD Stage 0 (%) 33 (55) 1 (%) 4 (7) 2 (%) 9 (15) 3 (%) 6 (10) 4 (%) 7 (11) Unknown (%) 1 (2) Number of GVHD sites 1 (%) 40 (67) 2 (%) 15 (25) ≥3 (%) 5 (8) Day 28 Response CR (%) 11 (18) PR (%) 9 (15) No Response (%) 11 (18) GVHD Progression (%) 5 (9) Died by Day 28 (%) 22 (37) Progression of Malignancy (%) 2 (3) Figure 1. OS, starting at day 29, stratified by response. Figure 1. OS, starting at day 29, stratified by response. Disclosures Alousi: Therakos, Inc: Research Funding.

The use of unrelated donors matched in all alleles of HLA-A, -B, -C, and -DRB1 loci has been associated with superior outcomes compared with those having 1 or more mismatches. Recent studies showed increased transplant-related mortality (TRM) with the use of HLA-DPB1 mismatched donors supporting the notion that the ideal volunteer unrelated donor should fully match at HLA-A, -B, -C, and -DRB1 and lack -DPB1 mismatches. The issue of the effect of HLA-DPB1 mismatch on the disease progression rate is still controversial and we aimed to investigate the impact of HLA-DPB1 mismatch in the graft versus host direction on transplant outcomes in patients categorized according to the recently defined disease risk index (DRI) for disease risk classification. Our study cohort included 1,211 transplant patients with hematological malignancies whohave received an hematopoietic stem cell transplant (HSCT) from an unrelated HLA-A, -B, -C,-DRB1 matched donor by high resolution typing (8/8 matched) after 2005 through 2014. The study cohort had a median age of 55 (range, 19-77); the hematopoietic stem cell source was peripheral blood (PB) in 698 and bone marrow (BM) in 513 patients. Disease risk index (DRI) at HSCT was high or very high in 382 (33%), intermediate in 598 (51%), low in 185 (16%) patients. Of the pairs, 1,154 (95%) were matched atHLA-DQB1 and 1,116 (92%) at HLA- DRB3/4/5 by high resolution testing. However, 633 (52%) had mismatch at one of the DPB1 alleles and 208 (17%) had two mismatches. There was association between matching for DPB1and matching for DRB3/4/5 (p=0.002) but not with DQB1. In PB recipients, there was a highly significant decreaseof disease progression in DPB1 mismatched pairs (one and two allele; HR=0.7, p=0.01 and HR=0.6, p=0.01 respectively) as compared tothose pairs with DPB1 matched. The impact of mismatches at one or two alleles were not different on disease progression (HR=1.2, p=0.4). However, the impact of DPB1 mismatch on disease progression was not uniform in different disease risk groups by DRI. Mismatch at DPB1 significantly decreased disease progression only in the intermediate risk group (HR=0.5, p=0.002) but not in low risk and high/very high disease groups by DRI (HR=0.9, p=0.8 and HR=0.7, p=0.1 respectively) (Figure 1a-c). In BM recipients, increasing number of DPB1 incompatibilities decreased disease progression (HR=0.9, p=0.4 and HR=0.6, p=0.1 for 1 and 2 allele mismatches respectively) but did not reach significance. Mismatches at HLA-DQB1 and -DRB3/4/5 had no impact on disease progression in both PB and BM recipients. Pairs with one or two allele-level DPB1 mismatches increased TRM compared with DPB1 matched pairs in PB (HR=1.5, p=0.04 and HR=1.9, p=0.006 respectively) and BM recipients (HR=1.8, p=0.03 and HR=1.9, p=0.05). There was no difference between two and one allele DPB1 mismatched for TRM in PB and BM recipients. Multivariate analyses revealed that the negative impact of DPB1 mismatch on TRM was not uniform in younger or (?) older patients. Interestingly, DPB1 mismatches increased TRM only in younger (aged We next analyzed the impact of DPB1 matching on progression free survival (PFS) and did not observe any impact of DPB1 mismatches on PFS in PB (HR=0.9, p=0.9) and BM (HR=1.12, p=0.6) recipients. Subgroup analyses by DRI to identify a specific risk group that the use of HLA-A, -B, -C and -DRB1 matched but DPB1 mismatched unrelated donor might lead to improved PFS did not reveal any particular risk group in both PB and BM recipients. Thus, in recipients of HLA-A, -B-C and DRB1 allele-level matched unrelated donors a mismatch for DPB1 is associated with a significantlydecreased risk of disease progression with no impact on PFS in intermediate risk group by DRI. Further analysis permissive vs. non-permissive DPB1 mismatches would be warranted. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Disclosures No relevant conflicts of interest to declare.

Introduction: Age at diagnosis is of prognostic value in Hodgkin's lymphoma (HL) patients. However, there is paucity of data on the impact of age on outcomes of autologous hematopoietic transplantation (auto-HCT) for patients with relapsed and refractory HL. We studied impact of age at diagnosis on long-term outcomes of patients with HL undergoing auto-HCT. Patients and Methods: All consecutive patients with relapsed/refractory HL who underwent auto-HCT at our center between January 1996 and December 2010 were included. Baseline patient and disease characteristics were collected. As HL has bimodal peak incidence betweenages of 15 and 34 years and over age of 50 to 55 years, we stratified patients into 3 groups: > 55, 26 to 55 years, and ≤ 25 year age groups. We compared overall survival (OS), progression free survival (PFS), relapse rate and rates of secondary malignancies between these groups. As the outcomes were similar between ≤ 25 and 26 to 55 years groups, subsequent analysis of these two groups was done together as ≤ 55 years vs. > 55 years groups. Baseline patient and disease-related characteristics were compared using the chi-square test for categorical variables and Mann Whitney's rank-sum test for continuous variables. Actuarial OS was estimated using the Kaplan-Meier method. Prognostic factors for OS, disease progression and non-relapse mortality (NRM) were assessed on univariate and multivariate analyses using Cox proportional hazards regression analysis. Results: 30 (9.7%) patients were > 55, 168 (54.1%) patients were between 26 to 55, and 112 (36.1%) were ≤ 25 years of age. At a median follow-up of 80 months, patients > 55 were at significantly higher risk for mortality with hazard ratio (HR) of 2.3 (95% CI, 1.3-4.2; P = 0.007) compared to patients ≤25 years of age. There was no difference in mortality when between age 26 to 55 years and ≤ 25 years group (HR 1.0; 95% CI, 0.6-1.6; P = 0.9). Risk for progression was similar between the 3 groups, with HRs of 1.3 (95% CI, 0.7-1.5; P = 0.5) and 1.2 (95% CI, 0.8-1.8; P = 0.3) for > 55 group and 26 to 55 groups, respectively compared to ≤ 25 years group (Table 1). Patients > 55 years at diagnosis had significantly higher incidence of secondary malignancies mostly MDS/AML(30% vs. 8%; P 55 years at diagnosis who receive auto-HCT for relapsed/refractory HL experience higher mortality from secondary malignancies. | Outcomes | Entire Cohort | > 55 years N = 30 | ≤ 55 years N = 280 | P value | | ---------------------------------------------- | ------------- | ------------------------ | ------------------------- | ------- | | OS | 65% (59-71) | 27% (9-49) | 69% (63-74) | 0.003 | | PFS | 54% (48-60) | 31% (12-53) | 56% (50-62) | 0.2 | | CI of progression | 41% (26-64) | 52% (36-75) | 37% (32-44) | 0.7 | | CI of NRM | 8% (5-12) | 33% (16-65) | 5% (3-9) | 0.001 | | CI of second malignancy | 11% (7-16) | 30% (16-57) | 8% (5-14) | < 0.001 | | CI of second malignancy excluding skin cancers | 9% (6-13) | 22% (10-49) | 7% (4-12) | 0.003 | * SHAPE * P=0.001 * P

