Search

Purpose: To compare outcomes between patients with relapsed follicular lymphoma who received a nonmyeloablative allogeneic stem cell transplant (alloSCT) and those who received an autologous transplant (autoSCT). Patients and Methods: We evaluated 194 patients with follicular lymphoma who received an alloSCT (n = 98) or autoSCT (n = 96) at MD Anderson Cancer Center (Houston, TX). The transplant type used was based on donor availability and by Medicare reimbursement guidelines. Patients who received an alloSCT were enrolled in four consecutive trials in which they received fludarabine, cyclophosphamide (or bendamustine), and rituximab conditioning. autoSCT patients received R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan). Results: The median follow-up of survivors was 108 months for the alloSCT group and 102 months for the autoSCT group. Overall survival was significantly better for patients who received an alloSCT compared with those who received an autoSCT (62% vs. 46%; P = 0.048). Similarly, progression-free survival rates were 52% in patients who received an alloSCT and 31% in those who received an autoSCT (P < 0.001), and the 8-year relapse rates were 11% and 43%, respectively (P < 0.0001). Only three patients in the alloSCT group relapsed beyond 3.5 years. In the alloSCT group, the rates for grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 to 4 acute GVHD, and extensive chronic GVHD were 22%, 9%, and 38%, respectively. In the autoSCT group, the 8-year incidence of secondary myelodysplasia was 11%. Nonrelapse mortality was similar between the two groups (15% vs. 11% at 8 years; P = 0.27). Conclusions: This study shows that alloSCT is curative and confers superior survival compared with autoSCT in patients with follicular lymphoma.

How to best use tyrosine kinase inhibitors (TKIs) of BCR-ABL after allogeneic stem cell transplantation for Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) is unknown but will almost certainly not be addressed by a definitive randomized trial. Saini and colleagues provide a large body of observational data to reinforce earlier circumstantial evidence favoring prophylactic use of TKIs for at least 2 years posttransplant.

Fluid overload (FO) grade ≥2 (more than 10% weight gain from baseline) has recently been recognized as an important toxicity associated with a high rate of nonrelapse mortality in recipients of allogeneic hematopoietic cell transplantation (AHCT). The causes for FO remain unclear. We hypothesized that endothelial damage, possibly due to treatments received prior to AHCT, may be associated with this toxicity and sought to determine whether the Endothelial Activation and Stress Index (EASIX) (defined as lactate dehydrogenase [U/L] × creatinine [mg/dL]/platelets [109 cells/L]) correlates with grade ≥2 FO in 2 cohorts of recipients of AHCT at our institution. We tested our hypothesis in a cohort of 145 consecutive recipients (study cohort) of AHCT transplant from HLA-haploidentical donors and validated the findings in a cohort of 449 (validation cohort) recipients of AHCT from HLA-matched donors who underwent transplantation between 2010 and 2015. Predictors of grade ≥2 FO were evaluated using competing risks regression in univariate analysis and classification and regression tree (CART) analysis in multivariate analysis. The cumulative incidence of grade ≥2 FO was estimated considering death as a competing risk. EASIX scores were evaluated based on log2-transformed values. Optimal predictive EASIX cutoff values were determined based on receiver operating characteristics curve analysis. Grade ≥2 FO occurred in 21% and 6% of the study and validation cohorts, respectively, with the majority of these cases being diagnosed before the day of AHCT. Median log2 EASIX score at admission was 2.4 (interquartile range [IQR], 1.3, 3.7) and 2.5 (IQR, 1.4, 3.9) in the 2 respective cohorts. In univariate analysis, high EASIX at admission was a significant predictor of grade ≥2 FO in the study (cutoff: 4.4, hazard ratio [HR] = 4.8, P 60 years (HR = 9.6, P = .04) in the validation cohort. At admission, the prevalence of EASIX score of >4.3 (18% versus 17%, P = .9) was not different between the diabetics and nondiabetics. EASIX score at admission is a significant predictor of grade ≥2 FO in recipients of AHCT from HLA-haploidentical or HLA-matched donors. Independently of EASIX, older patients with low weight were associated with increased risk of grade ≥2 FO for recipients of HLA-haploidentical transplants. For the HLA-matched cohort, diabetes and older age were associated with increased FO risk. These findings require validation in external cohorts.

Background: Relapse is the major cause of failure after autologous stem cell transplantation (autoSCT) for patients (pts) with lymphoma. Targeting immune checkpoints with ipilimumab (Ipi) could result in lasting responses but only in few pts. We have previously reported that combination strategies of Ipi with lenalidomide (LEN) 10 mg (Ipi+LEN) resulted in enhanced immune activity manifested by a significant increase in the numbers of ICOS+CD4+FoxP3- T cells (Khouri I et al. Clin Cancer Res 2018:1011-1018). We have demonstrated proof-of-principle of this activity in one pt with refractory double hit lymphoma (DHL) (failed an autoSCT then relapsed after an allogeneic SCT) and another pt with CLL (failed ibrutinib, CART cell, and allogeneic SCT). Both pts then achieved complete remission with Ipi+LEN that has lasted 5+ and 4+ years, respectively. Hence, we have used Ipi+LEN to prevent relapse after autoSCT in pts with high-risk lymphoma, including double-expressor (DEL)/DHL who have been reported to have a 0% progression-free survival (PFS) rate at 4-years after autoSCT (Herrera et al. J Clin Oncol. 2017; 35:24-33). Patients andMethods: In this prospective trial, pts with lymphoma were enrolled within 6 months post-autoSCT. Inclusion criteria included: age 18 to 80 years; an ECOG PS 0-2; adequate liver (bilirubin and liver enzyme concentrations up to two times the upper limit of normal), renal (serum creatinine < 1.6 mg/dl) , cardiac (ejection fraction 45%), and pulmonary (diffusing capacity of the lung for carbon monoxide 40% of predictive value) function; no active infections; ANC ≥ 1.5x109/L and a platelet count ≥ 75x109/L. Treatment consisted of LEN 10 mg PO daily for 21 days (cycles 1) alternating with Ipi 3 mg/kg IV on day 1 (Cycle 2) for up to 8 cycles. LEN dose reduction was permitted to 5 mg based on standard clinical practice. Results: Twenty-three pts were enrolled in the study. The median age at autoSCT was 56 years (range, 33-74). Fifteen (65%) were males and 5 (22%) pts had an HCT-CI ≥ 3. The median # of prior chemotherapies excluding their SCT was 2 (range, 1-5). Two pts had failed a prior autoSCT and were enrolled after a second transplant. Histologies included [DEL/DHL (n=8, 35%), DLBCL nonDEL/nonDHL (n=6, 23%), mantle cell lymphoma (MCL) (n=4, 17%; including 2 with 2 prior transplants, 1 with CNS involvement, 2 had blastoid histology, 1 in partial response to induction chemotherapy), follicular lymphoma (n=1; 4%; 3 prior therapies) Hodgkin's disease (n=2, 9%; including 1 with persistent PET+ post-transplant), angioimmunoblastic t-cell lymphoma (n=2, 9%). Most pts received R-BEAM (n=17, 74%) or BEAM (n=3, 13%) conditioning for their autoSCT. Median # of cycles of immunotherapy received after autoSCT was 5 (range, 2-8). Two pts are continuing their pre-planned treatment. Median follow-up duration was 35 months (range, 4-78 months). The 3-year rates of overall survival (OS) and PFS were 92% and 73%, respectively (Figure 1). Only 1 death was observed: this occurred in a pt with MCL who received 2 prior autoSCT and then developed post-transplant lymphoproliferative disorder without any evidence of MCL recurrence. The most common other grade 3-4 AEs were 10 events of neutropenia, anemia (1), perianal infection (1), and one developed pulmonary embolism on therapy. All AEs resolved. An immune-related AE occurred in one patient (dermatitis, gr 3) after the second ipilimumab dose and resolved with steroids. DEL/DHL group (n=8): This group was heavily pre-treated. The median # of prior chemotherapies excluding their SCT was 3 (range, 1-5). Five have failed DA-REPOCH, one had failed R-Hyper-CVAD and one was induced with R-CHOP. With a median follow-up of 35 months (range, 4-78months), all pts remain alive. One patient with DEL/DHL who was transplanted during second remission relapsed at 1.6 months after initiating therapy (just after finishing the cycle 2). All others remain in complete remission (Figure 2). Conclusions: Maintenance therapy with Ipi+LEN after autoSCT for high-risk lymphoma shows encouraging survival rates, including pts with DEL/DHL who usually have dismal outcomes. The treatment has favorable toxicity profile. These results warrant a randomized trial for confirmation. Disclosures Khouri: Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Lee:Seattle Genetics: Research Funding; Oncternal Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Guidepoint Blogal: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Nastoupil:Pfizer: Honoraria, Research Funding; Gilead/KITE: Honoraria; Merck: Research Funding; Genentech, Inc.: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Gamida Cell: Honoraria; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karus Therapeutics: Research Funding. Iyer:Merck: Research Funding; Afffimed: Research Funding; Spectrum: Research Funding; Target Oncology: Honoraria; Legend Biotech: Consultancy; CRISPR: Research Funding; Curio Biosciences: Honoraria; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Trillium: Research Funding; Daiichi Sankyo: Consultancy. Flowers:TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; National Cancer Institute: Research Funding; Bayer: Consultancy; Kite: Research Funding; Eastern Cooperative Oncology Group: Research Funding; AbbVie: Consultancy, Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Celgene: Consultancy, Research Funding; Acerta: Research Funding; BeiGene: Consultancy; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Champlin:Genzyme: Speakers Bureau; Johnson and Johnson: Consultancy; Omeros: Consultancy; Actinium: Consultancy; Takeda: Patents & Royalties; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy. Sharma:BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Oncolytics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Glympse: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAb: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Maintenance therapy with Ipilimumab and Lenalidomide after transplantation

Although bortezomib and rituximab have synergistic activity in patients with lymphoma, and can both attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem-cell transplantation (alloSCT). In this phase 1/2 trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 – 1.3 mg/m(2) per dose) was administered intravenously on days −13, −6, −1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results to a historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B-cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and unrelated matched donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m(2). The weighted cumulative incidences of grade II-IV and grade III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival has not been reached in patients age ≤50 years and who had a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.

In patients with chronic lymphocytic leukemia (CLL), persistence of disease after allogeneic stem cell transplantation (alloSCT) can result in poor outcomes. In an effort to improve these outcomes, patients with persistent CLL who were 90 to 100 days beyond alloSCT with no evidence of graft-versus-host-disease (GVHD) were randomized to receive lenalidomide or standard care (withdrawal of immunosuppression followed by donor lymphocyte infusion). Lenalidomide was initiated at 5 mg every other day and increased to 10 mg daily, if tolerated, in each patient. Of 38 patients enrolled, 17 (45%) met the eligibility criteria for randomization. Of these 17 patients, 8 were randomized to undergo lenalidomide therapy. Five (62%) patients had to stop taking the drug because of toxicity. The main reason for drug discontinuation was acute GVHD in 43% of patients. This incidence was 11% in the patients who were randomized to not receive lenalidomide. With a median follow-up of 2.6 years, the median survival was 3.4 years for those receiving lenalidomide. This was not reached in patients randomized to not receive lenalidomide and in patients in complete remission who were not randomized. These results suggested that treatments other than lenalidomide are needed for persistent CLL after alloSCT.

Summary There is limited information regarding the immunological predictors of post-allogeneic stem cell transplant (alloSCT) outcome in chronic lymphocytic leukaemia (CLL), such as mixed T-cell chimerism. We analysed 143 consecutive patients with relapsed/refractory CLL, transplanted between 2000 and 2012, to determine the prognostic relevance of mixed chimerism post-alloSCT and the ability of post-transplant immunomodulation to treat relapse. Mixed T-cell chimerism occurred in 50% of patients at 3 months and 43% at 6 months post-alloSCT; upon 3- and 6-month landmark analysis, this was associated with inferior progression-free survival (PFS) [Hazard ratio (HR) 1·93, P = 0·003 and HR 2·58, P

We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n = 52) or matched unrelated donor (n = 55) transplant for ALL in first complete remission (n = 62), second complete remission (n = 28), or more advanced disease (n = 17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n = 34), t(4;11) (n = 4), or complex cytogenetics (n = 7). Clo 40 mg/m2 was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32 mg/m2. The target daily area under the curve was 5500 µmol/min for patients aged 59 years. With a median follow-up of 3.3 years among surviving patients (range, 1 to 5.8 years), the 2-year progression-free survival (PFS) for patients undergoing HSCT in first complete remission (CR1), second complete remission (CR2), or more advanced disease was 62%, 34%, and 35%, respectively. The regimen was well tolerated, with nonrelapse mortality (NRM) of 10% at 100 days and 31% at 2 years post-HSCT. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) for patients undergoing HSCT in CR1, CR2, or more advanced disease was 70%, 57%, and 35%, respectively. Among 11 patients aged >59 years treated with reduced-dose Bu in CR1 (n = 7) or CR2 (n = 4), 4 remain alive and disease-free, with a median follow-up of 2.6 years (range, 2 to 4.7 years). Only the presence of minimal residual disease at the time of transplantation was associated with significantly worse PFS and OS in multivariate analysis. Our data indicate that the Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. OS and NRM rates compare favorably with those for traditional myeloablative total body irradiation-based conditioning regimens.

