Hematopoietic Cell Transplantation Preparative Regimens Research Articles

Effects of Total Body Irradiation on Hematopoietic Cell Transplantation Outcomes in Pediatric Acute Myeloid Leukemia with Prior Central Nervous System Involvement

The implications of previous central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT) remain inadequately understood. Patients with CNS disease require more upfront CNS directed intrathecal therapy, but little is known about whether transplant conditioning regimens should be intensified or if previous CNS involvement impacts post HCT outcomes. While total body irradiation (TBI) remains standard for pediatric acute lymphoblastic leukemia myeloablative conditioning, it has been largely replaced with chemotherapy-only myeloablation in pediatric AML, primarily due to toxicity and late effects associated with TBI. In the setting of previous CNS involvement, it has been suggested that TBI-based myeloablation may have advantages due to superior CNS tissue penetration and thus decreased rates of AML relapse post HCT. We analyzed a publicly available dataset derived from the Center of International Blood and Marrow Transplantation Research (CIBMTR) registry to characterize the impact of TBI in HCT preparative regimens in pediatric AML patients with a history of CNS involvement. The study dataset was obtained from the CIBMTR data repository. The study cohort included patients aged ≤21 years who underwent initial allogeneic HCT with myeloablative conditioning for de novo AML in the first or second complete remission between 2008 and 2016, who provided consent for research. Patients with mismatched related donor transplant and non-calcineurin inhibitor graft-versus-host disease (GVHD) prophylaxis were excluded. The dataset was further modified by excluding patients with missing disease site data or those with non-CNS extramedullary disease. Patients were categorized as CNS-positive or -negative AML (AML-CNS(+) and AML-CNS(-), respectively) based on the disease status at diagnosis. Cox regression model and Fine Grey methods were employed to delineate the effects of TBI and CNS disease on key HCT outcomes. The study cohort comprised 550 pediatric AML patients, of which 25% (n =136) were AML-CNS(+). CNS involvement was more prevalent in patients aged 0-3 years, patients who were in the second complete remission, and those with a mismatched unrelated donor or umbilical cord blood. AML-CNS(+) patients demonstrated a lower relapse rate (hazard ratio [HR]: 0.50, 95% confidence interval: 0.33-0.76) compared to AML-CNS(-) patients, with comparable disease-free survival (DFS) and overall survival (OS) (p =0.10 and 0.20, respectively) in the two cohorts. The entire TBI treated cohort showed an association with increased risks of Grade 2-4 acute GVHD, bloodstream infections, and endocrine dysfunction. TBI use within the AML-CNS(+) cohort was associated with a lower relapse rate but increased risks of non-relapse mortality and a trend of higher grade 3-4 acute GVHD. In this population-based analysis of pediatric patients with de novo AML undergoing HCT, TBI-based conditioning regimens did not confer an advantage in DFS or OS compared to non-TBI regimens, irrespective of CNS disease status. However, TBI use was associated with increased risks of short- and long-term comorbidities. These findings underscore the need for careful consideration of TBI in pediatric AML.

Impact of Hematopoietic Cell Transplantation on Cardiovascular Risk Factors and Insulin Sensitivity