Background: Post-transplantation cyclophosphamide (PTCy) is an effective strategy to prevent GVHD after haploidentical or HLA-matched related or unrelated donor hematopoietic stem cell transplantation (HSCT). Our study aim was to determine its efficacy in HLA-mismatched unrelated donor (MMUD) HSCT. Methods: We included 113 consecutive adult patients with high risk hematological malignancies who underwent one-antigen MMUD (9/10-matched) bone marrow (BM) or peripheral blood (PB) HSCT after myeloablative or reduced-intensity conditioning at our institution from 2009-2013. Outcomes were compared between (a) conventional GVHD group (n=71) that received in-vivo T-cell depletion with ATG, tacrolimus and methotrexate and (b) PTCy group (n=41) that received PTCy (50 mg/kg/day IV on days 3 and 4) with tacrolimus and MMF. After exclusion of 29 patients with isolated HLA-DQ mismatches, a separate analysis was performed in 84 patients with 7/8 HLA-MUD HSCT; 38 patients received PTCy while 46 patients received conventional prophylaxis. Results: Patients in the conventional group were marginally older (median 54 years; range 19-74) than those in the PTCy group (median 50 years; range 20-64). PB was used more frequently as a graft source in the conventional group (38% vs 17%, p=0.02). PTCy group included more patients with HLA class-I mismatches (87.8%) compared to conventional group (56.9%). There were no other differences between the groups. Incidence of grade II-IV (37% vs 36%, p=0.8) or grade III-IV (17% vs 12%, p=0.5) acute GVHD at day 100 post-transplant was not different between the groups. [Figure 1] Incidence of grade II-IV acute GVHD at day 30 was significantly lower after PTCy compared with conventional prophylaxis (0% vs 15%, p In patients with HLA class-I mismatch, PTCy was associated with significantly reduced risk of grade II-IV, but not grade III-IV, acute GVHD at day 30 (p=0.01). However, there were no differences in acute grade II-IV GVHD (HR 1.1, 95% C.I. 0.5-2.5, p=0.7) or acute grade III-IV GVHD (HR 1.5, 95% C.I. 0.4-5.4, p=0.5) by day 100 between the groups. Comparing patients with 7/8-HLA-MUD HSCT, no patient in PTCy group developed acute GVHD at day 30 compared with 8 patients in conventional group (p=0.005). There were no differences in incidence of grade II-IV (HR 1, 95% C.I. 0.5-2.1, p=0.9) or grade III-IV (HR 1.1, 95% C.I. 0.3-3.3, p=0.9) acute GVHD at day 100, chronic GVHD at 6 months (HR 0.8, 95% C.I. 0.2-2.9, p=0.7), 1-year (HR 0.8, 95% C.I. 0.3-2.2, p=0.6) or 2-years (HR 0.7, 95% C.I. 0.2-1.9, p=0.5) between the groups. Conclusion: Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA-MMUD HSCT. Disclosures Alousi: Therakos, Inc: Research Funding.

Background: Ibrutinib has demonstrated efficacy in clinical trials for relapsed and refractory MCL and CLL. There is a paucity of information regarding its safety and efficacy after failing alloSCT. Clinical data suggest that B-cell dysfunction contributes to chronic graft-versus-host-disease (GVHD). It is speculated that this may be due to hyper-responsiveness of the B-cell receptor, which can be abrogated by disrupting the signaling downstream by the use of ibrutinib. Purpose: To study the safety, toxicity, survival rates and risk of GVHD in patients with CLL and MCL who relapsed post an alloSCT at our center. Methods: Retrospective review in MCL and CLL pts who received ibrutinib post alloSCT between 12-1-2011 and 12-1-2014. The study was approved by IRB. Results: We identified 22 pts with CLL (n=16) and MCL (n=6) who failed alloSCT with either nonmyelablative (n=17, 77%) or ablative (n=5, 23%) conditioning. Twelve (55%) received their transplants from HLA-compatible siblings and 10 (45%) from unrelated donors. Median time from alloSCT to progression was 12 months (range, 5-94 months). Ten (45%) failed to respond to donor lymphocyte infusion (DLI). The median time from progression post alloSCT and starting ibrutinib was 17 months (range, 0.5-88 months).When starting ibrutinib, median age was 63 (range, 47-73) years. Ten (43%) pts had bulky disease. Median β2-microglobulin was 4 mg/L (range, 2.7-10). Five (23%) CLL had 17p deletion. Median hemoglobin in CLL pts was 12.3 g/dL (range, 9.2-17.6), median platelets was 109,000/ µL (range, 8000-301,000), median absolute lymphocyte counts were 2,300/µL (range, 310-64,400). All MCL pts had elevated Ki-67 of >30% and 5 (83%) were blastoid. Median % of donor T cell (range, 27-100) and myeloid cells (range, 84-100) was both 100%. The ibrutinib starting dose was 420 mg in 12 (55%) and 560 mg in 10 (45%) pts. With a median follow-up time of 15 (range, 4-38) months, median overall survival (OS) was not reached for CLL, whereas this was of 17 months for MCL pts. Eighteen-month OS rate for CLL and MCL pts were 87% and 33%, respectively (P=0.08) and the 18-month progression-free survival rates were 87% and 33%, respectively (P=0.03). Survival rates were similar in CLL pts with or without 17p deletion. At the time of this analysis, 12 (75%) CLL pts (3 in CR, 4 in PR, 4 in stable disease and one with progressive disease) and 3 (50%) MCL pts (1 in PR, I in stable and 1 with progressive disease) remain alive. Ten episodes of grade 2 infection (3 of which were related to pneumonia) and one septic shock occurred during the course of ibrutinib treatment. Two of these infections occurred in the setting of severe neutropenia. One (5%) pt developed atrial fibrillation that required cardioversion. One (5%) pt experienced bleeding post a tooth extraction that required hospitalization and transfusions. With their prior alloSCT course and DLI, 8 (36%) pts had grade 1-2 acute GVHD, 3 (14%) had acute grade 3-4 GVHD and 7 (32%) had chronic GVHD. At the time ibrutinib was started, all pts were off immunosuppression and 3 had signs of limited chronic GVHD. At ibrutinib initiation, the 3 pts with limited chronic GVGD progressed to extensive GVHD at 43, 105 and 153 days respectively. All 3 had involvement of the mouth, skin (one with severe scleroderma) and 1 had acute gastro-intestinal diarrhea and bleeding. All responded to initiating tacrolimus, systemic steroids and reducing the ibrutinib dose. Conclusions: Our results show that the use of ibrutinib after alloSCT is safe in pts who do not have active GVHD. The treatment can improve OS especially in CLL pts. This warrants further studies incorporating the drug in an upfront transplant strategy. Disclosures No relevant conflicts of interest to declare.

