Hematopoietic Cell Transplantation Group Research Articles

A national survey of screening and management of hypogammaglobulinemia in Canadian transplantation centers

Infection remains one of the most common transplant-related causes of death in patients undergoing transplantation. Secondary hypogammaglobulinemia (HGG) as a component of immune suppression and deficiency is associated with both solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). Available data and clinical experience for the supplementation of immunoglobulin (Ig) in these patients is conflicting, and differing clinical opinion accounts for non-uniform practice in the use of Ig treatment. We aimed to survey lead transplant practitioners for current practice around polyvalent Ig use in post-transplant recipients across Canada. We performed a survey study using short questionnaires to estimate rate of screening of HGG, use of polyvalent Ig, and physician's opinion on Ig treatment and infection prevention. Directors of 24 SOT and 23 HCT centers across Canada were invited to participate in the survey via an electronic mail. Overall response rate was 63.8%. Twenty percent of SOT programs routinely measured Ig levels pre-transplant compared to 33% of allogeneic (allo-) and 21% of autologous (auto-) HCT programs. Post-transplant Ig levels were measured in 13%, 75%, and 29% in SOT, allo-HCT, and auto-HCT, respectively. The SOT and auto-HCT groups indicated that they do not prescribe Ig therapy (100% and 86%), contrary to the allo-HCT group (42%). Of the respondents in the SOT, allo-HCT, and auto-HCT groups, 60%, 67%, and 36%, respectively, thought infections could be prevented with intravenous immunoglobulins (IVIg). A majority of respondents indicated they would be interested in participating in a randomized controlled trial evaluating the use of IVIg in the SOT and in both HCT groups (100%, 83%, and 57%, respectively). Our study shows significant variation in practice between SOT and HCT centers with respect to screening and management of HGG. There is willingness to participate in a randomized controlled trial to address whether Ig treatment reduces infection in post-transplant recipients.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome after hematopoietic cell transplantation for lymphoma

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P<0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.

Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome in Lymphoma Patients Receiving Hematopoietic Cell Transplantation

▪Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for malignant lymphoma (ML). The option of high-dose therapy with autologous HCT or allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed ML. We retrospectively analyzed incidence, outcome, and risk factors for the development of t-AML/MDS in ML patients treated with autologous or allogeneic HCT. A total of 13,810 ML patients received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, ML patients receiving autologous HCT (1.38%; 95% confidence interval [CI], 1.09-1.68; at 3 year after autologous HCT) have a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37%; 95%CI, 0.06-0.67; at 3 year after allogeneic HCT). Median time from HCT to t-AML/MDS after autologous and allogeneic HCT was 957 and 414 days, respectively. Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT are high-stage risk (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or radiotherapy-conditioning (P=0.002), respectively. The additional data collection from 46 transplant centers was available for 62 of 220 patients with t-AML/MDS: 56/211 (26.5%) of t-AML/MDS patients receiving autologous HCT and 6/10 (60%) receiving allogeneic HCT. Information on cytogenetic and/or molecular genetic evaluation was available for 62 patients: 41/56 patients (73%) receiving autologous HCT and 6/6 patients (100%) receiving allogeneic HCT had cytogenetic abnormalities. Abnormalities in chromosome 5 and/or chromosome 7 were found in 28/56 (50%) after autologous HCT and 5/6 (83%) after allogeneic HCT. Balanced translocations, such as mixed-lineage leukemia rearrangement 11q23 and t(15;17), were detected in 4/56 patients (7%) after autologous HCT and 0/6 patients after allogeneic HCT. Complex karyotypes were observed in 17/56 patients (30%) after autologous HCT and 4/6 patients (67%) after allogeneic HCT. Allogeneic HCT for t-AML/MDS was available for 20/62 patients (32%): 18/56 (32%) after autologous HCT and 2/6 (33%) after allogeneic HCT. Among 56 patients in the autologous HCT group, t-AML/MDS patients who underwent allogeneic HCT had a significantly better OS from onset of t-AML/MDS compared with those who did not undergo allogeneic HCT (median OS 72 vs. 60 months, P=0.043), whereas the number of patients with high-disease risk was significantly higher in patients who did not undergo allogeneic HCT. Among 6 patients in the allogeneic HCT group succumbed to their disease: 2/2 patients who underwent allogeneic HCT died due to transplant-related toxicities and 4/4 patients who did not undergo allogeneic HCT died due to secondary malignancies in the CR state of lymphoma after the primary allogeneic HCT. When compared with the group of patients with t-AML/MDS after autologous and allogeneic HCT, the number of patients with Ann Arbor stage 4 and the percentages of patients receiving conditioning with etoposide were significantly higher in the autologous HCT group. The number of HCT, the percentages of patients receiving conditioning with total body irradiation and fludarabine, the longer duration of G-CSF, the later neutrophil engraftment and higher scores of revised international prognostic scorin system for MDS were significantly higher in the allogeneic HCT group. In conclusion, t-AML/MDS is rare but ML patients with t-AML/MDS after HCT are associated with a poor prognosis. Thus, novel treatment strategies for ML should aim at a reduction of chemotherapy and a reduced number of HCT to reduce the risk of developing t-AML/MDS. In addition, strategies to select ML patients more carefully for autologous HCT to exclude ML patients with high-stage risk may allow the identification of individual ML patients at particular high risk for t-AML/MDS. Allogeneic HCT might be an alternative to autologous HCT in ML patients at high risk for t-AML/MDS. Finally, the further optimization of allogeneic HCT might increase the cure rates among ML patients diagnosed with t-AML/MDS after autologous HCT. DisclosuresIida:SymBio Pharmaceuticals: Research Funding. Suzumiya:Toyama Chemical: Research Funding; Kyowa Hakko kirin: Research Funding; Takeda: Honoraria; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Astellas: Research Funding.

