Andersen, N.N.S.

Bruno, B.

Chauncey, T.

Hogan, W.J.

Maloney, D.

Sandmaier, B.M.

Sorror, M.L.

Storb, R.

Storer, B.

Biology of Blood and Marrow Transplantation

English

M.L. Sorror

B. Storer

B.M. Sandmaier

T. Chauncey

B. Bruno

N.N.S. Andersen

W.J. Hogan

R. Storb

D. Maloney

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Early Results of a Phase II Study Adding Peri-Transplant Rituximab to Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients (PTS) with High-Risk Fludarabine-Refractory Chronic Lymphocytic Leukemia (Cll)

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Poster Session I S289Table. (Continued )HCT(79 pts)No HCT(38 pts)P-valuelogisticregressionUnfavorable cytogenetics (n) 30 (37%) 7 (18%) 0.18Secondary AML (n) 39 (49%) 15 (39%) 0.32Early relapse (n) (>5%marrow blasts within4.9 months of CR1(range 0.9-10, median 3.75)0 (0%) 13 (34%) <0.001Twenty-four of the 38 (63%) non-HCTpatients wereHLA-typedand matched donors were found for 13 of these 24 patients (54%; 5related, 8 unrelated). Seven of the 14 non-typed patients (50%) hadfinancial barriers or refusedHLA-typing. Only 2 of these 38 (5%) re-ceived HCT beyond CR1.Conclusion: These data suggest that HCT can be performed inCR1 in the majority of high-risk AML patients in whom it is cur-rently recommended. Patients in whom HCT is not done are char-acterized by a poorer performance status (but not older age) and byearly relapse. In the absence of these 2 factors,.75%of patients withhigh-risk AML under the age of 75 can receive HCT in CR1. A na-tional study is planned to assess the extent to which these results canbe generalized.229CLINICAL TRIAL EVALUATING DC/AML FUSION CELL VACCINATIONALONE AND IN CONJUNCTION WITH PD-1 BLOCKADE IN AML PATIENTSWHO ACHIEVE A CHEMOTHERAPY-INDUCED REMISSIONRosenblatt, J.1, Stone, R.2, Avivi, I.3, Uhl, L.1, Neuberg,D.2, Joyce, R.M.1,Tzachanis, D.1, Levine, J.D.1, Boussiotis, V.1, Zwicker, J.1, Arnason, J.1,Luptakova, K.1, Steesma, D.2, DeAngelo, D.2, Galinsky, I.2, Vasir, B.2,Somaiya, P.1, Mills, H.1, Yuan, E.1, Bonhoff, J.1, Delaney, C.1,Drummy, N.1, Nicholson, L.2, Stroopinsky, D.1, Held, V.3, Katz, T.3,Rowe, J.3, Kufe, D.2, Avigan, D.E.1 1Beth Israel Deaconess Medical Cen-ter, Boston, MA; 2Dana-Farber Cancer Institute, Boston, MA; 3RambamMedical Center, Haifa, IsraelA promising area of investigation in AML is the development ofcancer vaccines that educate host immunity to target leukemia cells,including the stem cell compartment. Our group has developeda cancer vaccine in which dendritic cells (DCs) are fused to autolo-gous tumor cells, resulting in the presentation of multiple tumor an-tigens and eliciting a broad immune response. A challenge todeveloping a more effective tumor vaccine is overcoming inhibitorypathways, including the PD1/PDL1 pathway, contributing to tu-mor-mediated immune suppression. We are conducting a clinicaltrial in which AML patients who are in remission following chemo-therapy receive three monthly doses of DC/AML fusion cells alone(cohort 1) or in conjunction with anti-PD1 antibody, CT-011 (co-hort 2). To date, 21 patients (mean age 57 years) have been enrolled.Patients underwent tumor collection from either bone marrow (N514), 20 cc of peripheral blood (N 5 5), or leukapheresis product(N 5 2). The mean tumor yield and viability was 8.43x108 cellsand 99% respectively. Patients achieving remission following che-motherapy underwent leukapheresis for DC generation. Adherentperipheral blood mononuclear cells were cultured in the presenceof GM-CSF and IL-4 for 5-7 days, and exposed to TNFa for 48hours to generate mature DCs. One patient died during inductionchemotherapy, one patient did not collect a sufficient number of tu-mor cells for vaccine generation, and 3 patients were removed fromstudy to undergo allogeneic transplantation. Vaccine was generatedin 12 patients at a dose of 5x106 fusions cells, mean fusion efficiencyof 31%, and viability of 87%. As ameasure of their activity as antigenpresenting cells, the capacity of fusion cells to stimulate allogeneic Tcell proliferation ex vivo was quantified. In contrast to the leukemiacells (mean stimulation index (SI) 4.4), the DC and fusion cells werepotent stimulators (mean SI 24.1 and 15.5, respectively). Vaccinationwas initiatedwithin 12 weeks from count recovery following comple-tion of chemotherapy. 