Background: Venetoclax has shown a promising benefit in patients (pts) with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). There is paucity of information about the efficacy and risk of GVHD with alloSCT post venetoclax -based therapy. Methods: We conducted a retrospective analysis of 35 AML/ALL pts who received alloSCT following venetoclax-based therapies between 2013-2018 at MD Anderson Cancer Center. Results: Median age at alloSCT was 60 years and 23 (66%) pts had an age-adjusted HCT-CI score > 3. Disease diagnosis - AML (n=31; 89%), ALL (n=4; 11%). Disease status in pts with AML at study entry was CR1 (n=11; 35%), CR2/CR3 (n=6; 19%), Cri (n=2, 6%), hypoplastic marrow (n=2; 6%) or refractory disease (n=10; 32%). ALL pts were in CR1 (n=2) or CR2 (n=2). Sixteen (46%) pts were MRD-negative by flow cytometry on marrow samples pre-alloSCT, 7 (20%) were MRD-positive, and 10 (29%) had active disease; 2 pts had hypoplastic marrow. Median lines of prior therapies was 2 (range 1-7) and 6 (17%) pts had failed a prior alloSCT. Disease risk index was intermediate (n=18 of 34; 53%) or high/very-high (n=16 of 34; 47%). Venetoclax was provided in combination of hypomehylating (HMA) agents or other chemotherapies in 26 (74%) and 9 (26%) pts, respectively. Median duration of venetoclax-based treatment was 2.0 months (range 0.5- 4.6). Most pts (83%) continued their therapy as a bridge to alloSCT. Venetoclax was discontinued in 6 (17%) pts due to adverse events (n=4) or progression (n=2). Conditioning regimens were melphalan-based reduced intensity (n=26, 74%), or busulfan-fludarabine regimens (n=9; 26%). Donor source was matched unrelated (n=13, 37%), or related (n=9; 26%); haplo (n=12; 34%) and mismatched unrelated (n=1; 3%). Cell source was from peripheral blood (n=24; 69%) or bone marrow (n=11; 31%). GVHD prophylaxis consisted of tacrolimus with either post-transplant cyclophosphamide in 25 (71%) pts or methotrexate in 10 (29%) pts. Seven (20%) pts (3 with active disease, 2 MRD-positive and 2 were MRD-negative pre-alloSCT)) received maintenance therapy with agents other than venetoclax (Vidaza=2, Sorafenib =2, SGI =1, Ponatinib =1, Asparginase = 1) post alloSCT at a median of 3 months (range, 2-4 months). Median time to ANC >500 was 15.5 days (range, 10-24), and platelets counts >20 k was 22.5 days (range, 11-46). The cumulative incidence (CI) of acute 2-4 and 3-4 GVHD was 29% and 9%, respectively. Risks associated with 100 day-acute 2-4 GVHD were evaluated in univariate analyses. Factors evaluated were age, HCT-CI, # prior lines of therapies, prior alloSCT, type GVHD prophylaxis, donor type, cell source, female donor to male recipients, prior PD-1 therapy (n=3) , types of combination of venetoclax duration of treatment and timing of last venetoclax treatment to alloSCT. Only venetoclax timing to alloSCT was associated with significant risk. The CI of acute 2-4 GVHD in patients who discontinued venetoclax ≤ 2 weeks (n=11, 31%) vs > 2 weeks (n=24, 69%) was 55% vs 17% (P = 0.020; Figure 1), respectively [HR 0.24, 95% confidence interval 0.07-0.80; P = 0.020). . With a median follow up among surviving pts of 18.4 months (range 3.5-31.4), the 1-year rates of OS, PFS, and NRM were 72%, 57% and 12% respectively. Twelve patients died: 8 due to progression, 2 of GVHD, 1 of infection and 1 of unknown cause. Disease status was the only predictor of OS in univariate analysis. Pts who were MRD-negative pre-alloSCT had a 1-year OS of 92% while the 1-year OS in pts who were CR/MRD+ and those with active disease was 38% and 70%, respectively (Figure 2). No factor evaluated was significantly associated with NRM. Conclusions: Our data show that the use of venetoclax-based therapy as a bridge to alloSCT does not increase the risk of NRM or delayed engraftment. It does improve OS by inducing CR/MRD-negativity in high-risk acute leukemia. It may be prudent however to discontinue therapy > 2 weeks before alloSCT in order to avoid a higher risk of acute GVHD. Disclosures Jabbour: BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Daver:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Konopleva:Cellectis: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Ascentage: Research Funding; Agios: Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Kisoji: Consultancy; Ablynx: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding. DiNardo:Novartis: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria; Calithera: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; MedImmune: Honoraria; Jazz: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding. Ravandi:Orsenix: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding. Kadia:Pulmotec: Research Funding; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding; Cellenkos: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Ascentage: Research Funding; Novartis: Honoraria; Incyte: Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Astellas: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding. Alousi:Incyte: Honoraria, Research Funding; Alexion: Honoraria; Therakos: Research Funding. Oran:Arog Pharmaceuticals: Research Funding; Celgene: Consultancy; ASTEX: Research Funding. Kebriaei:Amgen: Other: Research Support; Pfizer: Other: Served on advisory board; Ziopharm: Other: Research Support; Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board; Jazz: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Kantarjian:Aptitute Health: Honoraria; BioAscend: Honoraria; Adaptive biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Oxford Biomedical: Honoraria; Immunogen: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Janssen: Honoraria; Delta Fly: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Champlin:Omeros: Consultancy; Actinium: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Genzyme: Speakers Bureau; Takeda: Patents & Royalties; Johnson and Johnson: Consultancy. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

Forty patients (median age, 31 years; range, 20 to 63) with Hodgkin lymphoma underwent an allogeneic stem cell transplant with the gemcitabine–fludarabine–melphalan reduced-intensity conditioning regimen. Thirty-one patients (77%) had undergone a prior autologous stem cell transplant, with a median time to progression after transplant of 6 months (range, 1 to 68). Disease status at transplant was complete remission/complete remission, undetermined (n = 23; 57%), partial remission (n = 14; 35%), and other (n = 3; 8%). Twenty-six patients (65%) received brentuximab vedotin before allotransplant. The overall complete response rate before allotransplant was 65% in brentuximab-treated patients versus 42% in brentuximab-naive patients (P = .15). At the latest follow-up (October 2015) 31 patients were alive. The median follow-up was 41 months (range, 5 to 87). Transplant-related mortality rate at 3 years was 17%. Pulmonary, skin toxicities, and nausea were seen in 13 (33%), 11 (28%), and 37 (93%) patients, respectively. At 3 years, estimates for overall and progression-free survival were 75% (95% CI, 57% to 86%) and 54% (95% CI, 36% to 70%). Overall incidence for disease progression was 28% (95% CI, 16% to 50%). We believe the gemcitabine–fludarabine–melphalan regimen allows moderate dose intensification with acceptable morbidity and mortality. The inclusion of gemcitabine affected nausea, pulmonary, and likely skin toxicity. Exposure to brentuximab vedotin allowed more patients to reach allogeneic stem cell transplantation in complete remission. With over 50% of patients progression-free at 3 years, allogeneic stem cell transplantation with reduced-intensity conditioning remains an effective and relevant treatment option for Hodgkin lymphoma in the brentuximab vedotin era.

Lymphoblastic lymphoma (LBL) is an aggressive lymphoma pathologically similar to lymphoblastic leukemia, but primarily presents with nodal or extra-medullary involvement. The aim of this study is to describe outcomes of patients undergoing stem cell transplantation (SCT) for LBL compared to historical data. Thirty-nine patients, of which 54% lacked complete remission (CR), received SCT for LBL between 1990 and 2015; 31 allogeneic and eight autologous. Overall survival (OS) and progression free survival (PFS) at three years for the entire cohort was 41%, the cumulative incidence (CI) of non-relapse mortality (NRM) was 18% at one year, and CI relapse mortality was 28% at one-year and 36% at three years; results similar to historical reports. On multivariate analysis, the use of total-body irradiation (TBI) based conditioning and transplantation in CR were independently predictive of OS and PFS. For patients requiring SCT for LBL, CR and TBI-based conditioning prior to allogeneic SCT may provide improved disease control.

Haploidentical transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PTCy) is increasingly utilized for the treatment of lymphoma and almost exclusively with the nonmyeloablative fludarabine (Flu)/cyclophosphamide/total body irradiation (TBI) conditioning regimen. We present early results of a reduced-intensity (RIC) regimen utilizing fludarabine and melphalan (FM) for the treatment of advanced lymphoma. All patients with a diagnosis of lymphoma or chronic lymphocytic leukemia (CLL) who received Haplo-SCT at the University of Texas MD Anderson Cancer Center between 2009 and 2014 were reviewed (N = 22). Patients received Flu 160 mg/m(2) and melphalan 100 mg/m(2) to 140 mg/m(2) with thiotepa 5 mg/kg or 2 Gy TBI. Because of concerns of increased treatment-related mortality (TRM) with the melphalan 140 mg/m(2) regimen (FM140), a RIC regimen with melphalan 100 mg/m(2) (FM100) was devised. Rituximab was included for CD20(+) disease. Graft-versus-host disease prophylaxis consisted of PTCy 50 mg/kg on days +3 and + 4, tacrolimus, and mycophenolate mofetil. Sixty-eight percent of all patients were not in complete remission at the time of transplantation. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire cohort were 54%, 1-year TRM was 19%, and the cumulative incidence of relapse at 2 years was 27%. Two-year PFS for Hodgkin lymphoma, non-Hodgkin lymphoma, and CLL/small lymphocytic lymphoma were 57%, 51%, and 75%. Patients treated with FM100 compared to FM140 had equivalent PFS (71% versus 37%, P = .246) and OS (71% versus 58%, P = .32). These early results establish Flu and melphalan 100 mg/m(2) with 2 Gy TBI or thiotepa 5 mg/kg as a very promising conditioning regimen for the treatment of advanced lymphoma with Haplo-SCT and PTCy.

Background Fluid overload (FO) grade ≥ 2 (more that 10% weight gain from baseline) has recently been recognized as an important toxicity associated with non-relapse mortality in recipients of allogeneic stem cell transplantation (alloSCT).1 The causes for fluid accumulation remain unclear. We hypothesized that endothelial damage due to treatments received prior to alloSCT may be associated with this toxicity and sought to determine whether the Endothelial Activation and Stress Index2 (EASIX), (defined as lactate dehydrogenase (U/L) × creatinine (mg/dL)/ thrombocytes (109 cells per L), correlates with grade ≥ 2 FO and overall survival (OS) in 2 cohorts of recipients of alloSCT at our institution. The first cohort included 145 recipients of haploidentical (haplo) transplantation, and the second 449 recipients of alloSCT from HLA-matched donors, as previously described.1 Methods Predictors (listed in table) of grade ≥ 2 FO and 6-months OS were evaluated using Cox's proportional hazards regression analysis on univariate analysis, and classification and regression tree (CART) analysis on multivariate (MV) analysis. EASIX scores were evaluated based on log2 transformed values. Results Median log2 EASIX score in the 2 cohorts was 2.4 (IQR: 1.3, 3.7) and 2.5 (IQR 1.4, 3.9) at admission, and 3.1 (IQR 2.2, 3.9) and 2.8 (IQR 1.7, 3.9) at transplant, respectively. CART analysis identified EASIX > 4.4 at admission to be an independent predictor of grade ≥ 2 FO in the haplo (HR=7.5, p 55 years recipients in the haplo cohort, and diabetes (HR=35, p=0.001) and age >60 years (HR=8.1, p=0.06) in the matched cohort. In patients with grade ≥ 2 FO, EASIX >4.4 at SCT was the only significant predictor of OS (HR=4.1, p=0.002). This effect was consistent in both cohorts (Figure A). In patients with grade 0-1 FO, MV analysis showed EASIX >3, comorbidity index score >3, and active disease at SCT to be independent adverse predictors of OS. OS was lowest (60%, reference) in patients with EASIX> 3 and comorbidity score >3, and this effect was consistent in both cohorts (Figure B). OS was significantly higher in patients with EASIX >3 and comorbidity score ≤3 (73%, p