The use of hematopoietic cell transplantation (HCT) for treating malignant conditions in children has increased over the past five decades, leading to a growing population of long-term survivors.This population of childhood HCT survivors faces increased risks of adverse medical effects due to cancer treatments, including adverse cardiovascular disease (CVD) risk factors such as metabolic syndrome, insulin resistance. but the impact of exposure to HCT preparative conditioning regimen has not been clearly delineated. These risk factors, including obesity, dyslipidemia, hypertension, and insulin resistance (IR), are significant contributors to premature cardiovascular disease and represent a leading cause of non-relapse deaths in childhood cancer and HCT survivors. This study aimed to assess the early development of CVD risk factors and their relationship to insulin resistance in a large population of pediatric and young adult HCT survivors of childhood hematologic malignancies. The study compared their cardiovascular risk profiles, insulin resistance (measured by euglycemic hyperinsulinemic clamp studies), and body composition (determined by dual X-ray absorptiometry - DXA) with a cohort of sibling controls. We enrolled 151 HCT recipients (26.36 ±0.90 years at study enrollment; time since HCT of 2.6-31.5 years) and 92 sibling controls to complete at cardiovascular risk assessment including insulin sensitivity by hyperinsulinemic euglycemic clamp, anthropometry, body composition by dual X-ray absorptiometry, blood pressure, and serum biomarkers. We used linear models to test for mean differences in all continuous outcomes between survivors and siblings, accounting for intra-family correlations with generalized estimating equations. Recipients of HCT were found to have lower insulin sensitivity and more likely to have adverse CVD risk factors in comparison to their healthy siblings. Significantly higher percent fat mass and visceral adipose tissue, and significantly lower lean body mass were noted in HCT recipients than sibling controls despite having a similar body mass index between the two groups. Total body irradiation in the conditioning regimen was one of the strongest factors associated with lower insulin sensitivity, dyslipidemia and abnormal body composition leading to sarcopenic obesity. This study reveals that pediatric and young adult HCT survivors are more insulin resistant and have a higher prevalence of adverse cardiovascular risk factors compared to sibling controls. The presence of cardiovascular risk factors at a relatively young age raises concerns about an escalating trajectory of cardiovascular disease in this population. Therefore, regular monitoring of HCT survivors for cardiometabolic risk factors and early intervention will be crucial for preventing cardiovascular-related complications in the future. The findings underscore the importance of survivorship care for pediatric and young adult HCT survivors, with a focus on managing cardiovascular risk factors and promoting a healthy lifestyle to mitigate long-term adverse effects. Early identification and targeted interventions can significantly improve the long-term health outcomes of this vulnerable population, reducing the burden of cardiovascular disease and related complications.

Vascular Structure and Function in Cancer Survivors after Hematopoietic Stem Cell Transplantation

This study examined the effects of hematopoietic cell transplantation (HCT) and associated preparative regimens on vascular structure and function. Measures of carotid artery stiffness and brachial artery endothelial-dependent dilation were obtained in patients who had survived ≥ 2 years after HCT for hematologic malignancy and were diagnosed at ≤21 years. HCT survivors (n = 108) were examined: 66 received total body irradiation (TBI) alone or with a low-dose cranial radiation boost (TBI±LD-CRT), 19 received TBI plus high-dose cranial radiation (TBI+HD-CRT), and 23 received a chemotherapy-only preparative regimen (CHEMO). Siblings (n = 83) were invited to participate as control subjects. Although endothelial-dependent dilation did not differ between siblings and HCT survivors, carotid cross-sectional compliance, cross-sectional distensibility, diameter compliance, and diameter distensibility were greater in siblings than HCT survivors. Comparing the HCT preparative regimens, carotid cross-sectional compliance, cross-sectional distensibility, diameter compliance, diameter distensibility, and incremental elastic modulus were significantly lower in the TBI+HD-CRT group compared with siblings or with TBI±LD-CRT and CHEMO treatment groups. Cross-sectional distensibility and diameter compliance were significantly lower in the TBI±LD-CRT group compared with siblings. TBI±LD-CRT and CHEMO groups did not differ from each other in these vascular measures. HCT preparative regimens containing TBI+HD-CRT resulted in greater arterial decrements, indicating increased risk for cardiovascular disease.

Neurocognitive Trajectory of Patients with Childhood Cerebral Adrenoleukodystrophy Who Received Allogeneic Hematopoietic Cell Transplantation at an Early Stage of Cerebral Disease