4 patients have completed vaccinations, and 3are undergoing vaccination. Vaccine related adverse events includedvaccine site reactions, ankle pain and edema. Biopsy of a vaccine sitereaction demonstrated a dense T cell infiltrate. Peripheral blood isbeing collected prior to and serially following vaccination. Immuneresponse targeting leukemia cells, leukemic stem cells, and leukemiaassociated antigens will be assessed.230EARLY RESULTS OF A PHASE II STUDY ADDING PERI-TRANSPLANT RIT-UXIMAB TO NONMYELOABLATIVE CONDITIONING AND ALLOGENEICHEMATOPOIETIC CELL TRANSPLANTATION (HCT) FOR PATIENTS (PTS)WITH HIGH-RISK FLUDARABINE-REFRACTORY CHRONIC LYMPHOCYTICLEUKEMIA (CLL)Sorror, M.L.1,2, Storer, B.1,2, Sandmaier, B.M.1,2, Chauncey, T.1,2,3,Bruno, B.4, Andersen, N.N.S.5, Hogan, W.J.6, Storb, R.1,2,Maloney, D.1,2 1Fred Hutchinson Cancer Research Center, Seattle, WA;2University of Washington, Seattle, WA; 3Seattle Veterans Administra-tion Medical Center, Seattle, WA; 4University of Torino, Torino, Italy;5The Rigshospitalet, Copenhagen, Denmark; 6Mayo Clinic, Rochester,MNCLLpts who are fludarabine-refractory or possess unfavorable cy-togenetics have short survivals with conventional therapies. Non-myeloablative allogeneic HCT may provide long-term diseasecontrol. Disease progression is the major risk within the first yearafter HCT (median 3.3 months), until development of graft-versus-leukemia (GVL) effects. Treatment with anti-CD20monoclonal an-tibody (rituximab) in the early post-transplant period could improvedisease control: 1) directly by antibody-dependent cytotoxicity and2) indirectly by promoting cross-presentation of cell-derived pep-tides causing earlier and/or more robust GVL effects. To date, 20pts have been enrolled on a phase II trial comprising fludarabine,30 mg/m2 (days -4, -3, and -2) and 2 Gy total body irradiation (day-1) together with rituximab, 375 mg/m2 (days -3, +10, +24, and+38). Grafts were from HLA-matched related (n 5 6) or unrelated(n 5 14) donors. Median age was 61 (range 37-74) years. Pts wereolder, had higher comorbidity scores, more frequently received un-related grafts, and more frequently had unfavorable cytogeneticscompared to a historical control group of 128 pts treated with thesame regimen except for peri-transplant rituximab (Table).Table. Comparison of Pre-transplant Characteristics AmongPts Treated with Nonmyeloablative Conditioning and Alloge-neicHCTEitherWith (n520) orWithout (n5128)RituximabNo Rituximab Rituximab(n 5 128),n (%)(n 5 20),n (%) pAge, years $60 32 (26%) 14 (70%) 0.00010 51 (32%) 2 (10%)HCT-CI scores 1-2 42 (37%) 7 (35%) 0.05$3 35 (31%) 11 (55%)Response to lasttreatmentprior to HCTRelapse/refractory73 (57%) 12 (60%) 0.80CR or PR 55 (43%) 8 (40%)Fludarabine-refractory Yes 117 (91%) 20 (100%) 0.17Lymph node size$5 cmYes 33 (26%) 6 (30%) 0.69Campath within12 months priorto HCTYes 30 (23%) 5 (25%) 0.88Donor type Unrelated 55 (43%) 14 (70%) 0.02ChromosomalabnormalitiesUnfavorable* 50 (64%) 19 (95%) 0.0002Favorable† 78 (36%) 1 (5%)*Includes deletion 17p, P53 mutation, deletion 11q23, or more than 3cytogenetic abnormalities.†Includes deletion 13q, normal chromosomes, and triosomy 12.After a median follow up of 13.6 (range: 3.4-26.5) months follow-ing HCT, none of the 20 pts have experienced progression orS290 Poster Session Irelapse. Five pts have died (median 9 months), 2 from graft-versus-host disease (GVHD), 2 infections, and 1 elected Hospice care afterexperiencing renal failure. Last disease responses were complete re-mission (n5 8), partial remission (n5 6), stable disease (n5 5), not-evaluated (n 5 1). The incidences of grades II and III-IV acuteGVHD were 60% and 15% respectively, and chronic GVHD was46% at 1-year. Estimated 1-year rate of non-relapse mortality(NRM), relapse, progression-free (PFS), and overall survivals (OS)were 33%, 0%, 67%, and 67% respectively. Patients receivingperi-HCT rituximab had lower HR for relapse (HR:0, p 5 0.001),comparable HR for NRM (HR:1, p 5 0.9) and OS (HR:0.7, p 50.45), and a trend for lower HR for PFS (HR:0.5, p 5 0.07)compared to the historical control group. At day 84, median CD3chimerisms were 99% vs 95% (p 5 0.08), respectively.After adjusting for the previous 4 significant covariates, PFS wasbetter (HR:0.4, p 5 0.04) among the rituximab group. Peri-transplant rituximab is a promising addition to nonmyeloablativeHCT and may decrease early disease progression by allowing thegeneration of potent GVL effects.231LEUKEMIC TRANSFORMATION OF PHILADELPHIA-NEGATIVE MYELO-PROLIFERATIVE NEOPLASMS: RESULTS OF A TREATMENT ALGORITHMEMPLOYING ALLOGENEIC TRANSPLANTATION USING RELATED ANDUNRELATED DONORSKennedy, J.A.1, Atenafu, E.G.2, Messner, H.3, Brandwein, J.M.3,Craddock, K.J.4, Lipton, J.H.3, Minden, M.D.3, Schimmer, A.D.3,Schuh, A.C.3, Yee, K.W.3, Gupta, V.3 1University of Toronto, Toronto,ON, Canada; 2PrincessMargaret Hospital, Toronto, ON, Canada; 3Prin-cess Margaret Hospital, Toronto, ON, Canada; 4University Health Net-work, Toronto, ON, CanadaLeukemic transformation (LT) is a rare but fatal complication ofPhiladelphia-negative myeloproliferative neoplasms (MPNs) forwhich optimal treatment strategies are not known. LT is generallyconsidered incurable with induction chemotherapy alone.At our centre, we have adopted a treatment strategy for LTwhere patients within the transplant age group who have a reason-able fitness level are offered induction therapy. Subsequently, thosewho achieve complete remission (CR/CRi) or revert back toa chronic MPN (cMPN) state are considered eligible for allogeneictransplantation (allo-SCT) if a suitable related or unrelated donoris available. Alternatively, those who are not candidates for theaforementioned strategy are offered supportive therapy includingclinical trials.We evaluated clinical outcomes of this treatment approach in 75patients with LT diagnosed between 1998 and 2011. Prior to LT,MPN diagnoses were: PV, 16%; ET, 16%; primary MF, 28%;post-PV/ET MF, 25%; and MPN-U, 15%. 39 (52%) patientswere treated with curative intent (induction chemotherapy +/-allo-SCT) while the remainder were treated with non-curative in-tent. At the time of LT, the curative intent cohort differed fromthe non-curative group in terms of median age (57 vs. 72 yrs,P\0.0001), performance status (ECOG#1 in 92% vs. 58%, p 50.001), serum albumin (38 vs. 35 g/L, p 5 0.008) and the frequencyof normal cytogenetics (47% vs. 20%, p 5 0.03) respectively.Among all patients, the 2-year overall survival (OS) from the timeof LT was 15%. Outcomes were significantly improved in individ-uals treated with curative vs. non-curative intent (2-year OS, 25%vs. 4%, P\ 0.0001). Among the curative group, 30/39 achieved ei-ther CR (n 5 19) or reversion to cMPN (n 5 11). Suitable donorswere identified for 24 (80%) of these responders and 17 (57%) un-derwent allo-SCT.Median time to transplant was 177 days. Survivalof patients undergoing allo-SCT was significantly better comparedto those who achievedCR/cMPNpost-induction but were not trans-planted (2-year OS, 46% (n5 17) vs. 15% (n5 13), P5 0.035). Toavoid a time to transplant bias, a landmark analysis was done compar-ing survival between the transplant cohort and non-transplanted pa-tients who survived at least 177 days (n5 13), and similar results wereobserved (2-year OS 46% vs. 15%, p 5 0.035).Our results demonstrate the curative potential of intensive induc-tion therapy followed by allo-SCT in select patients with LT pre-ceded by MPN.232LOW DAY 100 TRANSPLANT-RELATED MORTALITY (TRM) FOLLOWINGCLOFARABINE (CLO) IN COMBINATION WITH CYTARABINE AND TOTALBODY IRRADIATION (TBI), MYELOABLATIVE CONDITIONING (MAC)AND ALLOGENEIC STEM CELL TRANSPLANTATION (ALLOSCT) IN CHIL-DREN, ADOLESCENTS AND YOUNG ADULTS (CAYA) WITH POOR-RISKACUTE LEUKEMIARadhakrishnan, K.1, Ricci, A.M.2, Geyer,M.B.3, Harrison, L.1, Duffy, D.1,Ozkaynak, F.1, Satwani, P.2, Cheerva, A.C.4, Talano, J.5, Moore, T.B.6,Gillio,A.P.7, Baxter-Lowe,L.A.8,Cairo,M.S.1 