We compared outcomes of adult patients receiving T-cell-depleted (TCD) hematopoietic SCT (HCT) without additional GVHD prophylaxis at Memorial Sloan Kettering Cancer Center (MSKCC, N=52), with those of patients receiving conventional grafts at MD Anderson Cancer Center (MDACC, N=115) for ALL in CR1 or CR2. Patients received myeloablative conditioning. Thirty-nine patients received anti-thymocyte globulin at MSKCC and 29 at MDACC. Cumulative incidence of grades 2-4 acute (P=0.001, 17.3% vs 42.6% at 100 days) and chronic GVHD (P=0.006, 13.5% vs 33.4% at 3 years) were significantly lower in the TCD group. The non-relapse mortality at day 100, 1 and 3 years was 15.4, 25.0 and 35.9% in the TCD group and 9.6, 23.6 and 28.6% in the unmodified group (P=0.368). There was no difference in relapse (P=0.107, 21.3% vs 35.5% at 3 years), OS (P=0.854, 42.6% vs 43.0% at 3 years) or RFS (P=0.653, 42.8% vs 35.9% at 3 years). In an adjusted model, age >50, cytogenetics and CR status were associated with inferior RFS (hazard ratio (HR)=2.16, P=0.003, HR=1.77, P=0.022, HR=2.47, P

Background Extra-Nodal natural killer/T-cell lymphoma (ENKL) is a rare lymphoma representing approximately 5-10% of T-cell non-Hodgkin lymphomas diagnosed in the United States each year. Patients with advanced stage III/IV ENKL and relapsed refractory ENKL have a poor prognosis even despite aggressive therapy and stem cell transplantation (SCT). We conducted a review of the management of 37 patients with advanced-stage and relapsed/refractory ENKL in a predominantly non-Asian cohort evaluating both chemotherapy and SCT outcomes. Patients and Methods We evaluated clinical outcomes in all patients treated for advanced stage III/IV or relapsed/refractory ENKL at MD Anderson cancer center between 2000-2014. Next, we collected stem cell transplant data from four transplant institutions to further evaluate outcomes of both allogeneic (allo-SCT) and autologous (auto-SCT) stem cell transplantation in ENKL. Results OS and PFS were 73% and 45% at one year, and 30% and 19% at 3-years, respectively. SMILE chemotherapy was more effective in maintaining a CR compared to CHOP (83% vs 17%). Only achievement of CR was prognostic for OS (HR 0.245, p=0.002) and PFS (HR 0.072, p) Conclusion Our results suggest that achievement of a CR is imperative in patients with advanced ENKL, and is desirable for any patient for whom auto-SCT is utilized. SMILE-based chemotherapy appeared effective in attaining a CR, and was also an effective salvage regimen. For patients attaining a first CR, auto-SCT should be strongly considered, but should definitely be utilized in patients attaining CR2. For patients with refractory disease, allo-SCT can be considered in a selected group of patients.

Fluid overload (FO) commonly occurs during hospitalization for allogeneic hematopoietic stem cell transplantation. We hypothesized that FO is associated with transplantation outcomes and evaluated this complication in 2 cohorts of patients. FO was graded based on post-transplantation weight gain, symptoms, and need for treatment, scored in real time by an independent team. The first cohort (study cohort; n = 145) underwent haploidentical transplantation for hematologic malignancies following a melphalan-based conditioning regimen. In univariate analysis, factors associated with day +100 nonrelapse mortality (NRM) were FO grade ≥2 (hazard ratio [HR], 15; 95% confidence interval [CI], 4.2 to 55; P .001), creatinine1 mg/dL (HR, 4.7; 95% CI, 1.6 to 14; P = .005), and age55 years (HR, 4.5; 95% CI, 1.5 to 13; P = .008). In multivariate analysis, factors associated with day +100 NRM were FO grade ≥2 (HR, 13.1; 95% CI, 3.4 to 50; P .001) and serum creatinine level1 mg/dL at transplantation admission (HR, 3.5; 95% CI, 1.1 to 11; P = .03). These findings were verified in a separate cohort (validation cohort) of patients with acute myelogenous leukemia/myelodysplastic syndrome who underwent HLA-matched transplantation with busulfan-based conditioning (n = 449). In multivariate analysis, factors associated with day +100 NRM were FO grade ≥2 (HR, 34; 95% CI, 7.2 to 158; P .001) and, in patients with FO grade2, advanced disease status (HR, 5; 95% CI, 1.1 to 22; P = .03). A higher NRM translated to significantly poorer 1-year overall survival rates for patients with FO ≥2 than for patients without FO (70% versus 42%, P .001 in the study cohort and 64% versus 38%, P .001 in the validation cohort). In conclusion, FO grade ≥2 is strongly associated with higher NRM and shorter survival and should be considered an important prognostic factor in transplantation.

Purpose: The roles of allogeneic vs autologous SCT for pts with relapsed FL are under debate. Past studies suggested that allogeneic SCT has a lower relapse rate due to a graft-versus-lymphoma effect, but the risks of graft-versus-host disease (GVHD) and early death negated any survival benefit over ASCT. NMAT allows the performance of transplants with a lower toxicity. Efforts to answer address the debate were attempted through a prospective Blood and Marrow Transplant Clinical Trials Network randomized trial; however it was closed early due to a low accrual. In this report, we compared the outcomes of NMAT vs. ASCT in pts with relapsed FL at a single center. Methods: Pts with relapsed FL received an NMAT if they had an 8/8 HLA-matched adult donor. Pts who had no suitable donors or were not able to have an NMAT due to Medicare/Medicaid reimbursement guidelines received instead an ASCT if they had chemo-sensitive disease (PR or CR) and no bone marrow involvement by disease. Organ eligibility criteria were comparable between the two transplant groups. Conditioning for NMAT consisted of fludarabine (30 mg/m2 daily x3), cyclophosphamide (750 mg/m2 daily x3) (or bendamustine 130 mg/m2 daily x3), rituximab (375 m2 day -13, then 1000 mg/m2 days -6,+1 and +8) +/- Yttrium-90 ibritumomab tiuxetan (0.4 mCi/kg) (Blood 2012 ;119:6373; Blood 2014;124:2306). Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin of 1 mg/kg was given on days -2 and -1 in patients receiving a matched-unrelated donor (MUD) transplant. Pts with ASCT underwent chemo-mobilization of stem cells with rituximab for in-vivo purging; rituximab was also given on days+1 and +8 with BEAM conditioning (Clin Cancer Res 2018; 24:2304-11). This study was IRB-approved at our center. Results: The study included 98 NMAT and 96 ASCT pts treated between 2000-2017. Median age was 53 and 56 yrs, respectively and 24 (24%) and 32 (33%) pts were older than 60 yrs (P=0.21). Male gender was 50% vs 48%, respectively. Eleven NMAT pts (11%) and 18 ASCT (19%) pts had an HCT-CI of > 4 (P=0.16). The time from diagnosis to transplant was 38 months in both groups. Rituximab-chemo induction was received in 54 (55%), and 66 (69%) pts at diagnosis, respectively (P=0.056). Seventy-one NMAT (72%) and 61 ASCT (64%) pts relapsed within 2 yrs of their induction chemotherapy (P=0.22). Most pts (94% and 100%) received transplant from peripheral blood. Significant differences between treatment groups were observed for disease status, prior number of chemotherapies, and year of SCT. More pts receiving NMAT had refractory disease compared with the ASCT group (P=0.018). In addition, a higher percentage of NMAT pts had bulky disease (P=0.016), had a transplant > 1st relapse (P=0.001), received > 3 prior chemotherapies (P=0.003), and had a transplant between 2000-2005 rather than later years (P=0.033) compared with the ASCT pts. NMAT transplant characteristics included MUDs in 28 (29%) patients, 42 (43%) ABO-mismatched and CMV was reactive in 80% of pts and/or donors. With a median follow-up for NMAT pts of 98 months (range, 3-208 months) and 94 months (range, 1-207 months) for ASCT pts, overall survival was significantly better for NMAT patients compared to ASCT patients (62% vs 46%; P=0.048) (Figure 1). Similarly, progression-free-survival was better for NMAT pts compared to ASCT pts (52% vs 31%; P 60 yrs of age. The CI of grade II-IV and III-IV acute GVHD in the NMAT group was 22% and 9%, respectively. The CI of chronic extensive GVHD was 38%. The 8-year CI of secondary MDS/AML in the ASCT group was 12%, which progressively increased to 21% at end of assessment. Non-relapse mortality was similar between the two groups (Figure 3). Conclusions: This is the first study to show that NMAT confers a superior survival in pts with relapsed/FL compared with ASCT. Our conclusions are supported by long-term follow-up. A collaborative effort is needed to allow Medicare/Medicaid pts with high-risk relapsed FL to benefit from NMAT. Disclosures Nastoupil: Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Consultancy, Research Funding. Bashir:Amgen: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Qazilbash:Bioclinica: Consultancy; Amgen: Other: Advisory Board; Autolous: Consultancy; Speaker: Other: Speaker.

We investigated the safety and early disease control data for i.v. busulfan (Bu) in combination with clofarabine (Clo) in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation (SCT). Fifty-one patients (median age, 36 years; range, 20-64 years) received a matched sibling (n = 24), syngeneic (n = 2), or matched unrelated donor transplant (n = 25) for acute lymphoblastic leukemia in first complete remission (n = 30), second complete remission (n = 13), or active disease (n = 8). More than one-half of the patients had a high-risk cytogenetic profile, as defined by the presence of t(9;22) (n = 17), t(4;11) (n = 3), or complex cytogenetics (n = 7). Clo 40 mg/m(2) was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic SCT 2 days later. The Bu dose was based on drug clearance, as determined by the patient's response to a 32-mg/m(2) Bu test dose given 48 hours before the high-dose regimen. The target daily area under the receiver-operating characteristic curve was 5500 μM/min for patients age60 years and 4000 μM/min for those age ≥60 years. The regimen was well tolerated, with a 100-day nonrelapse mortality rate of 6%. With a median follow-up of 14 months among surviving patients (range, 6-28 months), the 1-year overall survival, disease-free survival, and nonrelapse mortality rates were 67% (95% confidence interval [CI], 55%-83%), 54% (95% CI, 41%-71%), and 32% (95% CI, 16%-45%), respectively. For patients undergoing SCT in first remission, these respective rates were 74%, 64%, and 25%. Our data indicate that the combination of Clo and Bu provides effective disease control while maintaining a favorable safety profile.

Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including chronic lymphocytic leukemia (CLL). This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery, and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared to the FCR (fludarabine, cyclophosphamide, rituximab) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received BFR (bendamustine, fludarabine, rituximab) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR- vs. only two (3%) FCR-treated patients did not experience severe neutropenia (P = < 0.001). The 3-year overall survival estimates for the BFR and FCR groups were 82% and 51% (P = 0.03) and the 3-year progression-free survival estimates were 63% and 27% (P = 0.001). The 2-year treatment-related mortality was 8% and 23% and the incidence of grade 3 or 4 GVHD was 4% and 10%, respectively. This study is the first to report that addition of bendamustine to alloSCT conditioning for CLL patients is associated with improved survival and lower mortality, myelosuppression, and GVHD.

This study aims to provide a detailed analysis of allogeneic stem cell transplantation (allo-SCT) outcomes in a large T-cell acute lymphoblastic leukemia (T-ALL) cohort with a specific emphasis on the effects of pre-transplant minimal residual disease (MRD) and disease subtype, including the aggressive early-thymic precursor (ETP) subtype. Data from 102 allo-SCT patients with a diagnosis of T-ALL from three centers were retrospectively analyzed. Patients were grouped into four T-ALL subtypes: ETP, early, cortical and mature. At 3 years, overall survival (OS), PFS, non-relapse mortality and cumulative incidence (CI) progression were 35, 33, 11 and 55%, respectively. Patients transplanted in first complete remission (CR1) had a 3-year OS of 62% versus those transplanted in CR2 or greater (24%) (hazards ratio 1.6, P=0.2). Patients with MRD positivity at the time of transplant had significantly higher rates of progression compared with those with MRD negativity (76 vs 34%, hazards ratio 2.8, P=0.006). There was no difference in OS, PFS or cumulative incidence (CI) progression between disease subtypes, including ETP (n=16). ETP patients transplanted in CR1 (n=10) had OS of 47%, comparable to other disease subtypes, suggesting that allo-SCT can overcome the poor prognosis associated with ETP. MRD status at transplant was highly predictive of disease relapse, suggesting novel therapies are necessary to improve transplant outcomes.

Progressive disease (PD) remains the main cause of treatment failure following reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allo-SCT) in Hodgkin lymphoma (HL) [1]. The dise...