Adrenoleukodystrophy (ALD) is an X-linked disorder of very long chain fatty acid metabolism which may manifest with adrenal gland and/or central nervous system disease. Thirty-five percent of affected boys develop cerebral involvement (cALD) during childhood. Characterized by progressive cerebral demyelination and resulting in devastating neurological and cognitive decline, cALD is usually fatal within years of clinically-evident disease. The only treatment known to enhance long-term survival and stabilize cerebral disease for boys with cALD is hematopoietic cell transplantation (HCT). It is well-established that the risk for negative long-term outcomes is significantly lower when HCT occurs at an earlier stage of cerebral white matter disease (ALD MRI severity score [Loes score] < 10). Nevertheless, there is limited knowledge of broad-based neurocognitive outcomes of patients transplanted with early-disease cALD. We studied all patients who underwent HCT for cALD at the University of Minnesota between January 1, 1991 and October 20, 2014. HCT preparative regimens varied with time, although most patients underwent myeloablative conditioning. Transplant allograft sources varied. Neurocognitive data were available for 63 patients who had a pre-transplant Loes MRI severity score < 10. Within this cohort, patients with less extensive cerebral disease (Loes ≤ 4) at the time of HCT had significantly higher scores on baseline tests of intellectual functioning than those with more cerebral involvement (Loes >4). This difference was particularly apparent on measures of nonverbal (visual) reasoning and processing speed. Furthermore, patients with more MRI-evident white matter disease at HCT showed more dramatic declines in neurocognitive test performance over time. In a subset of 20 patients who were followed for at least 4 years post-transplant, 15 patients (75%) demonstrated significant neurocognitive deficits (>1.5 SD below the mean) in at least one of the following domains: overall intellectual functioning (30%), attention (39%), verbal memory (33%), visual-motor integration (40%) and fine motor skills (58%). Results of this study provide evidence that within this patient group (boys undergoing HCT for cALD with Loes score < 10), patients have better neurocognitive outcomes when minimal cerebral disease is evident on neuroimaging prior to transplant. These data represent the largest analysis of cognitive outcomes in patients with early-disease cALD who underwent HCT. Our findings provide a benchmark for comparison to alternative or additional interventions for patients with cALD. Opportunities to enhance standard methods of detecting early cerebral disease and to intervene at the earliest possible stage of cALD should be explored. The emergence of newborn screening for adrenoleukodystrophy will provide avenues for improved pre-transplant monitoring and timing of intervention to preserve cognitive functioning and quality of life among patients with cALD. DisclosuresNo relevant conflicts of interest to declare.

Prognostic Significance of Pulmonary Function Test Abnormalities in Patients with Dyskeratosis Congenita

▪Introduction: Pulmonary fibrosis (PF) is a known complication in patients with dyskeratosis congenita (DC), reported in 15-20% of patients. PF is more common in older individuals with DC who may or may not have the classical clinical features of DC. PF in younger DC patients has been reported mainly in the setting of hematopoietic cell transplantation (HCT). There are no prospective studies of pulmonary function tests (PFT) in patients with DC.Objectives: To determine baseline pulmonary function status in patients with DC, association of PFT abnormalities with development or progression of pulmonary disease, and pulmonary outcomes in patients who did or did not receive HCT.Methods: DC patients older than 5 years of age underwent PFTs as part of a prospective IRB-approved cohort study at the NIH from 2002-2015. Data were obtained from spirometry [forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC)], lung volumes [total lung capacity (TLC)] and carbon monoxide diffusion capacity (DLCO). PFT abnormalities were classified as restrictive (normal FEV1/FVC and low TLC), obstructive (low FEV1/FVC and normal TLC) or mixed (low FEV1/FVC and low TLC) according to the American Thoracic Society Task Force guidelines. A low value was < lower limit of normal adjusted for age, sex, race and height. DLCO was also adjusted for hemoglobin. PFT data were analyzed in relation to the DC triad (nail dystrophy, skin pigmentation, leukoplakia), severe bone marrow failure (BMF needing treatment) and telomere length by flow FISH. Patients were followed through 2015. Pulmonary outcomes were compared in those with or without PFT abnormalities at evaluation and in those who did or did not receive HCT. P value <0.05 was significant.Results: Fifty-one patients with DC had PFTs, median age 19 yrs (range 6 - 69). Spirometry was abnormal in 16 patients (31%): 13 had restriction, 2 had obstruction, and 1 had a mixed pattern. DLCO was reduced (<80% of the predicted) in 32/49 patients (65%): 17 had mild (>60%), 13 had moderate (40-60%) and 2 had severely reduced (<40%) DLCO. All patients with abnormal spirometry had reduced DLCO compared with 18/35 (48%) with normal spirometry (p<0.0001). Patients with abnormal spirometry were more likely to have moderate/severe diffusion defects (10/16 vs 5/35; p=0.02), and severe BMF (12/16 vs 10/35; p=0.003) than those with normal spirometry. Telomere length and 2 or more features of the DC triad were not associated with PFT abnormality.Fourteen patients (27%) developed pulmonary disease at a median follow-up of 6 yrs (range 0.1 - 12 yrs) and a median age of 17 yrs (11 - 65): 10 had PF with interstitial honeycomb pattern on chest CT and 4 had pulmonary arteriovenous malformation (AVM) and mild fibrosis. Patients with abnormal spirometry and moderate/severely reduced DLCO were more likely to develop pulmonary disease than those with normal spirometry (12/16 vs 2/35; p<0.0001). Fourteen patients received a HCT (3 prior to and 11 after PFT evaluation) at a median age of 12 yrs (range 3 - 29). Eight of the 14 (57%) developed pulmonary disease 1 - 5 yrs after HCT (median 4 yrs) while 6/37 (16%) non-HCT patients developed PF (p=0.01). Transplanted patients developed pulmonary disease at a younger age than non-transplanted (median age 15 yrs, range 11 - 22 vs 54 yrs, 25 - 65; p=0.001), and had mutations in TINF2 (n=3), RTEL1, DKC1, WRAP53 (1 each); gene unknown (n=2). DC genes mutated in older non-HCT patients with PF were TERC (n=4), TERT (n=1), and unknown (n=1). The independent impact of severe DC phenotype, BMF, and HCT on pulmonary outcome could not be distinguished in young patients as most patients with severe disease had BMF and received HCT. There was no difference in PF among those who did or did not receive radiation for HCT. Four of the 10 deaths were due to PF.Conclusion: More than 30% of patients with DC have restriction and moderate/severe diffusion defect on PFTs, and these are more common in patients with severe BMF. PFT abnormalities are significantly associated with progression to PF, although they may also signal the presence of AVMs, a less common pulmonary manifestation of DC. PF in older patients is a known manifestation of the telomere biology disorder. It is unclear whether pulmonary disease in young patients is a feature of severe DC or the toxicity of HCT preparative regimens. Larger prospective studies are needed to confirm the predictive value of PFTs for future lung disease in patients with DC. DisclosuresNo relevant conflicts of interest to declare.