Introduction: Double-unit cord blood (CB) transplantation (DCBT) after myeloablative conditioning, where one CB unit is expanded ex-vivo with mesenchymal precursor cells (MPC)-co-culture led to significantly improved neutrophil and platelet engraftment compared to historical controls.1 Our aim was to determine the efficacy of this technique after reduced-intensity conditioning (RIC) regimens. Methods: We evaluated consecutive adult patients with hematological malignancies who received RIC regimens followed by DCBT where one unit was infused unmanipulated and second unit was expanded ex-vivo with MPC prior to infusion ("MPC group" n=27), as described previously,1 andcompared themwith historical cohort who received two unmanipulated CB units ("controls" n= 51) from 2003-2015. Two RIC regimens were used - Flu/Cy/TBI (flu 40 mg/m2, cy 50 mg/kg and TBI 200cGy) (n=40) and Flu/Mel (flu 40 mg/m2 and mel 140 mg/m2) (n=38) with rabbit ATG 3mg/kg. Tacrolimus and MMF were used for GVHD prophylaxis. Primary endpoint was median time to engraftment of neutrophils (≥ 0.5 X 109/L X 3 consecutive days) and platelets (≥ 20 X 109/L X 7 consecutive days without transfusion). Results: Diagnoses were AML/MDS (N=38; 49%), ALL (N=13; 17%),NHL (N=18; 23%), HD (N=3; 4%), CML (N=1; 1%), and CLL (N=4; 5%). Baseline patient characteristics were similar among the groups [Table 1]. Majority of CB units (66%) were 5-6/8 matched at HLA-A, B, C and DRB1 by high resolution testing. Infused median total nucleatedcells (TNC) (x107/Kg) were 4 and 8, and median CD34 cells (x105/Kg)were 4.3 and 19.7, respectively for control and MPC groups. Co-culture with MPCs led to expansion of TNC by a median of 11.1 and of CD34+ cells by a median of 49.3. Among engrafted patients, median time to neutrophil engraftment was 12 (range 1-28) days in MPC group as compared with 16 (range 5-48) days in controls (p=0.02); the median time to platelet engraftment was 31 days and 37 days, respectively (P=0.3). On day 26, the cumulative incidence of neutrophil engraftment was 78% in MPC group versus 67% in controls (P=0.1). On day 60, the cumulative incidence of platelet engraftment was 74% and 74%, respectively (P=0.7). [Figure 1] Conditioning regimen also affected the time to neutrophil recovery. Among patients with Flu/Mel, the median time to neutrophil engraftment was 14 days in MPC-group (n=13) compared with 22 days in controls (n=19) (p=0.001). Patients with Flu/Cy/TBI regimen had faster time to engraftment; median time to neutrophil engraftment was 6 days in MPC group (n=10) and 11 days in controls (n=27) (p=0.04). However, the median time to platelet engraftment was similar in MPC- and control groups in patients who received either Flu/Mel (37 vs 44 days, p=0.1) or Flu/Cy/TBI regimen (29 vs 31 days, p=0.5). There was no difference in the cumulative incidence of day 100 non-relapse mortality (4% vs. 11%, p=0.6), 6th month mortality (25% vs 24%, p=0.6), grade II-IV acute GVHD (28% vs 27%, p=0.9), 2-year chronic GVHD (29% vs 20%; p=0.9) and estimates of 2-year OS (32% vs. 34%) between patients with ex-vivo expanded and unmanipulated CB units. Conclusions: Transplantation of CB units expanded with MPC appeared to be safe and effective. Using MPC-expanded CB units significantly improved time to engraftment following Flu/Mel or Flu/Cy/TBI RIC regimens as compared with unmanipulated units. Table 1. Patient characteristics Control(N=51) MSC group(N=27) P value Age, years (median, interquartile range) 57 (48, 63) 59 (49, 67) 0.3 Disease Status CR1/CR2 20 (40%) 12 (45%) Advanced 31 (61%) 15 (56%) 0.7 Disease Risk Index, n (%) V. High/High 8 (16%) 9 (33%) Intermediate 38 (75%) 16 (59%) Comorbidity index 0-1 24 (47%) 13 (48%) 2-4 22 (43%) 11 (41%) >4 5 (10%) 3 (11%) 0.97 Flu/Mel regimen 22 (43%) 16 (59%) 0.2 References 1. de Lima M, McNiece I, Robinson SN, et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. NEJM. 2012;367(24):2305-2315 Disclosures Kaur: UT MD Anderson Cancer Center: Employment. Alousi:Therakos, Inc: Research Funding. Skerrett:Mesoblast: Employment. Burke:Mesoblast: Employment.