Purpose: We have previously reported the outcomes of NMA alloSCT in 47 patients with relapsed/chemosensitive follicular lymphoma (FL) who received a matched sibling donor (MSD) after FCR conditioning (Khouri, Blood 2008;111:5530). In subsequent trials, eligibility was expanded to include transplants from matched unrelated donors (MUDs) using a 90yttrium ibritumomab tiuxetan (90YIT)-based regimen (Khouri, Blood 2012 ;119:6373) or, more recently, BFR (bendamustine, fludarabine, rituximab; Khouri, Blood 20014;124:2306) conditioning. Herein we report on long-term outcomes in 98 FL patients treated on these 3 consecutive trials between 1999-2017. Methods: The BFR regimen (N=20) consisted of bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation, thus substituting for the cyclophosphamide in the FCR regimen (N=47) . The dose and schedule of fludarabine (30 mg/m2 IV daily x3) and rituximab (375 mg/m2 IV on day -13 and 1000 mg/m2 on days -6, +1, and +8) were similar in both regimens. 90YIT-regimens (N=31) : A diagnostic dose of 111In-ibritumomab was administered on day-14, followed by a fixed dose of 0.4 mCi/kg 90YIT on day -7; FC or BF chemo was then administered at the same dose and schedule (days -5 to -3) as described above. Tacrolimus and methotrexate was used for GVHD prophylaxis. In addition, thymoglobulin of 1 mg/kg was given on days -2, -1 in patients receiving a MUD transplant. Results: Median age was 53 years (range, 29-71) and 24 patients (24%) were >60 years. Twenty-eight patients (29%) had a HCT-CI of ≥ 3. The median prior number of treatments was 3 (range, 2-9); 51 patients (52%) had rituximab-chemo induction at diagnosis. Seventy-one patients (72%) relapsed within 2 years of their induction treatment and median duration of last remission prior to alloSCT was < 1 year in 61% of patients. At transplant, 82 patients (84%) had chemosensitive disease (46% CR, 38% PR); 16% had refractory disease; 22% were PET+; and 20% had elevated serum LDH. Seventy patients (71%) had a transplant from a MSD and 28 (29%) from MUDs; 15 (15%) transplants had female-to-male donors, and 42 (43%) were ABO-mismatched. In addition, CMV was reactive in 80% of patients/ and or donors. Most patients (94%) had alloSCT from peripheral blood. Median number of CD34-positive cells infused was 4.9 x 106/kg. A significant difference in ANC recovery between the 3 conditioning regimens was observed. Neutrophil counts recovered to > 0.5 x 109/L a median of 0 days (range 0-16) for the BFR groups vs. 10 days (range, 0-17) and 11 days (range, 5-17) for the FCR and 90YIT-regimen groups, respectively (p 1st relapse, >2 prior chemotherapies, duration of last remission prior to alloSCT < 1 year, ≥ 3 comorbidities, elevated LDH, acute II-IV GVHD, chronic extensive GVHD were associated with inferior OS. By multivariable analysis (MVA), duration of last remission prior to alloSCT ( Disclosures Jabbour: Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Abbvie: Research Funding; Takeda: Consultancy, Research Funding. Oran:AROG pharmaceuticals: Research Funding; ASTEX: Research Funding; Celgene: Consultancy, Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

Background High-dose chemotherapy (HDC) using sequential cycles of carboplatin/etoposide is curative for relapsed germ-cell tumors (GCT). However, outcomes of high-risk patients in advanced relapse remain poor. We previously developed a new HDC regimen combining infusional gemcitabine with docetaxel/melphalan/carboplatin (GemDMC), with preliminary high activity in refractory GCT. Given the high vascular endothelial growth factor expression in metastatic GCT and the synergy between bevacizumab and chemotherapy, we studied concurrent bevacizumab and sequential HDC using GemDMC and ifosfamide/carboplatin/etoposide (ICE) in patients with poor-risk relapsed or refractory disease. Patients and methods Eligibility criteria included intermediate/high-risk relapse (Beyer Model), serum creatinine ≤1.8 mg/dl and adequate pulmonary/cardiac/hepatic function. Patients received sequential HDC cycles with bevacizumab preceding GemDMC (cycle 1) and ICE (cycle 2). The trial was powered to distinguish a target 50% 2-year relapse-free survival (RFS) from an expected 25% 2-year RFS in this population. Results We enrolled 43 male patients, median age 30 (20–49) years, with absolute refractory (N = 20), refractory (N = 17) or cisplatin-sensitive (N = 6) disease, after a median 3 (1–5) prior relapses. Disease status right before HDC was unresponsive (N = 24, progressive disease 22, stable disease 2), partial response with positive markers (PRm+) (N = 8), PRm- (N = 7) or complete response (N = 4). Main toxicities were mucositis and renal. Four patients (three with baseline marginal renal function) died from HDC-related complications. Tumor markers normalized in 85% patients. Resection of residual lesions (N = 13) showed necrosis (N = 4), mature teratoma (N = 2), necrosis/teratoma (N = 3) and viable tumor (N = 4). At median follow-up of 46 (9–84) months, the RFS and overall survival rates are 55.8% and 58.1%, respectively. Conclusions Sequential bevacizumab/GemDMC–bevacizumab/ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the results expected in this difficult to treat population. ClinicalTrials.gov NCT00936936.

Progressive disease remains the main cause of treatment failure following allogeneic stem cell transplantation (allo-SCT) for Hodgkin lymphoma (HL), and the role of donor leukocyte infusions (DLIs) in the management of disease recurrence is still being actively debated [1-3]. While published studies on this issue are sketchy, response rates (i.e. complete plus partial responses) in the 30-50% range have been reported but their durability, as well as their ultimate impact on patient survival are not always clear [4-5]. In one recent report, nineteen (79%) of 24 HL patients receiving DLIs for relapse following in vivo T-cell depletion with their alemtuzumab-based conditioning regimen experienced a response, which was durable in many cases [6]. A seemingly higher likelihood of durable responses to DLIs following alemtuzumab-based conditioning had been postulated previously [7]. The role of concomitant chemotherapy with the DLIs (if any) is unclear. We wish to contribute to this debate by providing an update on our initial reports on this topic [8, 9]. Between 1999 and 2010, a total of 27 patients with relapsed/refractory HL following unmanipulated allo-SCT received a total of 55 DLIs as immunotherapy for treatment of progressive disease (PD). We feel that the designation “donor leukocyte infusion” is preferable to “donor lymphocyte infusion”, as clearly the infused product contains additional cell types in addition to lymphocytes, such as monocytes, natural killer (NK) cells, etc. The decision between a DLI (with or without prior chemotherapy) and alternative forms of salvage therapy was made on a case-by-case basis. The DLIs did not undergo any form of manipulation or cell selection. These patients' characteristics are outlined in Table 1. The DLI was ordinarily preceded by a taper in their immunosuppression (if still ongoing). Their median age was 30 years (19-60; M/F 19/8), and 21/27 (78%) had a history of prior autologous SCT. Seventeen patients received more than one DLI (range 2-5). Seventeen had a matched sibling/parent donor and ten a matched unrelated donor. In all but two cases the conditioning regimen included fludarabine plus cyclophosphamide or melphalan plus/minus antithymocyte globulin. The median time to PD after allo-SCT was 5 months (range 1-21). The median time from PD to the first DLI was 4 months (range 1-34). This retrospective study was approved by the University of Texas M.D. Anderson Cancer Center Institutional Review Board. All patients provided written informed consent to their treatment. In ten patients (37%) prior salvage chemotherapy was administered immediately prior to at least one of their DLIs. This was done at the discretion of the attending physician following the patient. The pre-DLI chimerism status was 2/27 mixed and 25/27 full donor. For details on response criteria definitions, please refer to our original reports [8, 9]. Table 1 Patient characteristics. Ten of 27 (37%) patients had a complete/partial response (CR/PR) following at least one of their DLIs. Six of 27 patients (22%) achieved CR/CRU (complete response, unknown), and four of 27(15%) achieved a PR. The median response duration was 7.5 months (range 0.5-20). Of these ten responders, ten (100%) developed graft-vs.-host disease (GVHD) and half of them (50%) had received concomitant chemotherapy. Of the ten patients who received only one DLI, two (20%) had chemotherapy prior to their DLIs. One (10%) had a CRU and the other had stable disease (SD) (10%). Of the remaining eight that did not have chemo prior to DLI, 2 (20%) had CRU, 3 (30%) had PR, 2 (20%) had SD and 1 (10%) had PD. The median CD3+ cell dose administered was 49.8 ×106/ kg (range 0.05-285). GVHD developed (or flared) following the DLI in 45/55 cases (82%). After the DLI mixed chimerism (n=2) was converted to complete (or near-complete) donor chimerism. At the latest follow-up (March 2011), five patients (18%) are alive (two in CR). For these five survivors, the follow-up after the first DLI is 41 months (range 4-62). Four of them (80%) did not receive chemotherapy with their DLI(s), while one did. Twenty-two patients expired. Their median survival after the first DLI is 14 months (range 4-64). Causes of death included PD (n=15; 68%) and non-relapse mortality (n=7; 32%). In the latter group, causes of death included intracranial hemorrhage (n=1), pneumonia (n=4), fungal sepsis (n=1), and chronic GVHD (n=1). The actuarial estimate for overall survival at 4 years from the first DLI for the whole group (n=27) is 20% (95% CI 7-38) (Figure 1). Figure 1 Overall 4-year survival from the first donor leukocyte infusion (DLI) for the whole group (n=27). We readily acknowledge the many limitations of this study. They include the retrospective nature of the analysis itself, a small sample size, the long duration of the study period, patient selection and heterogeneity, as well as concomitant chemotherapy administration in some of the cases. Nevertheless, these data suggest that DLIs for immunotherapy of recurrent HL following unmanipulated allo-SCT have significant (albeit not always durable) activity, and a subset of patients become long-term survivors. They also indicate that administration of multiple DLIs is feasible in selected patients. Responses were always associated with the development of GVHD, a finding which would support the presence of a graft-vs.-HL effect. The role (if any) of concomitant chemotherapy cannot be clarified from these limited data. PD (and not GVHD) was the main cause of mortality following DLIs. That being said, the long-term prognosis for DLI-treated HL patients after an allo-SCT is clearly unsatisfactory. The therapeutic landscape in this area is changing rapidly. The role of DLIs should be reassessed in the contest of new and effective agents currently increasingly available in the salvage setting for HL, such as brentuximab (SGN-35) and panobinostat [10, 11]. While their track record in treating recurrences following allo-SCT is still limited, the preliminary data look quite encouraging [12]. These agents would avoid the significant morbidity and mortality associated with the development of GVHD, which seems required in many (and possibly most) cases to achieve a response.

4519 Background: Tandem HDC with carbo/etoposide (CE) is curative for a portion of relapsed GCT pts. However, outcomes of refractory or high-risk relapsed pts remain poor. We tested a new HDC regimen of GemDMC, based on DNA damage repair inhibition. We combined BEV with HDC given their potential synergy and the high vascularity of GCT metastases. Methods: Eligibility: Intermediate (int)/high-risk (Beyer Model), creatinine ≤1.8 mg/dL and adequate organ function. HDC included BEV (5 mg/kg) preceding GemDMC (HDC #1) and ifosfamide/CE (ICE) (HDC #2). Following accrual of 42 pts, we amended the trial omitting BEV. The trial was powered to distinguish a target 50% 2-yr RFS from an expected 25% in this population. Results: We enrolled 69 male pts in cohorts 1 (BEV, N=42) and 2 (no BEV, N=27) (Table). Pts were heavily pretreated and most had refractory tumors. Main AE: mucositis and renal (4 HDC-related deaths in cohort 1, 1 in cohort 2). Tumor markers normalized in 90% pts with active tumors at HDC. After HDC, 19 pts were in CR and 28 in PRm- (of these, 22 had residual lesions resected with no viable tumor found in 20/22, 2 xRT, 4 monitored). Median f/u = 39 (2-105) mo. The 2-yr RFS rates in cohorts 1 and 2 = 52% and 78%, respectively. Their respective 2-yr OS rates = 55% and 81%. Conclusions: Sequential HDC with GemDMC–ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the anticipated results. Addition of BEV increases toxicity but not tumor control. Clinical trial information: NCT00936936. [Table: see text]