Final Results of Northern Italy Leukemia Group (NILG) Trial 10/07 Combining Pediatric-Type Therapy with Minimal Residual Disease Study and Risk-Oriented Hematopoietic Cell Transplantation in Adult Acute Lymphoblastic Leukemia (ALL)

Introduction. The application of Pediatric-Type Therapy (PTT) programs to adults with ALL can improve outcome significantly despite higher age-related toxicity. Recent series reported survival rates ≥ 50%, but only few combined PTT with Minimal Residual Disease (MRD) study for risk-oriented Hematopoietic Cell Transplantation (HCT) and/or explored the value of specific PTT element such as higher dose, lineage-targeted MTX up to 5 g/m2. Methods. To improve over prior data, NILG protocol 10/07 (Clinical.Trials.gov NCT-00795756) for unselected adult patients aged 18-65 years combined PTT together with MRD study for risk/MRD-based HCT. The 8-course program consisted of a 5-drug complete remission (CR) induction (cycle no. 1; imatinib added if Ph+) followed by 3 modified BFM blocks (no. 2, 4 and 6), 3 lineage-targeted MTX blocks (no. 3, 5 and 7; MTX 5 g/m2 for T-ALL and 2.5 g/m2 for B-ALL [1.5 g/m2 if age > 55 years or Ph+]; no. 3 and 7 with high-dose Ara-C 2 g/m2 x4, no. 5 with L-Asp 10,000 IU/m2 x2) and reinduction (no. 8). CNS prophylaxis was with triple intrathecals or liposomal cytarabine (Haematologica 2015;100:786). MRD was studied molecularly with sensitive probe(s) (sensitivity 10-4 or greater) on marrow samples obtained at end of induction (week 4, w4) and after cycles 3 (w10), 5 (w16), 7 (w22) i.e. after 1st, 2nd and 3rd lineage-targeted MTX block. Patients were risk-stratified at diagnosis and after MRD analysis for the purpose of allocation to HCT or conventional maintenance. The HCT allocation cohort consisted of predefined very high-risk patients (vHR: WBC >100, highly adverse cytogenetics, pre-T/mature T-ALL) regardless of MRD, of HR patients without MRD study (HR: late CR; B-ALL with WBC >30 or pro-B phenotype), and of HR or standard-risk (SR) patients with MRD ≥ 10-4 at w10/16 or positive at w22. Conversely, the maintenance allocation cohort consisted of SR and HR patients with MRD Results. 205 patients were enrolled, with a median age of 41 years (range 17-67 years, 11% > 60 years). 55% were male, 42 had Ph+ ALL, 119 Ph- B-ALL and 44 T-ALL. Of 163 patients with Ph- ALL, 45% were SR, 13% HR and 42% vHR. CR rate was 98% in Ph+ ALL and T-ALL, and 83% in Ph- B-ALL (88% vs 58% in patients ≤ vs > 60 years, P .0013). The MRD study was successful in 109/142 CR patients with Ph- ALL (77%), contributing to the final risk classification in 63 patients, of whom 41 were MRD responsive (65%) and 22 MRD resistant (35%). Altogether, 55 CR patients constituted the maintenance allocation group (39%) and 87 the HCT allocation group (61%), which included mainly vHR patients (n=61, 43%) selected for HCT independently of MRD study results. According to intention-to-treat, median OS is not reached (53% at 5 years, figure) and median DFS is 4.8 years (48% at 5 years). In Ph- ALL, 5-year OS/DFS are 74%/61% in T-ALL (medians not reached) and 48% each in B-ALL (medians 3.9 and 4.7 years). Median OS is not reached in both HCT and maintenance allocation groups (58% and 73% at 5 years, respectively, P .078), with a median DFS of 4.7 years (48% at 5 years) versus not reached (59% at 5 years) (P .19). Treatment adherence was good with some exceptions in maintenance allocation group (6 HCT, 11%) and a transplant realization of 68% (53 allogeneic; 6 autologous) in HCT allocation group. With HCT, 5-year incidence of nonrelapse mortality was 17%. The MRD analysis proved that DFS of patients achieving an MRD response Conclusion. The current PTT and MRD-based risk-oriented strategy was applicable to adults with ALL in a wide age range, with some limitations in patients > 60 years. 5-year OS and DFS of 55% and 52% respectively in Ph- patients aged up to 65 years represent an improvement over prior NILG study (5-year OS and DFS of 36% and 35% respectively). MRD was essential in orientating the HCT choice in SR and HR patients and retained a major prognostic role in all patients. Optimizing the early MRD response with new immunotherapeutics and clarifying the role of HCT in MRD responsive vHR patients are some relevant topics of future research. Disclosures Ciceri:MolMed SpA: Consultancy. Vitolo:Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Roche: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Gallamini:Millenium Takeda: Membership on an entity9s Board of Directors or advisory committees.

The Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) and Treatment with Ruxolitinib on Survival in Patients with Myelofibrosis