Pilot experience with opebacan/rBPI 21 in myeloablative hematopoietic cell transplantation

Bacterial infection and inflammation contribute significantly to the morbidity and mortality of myeloablative allogeneic hematopoietic cell transplantation (HCT). Endotoxin, a component of the outer membrane of Gram-negative bacteria, is a potent inflammatory stimulus in humans. Bactericidal/permeability increasing protein (BPI), a constituent of human neutrophil granules, binds endotoxin thereby precluding endotoxin-induced inflammation and also has direct anti-infective properties against bacteria. As a consequence of myeloablative therapy used in preparation for hematopoietic cell infusion, patients experience gastrointestinal leak of bacteria and bacterial toxins into the systemic circulation and a period of inflammatory cytokine elevation associated with subsequent regimen-related toxicities. Patients frequently become endotoxemic and febrile as well as BPI-deficient due to sustained neutropenia. To examine whether enhancing endotoxin-neutralizing and anti-infective activity by exogenous administration of a recombinant N-terminal fragment of BPI (rBPI 21, generic name opebacan) might ameliorate regimen-related toxicities including infection, we recruited patients scheduled to undergo myeloablative HCT to participate in a proof-of-concept prospective phase I/II trial. After the HCT preparative regimen was completed, opebacan was initiated 18-36 hours prior to administration of allogeneic hematopoietic stem cells (defined as Day 0) and continued for 72 hours. The trial was to have included escalation of rBPI 21 dose and duration but was stopped prematurely due to lack of further drug availability. Therefore, to better understand the clinical course of opebacan-treated patients (n=6), we compared their outcomes with a comparable cohort meeting the same eligibility criteria and enrolled in a non-interventional myeloablative HCT observational study (n = 35). Opebacan-treated participants had earlier platelet engraftment (p=0.005), mirroring beneficial effects of rBPI 21 previously observed in irradiated mice, fewer documented infections (p=0.03) and appeared less likely to experience significant regimen-related toxicities (p=0.05). This small pilot experience supports the potential utility of rBPI 21 in ameliorating HCT-related morbidity and merits further exploration.

Pilot experience with opebacan/rBPI 21 in myeloablative hematopoietic cell transplantation.