The combination of IV Bu and Flu is an effective and well-tolerated HCT conditioning regimen for patients with advanced acute leukemia. However, relapse remains the main reason for treatment failure. We combined two nucleoside analogues Flu and Clo, and showed cytotoxic synergy when combined with Bu, first in pre-clinical models, and subsequently in a randomized clinical study (Andersson BBMT 2011). We selected the optimized regimen from Andersson et al, and combined with escalating doses of the histone deacetylase inhibitor vorinostat in attempts to augment disease control without increasing toxicity. Herein, we describe our initial experience with this novel regimen for patients with advanced acute leukemia or MDS undergoing allogeneic HCT. Methods: Vorinostat (200mg to 1200mg) was escalated in cohorts of 3 patients, and administered 1 hour prior to the fixed regimen of Flu 10 mg/m2 followed by Clo 40 mg/m2 followed by Bu. The nucleoside analogs were infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 5500 μMol-min ± 5%. Dilantin was given for seizure prophylaxis. GVHD prophylaxis was based on tacrolimus andmini-MTX, with the addition of rabbit anti-thymocyte globulin (4 mg/kg total dose) for unrelated donor transplants. The presence of minimal residual disease (MRD) was determined by multiparameter flow cytometry. Results: 21 patients (7 AML, 14 ALL) with median age 43 years (range 19-60) received an allogeneic matched sibling (n=10) or unrelated donor (n=11) HCT in CR1 (n=13), CR2 (n=1), primary induction failure (n=5), or relapse (n=2). Twelve patients had MRD or overt disease present at time of HCT. Ten patients had high-risk karyotype defined by t(9;22) (n=3), t(4;11) (n=2), complex (n=2), or del 5 or 7 (n=3). Median time from diagnosis to HCT was 5 months (range 3-48). Median time to ANC > 0.5 x 109/L and platelets > 20 x 109/L were 11 (range 10-15) and 12 days (5-30), respectively. Excluding grade 1 toxicities, the most commonly reported toxicities were nausea with maximum grade 2 (71%), followed by grade 2 or 3 mucositis (64%). Grade 2 or 3 reversible elevation of liver function tests was noted in 54% of pts, including 1 case of reversible VOD. No renal toxicities were noted. Two patients with prior systemic treatment for acute GVHD died of infections (disseminated adenovirus and E.coli sepsis). Ten patients achieved CR and clearance of MRD by day +30 after HCT; one patient had progressive disease and on patient died before disease restaging. Eighteen patients achieved 100% donor chimerism at 30 days following HCT, 2 patients remain with mixed chimerism by 100 day assessment following HCT, and 1 patient died before assessment. The incidence of grades II-IV acute GVHD is 43% and chronic extensive GVHD among 18 evaluable patients is 24%. With a median follow-up of 10 months among surviving patients (1-22), overall and progression-free survival at 6 months is 95% and 71%, respectively. Early results suggest excellent disease control in MRD negative patients (Figure). Conclusion: The Vorinostat-Flu-Clo-Bu combination is well-tolerated and did not add appreciable toxicity in these patients with high-risk leukemia. Longer follow-up is needed to better assess disease control. Figure Figure. Disclosures Ciurea: Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Patel:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

Introduction Treatment outcomes for adult patients with relapsed ALL are limited. Allogeneic hematopoietic cell transplantation (HCT) is the only curative option in a small subset of patients. We sought to investigate the optimal extent of therapy required prior to proceeding to transplant in second complete remission (CR2). Methods 126 consecutive patients with ALL in CR2 underwent HCT at MD Anderson Cancer Center between January 2004 to December 2015. The patient and transplant characteristics are described in table 1. The probabilities of outcomes were calculated with the Kaplan-Meyer method. Variables found to be significant at the p Results Median follow-up was 38.4 months (range 6-125). The 3-year overall survival (OS), progression-free survival (PFS) and transplant-related mortality (TRM) were 34.6%, 29.5% and 33.2%, respectively. Eighty-three patients received at least one course of chemotherapy after achieving CR2 (median 2, range 1-6). These patients had significantly better OS, PFS and relapse rate than the 34 patients that went to transplant immediately after achieving CR2. Namely, 43.8% vs 7.6% (p=0.002), 39.4% vs. 5.1% (p=0.002) and 37.9% vs. 89.5% (p Patient's age, performance status, comorbidity index and graft source were also predictive for outcome. In multivariate analysis receiving at least one additional course of chemotherapy after achieving CR2 (RR=0.53, CI=0.31-0.91, p=0.02), age>45 (RR=2.06, CI=1.20-3.53, p=0.009), alternative graft sources (RR=1.81, CI=1.09-2.97, p=0.02) and Karnofsky 45 (RR=1.92, CI=1.15-3.20, p=0.01) and Karnofsky Conclusion: The outcome of patients with relapsed ALL who proceed to HCT immediately after achieving CR2 is dismal. Our data supports the notion that patients should receive at least one additional course of treatment after achieving CR2 prior to transplantation, regardless of MRD status. However, our observations must be interpreted with caution as this was not an intent to treat analysis so we could not adjust for loss of patients prior transplantation. Further analysis on an intent to treat basis is underway. Disclosures Ciurea: Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Jabbour:Pfizer: Research Funding; BMS: Consultancy; ARIAD: Research Funding; Pfizer: Consultancy; Novartis: Research Funding; ARIAD: Consultancy. Kantarjian:BMS, Pfizer, Amgen, Novartis: Research Funding. Champlin:Intrexon: Equity Ownership, Patents & Royalties; Ziopharm Oncology: Equity Ownership, Patents & Royalties.

Introduction: The number of available salvage agents for patients with relapsed ALL has significantly increased in the last 5 years. Furthermore, these recent therapies, such as antibody and T-cell therapy, have a distinct mechanism of action and toxicity profile compared to conventional multi-drug chemotherapy combinations which have been the mainstay of ALL treatment. We sought to investigate the potential efficacy and toxicity of these agents when used prior to allogeneic hematopoietic cell transplantation (HCT), and to compare overall transplant outcomes with these different types of therapies. Methods: 126 consecutive patients with ALL in second complete remission (CR2) underwent HCT at MD Anderson Cancer Center between January 2004 and December 2015. The patient and transplant characteristics are described in Table 1. The probabilities of outcomes were calculated with the Kaplan-Meyer method. Variables found to be significant at the p Results: With a median follow-up of 38.4 months (range 6-125), the 3-year overall survival(OS), progression-free survival (PFS) and transplant-related mortality (TRM) rates were 34.6%, 29.5% and 33.2%, respectively, for the entire group. Patients receiving well-matched transplant donors fared better than those receiving mismatched donors (Figure 1). Second CR was attained in 104 patients with the first line of salvage therapy. Salvage therapy consisted of HyperCVAD-based chemotherapy alone in 57 patients, chemotherapy plus tyrosine kinase inhibitors (TKI) in 18, chemotherapy plus rituximab in 11, chemotherapy plus inotuzumab in 5, inotuzumab monotherapy in 12, and blinatumomab monotherapy in one patient. We found no statistical difference in OS, PFS or TRM following transplant based on these prior therapies. Furthermore, we found no difference in the expected probabilities of acute or chronic GVHD. In the 8 patients treated with blinatumomab monotherapy for first or subsequent salvage, all 8 progressed following transplant at a median of 4.5 months. Eight out of 126 (6.3%) patients developed VOD; 3 out of 26 (11.5%) patients treated with inotuzumab developed VOD, but this did not impact TRM post HCT compared with other treatment groups. Conclusions: Transplant outcomes were not different following antibody or T-cell salvage therapy as compared to conventional chemotherapy in this single center, retrospective study. Larger numbers of patients will need to be studied as we continue to incorporate these newer therapies into our treatment regimens. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board. Jabbour:BMS: Consultancy; ARIAD: Consultancy; Pfizer: Research Funding; Pfizer: Consultancy; Novartis: Research Funding; ARIAD: Research Funding. Kantarjian:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Champlin:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

s / Biol Blood Marrow Transplant 21 (2015) S185eS205 S196 and low TRM and should be further investigated in prospective clinical trials.

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.

Introduction: Extra-nodal Natural Killer/T-Cell Lymphoma, Nasal Type (ENKL) is an aggressive, rare variant of non-Hodgkin lymphoma most frequently found in Asia, with 5-year survival estimates of 30-45%. The utility of stem cell transplant (HSCT) has been evaluated in a number of primarily small retrospective studies, almost exclusively from Asia, in which outcomes appear to be improved with HSCT by 10-20%. We conducted this study with the aim to determine the outcomes of autologous (AUTO) and allogeneic (ALLO) HSCT in patients with ENKL. Methods: This multi-center study was conducted in collaboration with 4 different centers, 3 in the United States, and 1 in Singapore. All patients with a diagnosis of ENKL who received either AUTO or ALLO HSCT after January 1, 2000 were eligible. Univariate probabilities of overall survival (OS) and progression-free survival (PFS) were estimated utilizing the Kaplan-Meier method using IBM SPSS version 22.0. Probabilities of non-relapse mortality (NRM) and relapse mortality (RM) were calculated by the cumulative incidence (CI) procedure to accommodate for competing risks utilizing EZR software. The log-rank test was used to assess for differences between groups in regard to OS and PFS, and the Fine-Gray analysis was performed to compare outcomes with competing risks. Results: Twenty-seven patients, with median age of 48 years (range 22-68), and a median of 2 prior chemotherapy lines (range 1-5) received HSCT for ENKL; 14 AUTO and 13 ALLO, of which 70% were performed at MD Anderson. Sixty-seven percent were male, 30% were not in complete remission (CR) at transplant, and 40% had an NK-IPI risk group of 3-4. Seventy-four percent of patients received myeloablative (MAC) conditioning, with the most common regimen being BEAM in 55% of ALLO and 65% of AUTO. All patients received peripheral blood as the stem cell source except one who received cord blood. With a median follow-up time of 11 years, OS and PFS for the entire group were 51% and 50%. The CI NRM was 19% at 1 and 2 years and the CI RM was 16% at 1 year, 26% at 2 years, and 40% at 11 years (Figure 1). Amongst ALLO recipients, there were 2 cases of grade II-IV acute GVHD (14% of ALLO) and 5 cases of chronic GVHD (1 limited, 4 extensive, 36% of ALLO). PFS was significantly better for patients in CR versus those not in remission at transplant (67% vs 13%, p=0.002). There was no impact of MAC vs non-MAC conditioning, disease stage at diagnosis (I-II vs III-IV), prior number of chemotherapy lines, comorbidity index, NK-IPI risk group 1-2 vs 3-4, age >50, sex, or race on PFS or OS. We did an exploratory analysis of transplant outcomes between the AUTO versus ALLO groups. More patients in the ALLO group (46% vs 17%, p=0.082) were not in CR at transplant, though other characteristics were balanced. PFS for AUTO versus ALLO was 67% vs 31% at 1 and 3 years (p=0.032), (Figure 2). OS for AUTO vs ALLO was 75% vs 54% at 1 year, and 64% vs 39% at 3 years, (p=0.146). One patient received an ALLO with progressive disease and survived. Additionally, 3 of 4 patients who received ALLO after prior AUTO survived, though one died of a second malignancy 11 years post-transplant. One of these patients received a prior AUTO but developed graft failure and subsequently received an ALLO and was counted in the ALLO group. CI NRM was higher in the ALLO vs AUTO group at 1 year (39% vs 0%, p=0.013). CI of RM was higher in the first year in the AUTO vs ALLO group at 1 year (26% vs 8%), though by 3-years this difference was not significant (36% vs 23%, p=0.472). Conclusion: Here we present the results of a multi-center study of patients who received a HSCT for ENKL. Our results are similar to those seen in Asian studies, with long-term PFS and OS of 50%, demonstrating that HSCT is an effective therapy for patients with ENKL. Patients in CR at transplant had better OS and PFS than those not in CR; therefore, complete remission should be the goal prior to HSCT for ENKL. ALLO is an effective treatment option for relapse post-AUTO or for progressive disease at transplant, with less relapse than AUTO, particularly within the first year. This is particularly interesting given that 46% of patients who received ALLO were not in remission at transplant, indicating a strong graft-versus-lymphoma effect. However, these results are limited by an increased NRM. Strong consideration for AUTO should be given to patients who are in CR at the time of transplant, and ALLO should primarily be reserved for refractory disease or relapse post-AUTO. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Brammer: Celgene: Research Funding. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Maziarz:Novartis: Consultancy; Athersys: Consultancy, Patents & Royalties, 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.