Allogeneic HCT is curative in myelofibrosis (MF) with a survival (OS) advantage compared to non-JAK-inhibitor treatments in patients (pts) with Int-2/high-risk DIPSS (Kroeger et al, Blood 2015). On the other hand, data demonstrate a OS benefit of the JAK1/JAK2 inhibitor ruxolitinib (RUX) in intermediate (Int)-2/high-risk IPSS (Cervantes et al, Blood 2013; Verstovsek et al, Haematologica 2015). Yet, comparative data to the impact of RUX and HCT on OS are lacking. This was pursued retrospectively at the University of Leipzig in light of clinical-, cytogenetic-, phenotype-driver-, and somatic mutations-based prognostic variables.Patient and Methods: RUX became available in November, 2009. MF pts (n=137; median age 58y) seen afterwards were included with the exception of MPL + pts (small number). Characteristics are shown in table 1. RUX was given for spleenomegaly and/or constitutional symptoms [n=76 (55%)]. Irrespective of RUX, a donor search was initiated in int-2 and high-risk IPSS pts < 70 y and HCT performed if a suitable donor identified. Based on this biologic randomization, 50 (37%) received HCT, 58 (42%) continued with RUX (median exposure 19 months), and 29 (21%) pts had other options. The RUX- and HCT-groups were balanced in terms of IPSS, platelets, cytogenetic-, and epigenetic molecular-risks. Treatment was initiated within the first year (median 10 months), thus probability of OS 5 years after diagnosis was calculated (SPSS20 software). Cytogenetic-risk was conducted according to Caramazza et al. Leukemia 2011. Somatic mutations detected by NGS were used to calculate molecular-risk (Vannucchi et al. Leukemia 2013).Results: Median OS time was 6.8 y. The RUX-group was older (median age 64 y) with profound spleenomegaly and a higher JAK2 V617F allele burden compared to the HCT group (median age 55 y) (p<0.0005). The 56% OS at 5 years in the RUX group was comparable to that after HCT (60%; p=0.5). In the transplant setting, prior RUX-treatment (n=21; OS 65%) had no negative impact compared to up-front HCT (n=29; OS 55%) (p=0.9). Whilst IPSS low-/int-1-risk retained its survival impact (p=0.04), OS at 5 years was comparable for int-2 and high-risk. OS in the HCT and RUX groups for int-2 was 59% and 62% respectively (p=0.4) and for high-risk IPSS 54% and 50% respectively (p=0.2). Advanced age was associated with an inferior OS (p=0.002) and correlated with higher IPSS, transfusion-dependency and thrombocytopenia. In the HCT group, OS in pts <50 y was 91% vs. 49% in pts >50 y (p=0.001). In the RUX group, age <60 and not <50 y was OS-relevant [79% in pts <60y vs. 43% in those >60 y (p=0.02)]. No prognostic implication of anemia, WBC, peripheral blasts, and constitutional symptoms could be detected with both treatments. OS in JAK2 + pts was similar to CALR + pts in both therapy cohorts (p=0.3). Triple negativity retained its detrimental influence (p<0.0001) even after HCT, with frequent AML-typical mutations (transcription and/or signaling genes) and a leukemic transformation (LT) rate of 35%. Although spliceosome mutations were associated with anemia (p=0.004)/transfusion-dependency (p=0.006) and mutations in chromatin modifiers (ASXL1, EZH2) with splenomegaly(p=0.02),high-molecular epigenetic risk had no impact on OS or LT in the treatment groups. Unfavourable cytogenetics were associated with LT (p=0.04) but not OS in the two groups. Of the 24 pts with a LT, 15 (62%) received no RUX and no HCT.Conclusions: Our data imply that, besides allogeneic HCT, a prolonged JAK1/JAK2 inhibition could, at least partly, attenuate most of the prognostic detrimental parameters. Pre-treatment with ruxolitinib prior to HCT does not seem to have a negative impact on survival. It is the first time where outcome with a non-transplant procedure is shown to be comparable to that after HCT in MF, even in high-risk disease. This needs to be verified in prospective randomized trials to define the role of allogeneic HCT in the era of JAK1/JAK2 inhibition.Table 1Patients characteristics ( n = 137 )VariableImpact on OSImpact on LTMedian age (years)580.0020.6JAK2+/CALR+/Double negative (%)63 / 20 / 17<0.00050.04Median number of MF-related mutations (range)1 (0-5)0.40.07High-molecular risk profile (%)(ASXL1, EZH2, SRSF2, IDH1/2)33.60.80.7Mutations in transcription/signaling genes (%)280.30.008Unfavorable cytogenetics (%)300.10.04IPSS (Int-2 / high-risk) (%)34 / 410.040.2 DisclosuresRoskos:Novartis: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Influence of the Insertion Site on Central Venous Catheter Related Complications in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation, High Dose Therapy or Induction Therapy for Acute Leukemia

Central venous catheters (CVCs) are extensively used in patients undergoing hematopoietic cell transplantation (HCT) or induction chemotherapy for acute leukemia. In these patients CVCs are placed routinely either via internal jugular (IJV) or subclavian veins (SCV). Several studies have compared rates of complications between both insertion sites, particularly in the intensive care unit setting. However, to our knowledge there are no data in the literature comparing the insertion sites IJV versus SCV in patients undergoing allogeneic HCT or high dose therapy for hematologic malignancies. Thus, it was the purpose of this study to analyze systematically complications of CVCs at the different insertion sites in these patients.Patients and methods: All consecutive patients who were treated in the unit for adult HCT at our institution from 01/2011 to 06/2013 were included into this retrospective analysis. Inclusion criterion was insertion of a CVC due to allogeneic HCT, autologous HCT or induction therapy for AML or ALL. 3-lumen standard CVCs (Arrow, Reading, PA) were placed after informed consent either via the IJV or the SCV. CVCs were inserted by experienced physicians after disinfection by 70% propanolol under full barrier precautions. The insertion site was chosen at the responsible physician´s own discretion. CVCs were covered by chlorhexidine gluconate impregnated dressings, either as transparent polyurethane (Tegaderm CHG, 3M, Saint Paul, MN) or as sponge dressing (Biopatch, Ethicon, Cincinnati, OH). No patient received a systemic antibiotic prophylaxis. Reasons for premature removal of CVCs were suspected or proven CVC-related blood stream infection (BSI), progression of local infections at the insertion site, or any other CVC related severe adverse event. End points of this study were local infections, fever, BSI, duration of catheterization per CVC, congestion of the CVC, thrombosis, pneumothorax and suspected or proven catheter related deaths.Results: During the study period 255 CVCs were placed in 170 consecutive patients [median age: 59 years (range 19-79), F: n=63; M: n=107] due to allogeneic HCT (65 patients, 101 insertions), autologous HCT (30 patients, 33 insertions) or induction therapy for AML or ALL (75 patients, 121 insertions). Underlying diseases were AML (n=102), ALL (n=9), MDS (n=15), MPN (n=4), lymphoma (n=21) or plasma cell neoplasia (n=19). Out of the 255 CVSs 155 (61%) were sited via the IJV and 100 (39%) via the SCV. Among the 101 CVCs in the allogeneic HCT group 60 (60%) were placed in the IJV and 41 (41%) in the SCV. The median duration of catheterization/per CVC for the entire group was 16 days (range 3-49, IJV: 17, SCV: 15 days, ns). The corresponding data for the allogeneic HCT group were 18 (IJV) and 17 day (SCV). The events fever or local infection occurred in 75% (45/60) of IJV- and in 95% (39/41) of SCV-CVCs (p=0.0084) in the allogeneic HCT group. Moreover, in SCV-CVCs these events arose significantly earlier (median time to event 7 vs. 10 days in the IJV (p=0.012). Focusing only on the event local infection the results were also superior for the IJV-CVCs: 28/60 (47%) vs. 29/41(71%) for SCV-CVCs (p=0.026). For the entire cohort of CVCs data were similar: The events fever or local infection occurred in 127/155 (82%) of IJV- and 95/100 (95%) of SCV-CVCs (p=0.025). Median time to these events were 8 (IJV) vs. 10 days (SCV, p=0.0009). For local infections alone the differences were even more pronounced: 81/155 (IJV: 52%) vs. 81/100 (SCV: 81%, p<0.0001). There were no significant differences in the frequency of BSI between the insertion sites [entire group: IJV 46/155 (30%), SCV 20/100 (20%); allogeneic HCT group: IJV 14/60 (23%), SCV 12/41 (29%)]. Thrombosis or pneumothorax occurred only once, both with SCV-CVCs. Congestion of CVCs occurred in 20% (31/155) IJV- and in 24% (24/100) of SCV-CVCs (ns), respectively. Data for allogeneic HCT were 25% (15/60) in IJV- and 27% (11/41) in SCV-CVCs (ns). Out of the entire cohort 10 patients (7 x allogeneic HCT, 3 x induction therapy) died with an inserted CVC. 5 of them died due to BSI and therefore potentially CVC-related (3 x IJV, 2 x SCV).Conclusions: In contrast to earlier studies on patients without hematologic malignancies these data demonstrate clearly that CVCs placed in the SCV are not superior. Moreover, local infections and fever occurred significantly earlier and more frequent in SCV-CVCs in patients undergoing allogeneic HCT. DisclosuresNo relevant conflicts of interest to declare.