1NewYorkMedicalCollege,Valhalla, NY; 2Columbia University, New York, NY; 3Harvard MedicalSchool,Boston,MA; 4University of Louisville, Louisville, KY; 5MedicalCol-lege ofWisconsin, Milwaukee,WI; 6University of California at Los Angeles,Los Angeles, CA; 7Hackensack University Medical Center, Hackensack, NJ;8University of California at San Francisco, San Francisco, CABackground:CAYA with ALL or AML in third complete remission(CR3), refractory relapse (RR) or induction failure (IF) have an ex-tremely poor prognosis,\20% EFS (Gaynon, BJH, 2005, Wells etal, JCO, 2003). MAC prior to AlloSCT is associated with highTRM and is donor dependent: 5-20% for matched sibling, 10-40% for matched unrelated, and 20-52% for cord blood transplants.CLO, an inhibitor of DNA polymerase and ribonucleotide reduc-tase, has been shown to be safe and induce durable remissions,both in conjunction with busulfan in poor-risk AML (Magenau etal., Blood, 2011) and with Melphalan in poor-risk hematologic ma-lignancies in adults (van Besien et al, ASH,2009). CLO has signifi-cant activity in CAYA with relapsed ALL/AML (Jeha et al., JCO2006,2009) and synergy with cytarabine (Faderl et al, Blood,2005). We sought to determine safety, day-100 TRM, and overallsurvival (OS) of CLO, cytarabine and TBI followed by AlloSCT inCAYA with poor-risk ALL/AML.Methods: This is an ongoing multi-center phase I/II trial of a novelconditioning regimen of CLO (dose escalation: 40mg/m2 [n5 3], 46mg/m2 [n 5 3], 52 mg/m2 [n 5 17]) x5d, sequential (4 hrs later) cy-tarabine 1000 mg/m2 x6d and TBI (1200cGy) followed by AlloSCTfrommatched related or unrelated donors in CAYA with ALL/AMLin CR3, RR or IF. Pts with unrelated grafts received R-ATG.GVHDprophylaxis consisted of tacrolimus andMMF (Bhatia/Cairoet al., BBMT, 2009). Kaplan-Meier method was used to determinethe probabilities of engraftment, GVHD, TRM and OS.Results: 23 pts, median age: 10.8 yrs (1.5-20.7); M:F: 17:6, ALL/AML: 20:3 (9 CR3, 3 RR, 11 IF), 9 related donors, 14 unrelated do-nors (8 BM/PBSCs, 6 UCB). Median TNC and CD34 dose was4.76x108/kg and 4.84x106/kg for BM/PBSCs and 4.0x107/kg and2.8x105/kg for UCB, respectively. Probabilities of neutrophil andplatelet engraftment and grade II-IV aGVHD were 100%, 92.8%and 50.8%, respectively. All except one achieved 100% whole blooddonor chimerism by day 30. CLO dose was tolerable at 52mg/m2/d x5d without dose limiting toxicity. Probability of Day 100 TRMwas only 5%. Probability of 1-yr PFS and OS were 45% (CI95: 24-83%), and 44.6% (CI95: 24-68%) respectively.Conclusions: Preliminary results suggest this novel MAC regimenfollowed by AlloSCT is safe and well tolerated in CAYA withpoor-risk ALL/ AML with CLO dose of 52 mg/m2. Early resultsare encouraging with respect to low risk of day 100 TRM with thisconditioning regimen in this poor-risk population.233OUTCOMES OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION(HCT) IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): IMPACT OF MYE-LOABLATIVE (MA) VS. REDUCED-INTENSITY CONDITIONING (RIC) REG-IMENS, AND IMPACT OF TOTAL BODY IRRADIATION (TBI)-BASED MAVERSUS CHEMOTHERAPY (CT)-BASED MA CONDITIONINGLeis, J.F.1, Sabloff, M.2, Sobecks, R.M.3, Maziarz, R.T.4, Ahn, K.W.5,Zhu, X.5, Kalaycio, M.E.3, Cortes, J.6, Saber, W.5 On Behalf of theCIBMTR Chronic Leukemia Working Committee 1Mayo Clinic Arizona& Phoenix Children’s Hospital; 2The Ottawa Hospital Blood & MarrowTransplant Program; 3Cleveland Clinic Foundation; 4Origon Healthand Science University; 5CIBMTR, Medical College of Wisconsin;6M.D. Anderson Cancer CenterThere has been a marked change in transplant approaches of theCLL patient. MA conditioning has been shown to provide high

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Early Results of a Phase II Study Adding Peri-Transplant Rituximab to Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients (PTS) with High-Risk Fludarabine-Refractory Chronic Lymphocytic Leukemia (Cll)

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