Allogeneic HCT improves long-term disease control in pts with ALL, but the treatment-related mortality (TRM) associated with most myeloablative transplant conditioning regimens limits the benefits of HCT. Therefore, we investigated a novel regimen consisting of Clo combined with intravenous (i.v.) Bu in adult pts with ALL undergoing allogeneic HCT. Preliminary results were encouraging1, and we now report on long-term outcomes. Methods: Clo 40 mg/m2 was infused over 60 min, each dose followed by Bu 130 mg/m2 infused over 3 hours daily for 4 days followed by hematopoietic cell infusion 3 days later. Bu was infused either as a fixed dose per BSA, or to target an average daily AUC of 5,500 microMol-min for pts up to 60 years of age or 4000 microMol-min for pts greater than 60 years, determined by a test dose of Bu at 32 mg/m2 given 48 hours prior to the high dose regimen. Dilantin was administered for seizure prophylaxis. GVHD prophylaxis was based on tacrolimus andmini-MTX, with the addition of rabbit anti-thymocyte globulin (4 mg/kg total dose) for unrelated donor transplants. Results: 107 pts (91 B-lineage, 16 T-lineage) with median age 38 years (range 19-64 years) received an allogeneic matched sibling (n=52) or matched unrelated donor (n=55) HCT in CR1 (n=62), CR2 (n=28), or more advanced disease (CR3, n=2; incomplete recovery of counts, n=9; blasts >5%, n=6) .Complete remission was defined by 0.5 x 109/L and platelet count > 20 x 109/L were 11 (range 10-25 days) and 13 (8-109 days; 8 pts without recovery), respectively. All pts with measurable disease prior to HCT achieved CR by day +30 after HCT. Full donor chimerism by day 30 was achieved in 70% pts; 84% of pts eventually achieved full donor chimerism defined as 100% donor T-cells and myeloid cells. The incidence of grades II-IV and III-IV acute GVHD were 35% and 10%, respectively; 18% pts developed extensive chronic GVHD. With a median follow-up of 2.5 years among surviving patients (0.1-4.9 years), the 2-year overall survival rates for pts transplanted in CR1, CR2, or more advanced disease were 68%, 58%, and 34%, respectively, as illustrated in figure below; 2-year disease-free survival rates were 60%, 40%, and 35%, respectively. Non-relapse mortality (NRM) rates at 100 days and 2 years were 6% and 18%, respectively. Among 9 pts older than 60 years treated with reduced dose Bu in CR1 (n=5), CR2 (n=3) or more advanced disease (n=1), 5 remain alive and disease-free. Conclusion: The CloBu combination is well-tolerated in this cohort of adult pts with high-risk ALL who received a median of 9.2 months of intensive (mainly HCVAD-based) chemotherapy prior to receiving transplant. Overall survival and NRM compare favorably with traditional TBI-based regimens. 1. Kebriaei et al. Biol Blood Marrow Transplant. 2012 Dec; 18(12): 1819-1826. Figure 1. Figure 1. Disclosures Alousi: Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy.

In this study, we analyzed the long-term outcome of a risk-adapted transplantation strategy for mantle cell lymphoma in 121 patients enrolled in sequential transplantation protocols. Notable developments over the 17-year study period were the addition of rituximab to chemotherapy and preparative regimens and the advent of nonmyeloablative allogeneic stem cell transplantation (NST). In the autologous transplantation group (n = 86), rituximab resulted in a marked improvement in progression-free survival for patients who received a transplant in their first remission (where a plateau emerged at 3-8 years) but did not change the outcomes for patients who received a transplant beyond their first remission. In the NST group, composed entirely of patients who received a transplant beyond their first remission, durable remissions also emerged in progression-free survival at 5 to 9 years. The major determinants of disease control after NST were the use of a peripheral blood stem cell graft and donor chimerism of at least 95%, whereas the major determinant of death was immunosuppression for chronic graft-versus-host disease. Our results show that long-term disease-free survival in mantle cell lymphoma is possible after rituximab-containing autologous transplantation for patients in first remission and after NST for patients with relapsed or refractory disease.

Progressive disease (PD) remains the main cause of treatment failure following RIC allo-SCT in HL. In 08/2007 we elected to add gemcitabine (G), a highly active agent in relapsed/refractory HL, to our standard fludarabine (F) - melphalan (M) RIC (Anderlini et al, Haematol 93:257, 2008) in patients with relapsed/refractory HL undergoing allo-SCT. Subsequently, brentuximab vedotin (BV) was introduced as salvage therapy prior to allo-SCT in order to maximize response. The ultimate goal of this strategy is to augment cytoreduction pretransplant and improve OS/PFS while reducing PD. Main G-associated non-hematologic toxicities include pulmonary, skin toxicities and mucositis. Between 8/07 and 04/13, twenty-seven HL patients underwent an allo-SCT with the G-FM regimen. They had failed multiple conventional treatments (median prior chemotherapy regimens: 4), radiation therapy (44%) and a prior auto-SCT (70%). The median age was 31 years (range 20-46). Disease status at SCT was complete remission (CR) or undetermined (CRu) (n=17; 63%), partial remission (PR; n=9; 33%), and other (n=1; 4%). The median time to PD after auto-SCT was 5 months (range 1-68). Fourteen patients (52%) received BV prior to allo-SCT, and in seven (50%) it was the last therapy prior to allo-SCT. In these seven patients the CR rate after BV was 100%. The donor was an HLA-identical sibling (n=16) or matched unrelated donor (MUD; n=11). The conditioning regimen was G (800 mg/m sq IV x1), F (33 mg/m sq IV daily x4) and M (70 mg/m sq IV daily x2). Thymoglobulin (4 mg/kg IV) was added in MUD allografts. Twenty patients received peripheral blood progenitor cells, and seven bone marrow. Myeloid recovery was prompt, with an absolute neutrophil count >500/mcL at day +11 (median). Median platelet recovery at 20K/mcL was at day +13. Chimerism studies indicate 100% donor-derived engraftment in 23/23 evaluable patients (100%). There were three early (ie before day 30) deaths and one case of graft failure. Cumulative incidence of day 100 and overall transplant-related mortality (TRM) was 15% (both). Cumulative incidence of acute (grade II-IV) and chronic graft-vs-host disease (extensive) was 19% (95% CI: 9-42) and 39% (95% CI: 24-65), respectively. Pulmonary toxicity (NCI CTC v3) was seen in nine patients (33%). Grade 4-5 pulmonary toxicity was seen in three patients (13%). Otherwise it was grade 1-3 (n=6). Cutaneous toxicity (skin rash, responsive to steroid therapy) was seen in five patients (19%: grade 3 n=1; grade 1-2 n=4). Mucositis was seen in thirteen patients (48%). It was grade 3 (n=1) and grade 1-2 (n=12). The overall response rate (CR/CRU) prior to allo-SCT was 79% (11/14) in BV-treated patients vs. 46% (6/13) in BV-naïve patients (p=0.12, Fisher's exact). The overall response rate (CR/CRU) after allo-SCT was 85%, both in BV-treated and in BV-naïve patients. Six patients expired (graft rejection n=1, pneumonia n=2; respiratory failure n=1, PD n=2). Twenty-one patients are alive with a median follow-up of 18 months (range 4-55). At the last f/up, actuarial estimates for OS and PFS are 69% (95% CI: 41-86) and 55% (95% CI: 31-74), respectively. Cumulative overall PD incidence is 30% (95% CI 15-61). The seven patients who received BV as last line of therapy prior to allo-SCT are all alive and in CR/CRu. The G-FM140 regimen continues to show promise in this high-risk patient group. The inclusion of G may affect pulmonary toxicity, but TRM remained low. With the current BV-supported approach, the CR rate pretransplant may be improved. PFS (18-mo) in CR/CRu patients pretransplant seems to compare favorably to our FM140 experience in complete responders (80% vs 57%, p=0.20). While this BV-based transplant strategy needs further evaluation, the role of RIC allo-SCT in HL may need reassessment in the BV era. Disclosures: Off Label Use: Gemcitabine, fludarabine, melphalan, thymoglobulin (transplant conditioning).

Ex vivo T-cell depleted (TCD) allogeneic hematopoietic stem cell transplants (HCT) in patients with acute myeloid leukemia in complete remission (CR)lead to survival and relapse rates comparable to those with unmodified grafts, but with significantly less graft versus host disease (GVHD). TCD-HCT is also effective in patients with acute lymphoblastic leukemia (ALL), however it is not known how outcomes compare with those of patients receiving conventional grafts. In this study we compared the outcomes of patients receiving TCD-HCT at Memorial Sloan-Kettering Cancer Center (MSKCC) with patients receiving conventional grafts at MD Anderson Cancer Center (MDACC) for ALL in first or second CR. Patients 18 years of age or older, undergoing HCT between 2000 and 2010 were included in this retrospective analysis. 52 patients at MSKCC received TCD grafts and 129 patients at MDACC received conventional grafts. All patients at MSKCC received myeloablative HCT conditioning (MAC). No GVHD prophylaxis was given. At MDACC, 115 patients received MAC and 14 received reduced intensity conditioning; GVHD prophylaxis consisted of tacrolimus and mini-dose methotrexate, plus antithymocyte globulin for total dose 4 mg/kg for unrelated donors. Patient characteristics and outcomes are summarized in the Table. A greater percentage of patients in the conventional graft group received transplants from a matched related donor and from bone marrow as a stem cell source. Patients in the TCD group almost exclusively received grafts from peripheral blood. A significant difference in acute GVHD incidence was observed between the TCD and conventional groups, with 100-day cumulative incidence estimates of 17.3% and 40.3%, respectively (Gray's test p-value=0.007). A significant difference was also observed in chronic GVHD rates, with three-year estimates of 13.5% and 34.8% for the TCD and unmodified groups, respectively (Gray's test p-value=0.004). There was no statistical difference between TCD and unmodified groups with regards to OS (log-rank p-value=0.89, 3 year estimates 42.6% vs. 43.2%) or RFS (log-rank p-value=0.64, 3 year estimates 42.8% and 36.0%). The NRM at day 100, 1 year and 3 years were 15.4%, 26.9% and 37.8% in the TCD group and 10.1%, 23.5% and 28% in the unmodified group (Gray's test p-value=0.22). There was a lower relapse rate among patients who received TCD versus unmodified grafts (3 year estimates 19.4% vs. 36.0%, Gray's test p-value=0.05). Age >50 and was the only factor associated with inferior RFS (HR=1.74, p=0.01) and OS (HR=1.85, p=0.006). HCT is an effective treatment modality for patients with ALL with favorable results with either conventional or TCD allografts. Although the relapse rate was significantly lower after TCD-HCT, this would need to be confirmed in a prospective study. While 3-year OS rates are similar in both groups, TCD effectively reduces the rate of both acute and chronic GVHD. *: Median (range) * *: P-values were estimated using a chi-square test or Fisher's exact test for categorical variables and a Wilcoxon rank-sum test for continuous variables. OS and RFS were compared using a logrank statistics, while NRM, aGVHD and cGHVD were compared using Gray's test. ^: Good risk: Hyperdiploidy, del(9p); poor risk: Ph+, t(4;11), t(8;14); complex karyotype (≥5 abnormalities), hypodiploidy/near triploidy; standard risk: other. TCD-T-cell depleted; CR- Complete Remission; TKI- Tyrosine Kinase Inhibitors; RIC-Reduced Intensity Conditioning; MAC- Myeloablative Conditioning; RFS-Relapse Free Survival; OS- Overall Survival; NRM- Non-Relapse Mortality; aGVHD- acute Graft Versus Host Disease; cGVHD- chronic Graft Versus Host DiseaseFigure 1.Probabilities of overall (A) and relapse-free (B) survival in recipients of T cell depleted (TCD) and unmodified grafts.Figure 1. Probabilities of overall (A) and relapse-free (B) survival in recipients of T cell depleted (TCD) and unmodified grafts. Disclosures: No relevant conflicts of interest to declare.

Abstract 4157 Background: We previously reported promising results with nonmyeloablative (NMA) allogeneic transplantation for indolent non-Hodgkin's lymphomas (NHL) (Khouri et al, Blood 2012; 119:6373). This strategy is however less effective in aggressive, bulky, chemoresistant, or heavily pre-treated lymphomas. The BEAM-rituximab is a commonly used regimen in transplantation for NHL. Bortezomib has synergistic activity with rituximab, is effective against many NHL subtypes with moderate non-hematologic toxicity; in addition, animal models suggest that pre-transplant bortezomib may reduce the risk of GVHD. We hypothesized that the addition of bortezomib to the conditioning would enhance initial disease control and that remission could be later sustained via the GVL effect of the graft, with lesser GVHD. Methods: We included pts up to 70 yrs, with relapsed/refractory NHL, acceptable organ function, having a matched donor, and who were not eligible for NMA transplantation. Bortezomib was designed to be given iv in an escalated dose of 1.0, 1.3, and 1.6 mg/m2 days-13, -6, - 1 and + 2. Rituximab was given at a dose of 375 mg/m2 on day -13 and 1000 mg/m2 on days -6, +1, and +8, as previously described. BEAM consisted of carmustine 300 mg/m2day-6, cytarabine 100 mg/m2 and etoposide 100 mg/m2 twice/day, days -5 to -2, and melphalan100 mg/m2 on day-1. Tacrolimus and methotrexate was used for GVHD prophylaxis. In addition, thymoglobulin of 1 mg/kg was given on days -2, and -1 in pts receiving an unrelated donor. Results: The study included 35 pts [Aggressive DLBCL=20, Indolent (CLL/FL with aggressive features =15)]. All pts had relapsed disease after the best conventional therapy (-ies) available. Median age was 53 (range, 22–65) years. Median prior treatments were 3 (range, 1–7). At transplant, 14 pts (51%) had refractory disease and 23 (66%) were PET+. Twenty-two pts (63%) received their transplants from HLA-compatible siblings (Sibs) and 13 (37%) from unrelated donors (MUDs). Bortezomib could not be escalated beyond the initial 1.0 mg/m2 per dose due to toxicity (2 of 3 pts treated at 1.3 mg/m2 died of sepsis related to C.Difficile; since then all pts received flagyl prophylaxis till engraftment). Blood was the source of donor graft in 97% of pts. All pts engrafted donor cells. Median donor T cells at day 30 were 100%. With a median follow-up time of 24.5 months (range, 5–49), the OS for the aggressive and indolent histologies were 58% and 44%, respectively (p=0.5); PFS rates were 32% in both. Determinants of outcomes were related to donor type, and age. In pts 50 yrs, the 2-years OS and PFS for sibs were 62% and 45%, respectively, vs 0% for the MUDs (Fig 1). There was no difference in pts and disease characteristics, or histology distribution between the 4 groups. In pts < 50 yrs, 2-year treatment-related mortality in Sibs and MUDs was 22% and 17% (p=0.9); whereas the incidence was significantly higher in >50 yrs pts receiving MUDs (62% vs 37%, p=0.03). This difference may be related to a higher incidence in acute 2–4 GVHD in >50 yrs pts receiving MUDs transplants (62% vs 33% in pts >50yrs receiving Sibs transplants). In Conclusions: Our results suggest that in pts with high-risk NHL and who were not eligible for NMA allogeneic transplantation, the bortezomib-BEAM-rituximab conditioning has promising PFS rates of 40% at 2-years in pts younger than 50 yrs. Alternative strategies are needed for pts >50 yrs, receiving an unrelated donor transplant. Results warrant further study and refinement. Disclosures: Khouri: Millenium Pharmaceuticals: Research Funding.