Bacterial infection and inflammation contribute significantly to the morbidity and mortality of myeloablative allogeneic hematopoietic cell transplantation (HCT). Endotoxin, a component of the outer membrane of Gram-negative bacteria, is a potent inflammatory stimulus in humans. Bactericidal/permeability increasing protein (BPI), a constituent of human neutrophil granules, binds endotoxin thereby precluding endotoxin-induced inflammation and also has direct anti-infective properties against bacteria. As a consequence of myeloablative therapy used in preparation for hematopoietic cell infusion, patients experience gastrointestinal leak of bacteria and bacterial toxins into the systemic circulation and a period of inflammatory cytokine elevation associated with subsequent regimen-related toxicities. Patients frequently become endotoxemic and febrile as well as BPI-deficient due to sustained neutropenia. To examine whether enhancing endotoxin-neutralizing and anti-infective activity by exogenous administration of a recombinant N-terminal fragment of BPI (rBPI 21, generic name opebacan) might ameliorate regimen-related toxicities including infection, we recruited patients scheduled to undergo myeloablative HCT to participate in a proof-of-concept prospective phase I/II trial. After the HCT preparative regimen was completed, opebacan was initiated 18-36 hours prior to administration of allogeneic hematopoietic stem cells (defined as Day 0) and continued for 72 hours. The trial was to have included escalation of rBPI 21 dose and duration but was stopped prematurely due to lack of further drug availability. Therefore, to better understand the clinical course of opebacan-treated patients (n=6), we compared their outcomes with a comparable cohort meeting the same eligibility criteria and enrolled in a non-interventional myeloablative HCT observational study (n = 35). Opebacan-treated participants had earlier platelet engraftment (p=0.005), mirroring beneficial effects of rBPI 21 previously observed in irradiated mice, fewer documented infections (p=0.03) and appeared less likely to experience significant regimen-related toxicities (p=0.05). This small pilot experience supports the potential utility of rBPI 21 in ameliorating HCT-related morbidity and merits further exploration.

Radioimmunotherapy-Based Conditioning with Yttrium-90 Ibritumomab Tiuxetan Plus High Dose BEAM for Non-Hodgkin Lymphoma: Does the Regimen Matter?

Background: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) has played an important role in the treatment of relapsed or refractory non-Hodgkin lymphoma (NHL). Several studies demonstrate that standard-dose 90Y ibritumomab tiuxean (0.4 mci/kg) (Zevalin) plus high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (ZBEAM) is a well-tolerated HCT preparative regimen. Herein we report the outcomes of a prospective single-arm phase II study of ZBEAM conditioning in three CD20+ NHL histologic strata: mantle cell (MCL), diffuse large B cell (DLBCL), and follicular (FL)/transformed (TF). The study was designed to detect a 20% improvement in PFS, within each stratum, over historical rates for BEAM alone at 2-years post HCT with ~80% power, α=0.05.Patients and Methods: Patients with histologically confirmed CD20+ MCL, DLBCL, FL, or TF were eligible if they failed induction therapy, had relapsed disease or poor risk disease (Table 1). Patients with DLBCL or FL were classified as poor risk if they failed to achieve a complete response after induction chemotherapy or had high-/high-intermediate-risk features per the age-adjusted International Prognostic Index (IPI) at diagnosis. All MCL and TF lymphomas were considered poor risk, including those in first remission.Results: The median follow-up for surviving patients: 43 months (range: 3-79). The estimated PFS and overall survival (OS) probabilities at 3 years were between 47-75% and 82-91%, respectively (Table 2); non-relapse mortality (NRM) was <1% overall. Adverse events ≥ grade 3 within the first 100-days included grade 3 infection (n=8) per CTCAE 3.0, grade 3 GI toxicity (n=1) per Bearman Toxicity Scale and grade 4 infection (n=1) per CTCAE 3.0.Conclusion: Across histologies, high OS and low NRM confirm the safety and tolerability of the regimen, while improvements in 2-year PFS compared to historical controls in DLBCL and MCL are notable1-4 leading us to conclude that, in the case of MCL and DLBCL, RIT based conditioning improves outcome compared to high dose chemotherapy alone. The strikingly high PFS within the DLBCL subgroup, even though this strata had the highest percentage of induction failure patients serve as a basis for an ongoing multinational randomized phase III trial comparing ZBEAM to BEAM for the treatment of relapsed/ IF DLBCL.Table 1Patient and Disease Characteristics (#/% or median/range)VariableAll N = 116MCL N = 32DLBCL N = 46FL N = 20TF N = 18Disease status at HCT 1st complete remission 1st partial remission 1st relapse 2nd complete remission ≥3rd complete remission Induction failure29 (25) 7 (6) 20 (17) 20 (17) 3 (3) 37 (32)23 (72) 4 (13) 0 (0) 1 (3) 0 (0) 4 (13)4 (9) 1 (2) 8 (17) 12 (26) 0 (0) 21 (46)0 (0) 1 (5) 6 (30) 4 (20) 1 (5) 8 (40)2 (11) 1 (6) 6 (33) 3 (17) 2 (11) 4 (22)Prior regimens2 (1-7)1 (1-3)2 (2-7)3 (1-4)2 (1-3)Age at transplant, yr57 (23-75)60 (43-72)48 (23-75)57 (43-67)58 (41-65)Maintenance rituximab No Yes N/Aa103 (89) 12 (10) 1 (1)23 (72) 9 (28) 0 (0)44 (96) 2 (4) 0 (0)20 (100) 0 (0) 0 (0)16 (89) 1 (6) 1 (6)Abbreviations: MCL, mantle cell lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; TF, transformed lymphoma; HCT, hematopoietic cell transplantation; N/A, not available. a) The follow-up time for 1 patient had not reached Day +30 post-HCT at the time the analytical data were locked.Table 2Outcomes, % (95% CI)AllbN = 115MCL N = 32DLBCL N = 46FL/TF, combinedbN = 20/17, 37BEAM, historical estimates: 2-yr PFSN/A354545/35, 40ZBEAM, trial estimates: 2-yr PFS70 (61-78)78 (57-89)78 (62-87)54 (30-73)/57 (31-77), 56 (38-70)3-yr PFS66 (56-74)69 (54-79)75 (63-83)47 (36-58)/57 (42-70), 52 (35-67)3-yr OS85 (77-91)91 (72-98)83 (70-90)85 (65-94)/82 (60-92), 83 (67-92)Abbreviations: PFS, progression-free survival; OS, overall survival. b) At the time of abstract submission, the follow-up time for 1 of the 116 patients was not sufficient for outcomes to be reported (<100 days post-HCT).References 1) Mills W, et al. J Clin Oncol 1995;13:588-595. 2) Shimoni A, et al. Cancer 2012;118:4706-4714. 3) Kolstad A et al. Blood 2014;123:2953-2959. 4) Berger MD et al. Hematol Oncol 2015; doi:10.1002/hon DisclosuresKrishnan:celgene: Consultancy, Equity Ownership, Speakers Bureau; millennium: Speakers Bureau; onyx: Speakers Bureau; jannsen: Consultancy; jazz: Consultancy; spectrum: Consultancy. Off Label Use: Zevalin combined with BEAM. Nademanee:Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics Inc.: Research Funding; Spectrum: Research Funding. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau. Forman:Mustang: Research Funding; Amgen: Consultancy.