Introduction: Gastrointestinal Graft Versus Host Disease (GI GVHD) is a leading cause for non-relapse mortality (NRM) following allogeneic hematopoietic cell transplantation. Histologic confirmation of GI GVHD via endoscopic biopsy is considered standard practice with histologic grading reported as grades 0-4. Histologic grade 3-4 (crypt drop out/ broad areas of denudation) has been found to correlate with clinical severity and very high NRM. However, the prognostic value for the more common histologic grade 1 (increased apoptotic bodies) has been poorly described, leading to confusion in rendering therapy in patients with this finding. The goal of this study was to determine the impact on NRM for patients with histologic grade 1 in context of the presenting clinical stage. Methods: We evaluated 309 consecutive patients who underwent an initial, histologic confirmation for suspected GI GVHD within the first 6 months post-transplant between the years of 2009- 2012 at MD Anderson. The majority of the patients underwent an upper GI endoscopy with random biopsies obtained from the antrum and body of the stomach and duodenum along with an un-prepped sigmoidoscopy with random rectal biopsies. All slides were re-reviewed by a single pathologist experienced in GI GVHD. The overall histologic grade for a patient was defined as the maximum grade identified in any biopsy site. The presence of 4 or more apoptotic bodies in a biopsy fragment was required for histologic grade 1, and a biopsy fragment with 3 or fewer apoptotic bodies (formerly suggestive of or cannot exclude GVHD) was classified as negative (histologic grade 0). In order to be considered as negative for GVHD, the absence of apoptotic bodies was required for all biopsy fragments. Clinical stage 0 refers to patients who underwent endoscopic biopsy for mild lower GI GVHD symptoms but not severe enough for clinical stage 1, and remainder clinical stages were defined based on standard criteria. Results: Patient characteristics are described in Table 1. A total of 82 (26%), 101 (32%), 28 (9%), 53 (17%), and 45 (15%) patients were classified as having GI GVHD histologic grade 0-4, respectively. The distribution of histologic grade according to presenting clinical stage is shown in Figure 1. In univariate analysis, the presence of histologic grade 1 did not influence NRM for patients with isolated upper GI GVHD (HR 0.8, p=0.6), but was associated with increased NRM (HR 2.4, p=0.02) in patients with lower GI GVHD. Among patients with lower GI GVHD, the 4-years cumulative incidence (CI) of NRM was significantly higher in patients with clinical stages 3-4 versus 0-2 (61% vs 41%, p 0.002). However, the proportion of histologic grade 1 was comparable between these two groups (23% vs 32%, p=0.2). Therefore, we assessed the impact of histologic grade 1 in lower GI GVHD stratifying for clinical stage (0-2 vs 3-4). In univariate analysis, histologic grade 1 did not lessen the severity of GVHD in patients with clinical stage 3-4 (4-years % CI: 83%). In contrast, histologic grade 1 was associated with increased NRM in clinical stage 0-2 compared with histologic grade 0 (4-years % CI: 48% vs 18%). Multivariate competing-risk regression analysis confirmed the independent impact of histologic grade 1 in patients with clinical stages 0-2 (HR=3.05, p= 0.025) (Figure 2). The presence of multiple versus single positive biopsy site for histologic grade 1 did not influence NRM. Conclusion: Histologic grade 1 GI GVHD is not synonymous with "mild" GVHD and clinicians should use the term "mild" only to reflect clinical stage. The presence of histologic grade 1 in patients presenting with lower GI GVHD clinical stage 0-2 should not be dismissed since it independently impacts outcomes with 3-fold increased NRM. For patients who present with advanced lower GI GVHD (clinical stage 3-4), the presence of histology grade 1 does not lessen the markedly adverse impact of advanced clinical stage GVHD. Figure 1. Patient Characteristics Figure 1. Patient Characteristics Figure 2. Distribution of Clinical Stage Vs Histologic Grade Figure 2. Distribution of Clinical Stage Vs Histologic Grade Figure 3. Figure 3. NRM among patients with lower GI GVHD clinical stage 0-2 Disclosures Alousi: Therakos, Inc: Research Funding.

Lower Gastrointestinal Graft versus Host Disease (GI GVHD) is a major cause for GVHD related non-relapsed mortality (NRM). High dose corticosteroid is the initial therapy for suspected lower GI GVHD, and additional therapy is often required for steroid refractory cases. The identification of high-risk patients is critical as timely intensification of treatment through early institution of second line therapy improves outcomes. To develop a reliable lower GI GVHD risk scoring system, Gastrointestinal Acuity Score (GAS), we evaluated 210 consecutive patients who underwent endoscopic biopsy for suspected lower GI GVHD within 6 months from the transplant from 2009 to 2012 at M.D. Anderson Cancer Center. We first identified 5 significant prognostic factors that accounted for the increased NRM in lower GI GVHD using univariate analysis: histologic grade, clinical stage, age, multi-organ GVHD, and donor type (Table 1). Gender, donor cell type, conditioning regimen (myeloablative vs non-myeloablative), time of diagnosis, disease status did not significantly influence NRM. Next, we performed multivariate Classification and Regression Tree (CART) analysis that utilizes sequential binary decision nodes to categorize 197 patients into subgroups according to their risk profile and outcome (Figure 1). The decision tree identified 7 subgroups starting with the presence of multi-organ GVHD as the first major decision node. This was followed by clinical stage 3/4, Age > 40 years, histology grade 3/4, and histology grade 1. We then consolidated subgroups with comparable risk profiles into low, intermediate, and high NRM risk groups (Figure 1). The 3 NRM risk groups correlated with day 28 response, the need for second line therapy and overall survival (Figure 2). The complete response rates at day 28 from the initiation of steroid therapy were significantly lower in the high (15%, p In conclusion, we developed a novel risk scoring system, Gastrointestinal Acuity Score (GAS), incorporating histologic grades and clinical factors through multivariate CART analysis, and demonstrated that GAS predicts both early outcomes (day 28 CR rate and need for second line therapy) and late outcomes (NRM and overall survival) in patients with lower GI GVHD. Once prospectively validated in a larger cohort of lower GI GVHD patients, it will be of great use for clinicians with limited access to GVHD biomarker analysis in making treatment decisions as our new risk scoring system utilizes readily available variables. Figure 1. Univariate Analysis of risk factors for NRM at 1 year in Lower GI GVHD Figure 1. Univariate Analysis of risk factors for NRM at 1 year in Lower GI GVHD Figure 2. CART Analysis: Decision Tree for Risk Assessment Figure 2. CART Analysis: Decision Tree for Risk Assessment Figure 3. Need for second line therapy, NRM and OS Figure 3. Need for second line therapy, NRM and OS Disclosures Alousi: Therakos, Inc: Research Funding.

Unrelated cord blood transplant (CBT) is an alternative treatment option for patients who lack a matched donor. However, the optimal type and intensity of the preparative regimen remains unclear. We evaluated the toxicity and outcomes of a conditioning regimen consisting of melphalan 140 mg/m(2) (day - 8), thiotepa 10 mg/kg (day - 7), fludarabine 160 mg/m(2) over 4 days (days - 6 to - 3) and rabbit antithymocyte globulin (ATG) 1.25 mg/kg (day - 4) and 1.75 mg/kg (day - 3) (FMT). Forty-seven patients with advanced hematologic malignancies with a median age of 23 years (30 adults and 17 children) were treated. Sixty percent of patients were in remission at transplant. Ninety-one percent of the patients engrafted neutrophils after a median of 22 days, and all but one of the patients achieving donor engraftment had hematopoietic recovery with 100% cord blood-derived cells. Grade 3 gastrointestinal toxicity was the major non-hematopoietic toxicity, occurring in 32% of patients. Cumulative incidence of day-100 grade II-IV acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD) was 53% and 34%, respectively, and non-relapse mortality at day 100 and 2 years was 11% and 40%. Two-year disease-free and overall survival rates were 31% and 44%, respectively. These results suggest that FMT is a feasible conditioning regimen for patients undergoing CBT.

A total of 36 consecutive patients with AML in CR underwent reduced-intensity allogeneic hematopoietic SCT (RISCT) with fludarabine and melphalan conditioning. All patients were ineligible for myeloablative transplantation because of age or comorbidity. In total, 30 patients were in first CR and six patients were in second CR. Donors were siblings in 21 (58%) patients and were unrelated in 15 (42%) patients. Hematopoietic cell transplant specific comorbidity scores ⩾3 were present in 26 (72%) patients. With a median follow-up of 52 months (range, 34–103 months), OS and PFS rates at 4 years were 71% (s.e., 8%) and 68% (s.e., 8%), respectively. At 4 years, the cumulative incidence of non-relapse mortality was 20% (s.e., 7%) and of relapse mortality was 8% (s.e., 5%). Neither OS nor PFS was affected by older age (>60 years), unrelated donor, melphalan dose, or comorbidity score. At last follow up, of the 24 surviving patients, 21 (88%) had performance status (ECOG) of 0 without any active chronic GVHD requiring steroids. Hence, RISCT with fludarabine and melphalan conditioning produces durable long-term remission in older patients with AML.