Factors associated with hematopoietic cell transplantation (HCT) among patients in a population-based study of myelodysplastic syndrome (MDS) in Minnesota.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective erythropoiesis, and an increased risk of developing acute myeloid leukemia. Treatment planning for patients with MDS is a complex process, and we sought to better characterize hematopoietic cell transplantation (HCT) outcomes and the factors that play into decision-making regarding referral of adults with MDS for definitive therapy with HCT. Patients enrolled in a population-based study of MDS between April 2010 and January 2013 who underwent HCT within the first year after enrollment were included in this analysis. Age- and risk-matched MDS patient controls also enrolled during that time period were used as a comparison. Survival was significantly better in the HCT group (48 vs. 21%, log-rank p value 0.009). Non-HCT patients were more likely to have comorbidities, and HCT patients were more likely to have a college degree and an income >$80,000. All three of these variables were independently associated with HCT, but none impacted survival. Patients with MDS in our study who underwent HCT had better survival than a comparable group of patients who did not undergo HCT. With refined treatment techniques, more patients may be able to be considered for this therapy. More work needs to be done to determine why education and income appear to impact the decision to pursue HCT, but these factors may impact referral to an academic center where aggressive therapy like HCT is more likely to be considered.

Bone Mineral Density in Children with Fanconi Anemia after Hematopoietic Cell Transplantation

Fanconi anemia (FA) is an inherited DNA repair disorder associated with short stature and bone marrow failure, usually requiring hematopoietic cell transplantation (HCT). Although low bone mineral density (BMD) has been reported in leukemia patients after HCT, little is known about BMD in FA children after HCT (FA HCT). This study's goals were to compare BMD in FA HCT to BMD in healthy controls and in children who received HCT for hematologic malignancy (cancer HCT), and to test for associations between BMD and risk factors for bone loss. This cross-sectional study included 20 FA HCT, 13 cancer HCT, and 90 healthy controls, age-matched and <18 years old at evaluation. BMD Z-scores for total body (TBMD) and lumbar spine (LBMD) were measured by dual energy x-ray absorptiometry and adjusted for height-for-age Z-score (HAZ). FA HCT had lower mean TBMDHAZ Z-score (by .8 SD) and higher fraction with Z-score ≤ −1 than healthy controls (42% versus 11%). No LBMD deficits were detected. FA HCT and cancer HCT groups did not differ significantly in TBMD or LBMD Z-scores. In FA HCT patients, lower body mass index and lower percent fat were associated with lower BMD. This study highlights the importance of monitoring BMD to optimize bone health in FA patients.

Higher Leukemia Free Survival after Post-Induction Hematopoietic Cell Transplantation Compared to Consolidation Therapy in Patients >60 Years with Acute Myelogenous Leukemia (AML): Report from the AML 2004 East German Study Group (OSHO)

Treatment of elderly patients with AML remains challenging. While increasing doses of induction and consolidation chemotherapy have failed to improve outcome, efforts to decrease relapse rates using the graft-versus-leukemia effect have shown promising results in phase II studies. In the present analysis of the prospective OSHO 2004 study we evaluated the effect of post-induction hematopoietic cell transplantation (HCT) in comparison to conventional consolidation chemotherapy (CT) on outcome in elderly patients with AML.The OSHO 2004 study is part of the German intergroup study. Upon achieving complete remission (CR) after induction, patients were assigned to CT or HCT depending on the availability of a matched related or unrelated donor. Unrelated, single antigen mismatched donors were accepted in high risk situations. By April 2014 from 817 eligible patients, 505 entered CR (62%) after one or two induction therapies. From the 452 patients who received consolidation in CR 1, 31 patients (7%) relapsed and 10 (2%) died of complications during consolidation. No further therapy for medical reasons was given to 73 patients, 206 patients received second consolidation with cytarabine (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m² d1-2) and 132 patients underwent HCT. Most frequent conditioning regimens for HCT were low dose TBI (83%) and treosulfan/fludarabine (12%). Most of the patients received HCT from unrelated (80%) donors and the majority received grafts from HLA-identical (78%) donors. Our analysis was restricted to the 315 patients <75 years receiving either CT or HCT. Probabilities for overall survival (OS) and leukemia free survival (LFS) were estimated according to the Kaplan-Meier method and differences tested by the log-rank test. Relapse incidence (RI) and non relapse mortality (NRM) were described by estimating the cumulative incidence and testing the differences using the Gray’s test. Multivariate Cox regression models and competing risks regression models were used to identify independent prognostic variables for outcomes.The median age was 67 (60-74) and 65 (60-74) years in the CT and the HCT groups (p<0.0005), respectively. There were no differences between CT and HCT regarding gender, AML type (de novo, secondary or therapy related) and FLT3 mutation status. However more patients with mutated NPM1 were observed in the CT as compared to the HCT group (39% vs 28%; p=0.07) and more patients entered into remission after one induction in the CT as compared to the HCT group (89% vs. 81%; p=0.05). Low risk cytogenetics and normal karyotype were present more frequently in the CT than in the HCT arm (p<0.0005). The interval from CR to CT was 50 days and from CR to HCT 72 days (p<0.0005).Patients receiving related or unrelated matched/mismatched HCT had superior LFS than those receiving CT (32±5% vs. 13±4% at 8 years, respectively; p<0.0005). The difference was more distinct when only those patients with matched related or unrelated donors were compared to those receiving CT (36±6% vs. 13±4% at 8 years; p<0.0005). Similar figures were obtained for overall survival [OS, 35±5% matched/mismatched HCT vs. 24±4% for CT (p=0.18) and 41±6% for matched HCT patients vs. 24±4% for CT (p=0.09)]. RI was lower after HCT (40±5%) than after CT (79±5%; p<0.0001). In contrast, NRM was higher in HCT patients (28±7%) than in CT patients (9±11%; p<0.0001).Subpopulation analyses identified no difference in LFS and OS between matched related versus unrelated HCT. The difference in LFS between HCT and CT was highest in patients with normal karyotype, high risk cytogenetics and patients with non-monosomal karyotyp.Prognostic factors for LFS, OS, RI and NRM were analyzed in a multivariate analysis. Significant prognostic factors for LFS were cytogenetic risk (p=0.04), HCT (p=0.01) and FLT3 mutation status (p=0.07). OS was determined by cytogenetics p<0.01) with a trend for lower age (p=0.07) and HCT (p=0.14). Prognostic factors for RI were cytogenetics (p< 0.0006), FLT3 mutation status (p<0.03) and HCT (p<0.0005). NRM was influenced by HCT (p=0.002).Conclusions: HCT from related or unrelated donors improved LFS and OS in patients with AML over the age of 60 years and in particular in those with high risk cytogenetics or normal karyotype disease. The LFS of over 30% after 8 years achieved by HCT represents a marked improvement in the prognosis of patients with AML aged 60-75 years in CR1. DisclosuresAl-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Maschmeyer:Celgene: Consultancy.