Abstract 3072 Allogeneic hematopoietic stem cell transplantation (SCT) is the only effective treatment for high-risk or relapsed acute lymphoblastic leukemia (ALL). However, SCT carries high treatment-related mortality (TRM). There have been continuing efforts to refine criteria for patients who may benefit most from SCT. Minimal residual disease (MRD) at the end of induction or induction/consolidation therapy has emerged as the most significant risk factor for disease relapse in ALL patients, and has become an indicator for SCT or intensified chemotherapy. In addition, MRD prior to SCT is highly predictive for post-transplant relapse in the pediatric population. The significance of pre-SCT MRD in adult patients with ALL remains to be determined. Patients and methods: In this retrospective analysis, we examined the impact of MRD detected within one month prior to SCT on risk of disease progression in adult patients with ALL who were in complete remission, defined by less than 5% blasts in bone marrow by morphologic assessment and normal blood counts at time of SCT. MRD has been uniformly assessed in patients using multiparameter flow cytometry since 2004. Bone marrow aspirates were stained using a comprehensive panel of >=15 markers and 200, 000 cells were analyzed. MRD was scored as positive based on a distinct cluster of >=20 cells, showing a significant difference in the level of expression (>=3-fold) of >=2 antigens, in comparison to the known phenotype of benign immature B-cell precursors. Disease progression (relapse) was defined as leukemic blast count >= 5%. Therefore, limiting our data set to transplants performed during February 2004 through May 2010 at MD Anderson Cancer Center, we identified 98 patients with median age 34 years (range 19–68) treated with a median of 2 lines of chemotherapy (range 1–6) who received a matched sibling (n=51), matched unrelated (n=36), haplo-identical family (n=3), or cord blood donor (n=8) transplant for ALL of B-(n=86) or T-lineage (n=12) in CR1 (n=52), CR2 (n=39) or CR3 (n=7) using a myeloablative non-TBI based (n=62) or TBI-based (n=36) transplant conditioning regimen. GVHD prophylaxis was tacrolimus-based for all patients. Among 88 patients with available cytogenetic data at diagnosis, 59% were considered high risk defined by the presence of the t(9;22), t(4;11), hypodiploid or complex cytogenetics, 2% were classified as good risk by the presence of hyperdiploidy, and the remaining 34% were intermediate risk. Results: Ninety-two patients were evaluable for response and all had sustained CR following transplant; 6 had early death. With a median follow-up of 33 months among survivors (range 5.8–80.7), patients transplanted without detectable MRD at time of SCT had a significantly lower cumulative incidence of relapse than those transplanted with MRD, 30% versus 70%, p=.004 (Figure 1). There was also a trend for better 3-year PFS in the MRD negative group, 38% versus 13%, p=0.1. Additional factors, including disease stage at time of SCT, cytogenetic profile at diagnosis, donor relation, and development of GVHD were evaluated in a univariate analysis for relapse rate, PFS, and overall survival. Only the presence of MRD remained a significant predictor for relapse. Conclusion: This study demonstrates that the presence of MRD prior to SCT in adult ALL patients is a significant predictor for relapse. Improvements in our current therapies are urgently needed to improve the outcomes for MRD positive patients.Figure 1.The cumulative incidence of disease progression in adult patients with ALL undergoing SCT in remission is stratified by MRD.Figure 1. The cumulative incidence of disease progression in adult patients with ALL undergoing SCT in remission is stratified by MRD. Disclosures: No relevant conflicts of interest to declare.

Abstract 3003FN2 Objective: Progressive disease (PD) remains the main cause of treatment failure following RIC allo-SCT in HL (Peggs KS et al, BJH 2008: 143; 468). We elected to explore the feasibility of adding gemcitabine (G), a highly active agent in relapsed/refractory HL (Santoro A et al, JCO 2000 :18; 2615), to our standard fludarabine (F) - melphalan (M) RIC in patients with relapsed and refractory HL undergoing allo-SCT, with the ultimate goal to augment cytoreduction and reduce the incidence of PD. Main G-associated non-hematologic toxicities include pulmonary, skin toxicities and mucositis. Patients and Methods: Between 8/07 and 3/11, fifteen consecutive HL patients (Unique Patient Number/UPNs 1–15) underwent an allo-SCT with the G-FM regimen. They had failed multiple conventional treatments (median prior chemotherapy regimens: 4; range 2–9), radiation therapy (6/15) and a prior auto-SCT (7/15). The median age was 33 years (range 20–46). Disease status at SCT was chemosensitive relapse (n=4), untreated relapse (n=1), induction failure chemosensitive (n=2), complete remission undetermined (CRU1 and CRU2) (n=8). The median time to PD after auto-SCT was 10 months (range 3–19). The donor was an HLA-identical sibling (n=10) or matched unrelated donor (MUD; n=5, with UPN 6 having a 9/10 match). The conditioning regimen was G 800 mg/m sq IV x1 at day -7 (two patients, UPN 6 and UPN 7 received G 1000 mg/m sq IV x2, day -5 and day -2 as part of a dose escalation attempt stopped for excess toxicity), F (32 mg/m sq IV x4, day -5 to day -2), M (70 mg/m sq IV x2, day -3 and day -2; total dose 140 mg/m sq). Thymoglobulin (4 mg/kg IV) was added in MUD allografts. Graft-vs-host disease (GVHD) prophylaxis included tacrolimus and mini-dose methotrexate (5 mg/m sq). Results: Myeloid recovery was prompt, with an absolute neutrophil count (ANC)>500/mcL at day +12 (range 11–20). Median platelet recovery at 20K/mcL was at day +14 (range 9–26). Chimerism studies indicate 100% donor-derived engraftment in 13/13 evaluable patients (100%). Day 100/overall transplant-related mortality (TRM) were 2/15 (13%) and 2/15 (13%), respectively. Acute GVHD (grade II-IV) occurred in 8/14 evaluable patients, chronic GVHD in 7/13 evaluable patients (extensive in 7). Pulmonary toxicity was seen in four patients (26%). Grade 4 pulmonary toxicity was seen in UPN 6. Otherwise it was grade 1–2 (n=3). Cutaneous toxicity (skin rash, responsive to steroid therapy) was seen in five patients (33%: grade 3 n=1; grade 1–2 n=4). Mucositis was seen in nine patients (60%). It was grade 3 (n=1); grade 1–2 (n=8). Other organ toxicities were not seemingly markedly different from the ones seen with FM140 only. Three patients expired (graft rejection n=1, in UPN 6; CMV pneumonia n=1; PD n=1). Twelve patients are alive (ten progression-free, eleven in CR/CRU) with a median follow-up of 18 months (range 2–33). Actuarial rates of overall survival (OS) and progression-free survival (PFS) at 24 months are 87% (95% CI: 56–96) and 49% (95% CI: 18–74), respectively (see Figure). While a formal comparison with our historical experience with the FM140 regimen is clearly not possible, OS and PFS (actuarial estimates) at 24 months were 64% (95% CI: 49–76), and 32% (95% CI: 20–45), respectively (Anderlini et al, Haematol 2008; 93 :257). Conclusions: The addition of G to FM140 is feasible. Pulmonary, cutaneous toxicities, as well as mucositis, while clinically significant, were manageable and did not contribute to mortality in the patients treated with only one G dose. While quite encouraging, these data remain preliminary. The G-FM regimen deserves further study in a larger cohort of patients. Disclosures: Off Label Use: Gemcitabine, fludarabine and melphalan as part of conditioning regimen for allogeneic stem cell transplantation.

Abstract 3484 Allogeneic HCT improves long-term disease control in pts with ALL, but the treatment-related mortality (TRM) associated with most myeloablative transplant conditioning regimens limits the benefits of HCT. Therefore, we investigated a novel regimen consisting of Clo combined with intravenous (i.v.) Bu in patients with ALL undergoing allogeneic HCT. Methods: Clo 40 mg/m2 followed by Bu 130 mg/m2 were infused daily for 4 days followed by hematopoietic cell infusion 2 days later. Bu was infused either as a fixed dose per BSA, or to target an average daily AUC of 5,500 microMol-min for pts up to 60 years of age or 4000 microMol-min for pts greater than 60 years, determined by a test dose of Bu at 32 mg/m2 given 48 hours prior to the high dose regimen. Dilantin was given for seizure prophylaxis. GVHD prophylaxis was based on tacrolimus and mini-MTX, with the addition of rabbit anti-thymocyte globulin (4 mg/kg total dose) for unrelated donor transplants. The presence of minimal residual disease (MRD) was determined by multiparameter flow cytometry. Results: 14 pts (12 B-lineage, 2 T-lineage) with median age 29 years (range 21–64) received an allogeneic matched sibling (n=8) or matched unrelated donor (n=6) HCT in CR1 (n=7, 3 MRD positive), CR2 (n=6, 3 MRD positive), or refractory relapse (n=1). Nine pts had high-risk cytogenetic profiles as defined by the presence of t(9;22), t(4;11), or complex cytogenetics. The median time from diagnosis to HCT was 8.5 months (range 2–115) with a median 2 lines of chemotherapy received (range 1–3). Median days to ANC > 0.5 × 109/L and platelet count > 20 × 109/L were 12 (range 10–14) and 16 (13-23), respectively. The most common toxicity was mucositis (8 grade II, 2 grade III). Grade 3 reversible elevation of liver function tests was noted in 3 pts. No VOD or renal toxicity was noted. One pt with a prior history of stenotrophomas and fungal pneumonia died of pneumonia complications 18 days after HCT. Eleven pts are evaluable for response. All evaluable pts achieved CR clearing MRD by day +30 after HCT. Five pts achieved full donor chimerism at 30 days following HCT, 4 pts remain with mixed chimerism at 60 day assessment following HCT, and 1 pt progressed early. The incidence of grades II-IV acute GVHD is 40% (n=3 grade II GI, n=1 steroid refractory liver); chronic GVHD was not assessed due to short follow-up. With a median follow-up of 3 months among surviving patients (0.4-8), overall and disease-free survival is 92% at 3 months. Two pts in CR2 with persistent MRD at time of HCT progressed at a median 5 months following HCT. Two pts older than 60 years were treated on the reduced Bu dose arm, and both remain in continued remission. Conclusion: The CloBu combination is well-tolerated in this small cohort of patients with high-risk ALL who received a median of 8.5 months of intensive (mainly HCVAD-based) chemotherapy prior to receiving transplant. The clearing of MRD encourages further investigation of this regimen. Longer follow-up is needed to more completely assess disease control. Disclosures: Kebriaei: Otsuka Pharmaceuticals: Research Funding. Off Label Use: Busulfan and Clofarabine for trasplant conditioning. De Lima:Otsuka: Membership on an entity's Board of Directors or advisory committees. Champlin:Otsuka: Research Funding; Genzyme: Consultancy. Andersson:Otsuka: Consultancy.