One challenge in designing clinical trials for treatment of acute GVHD (aGVHD) is the lack of an established standardized end point to measure the success of therapies. To facilitate assessment of end points in clinical trials for treatment of aGVHD in the current allo-SCT era, a national workshop was recently organized. In this study, which was presented at the workshop, we evaluated the prognostic value of response to upfront therapy in a cohort of 83 patients who had been enrolled on two clinical trials testing novel therapies for aGVHD at our institution. Our results indicate that patients whose aGVHD has a CR or PR by day 28 after initiation of systemic therapy have a significantly lower 6-month cumulative incidence of non-relapse mortality (NRM) (16%) than patients whose aGVHD did not respond to therapy by day 28 (48%, P=0.005). Multivariate analysis based on the Cox proportional hazards regression analysis showed that the impact of response on NRM is independent of patient and aGVHD characteristics. Our data confirm the validity of using day-28 response as a primary end point in clinical trials for upfront therapy for aGVHD.

Patients with steroid-resistant acute graft versus host disease (aGVHD) have a dismal prognosis, with mortality rates in excess of 90%. We sought to identify a subgroup of patients less likely to benefit from initial therapy with corticosteroids as well as the impact of response on day 14 on outcome. Retrospective evaluation was performed of patients with biopsy-proven aGVHD treated with corticosteroids after allogeneic HSCT at M.D. Anderson Cancer Center from 1998 through 2002 (). Overall response to first-line therapy on day 14 was 56%. Grade III-IV aGVHD and hyperacute GVHD were the most significant factors predicting failure. Patients who fail to respond to steroids by day 14 should be considered for clinical trials. Severity of aGVHD, hyperacute GVHD, and sex mismatch could be integrated into prognostic scoring systems which may allow for pretreatment identification of patients unlikely to benefit from standard therapy with corticosteroids.

In spite of high-dose chemotherapy followed by autologous hematopoietic SCT multiple myeloma (MM) eventually recurs, highlighting the need for more effective treatment approaches. Patients received topotecan 3.5 mg/m(2) intravenously on days -6 to -2, melphalan 70 mg/m(2) intravenously on days -3 and -2 and CY 1 g/m(2) intravenously on days -6, -5 and -4. Overall response rate (ORR) consisting of complete response and partial response (CR+PR, PFS, OS and toxicity are reported. Between August 2002 to March 2004, 60 patients (34 men and 26 women) with a median age of 61 years (range 45-72) were enrolled. Forty-one patients were treated for consolidation of first remission, while 19 patients had relapsed/refractory disease. ORR was 85% (CR 12%, very good PR 43% and PR 30%). Median time to neutrophil (ANC0.5 × 10(9)/L) and plt engraftment (20 × 10(9)/L) was 10 (range 7-12 days) and 9 days (range 6-79 days), respectively. A majority of the common adverse events were grade 1-3 mucositis/stomatitis (65%), grade 1 or 2 nausea (59%) and grade 1 or 2 diarrhea (41%). Median PFS was 18.5 months and median OS has yet not been reached. In conclusion, topotecan, melphalan and CY is a safe and active conditioning regimen for auto hematopoietic SCT in MM. The ORR and PFS were comparable to high-dose melphalan.

Background Mismatched family donor and unrelated donor BM transplants are associated with a high risk of acute GvHD. While T-cell depletion is the best method to reduce risk of acute GvHD, there was a reluctance to use T-cell depletion in the mismatched setting because of increased risk of rejection and relapse. Partial T-cell depletion, by the panning of CDS and CD8 positive T cells may reduce complications related to GvHD without compromising outcomes. Method In a long-term follow-up of a Phase II study of partial T-cell depletion by panning for BM transplant, 32 recipients received transplants from a single-Ag (HLA A, B, or DR) mismatched family donor; or an HLA serologically-matched unrelated donor. Patients were studied for engraftment, GHD, relapse and survival. Results 30 (94%) of the patients marrow engrafted. The cumulative risk of Grade 2-4 acute GvHD was 62 ± 9%; of Grade 3–4 GvHD, 11 ± 6%. The 4-year cumulative risk of relapse was 18 ± 8% and actuarial survival was 44 ± 9%. Discussion Partial T-cell depletion had a low rate of severe acute GvHD without compromising engrafment or relapse risk.

Serologic evidence of resolved hepatitis B virus (HBV) infection has been associated with reactivation of hepatitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the true impact of this finding is unknown. We conducted a retrospective matched-control analysis of the outcomes of 76 patients with positive HBV core antibody (HBcAb) and negative HBV surface antigen (HBsAg) at the time of allo-HSCT for hematologic or solid malignancies. Control patients (matched controls), with negative serology for HBV and other viral hepatitides, were matched by age, diagnosis, disease risk, intensity of conditioning regimen, and donor type. In addition, the HBcAb-positive patients and all seronegative patients (all controls, n = 1858) undergoing transplantation during the same period were compared to adjust for other confounding effects. Patient characteristics and baseline hepatic function studies were similar in the HBcAb-positive and matched control groups. The cumulative incidence of hepatitis B reactivation (defined as the emergence of HBsAg in serum) was 11.6% at 3 years. There were no significant differences in overall survival, relapse, nonrelapse mortality, and incidence of acute graft-versus-host disease between the HBcAb-positive and control groups. Our data suggest that seropositivity for HBcAb and seronegativity for HBsAg at the time of transplantation does not seem to adversely affect outcome after allo-HSCT.

Haploidentical SCT (HaploSCT) has been most commonly performed using a myeloablative, TBI-based preparative regimen; however, the toxicity with this approach remains very high. We studied the feasibility of a reduced-intensity conditioning regimen in a phase II clinical trial using fludarabine, melphalan and thiotepa and antithymocyte globulin (ATG) for patients with advanced hematological malignancies undergoing T-cell depleted HaploSCT. Twenty-eight patients were entered in the study. Engraftment with donor-derived hematopoiesis was achieved in 78% of patients after a median of 13 days. Six patients experienced primary graft failure, three out of four tested patients had donor-specific anti-HLA antibodies (DSA) (P = 0.001). Toxicity included mostly infections. A total of 21 out of 22 patients with AML/myelodysplastic syndrome (MDS) achieved remission after transplant (16 with relapsed/refractory AML). Five out of the 12 patients (42%) with AML/MDS with