CD4+ T-Cell STAT3 Activity Is Increased before Acute Graft-Versus-Host Disease Onset and Its Pharmacologic Inhibition Selectively Controls Alloresponses

STAT3 is a key mediator of inflammation, and is associated with murine auto- and alloreactivity. Germline and somatic activating STAT3 mutations have correlated with human inflammatory disorders, including colitis and polyendocrinopathy. STAT3 phosphorylation is required for pathogenic Th17 differentiation, and antagonizes beneficial Treg development. We show that CD4+ T-cell STAT3 activity is elevated early after allogeneic hematopoietic cell transplantation (HCT) compared with healthy non-HCT controls, and identifies patients at risk of developing grade II-IV acute graft-versus-host disease (GVHD) before the onset of symptoms. Using human in vitro and murine in vivo systems, we demonstrate that STAT3 phosphorylation may be selectively targeted with S3I-201 to suppress the alloresponse while preserving graft-versus-leukemia (GVL). Peripheral blood T-cells were obtained on day +21 from consented HCT recipients lacking any signs of acute GVHD (n=5 non-HCT controls, n=18 HCTs). T-cell STAT3 Y705 activity was stimulated with a pulse of IL-6 (4000 IU/ml, 15 minutes) and measured by flow cytometry. Patients were followed for acute GVHD onset from day +22 to day +100. While resting STAT3 activity was very low in all groups, stimulated CD4+ STAT3 phosphorylation significantly increased among the patients that later developed acute GVHD during the observation period (Fig 1 A: non-HCT control: 8.83%; n=10 grade 0-I: 28.8%; n=8 grade II-IV: 67.6% median pSTAT3+/CD4+; P<.05 and <.001; Fig 1 B: representative histograms show day +21 STAT3 activity in a patient that never acquired GVHD v a patient that later developed grade II GVHD at day +43). The absolute number of pSTAT3+ CD4+ T-cells on day +21 was also increased among the patients that acquired grade II-IV acute GVHD (grade 0-1: 45.5; grade II-IV: 83.5 CD4+ T-cells/ul; P<.05). The total absolute number of CD4+ T-cells, and number and degree of pSTAT3+ CD8+ T-cells, was similar among all HCT groups. We previously demonstrated that S3I-201 suppressed human DC-allostimulated T-cells, selectively polarized STAT5 activity while inhibiting STAT3, abrogated Th17 responses, and permitted the expansion of potent antigen-specific inducible Treg (Betts et al, Journal of Leukocyte Biology, 2014). We now show S3I-201 prevents GVHD in vivo, where Balb/c mice received myeloablative irradiation (850 cGy) followed by an allograft of T-cell depleted or replete (1x10e6) C57BL/6 bone marrow (5x10e6). S3I-201 (2.5mg/kg or DMSO control) was given i.p. from day 0 to +7. S3I-201 significantly delayed GVHD onset and improved survival (Fig 2, 10 mice/group, 0% v 56% alive at day +60, P<.0001, n=2). To determine the effect of S3I-201 on GVL, similarly transplanted Balb/c mice additionally received 2000 luciferase-expressing A20 cells. In this pilot experiment, median survival for the vehicle-treated BM-A20 and T cell-A20 groups was 26 days, 40.5 days for S3I-BM-A20, and not reached for S3I-T cell-A20 (67% alive at day +60). Bioluminescence (IVIS 200) remained undetectable in both the T cell-A20 and S3I-T cell-A20 groups during the experiment. Moreover, as mTOR and STAT3 signaling both influence Th17 differentiation we show that concurrent exposure of human T-cells to rapamycin and S3I-201 optimally suppresses RORgammaT expression and enhances allo-inactivation (Fig 3 A: P<.05, <.001, n=3, Fig 3 B: colorimetric proliferation assay, DC:T 1:30, P<.05, n=4). Ongoing experiments are underway to study the effect of combined rapamycin and S3I-201 on GVHD and GVL in vivo. Our preclinical data implicates STAT3 activation early in the onset of acute GVHD, where its selective inhibition with S3I-201 controls alloreactivity without untoward impairment of Treg or GVL. Future investigation of this approach will incorporate specific STAT3 inhibition with rapamycin to develop novel GVHD prevention strategies, and validate the association of STAT3 activity with acute GVHD risk in a large cohort of patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Up-Front Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Arising from the Myelodysplastic Syndrome

In patients with secondary acute myeloid leukemia (s-AML) arising from the myelodysplastic syndrome (MDS), treatment outcome is unsatisfactory. We compared up-front allogeneic hematopoietic cell transplantation (HCT) to induction chemotherapy (IC) as an initial treatment in patients with s-AML arising from MDS. This retrospective study included 85 patients who were diagnosed with s-AML arising from MDS; 11 patients proceeded to up-front HCT without IC (HCT group) and 74 received IC (IC group) as an initial treatment for s-AML, 28 of whom subsequently underwent HCT. In the IC group, 41.9% achieved complete remission (CR) compared to 81.8% in the HCT group (p = 0.013). The HCT group showed a significantly longer event-free survival (EFS) than the IC group (median 29.2 vs. 5.2 months, p = 0.042). Overall survival of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 vs. 7.6 months, p = 0.149). After adjustment for other clinical factors, outcome in the HCT group was significantly better than in the IC group in terms of CR rate (hazard ratio, HR, 11.195; p = 0.007) and EFS (HR, 0.384; p = 0.029). Up-front HCT is a viable option in s-AML arising from MDS if an appropriate donor is available. © 2014 S. Karger AG, Basel