Abstract 3415 Poster Board III-303 High dose chemotherapy and SCT is an accepted treatment option for patients with relapsed lymphoid malignancies. Relapse remains a significant issue for patients with advanced disease. Predicting effective disease control with improved safety, we investigated the administration of intravenous (i.v.) busulfan (Bu) combined with melphalan (Mel) in patients with lymphoid malignancies undergoing ASCT. Patients and Methods Bu130 mg/m2 was infused daily for 4 days, either as a fixed dose per BSA (n=20), or to target an average daily AUC of 5,000 uMol-min ± 12% determined by a test dose of i.v. Bu at 32 mg/m2 given 48 hours prior to the high dose regimen (n=82), followed by a rest day, followed by two daily Mel doses at 70mg/m2. Stem cells were infused the following day. Dilantin was given for seizure prophylaxis. Results 102 patients (38 F/64 M) with non-Hodgkin's lymphoma (n=12), Hodgkin's lymphoma (n=49) and multiple myeloma (n=41) with median age 44 years (range 19-66) have been enrolled to date. The median number of prior chemotherapy regimens was 3 (range 1-6). At time of study entry, 88% of patients were in relapse (sensitive relapse n=70, refractory relapse n=19) and 12% were in second remission. The median CD34+ cell dose infused was 5.2 × 106/kg (range 0.7-12.5). Median days to ANC ≥ 0.5 × 109/L and platelet count ≥ 20 × 109/L were 10 (range 8-44) and 9 (7-141), respectively. There was no grade IV or V toxicity. The most commonly observed toxicities were grade I or II nausea and vomiting (77%), mucositis (67%), and diarrhea (55%)., Reversible grade III liver enzyme abnormalities were observed in 4% of patients; one patient developed reversible VOD. With a median follow-up of 2.1 years (range 0.2-4.3), the cumulative incidence of treatment-related mortality (TRM) at 100 days, 1 year, and 2 years was 1.0%, 3.1%, and 4.3%, respectively. Among patients with non-Hodgkin's or Hodgkin's lymphoma, the overall response rate was 90%, with 1- and 2-year PFS rates of 63% and 58%, respectively; 1- and 2-year OS rates were 90% and 82% respectively (Figure 1). PFS was significantly better in patients with chemo-sensitive lymphoma, 61% vs. 42% at 2 years, p=.03. Among patients with multiple myeloma, the overall response rate was 58%, with 1- and 2-year PFS rates of 67% and 44%, respectively; 1- and 2-year OS rates were 90% and 82%, respectively. Survival rates were not significantly different between the chemo-sensitive and chemo-refractory multiple myeloma patients. Conclusion Intravenous busulfan-melphalan is well-tolerated, and the individualized PK-directed dosing of i.v. busulfan likely contributes to the low toxicity profile of this regimen. The high response rate and disease control in patients with advanced disease is encouraging, and should be explored in larger phase II studies. Disclosures Andersson: Otsuka Pharmaceuticals: Consultancy.

The abnormal expression of P53 is prognostically important in patients (pts) with CLL treated with conventional chemotherapy. In order to determine its significance upon survival in CLL pts undergoing NST, we analyzed outcome of P53 expression in conjunction with clinical and laboratory parameters in 86 pts transplanted at the MD Anderson Cancer Center between 02/96 and 01/06. Pts were eligible if they had failed conventional chemotherapy and had an HLA-identical or one-antigen mismatched donor. <> Median age (range) was 58 (36–73), the majority (81.4%) were males and the median Hematopoietic Stem Cell Transplantation (HSCT) Co-morbidity score was 3 (range 0–8). Pts were heavily pretreated with advanced disease at time of transplant: 66% had 3 or more lines of chemotherapy regimens, 41 (48%) had failed alemtuzumab, 55/65 (85%) had Binet stage B/C, 19(22%) had experienced transformation to Richter’s, 31 (36%) had progressive disease, and 22 (33%) were gallium/PET positive. Twenty-eight of 39 pts (72%) tested had unmutated IgVH. Immunoglobulin (Ig) G, A and M were below normal in 68%, 78% and 50%, respectively. CD4 and CD8 levels were <> P53 has been commonly tested by FISH methodology. In this report, 37 pts were tested by FISH. As an alternative, immunohistochemistry (IHC) assessing the expression of P53 in the absence of P21 has been suggested as a surrogate for mutated P53 status. IHC was therefore performed using antibodies to P53 (clone DO7; DAKO, Carpinteria, CA), and P21 (clone SX118:BD Pharmingen, San Diego, CA) on paraffin-embedded bone marrow biopsies in 46 pts. Samples were reviewed for expression of P53 and P21 proteins by T.D. and C.B-R., who were blinded as to outcome. Samples were considered positive for P53 mutation only if 20% or more of the malignant cells expressed P53 protein, with less than 5% expressing P21 protein. <> Thirteen of 46 pts (28%) were tested positive for P53+/P21− by IHC, and 10 of 37 (27%) were FISH+. Twenty-one pts were tested by both IHC and FISH: results were concordant in 16 pts (76%); 3 pts were FISH+/IHC−; 2 pts were FISH−/IHC+. <> With a median follow-up time for surviving pts of 37 (range, 12–131) months, the estimated three-year survival of all 86 pts was 53%. Univariate Cox proportional hazards regression for OS that considered P53 results as well all other clinical variables described above showed that IgG level below normal range at transplantation (P=0.001), CD4 =3 (P=0.023), Richter’s transformation (P=0.038), and % lymphocytes in marrow (P=0.039) were significantly associated with time to death. A multivariate analysis that included all the covariates with P values <> NST may overcome the negative predictor significance of P53 mutation. Considering the poor outcome with conventional chemotherapy, these pts may be considered for NST early in the course of their disease, before experiencing further depletion of their immune system as reflected by IgG and CD4 levels.

In order to determine if the addition of rituximab (R) had changed the outcome of autologous stem cell transplantation (AUTO) in patients with mantle cell lymphoma (MCL), we examined the outcome of 86 patients transplanted at the MD Anderson Cancer Center, in first partial or complete remission (frontline AUTO, n=50) or for relapsed / refractory disease (salvage AUTO, n=36). <<>> Among frontline patients, 29 were transplanted in the pre-R era (AUTO-R), and 21 in the post-R era (AUTO+R). AUTO-R patients received homogenous treatment with hyper-CVAD induction and Cy- TBI conditioning. AUTO+R patients were treated with R-hyper-CVAD, hyper-CVAD and R-CHOP induction in 62%, 10% and 29% respectively, and R-Cy-TBI and R-BEAM conditioning in 43% and 52% respectively. Median age (range) at transplantation was 57 (42–66) and 56 (38–73) for the AUTO-R and AUTO+R groups respectively (p=0.91); other baseline characteristics including sex, time from diagnosis, performance status, stage, B-symptoms, B2m, LDH and MIPI were similar. Prior to transplantation, CR or unconfirmed CR (CRu) was present in 38% and 57% of AUTO-R and AUTO+R patients respectively (p=0.18), and 33 of 34 patients were negative on Gallium/PET scan. Following transplantation, CR/CRu was achieved in 93% and 100% patients respectively (p=0.50). Progression free survival (PFS) was similar between AUTO-R and AUTO+R patients for the first 2 years. However, after 2 years a clear difference emerged on the PFS curve with no relapses occurring among 9 AUTO+R patients followed between 30 and 96 months. In contrast, AUTO1-R patients experienced a continuous pattern of relapse (p=0.03 compared with AUTO+R patients). For patients remaining in remission at 2 years, no deaths had occurred in the AUTO+R group, whereas 15 of 22 AUTO-R patients had died. <<>> The 36 salvage patients had similar baseline characteristics as frontline patients, except for the proportion of patients with chemosensitive disease (100% vs 86%, p=0.01) and negative Gallium/PET scans (97% vs 71%, p=0.01), favoring the frontline group. In contrast to the results of frontline patients, no difference was observed in salvage patients by the use of R (p=0.52 and 0.50 for PFS and OS respectively). <<>> Autologous transplantation with rituximab has the potential to cure a proportion of patients with MCL, but only if performed during the first remission. Patients transplanted beyond first remission continued to experience a poor prognosis. Figure Figure

For patients with acute lymphoblastic leukemia (ALL) who relapse after allogeneic hematopoietic stem cell transplantation (HSCT), treatment options are limited, and the clinical course and prognostic factors affecting outcome have not been well characterized. We retrospectively analyzed outcomes of 123 adult patients with ALL who relapsed after a first HSCT performed at our center between 1993 and 2011. First-line salvage included second HSCT (n = 19), donor lymphocyte infusion with or without prior chemotherapy (n = 11), radiation therapy (n = 6), cytoreductive chemotherapy (n = 30), mild chemotherapy (n = 27), or palliative care (n = 23), with median postrelapse overall survival (OS) of 10 months, 6.5 months, 3 months, 4 months, 4 months, and 1 month, respectively. Despite a complete remission rate of 38% after first-line salvage in the treated patients, the OS rate remained limited with 1- and 2- year OS rates of 17% (95% confidence interval, 13 to 29) and 10% (95% confidence interval, 6 to 20), respectively. On univariate analysis, adverse factors for OS included active disease at the time of first HSCT and short time to progression from first HSCT (

We investigated the administration of intravenous (i.v.) busulfan (Bu) combined with melphalan (Mel) in patients with advanced lymphoid malignancies undergoing autologous stem cell transplantation. Bu 130 mg/m(2) was infused daily for 4 days, either as a fixed dose per body surface area (BSA), or to target an average daily area under the curve of 5000 μmol-min, determined by a test dose of i.v. Bu at 32 mg/m(2) given 48 hours prior to the high-dose regimen, followed by a rest day, followed by 2 daily doses of Mel at 70 mg/m(2). Stem cells were infused the following day. Eighty patients had i.v. Bu delivered per test dose guidance. The median daily systemic Bu exposure was 4867 μmol-min. One hundred two patients (Hodgkin lymphoma n = 49, non-Hodgkin lymphoma n = 12, multiple myeloma = 41) with a median age of 44 years (range: 19-65 years) were treated. The 2-year overall survival and progression-free survival rates were 85% and 57%, respectively, for patients with Hodgkin lymphoma, 67% and 64%, respectively, for patients with non-Hodgkin lymphoma, and 82% and 42%, respectively, for patients with multiple myeloma. The regimen was very well tolerated with treatment-related mortality at 100 days, 1 year, and 2 years of 1%, 3%, and 3%, respectively. Intravenous Bu-Mel was well tolerated. Disease control wa encouraging, and should be explored in larger phase II studies.

Background: Bendamustine is a novel active agent in CLL with favorable safety profile. We recently reported the preliminary results of allogeneic stem cell transplantation (alloSCT) in lymphoma/CLL patients (pts) after BFR conditioning (Khouri et al. Blood 2014; 124:2306). Herein, we report more mature outcomes in CLL pts. Results and safety were compared with a previous regimen using FCR (fludarabine, cyclophosphamide, rituximab). Patients and Methods: We studied 89 CLL pts treated on 3 trials (one includes FCR later changed to BFR) at our center. Twenty-six (29%) pts received BFR and 63 (71%) received FCR. The BFR regimen consisted of bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation, thus substituting the cyclophosphamide in the FCR regimen. The dose and schedule of fludarabine (30 mg/m2 IV daily on days -5 to -3) and rituximab (375 mg/m2 IV on day -13 and 1000 mg/m2 on days -6, +1, +8) were similar in both regimens. Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving a matched unrelated donor (MUD) transplant. Results: Patient characteristics were similar in both groups. This included median age (58 years in both), sex distribution, and median number of prior therapies (3 in both), % pts with β2-microglobulin >3 mg/L at study entry, refractory disease (38% in BFR vs. 48% in FCR, P=0.4), presence of 17p deletion [27% in BFR vs. (8/33) 24% in FCR], unmutated status [19/21 (90%) of BFR vs 22/24 (92%) in FCR] and peripheral blood stem cell source (92% in BFR vs. 87% in FCR). Donor/recipient CMV and sex-mismatched distributions were not significantly different between the groups. However, more patients received their transplants from unrelated donors in the BFR group than the FCR group (54% vs. 32%, P=0.05). Ten (38%) BFR pts vs 2 (3%) FCR pts did not experience severe neutropenia (P 50 years (79% vs 50%), β2-microglobulin >3 mg/L (73% vs 45%), >3 prior lines of therapy (70% vs 43%) and recent years of transplant (82% vs 47%). Treatment-related mortality was 11% and 27% (P=0.05) at 2-year. The incidence of acute grade 3 GVHD was 4% and 10% in the BFR and FCR groups, respectively, despite the higher % of MUD transplants in BFR. Grade 4 acute GVHD was not observed in either group. The 3-year incidence of extensive chronic GVHD in BFR vs FCR was 45% vs 58% (P=0.01). This difference in GVHD incidence may in part be explained by a lower absolute blood level of CD8+ T cells in BFR patients compared to the FCR group at 6 months (median 343 vs 538, respectively) and 9 months (median 208 vs 406, respectively) post alloSCT. Conclusions: This is the first study to show that conditioning in alloSCT for CLL impacts outcomes with an improved survival after BFR when compared to the FCR regimen. Disclosures No relevant conflicts of interest to declare.