The purpose of this retrospective study was to determine the incidence and predictive factors if any, of mobilization failure in lymphoma patients referred for autologous stem cell transplantation. A total of 588 lymphoma patients were referred for transplant consultation from January 2003 to December 2004. Predictors of mobilization failure were evaluated using logistic regression analysis including diagnosis, mobilization regimen, age, sex, type and number of prior chemotherapies, bone marrow cellularity, platelet count, white count, prior bone marrow involvement with malignancy, and prior radiation therapy. Two hundred and six patients were eligible for transplantation and underwent stem cell mobilization. Twenty-nine (14%) patients failed to mobilize adequate stem cells after the first attempt. For the entire group age (>or=60 versus

The long-term outcome of graft failure after allogeneic stem cell transplantation (SCT) has not been well described. To fill this knowledge gap we performed a retrospective analysis of patients with graft failure over a 10-year time period in a single institution. Cases were included for analysis if they had failed to achieve an absolute neutrophil count (ANC) of 500/μL or more by 28 days post-SCT or 42 days after cord blood transplantation (primary graft failure); had a decrease in their ANC to

Summary Tumor status, as determined by positron emission tomography or gallium scanning (PET/G), may be an important predictor of outcome for patients with diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplantation (ASCT). ASCT conditioning regimens that include rituximab may reduce the rate of relapse. We evaluated the influence of rituximab on overall and progression-free survival in patients with DLBCL based on PET/G status before ASCT. A retrospective review of all patients with chemosensitive DLBCL who underwent ASCT in the context of research protocols at our institution between 1995 and 2005 was performed. Our study included 174 patients. Disease status before ASCT, according to PET/G, was negative in 136 patients (78%), positive in 29 patients (17%), and unknown in nine patients (5%). PET/G status and rituximab use were the only factors predictive of progression-free survival in multivariate analyses: the hazard ratios for relapse were 2·9 for PET/G-positive versus -negative patients (P

We report an unusual case of Leber's hereditary optic neuropathy (LHON) in a 7-year-old boy with recurrent episodes of visual loss.A 7-year-old-boy developed acute severe bilateral optic neuropathy associated with mild optic disc edema. The patient was treated with high doses of systemic steroids followed by improvement in his vision. When the steroids were stopped his vision deteriorated. By the age of 14, this condition had recurred six times. At the age of 15, steroids were stopped and he was treated with azathioprin. At the age of 16, his visual acuity was 9/10 in his right eye and 8/10 in his left eye. Fundus examination showed bilateral optic atrophy. At the age of 15, his younger brother, 12 years old, developed severe visual loss in his left eye. Leber's hereditary optic neuropathy was suspected. Molecular genetic testing of their mother revealed the 11778 mtDNA mutation.In most patients with LHON, visual loss remains profound and permanent. However, recovery of even excellent central vision may occur years after visual deterioration. Recurrences of visual loss are extremely rare. LHON should be considered in any patient with acute bilateral optic neuropathy. In this patient, the visual improvement with corticosteroid treatment and no relapse with immunosuppressive treatment raises the problem of interrelated inflammatory optical neuropathy.

Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graft-versus-lymphoma immunity. The long-term effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days), and rituximab (375 mg/m2 for 1 day plus 1000 mg/m2 for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n = 45) or unrelated donors (n = 2). Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade 2-IV acute GVHD was 11%. Only 5 patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma.

Patients and methods: We present a retrospective analysis of 99 consecutive patients with relapsed non-Hodgkin’s lymphomas who were older than 65 years at the time of high-dose chemotherapy and autologous progenitor cell transplantation. Results: Median age at transplant was 68 years (range 65–82). Thirty-six percent of patients had a hematopoietic cell transplantation comorbidity index of >2 at the time of transplantation. The cumulative nonrelapse mortality was 8% [95% confidence interval (CI) 4–17] at 26 months and the 3-year overall survival (OS) was 61% (95% CI 49–71). On multivariate analysis, disease status at transplant and lactate dehydrogenase (LDH) > normal were significant predictors for OS (P = 0.002). Comorbidity index of >2 did not impact OS but did predict for higher risk of developing grade 3–5 toxicity (P = 0.006). Eight patients developed secondary myelodysplastic syndrome/acute myelogenous leukemia after transplantation (cumulative incidence 16%). Conclusions: Patients with relapsed lymphomas who are >65 years of age should be considered transplant candidates, particularly if they have chemosensitive disease and normal LDH levels at the time of transplantation. Patients with comorbidity index of >2 can also undergo transplantation with acceptable outcomes but may be at

A case of Susac syndrome in a child is reported with a review of the literature. A 14-year-old girl presented with headache, left hemiparesis, sphincter deficit, and cognitive deficits. The assessment consisted of neurological and ocular examination, imagery by cerebral magnetic resonance, lumbar puncture, and a biological and immunological assessment. Magnetic resonance imaging revealed numerous high signal intensities on T2-weighted images in the white and grey matter. The ophthalmologic examination found bilateral branch retinal artery occlusions. Twelve months later, she developed hearing loss. Infection assessment was negative and immunologic tests were normal. Susac syndrome is a rare disorder with a clinical triad of encephalopathy, branch retinal artery occlusions, and hearing loss. It is caused by a microangiopathy affecting the precapillary arterioles of the brain, retina, and inner ear. Susac syndrome usually affects young women in young adulthood and is extremely rare during childhood. The pathogenesis of this syndrome is unknown. The clinical course of Susac syndrome is characterized by recurrent attacks. Resolution usually occurs spontaneously. However, sensory and neurologic sequelae may be present. Treatment is not well codified and may include steroids, immunosuppressant drugs, and immunoglobulin. Susac syndrome should be considered in children when evaluating patients with branch retinal artery occlusion and encephalopathy.

BACKGROUND Multiple myeloma (MM) is the most common indication for high-dose chemotherapy with autologous stem cell transplantation (ASCT) in the U.S. and can be associated with substantial morbidity. Thorough assessment and understanding of symptoms and risk factors for symptom development after ASCT are logical first steps toward developing strategies aimed at reducing the symptom burden associated with this procedure. METHODS The authors performed a prospective evaluation of symptom burden among 64 patients with myeloma who underwent ASCT. Symptom data were collected using the M. D. Anderson Symptom Inventory (MDASI) at 4 time points: baseline, the day of stem cell infusion (Day 0), nadir of counts, and Day 30. Univariate analysis was performed to correlate pretransplantation variables with post-transplantation symptom burden at these time points. RESULTS MDASI scores increased significantly throughout transplantation, with most patients returning to baseline by Day 30 after the procedure. Patients with the highest MDASI scores at baseline had the highest MDASI scores at nadir (P = .02). Patients with prolonged time to transplantation and women had a trend toward higher nadir global symptom severity scores. These groups, as well as patients aged >60 years, had a trend toward higher nadir interference scores. CONCLUSIONS ASCT for MM was associated with significant but reversible symptom burden during the first 30 days, and the baseline symptom burden was the most important predictor of symptom burden after transplantation. The MDASI was useful as a tool for following the symptom burden associated with ASCT and may be used to evaluate interventions aimed at reducing transplantation-related morbidity in these patients. Cancer 2008. ©2008 American Cancer Society.