Allogeneic Hematopoietic Cell Transplantation in Septuagenarians

Allogeneic Hematopoietic Cell Transplantation in Septuagenarians

Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials

BackgroundDespite advances in understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM) and availability of more effective therapies, MM remains incurable. The autologous-allogeneic (auto-allo) hematopoietic cell transplantation (HCT) strategy is based on combining cytoreduction from high-dose (chemo- or chemoradio)-therapy with adoptive immunotherapy. However, conflicting results have been reported when an auto-allo HCT approach is compared to tandem autologous (auto-auto) HCT. A previously published meta-analysis has been reported; however, it suffers from serious methodological flaws.MethodsA systematic search identified 152 publications, of which five studies (enrolling 1538 patients) met inclusion criteria. All studies eligible for inclusion utilized biologic randomization.ResultsAssessing response rates by achievement of at least a very good partial response did not differ among the treatment arms [risk ratio (RR) (95% CI) = 0.97 (0.87-1.09), p = 0.66]; but complete remission was higher in the auto-allo HCT arm [RR = 1.65 (1.25-2.19), p = 0.0005]. Event-free survival did not differ between auto-allo HCT group versus auto-auto HCT group using per-protocol analysis [hazard ratio (HR) = 0.78 (0.58-1.05)), p = 0.11] or using intention-to-treat analysis [HR = 0.83 (0.60-1.15), p = 0.26]. Overall survival (OS) did not differ among these treatment arms whether analyzed on per-protocol [HR = 0.88 (0.33-2.35), p = 0.79], or by intention-to-treat [HR = 0.80 (0.48-1.32), p = 0.39] analysis. Non-relapse mortality (NRM) was significantly worse with auto-allo HCT [RR (95%CI) = 3.55 (2.17-5.80), p < 0.00001].ConclusionDespite higher complete remission rates, there is no improvement in OS with auto-allo HCT; but this approach results in higher NRM in patients with newly diagnosed MM. At present, totality of evidence suggests that an auto-allo HCT approach for patients with newly diagnosed myeloma should not be offered outside the setting of a clinical trial.

Comparative Efficacy of Tandem Autologous Versus Autologous Followed by Allogeneic Hematopoietic Cell Transplantation in Patients with Multiple Myeloma: A Systematic Review and Meta-Analysis

Abstract 4519 Background:Despite advances in our understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM) coupled with availability of more effective therapies, it remains an incurable disease. Combining cytoreduction from high-dose (chemo- or chemoradio-) therapy with adoptive immunotherapy forms the basis of an autologous-allogeneic (auto-allo) hematopoietic cell transplantation (HCT) strategy. However, when an auto-allo HCT approach is compared to tandem autologous (auto-auto) HCT, conflicting results have been reported. Accordingly, we performed a systematic review of published studies comparing auto-auto HCT with auto-allo HCT in patients with newly diagnosed MM. Methods:A systematic search of MEDLINE thru Nov 5, 2011, and pertinent conference proceedings, was conducted. Included studies allocated newly diagnosed MM patients to auto-allo HCT if an HLA-matched sibling donor was available versus auto-auto if sibling donor was not available (biologic randomization). Independent, dual data extraction was performed. Pooling of data from similar outcomes was done using the random-effects model. Results:Our search identified 152 publications, of which five (manuscript=four, abstract=one) met inclusion criteria. The five included trials enrolled 1538 patients (auto-allo=565, auto-auto=973). At least a very good partial response was assessed in one study (522 patients) and did not differ among the treatment arms [risk ratio (RR) (95% CI) = 0.97 (0.87–1.09), p=0.66]; but complete remission, assessed in five studies (1130 patients), was higher in the auto-allo HCT arm [RR(95% CI) =1.65 (1.25–2.19), p=0.0005]. Event-free survival did not differ among auto-allo HCT group versus auto-auto HCT group on per-protocol analysis [hazard ratio (HR) (95% CI) = 0.78 (0.58–1.05)), p=0.11] of three trials (409 patients), or ITT analysis [HR(95% CI) = 0.83 (0.60–1.15), p=0.26] in three trials (1229 patients). Overall survival (OS) did not differ among these treatment arms whether analyzed on per-protocol [HR(95% CI) = 0.88 (0.33–2.35), p=0.79] in two trials (214 patients), or by ITT [HR(95% CI) = 0.80 (0.48–1.32), p=0.39] analysis in three trials (1229 patients). Non-relapse mortality (NRM) was worse with auto-allo HCT [RR(95%CI) = 3.55 (2.17–5.80), p<0.00001] in four trials (1047 patients). Conclusion:Despite higher CR rates, there is no apparent improvement in OS with auto-allo HCT; but this approach results in higher NRM in patients with newly diagnosed MM. Disclosures:No relevant conflicts of interest to declare.

IS5-5 - Immediate Allogeneic Hematopoietic Cell Transplantation (HCT) in Acute Myeloid Leukemia (AML) Arising from Myleodysplastic Syndrome (MDS)

ABSTRACT Background In treating secondary AML arising from MDS, the complete remission (CR) rate after standard induction chemotherapy is low and relapse is common without allogeneic HCT. We therefore analyzed the benefit of immediate allogeneic HCT versus induction chemotherapy in AML arising from MDS. Methods Between 1991 and 2010, 95 patients were diagnosed with AML arising from MDS. After the diagnosis of AML, 10 patients received supportive care only. This retrospective study involved analysis of data from remaining 85 patients; 11 proceeded to immediate allogeneic HCT without induction chemotherapy (HCT group) and 74 were treated with induction chemotherapy (IC group). Results Patient characteristics at AML diagnosis were similar between the HCT and IC groups except total leukocyte counts, which were higher in the IC group than the HCT group (P = 0.009). Patients in the IC group were initially treated with induction chemotherapy consisted mostly of cytarabine plus daunorubicin or idarubicin, while those in the HCT group received allogeneic HCT from HLA matched sibling donors (n = 7) or unrelated volunteers (n = 4). CR was achieved in thirty-one patients (41.9%) in the IC group and 9 (81.8%) in the HCT group (P = 0.013). Of 74 patients in IC group, 28 underwent allogeneic HCT in the first CR (n = 13), primary refractory disease (n = 10), or the first or second relapse (n = 5). The median overall survival (OS) and event-free survival (EFS) were 8.3 and 6.4 months, respectively. Relapse probability at 5 years was 49.2%. The HCT group showed a significantly longer EFS than the IC group (median 29.2 versus 5.2 months, P = 0.042). OS of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 versus 7.6 months, P = 0.149). Relapse probability was not significantly different between the two groups (P = 0.278). After adjustment for other variables, the HCT group showed significantly better outcomes than did the IC group in terms of CR rate (HR, 11.195; 95% CI, 1.940–64.619; P = 0.007) and EFS (HR, 0.384; 95% CI, 0.163–0.905; P = 0.029). Conclusions Immediate allogeneic HCT is a viable option in AML arising from MDS if an appropriate donor is available.