Background The role of reduced-intensity conditioning allogeneic stem cell transplantation in relapsed/refractory Hodgkin’s lymphoma remains poorly defined. We here present an update of our single-center experience with fludarabine-melphalan as a preparative regimen.Design and Methods Fifty-eight patients with relapsed/refractory Hodgkin’s lymphoma underwent RIC and allogeneic stem cell transplantation from a matched related donor (MRD; n=25) or a matched unrelated donor (MUD; n=33). Forty-eight (83%) had undergone prior autologous stem cell transplantation. Disease status at transplant was refractory relapse (n=28) or sensitive relapse (n=30).Results Cumulative day 100 and 2-year transplant-related mortality rates were 7% and 15%, respectively (day 100 transplant-related mortality MRD vs. MUD 8% vs. 6%, p=ns; 2-year MRD vs. MUD 13% vs. 16%, p=ns). The cumulative incidence of acute (grade II–IV) graft-versus-host disease in the first 100 days was 28% (MRD vs. MUD 12% vs. 39%, p=0.04). The cumulative incidence of chronic graft-versus-host disease at any time was 73% (MRD vs. MUD 57% vs. 85%, p=0.006). Projected 2-year overall and progression-free survival rates are 64% (49–76%) and 32% (20–45%), with 2-year disease progression/relapse at 55% (43–70%). There was no statistically significant differences in overall survival progression-free survival, and disease progression/relapse between MRD and MUD transplants. There was a trend for the response status pretransplant to have a favorable impact on progression-free survival (p=0.07) and disease progression/relapse (p=0.049), but not on overall survival (p=0.4)Conclusions Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in progression-free survival Hodgkin’s lymphoma is associated with a significant reduction in transplant-related mortality, with comparable results in MRD and MUD allografts. Optimizing pretransplant response status may improve patients’ outcome.

We analyzed the clinical factors associated with late cytomegalovirus (CMV) reactivation in a group of 269 consecutive recipients of allogeneic stem cell transplant (SCT) for hematological malignancies. Eighty-four subjects (31%) experienced late CMV reactivation, including 64 with prior early reactivation and 20 with isolated late reactivation. Multivariate analyses were conducted in patients with early CMV reactivation to identify factors associated with late recurrence. Important risk factors included lymphoid diagnosis, occurrence of graft-versus-host disease (GVHD), greater number of episodes of early reactivation, persistent day 100 lymphopenia and the use of a CMV-seronegative donor graft. We combined these risk factors in a predictive model to identify those at relatively low, intermediate and high risk. The low-risk group (15% cumulative incidence, CI) encompassed patients without early CMV reactivation, and subjects transplanted for a myeloid malignancy from a matched-related (MR) donor without subsequent acute GVHD. The high-risk patients (73% CI) met all of the following criteria: (1) received an MR graft but developed GVHD, or received a non-MR graft irrespective of GVHD; (2) had more than two episodes of early reactivation; and (3) received a CMV-seronegative graft and/or remained persistently lymphopenic at day 100 after SCT. The remaining patients had an intermediate incidence of 32%.

Summary ZAP-70 (zeta-chain-associated protein 70 kDa) expression is associated with poor prognosis in patients with chronic lymphocytic leukaemia (CLL). This study evaluated the efficacy of non-myeloablative allogeneic stem cell transplantation in patients with advanced CLL and assessed the impact of ZAP-70 expression on the outcome. Thirty-nine sequential patients were included. All had previously been treated with fludarabine. All patients received a preparative regimen of fludarabine (30 mg/m2/d for 3 d), intravenous cyclophosphamide (750 mg/m2/d for 3 d), and high-dose rituximab. Immunohistochemical techniques on marrow biopsy samples were used to determine that ZAP-70 was expressed in 25 patients, whereas 13 other patients were ZAP-70 negative, and one was of indeterminate status. With a median follow-up time of 27 months, the estimated overall survival and current progression-free survival (CPFS) rates at 4 years were 48% and 44% respectively. Patients who were ZAP-70 positive had 56% survival, and their CPFS rate increased from 30% to 53% after a donor lymphocyte infusion. Multivariate analysis indicated that chemorefractory disease and mixed T cell chimerism at day 90, but not ZAP-70 positivity, were associated with the risk of disease progression after transplantation. These results demonstrate a potent graft-versus-leukaemia effect that can overcome the adverse prognostic effect of ZAP-70 expression.

Several chromosomal abnormalities detected by conventional cytogenetic analysis have an adverse impact on the outcome in myeloma patients. A wide spectrum of abnormalities involving chromosomes 1, 13, 14, and 17 has been described. We analyzed the outcome of 83 patients with clonal cytogenetic abnormalities, who underwent high-dose therapy and autologous stem cell transplantation for multiple myeloma at our institution. Clonal abnormalities were detected at diagnosis by conventional cytogenetic analysis in 83 patients. Patients underwent a single autologous transplant between April 2000 and May 2005. Preparative regimen was high-dose melphalan alone (73), or a combination of topotecan, melphalan, and cyclophosphamide (TMC = 10). The most commonly observed chromosomal abnormalities were deletion of chromosome 13 (32%), hyperdiploidy (21%), deletion of chromosome 1p (18%), and t (11; 14) in 7% patients. Median follow-up among surviving patients was 25.5 months. Median interval from diagnosis to autotransplant was 7.7 months (range: 2.5-52). Median progression-free survival (PFS) for the entire group was 19 months and the median overall survival (OS) was 52 months. On univariate analysis, both PFS and OS were significantly shorter in patients with deletion 1p (P = .001 and

Several clinical trials have shown the superiority of autologous stem cell transplantation over conventional dose therapy for patients with multiple myeloma. This treatment, however, is limited to younger patients (65 years) owing to concerns about toxicity and treatment-related mortality (TRM) in older patients. We treated 26 elderly myeloma patients (70 years), who received a preparative regimen of melphalan 200 mg/m2 (19 patients), melphalan 180 mg/m2 (six patients) or melphalan 140 mg/m2 (one patient). Twenty-two of the 26 patients were alive after a median follow-up of 25 months (range=8-74). Responses (complete+partial response) were seen in 20 patients (77%), five (19%) of which were complete responses. Median PFS was 24 months, whereas median OS has not been reached. Cumulative incidence of 100-day TRM was 0%. Three-year PFS and OS were 39% (range=16-61) and 65% (range=35-83), respectively. A low serum albumin (3.5 g/dl) was associated with a shorter PFS (P=0.02). Patients with relapsed disease at transplant, and an interval of12 months between diagnosis and autotransplant, had a shorter OS (P=0.0004 and 0.04). HDT and autologous transplant is safe and feasible in elderly myeloma patients.