Immediate Allogeneic Hematopoietic Cell Transplantation (HCT) in Acute Myeloid Leukemia (AML) Arising From Myelodysplastic Syndrome (MDS)

Abstract 2031 Introduction:Treatment of secondary AML arising from MDS is unsatisfactory. Induction rate of complete remission (CR) is low with standard inuction chemotherapy regimen and relapse is common without allogeneic HCT. Immediate allogeneic HCT without induction chemotherapy can be an option if an appropriate donor is available in patients whose disease progress into AML from MDS. We intended to analyze the benefit of immediate allogeneic HCT versus induction chemotherapy in patients with AML arising from MDS. Methods:Between 1991 and 2010, 95 patients were diagnosed with AML that had evolved from antecedent MDS. After the diagnosis of AML, 10 patients received supportive care only. This retrospective study involved analysis of data from remaining 85 patients; 11 proceeded to immediate allogeneic HCT without induction chemotherapy (HCT group) and 74 were treated with induction chemotherapy (IC group). The clinical outcomes between the HCT group and the IC group were compared. Results:Median age was 48 years (range, 18–78). Patient characteristics at the time of AML diagnosis were similar between the HCT and IC groups except total leukocyte counts, which were higher in the IC group than the HCT group (P=0.009). Patients in the IC group were initially treated with induction chemotherapy consisted mostly of cytarabine plus daunorubicin or idarubicin, while those in the HCT group received allogeneic HCT from HLA matched sibling donors (n=7) or unrelated volunteers (n=4). Thirty-one patients (41.9%) in the IC group achieved CR with induction chemotherapy, whereas 9 (81.8%) in the HCT group achieved CR after HCT (P=0.013). Of 74 patients in IC group, 28 underwent allogeneic HCT in their disease status of the first CR (n=13), primary refractory disease (n=10), or the first or second relapse (n=5). The median follow-up duration for surviving patients was 8.2 months (range, 0.2–171.3). During this time, 62 patients died, 16 relapsed after CR, and 68 died or relapse. The median overall survival (OS) and event-free survival (EFS) were 8.3 and 6.4 months, respectively. Relapse probability at 5 years was 49.2%. The HCT group showed a significantly longer EFS than did the IC group (median 29.2 vs. 5.2 months, P=0.042). OS of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 vs. 7.6 months, P=0.149). Relapse probability was not significantly different between the two groups (35.7% vs. 53.1% at 5 years, P=0.278). After adjustment for other variables, the HCT group showed significantly better outcomes than did the IC group in terms of CR rate (HR, 11.195; 95% CI, 1.940–64.619; P=0.007) and EFS (HR, 0.384; 95% CI, 0.163–0.905; P=0.029). Conclusions:Immediate allogeneic HCT is a viable option in AML arising from MDS if an appropriate donor is available. Disclosures:No relevant conflicts of interest to declare.

Comparison of 5-Azacytidine Versus Allogeneic Hematopoietic Cell Transplantation In Elderly (≥ 60 years) Patients with De Novo High-Risk MDS - a Retrospective Matched Pair Analysis

AbstractAbstract 3500 Background:Myelodysplastic syndromes (MDS) are a disease of the elderly in whom until recently, allogeneic hematopoietic cell transplantation (HCT) has not been considered a reasonable therapeutic option. Best supportive care (BSC), only including transfusion support, has been the standard of care for the majority of these patients (pts). However, innovations in transplant protocols have changed that approach resulting in an increased frequency of allogeneic HCT. Further, several innovative non-transplant therapeutic modalities for MDS pts have been developed. In fact, treatment with DNA-methyltransferase inhibitors (MTI) such as 5-azacytidine (5-aza) has changed the natural course of the disease and prolonged median survival by an average of 9 months compared to BSC. However, allogeneic HCT is currently still the only modality with proven curative potential, although there has been no true randomized trial comparison of HCT to 5-aza therapy only. Methods:Consequently, we performed a retrospective analysis in 126 pts, 60 –77, (median 64) years of age with de novo high-risk MDS according to FAB classification (RAEB n=88, RAEB-t n=20, CMML n=18) undergoing allogeneic HCT at a median of 9 months from initial MDS diagnosis. Cytogenetics were available in 108 pts (good: n=63, intermediate: n=18, poor: n=27), resulting in IPSS classification (in 107 pts) of INT-1 (n=28), INT-2 (n=45) or HIGH (n=34). The ECOG was available in 125 pts, and was either 0 (19%), 1 (66%) or >1 (15%). Prior to HCT, most pts had progressed to a higher stage than present at diagnosis (RAEB n=45, RAEB-t n=10, CMML n=10, AML n=61), the median blast count in the marrow being 12%. Patients were prepared for HCT with one of several reduced (RIC, n=78) or more conventional intensity (n=48) conditioning regimens followed by stem cells from either related (n=50) or unrelated (n=76) donors.The outcome of this high-risk MDS cohort was compared to patients from the French (GFM) 5-aza patient registry matched for age, gender, prior induction chemotherapy, time from diagnosis to therapy (either HCT or 5-aza), disease stage and cytogenetics at diagnosis as well as at start of therapy. The groups could be well matched except for age (median age 5-aza: 67 vs. HCT: 64; p=0.001). Further, the HCT group included more pts with a higher ECOG score (ECOG>0: 81% vs. 59%; p=0.05) prior to start of therapy. Results:With a median follow-up of 20 months for surviving pts from the start of therapy the estimated 3-year overall survival (OS) was 39% (95% CI, 30% to 48%) for HCT and 7% (95% CI, 0 to 16%) for 5-aza, respectively. In multivariate Cox regression analysis, ECOG score (p<0.001), disease stage p=0.021), cytogenetic risk group (p=0.002) and type of treatment (5-aza vs. HCT HR: 1.8; p=0.003) were associated with survival. Conclusion:These retrospective data suggest that allogeneic HCT from related or unrelated donors, using various conditioning approaches, might offer a meaningful survival benefit compared to 5-aza in patients with high-risk MDS, even in the 7th decade of life. There is a need for prospective clinical trials in order to determine the place of this approach within the growing therapeutic opportunities for pts with MDS. Disclosures:Platzbecker:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ades:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) relapsing after allogeneic hematopoietic cell transplantation (HCT).