Cytogenetics and Blast Count Determine Transplant Outcomes in Advanced AML Uday R. Popat, Rima Saliba, Betul Oran, Julianne Chen, Amin M. Alousi, Sairah Ahmed, Qaiser Bashir, Stefan O. Ciurea, Chitra Hosing, Roy B. Jones, Partow Kebriaei, Issa F. Khouri, Yago L. Nieto, Amanda Olson, Simrit Parmar, Nina Shah, Elizabeth J. Shpall, Muzaffar H. Qazilbash, Borje S. Andersson, Richard E. Champlin. Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX

BACKGROUND: Endothelial progenitor cells (EPCs) have been identified among hematopoietic tissue-derived progenitor cells that are mobilized into the peripheral blood (PB) as a result of tissue injury. It therefore seems likely that circulating EPCs have therapeutic potential by aiding in the neovascularization of ischemic tissue. This study provides clinical data on the availability of circulating EPCs at steady state and after recombinant human granulocyte–colony-stimulating factor (rHuG-CSF) mobilization and their collection by leukapheresis. STUDY DESIGN AND METHODS: Eight healthy donors underwent rHuG-CSF treatment over 4 days, followed by leukapheresis. Blood samples taken before rHuG-CSF treatment and before apheresis as well as apheresis-collected samples were analyzed by flow cytometry and by real time reverse transcription–polymerase chain reaction for cells expressing EPC-specific surface markers and tissue markers, respectively, and for EPC colony-forming cells. RESULTS: The median PB concentration of CD34+133+ vascular endothelial growth factor receptor-2 (VEGFR-2)-+ EPCs increased 8-fold from steady state to mobilized, and the concentration of CD34+133-VEGFR-2+ EPCs increased by 10-fold. This mobilization pattern was similar to that of hematopoietic CD34+, CD133+, and CD34+117+ progenitor cells. The increase in the median circulating colony-forming unit EPC concentration was 10-fold over baseline. The median absolute number of CD34+133+VEGFR-2+ cells collected by large-volume leukapheresis was 0.8 × 106 per kg of body weight. In addition, a small subset of immature CD133+34– cells coexpressing VEGFR-2 was identified in mobilized PB and in the apheresis collection. EPC-specific cells contained in the apheresis product were also identified as expressing mRNA for the CD31 antigen, Tie-2, and VEGFR-2. CONCLUSION: Circulating EPCs represent a novel blood cell component that can be collected by apheresis in large quantities and can be used clinically, either unmanipulated or EPC-selected, for therapeutic vasculogenesis.

(166)Holmium-DOTMP is a beta-emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high-dose radiation to the bone marrow. Phase I/II trials showed feasibility and tolerability when combined with high-dose melphalan with or without total-body irradiation (TBI) in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). The purpose of this study was to define the potential impact of (166)Holmium-DOTMP on outcomes in patients with MM undergoing ASCT. Retrospective review of transplant outcomes among patients with MM who received an ASCT between January 1998 to December 2001 with either melphalan 200 mg/m(2) or a (166)Holmium-DOTMP containing regimen as part of their initial therapy. Univariate analysis was performed for response, overall survival (OS), and event free survival (EFS). One hundred four patients were identified, of which 41 received a (166)Holmium-DOTMP containing regimen and 63 received melphalan alone. The (166)Holmium-DOTMP patients were divided into 2 groups according to the dose received (2400 mCi versusor = 2400 mCi). The (166)Holmium-DOTMP group had a trend towards a higher complete remission (CR) rate compared to patients receiving melphalan alone (51% versus 32%). The median EFS for the low-dose (166)Holmium-DOTMP, the high-dose (166)Holmium-DOTMP, and melphalan alone was 30, 23, and 19 months, respectively; the OS rate at 5 years for the 3 groups was 61%, 40%, and 43%, respectively. (166)Holmium-DOTMP, in combination with high-dose melphalan, can result in higher CR rates when given in optimal doses (2400 mCi) when compared to melphalan alone, and should be further tested in phase III trials in patients with MM undergoing ASCT.

Rituximab, an anti-CD20 human-mouse chimeric monoclonal antibody has been shown to improve response rates when it is combined with standard salvage chemotherapy in patients with relapsed or refractory intermediate-grade B-cell non-Hodgkin's lymphoma. A vast majority of these patients subsequently undergo high-dose therapy followed by stem cell transplantation. However, the impact of rituximab on stem cell mobilization kinetics is not well characterized. The purpose of this study was to study the effect of high-dose rituximab given with chemotherapy on stem cell mobilization in patients with intermediate-grade B-cell non-Hodgkin's lymphoma. Thirty-six patients received ifosfamide, etoposide, and rituximab followed by filgrastim for stem cell mobilization. The chemotherapy regimen was well tolerated. Thirty-four of 36 patients (94%) were able to mobilize at least 2 x 10(6) CD34+ cells/kg body weight after a median of 2 apheresis procedures. The median CD34+ cell dose collected per kilogram of recipient body weight was 6.5 x 10(6) (range, 4.65-31.15). All patients who subsequently underwent high-dose chemotherapy and stem cell transplantation experienced sustained engraftment. In conclusion, high-dose rituximab given during stem cell mobilization does not negatively affect stem cell mobilization kinetics.

High-dose steroids are the first line of treatment for acute graft-versus-host disease (aGVHD). Steroid myopathy is a debilitating steroid-induced complication that significantly impairs a patient's performance status. To determine the frequency and severity of steroid myopathy and other steroid related complications in patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) who developed grade >or=2 aGVHD after allogeneic hematopoietic stem cell transplantation (HSCT), we performed a retrospective analysis. Patients were included in the analysis if they had a diagnosis of AML/MDS, underwent an allogeneic HSCT between January 1996 and December 2001 and developed grade >or=2 aGVHD that was treated with 2 mg/kg of methylprednisolone and survived at least 100 days post transplant. A total of 70 patients fulfilled our inclusion criteria. Steroid myopathy was identified in 29 (41%) patients. Steroid myopathy was generally of moderate severity with severe debilitating steroid myopathy seen in only 3% of patients. We concluded that steroid myopathy is a common complication of high-dose steroid therapy after allogeneic HSCT in AML/MDS. Interventions aimed at preventing and treating this complication are warranted and need to be explored in prospective clinical trials.

We explored the safety and efficacy of rituximab administered in combination with the standard transplant conditioning regimen of cyclophosphamide (Cy) 120 mg/kg and total body irradiation (TBI) 12 Gy for adult patients with acute lymphoblastic leukemia (ALL). Patients were eligible if their disease expressed CD20. Rituximab was administered at 375 mg/m2 weekly for four doses beginning on day -7 of the conditioning regimen. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-five patients undergoing matched sibling (n = 23) or unrelated donor (n = 12) transplantation were studied, with a median age of 30 years (range 15-55 years). At 2 years, progression-free survival, treatment-related mortality, and overall survival were 30, 24, and 47%, respectively. There was no delay in engraftment or increased incidence of infection. The cumulative incidence of grade II-IV acute GVHD was 17%, and limited and extensive chronic GVHD was 43% at 2 years. The addition of rituximab to the standard Cy/TBI transplant conditioning regimen in ALL was safe and well tolerated, and there was a suggestion of decreased incidence of acute GVHD when compared to historically reported GVHD rates for this group of patients.