6539 Background: Disease relapse is a major cause of treatment failure after allogeneic HCT for AML and MDS. Therapeutic options after relapse are limited and the prognosis remains dismal. Methods: We analyzed 245 patients who received allogeneic HCT for MDS/AML using the conditioning regimen of fludarabine 40 mg/m2 and busulfan 130 mg/m2 for four days, between April 2001 and June 2008: 88 patients recurred. Results: Median age was 45 (range:18-66) years. Diagnosis was AML (n=72; 82%) or MDS (n=16; 18%). Donors were related (n=56) or unrelated (n=32). Relapse treatment: 21% (N=18) received supportive care only while 76% (N=67) received salvage (3 patients were lost to follow-up). Median complete remission (CR) duration after first HCT for the recurred group was 4 months; 67% of the patients relapsing <4 months received salvage treatment versus 90% of those that relapsed in >4 months (p=0.02). Salvage included: chemotherapy only (N=31), donor lymphocyte infusion (DLI) with or without chemotherapy (N=11), other (N=3), and second HCT with or without preceding salvage chemotherapy (n=22; 25%). Disease status at second HCT: CR2 (n=5) or active disease (n=17). Median survival after relapse was 3 months; 9 patients are alive (10%; 7 of 9 received second HCT. 2-year over all survival (OS) for second HCT and chemotherapy groups was 45% and 10%, respectively. Whereas 2-year OS was 0% for both DLI and supportive care only group. One-year OS was 45% (N=43) versus 10% (N=45) for patients whose post-transplant remission lasted >4 and <4 months, respectively (P=0.009). Conclusions: Survival after relapse is dictated primarily by post-transplant remission duration. A second HCT holds promise for long-term disease control in a subset of patients. 2-year OS 2-year OS Second allogeneic HCT 45% Chemotherapy 10% Donor lymphocyte infusion (DLI) 0% Supportive care only 0% CR duration after 1st HCT 1-year OS > 4 mo 45% < 4 mo 10% ü(p=0.009) No significant financial relationships to disclose.

Obesity Does Not Preclude Safe and Effective Myeloablative Hematopoietic Cell Transplantation (HCT) for Acute Myelogenous Leukemia (AML) in Adults

The incidence of excessive adiposity is increasing worldwide, and is associated with numerous adverse health outcomes. We compared outcomes by body mass index (BMI) for adult patients with acute myelogenous leukemia (AML) who underwent autologous (auto, n = 373), related donor (RD, n = 2041), or unrelated donor (URD, n = 1801) allogeneic myeloablative hematopoietic cell transplantation (HCT) using bone marrow or peripheral blood stem cells reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2004. Four weight groups by BMI (kg/m(2)) were defined: underweight <18 kg/m(2); normal 18-25 kg/m(2); overweight >25-30 kg/m(2); and obese >30 kg/m(2). Multivariable analysis referenced to the normal weight group showed an increased risk of death for underweight patients in the RD group (relative risk [RR], 1.92; 95% confidence interval [CI], 1.28-2.89; P = .002), but not in the URD group. There were no other differences in outcomes among the other weight groups within the other HCT groups. Overweight and obese patients enjoyed a modest decrease in relapse incidence, although this did not translate into a survival benefit. Small numbers of patients limit the ability to better characterize the adverse outcomes seen in the underweight RD but not the underweight URD allogeneic HCT patients. Obesity alone should not be considered a barrier to HCT.

Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia: Similar Efficacy of Non-Myeloablative and Myeloablative Conditioning; Long-Term Evaluation From the University of Minnesota.

Abstract 3385Poster Board III-273Allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) is increasingly utilized. We retrospectively analyzed outcomes of HCT for 43 patients with CLL at the University of Minnesota from February 1985 through March 2009 using myeloablative (MA, n=19) (total body irradiation [TBI] 1320 cGY in 8 fractions and cyclophosphamide [Cy] 60 mg/kg x 2 days) and non-myeloablative (NMA, n=24) preparative regimens (fludarabine 40 mg/m2 × 5 days or cladribine 50 mg/m2 IV with TBI 200cGy in 1 fraction and either oral busulfan [Bu] 8 mg/kg divided every 6 hours over 2 days or Cy 50 mg/kg x1 day). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine (CSA) and methotrexate in most MA patients and CSA and mycophenolate mofetil (MMF) for all NMA patients. Median follow up for survivors was 3.3 years. Nine-two percent of NMA HCT took place after 2000 whereas only 26% of MA HCTs happened during this time. Most patients were male (15/19 MA, 20/24 NMA). Time from diagnosis to treatment was nearly twice as long in NMA vs. MA patients (median 72 vs. 39 months) with MA patients progressing through a median of 3 regimens (range, 1-5) and NMA 4 (1-7). Poor-risk cytogenetics (11q-, 17p-) were found in 5 MA and 10 NMA patients. Seven and 13 patients were fludarabine refractory in the MA and NMA groups, respectively. Eighteen patients in the MA group had matched related donors (MRD), while only 10 MRD were amongst the NMA patients. Umbilical cord blood stem cells were used in 12 NMA patients. Neutrophil recovery was slightly faster after NMA HCT vs. MA (median 12.5 vs. 18.5 days; p=0.14). Incidence of acute GVHD, grades II-IV, was similar (p=0.11) but grades III-IV at day 100 was more frequent in the NMA than the MA group (33% vs. 5%, p=0.04). The chronic GVHD incidence was 43% (95% CI, 18-68%) in MA and 29% in NMA (11-47%, p=0.08) patients. Transplant-related mortality (TRM) at 1 year was 42% (20-64) in the MA arm vs. 25% (8-42) (p=0.34) for the NMA group. Relapse rates at 3 years were higher in the NMA HCT group (MA 18% [0-36] vs. NMA 26% [8-44]). Three-year progression-free survival (PFS) was similar in MA (33% [13-55]) and NMA (39% [19-58]) patients (p=0.61). Overall survival at three years was also similar (MA 37%, [15-60] vs. NMA 52%, [30-70]) (p=0.28). While these data suggest that dose intensity may affect TRM and relapse, NMA HCT yields equivalent and encouraging PFS and OS as compared to MA HCT. Our results support further investigation of the role of allogeneic transplantation in the treatment of high risk and advanced CLL. Disclosures:No relevant conflicts of interest to declare.