Abstract 12011: Vascular Function in Leukemia Survivors After Hematopoietic Cell Transplantation

Introduction: Previously, we have documented the effects of radiation and/or chemotherapy on vascular structure and function in childhood cancer survivors. To date, little is known about the effects on vascular health of the hematopoietic cell transplantation (HCT) preparative regimen (total body irradiation [TBI] and high dose chemotherapy) that often accompanies this treatment. Hypothesis: HCT preparative regimens utilizing TBI would result in a decrement in arterial function in HCT survivors than those that did not utilize TBI. Methods: Measures of carotid artery stiffness (compliance, distensibility) and intima-media thickness (cIMT) were obtained from ultrasound imaging in patients who had survived &gt;2 years after HCT for hematologic malignancy and were diagnosed at age &lt;21 yrs. Siblings (n=122) were invited to participate as controls. A total of 87 HCT survivors were examined; 50 received TBI only, 17 received TBI plus central nervous system irradiation (TBI+CNS); another 20 received a chemotherapy only preparative regimen ([CHEMO], most busulfan + cyclophosphamide). Results: Although cIMT did not differ between siblings and HCT survivors, both carotid cross-sectional compliance (CSD) and carotid diameter distensibility (DD) were greater in siblings than HCT survivors (Table). Comparing the different HCT preparative regimens, cIMT did not differ significantly between siblings and the three preparative regimen groups. However, both CSD and DD were significantly lower in TBI+CNS and TBI subjects compared to siblings. Also, carotid incremental elastic modulus (IEM) was significant higher in TBI+CNS than in the TBI only, CHEMO, and sibling groups. Conclusion: These results demonstrate that HCT preparative regimens containing TBI result in greater arterial decrements indicating increased risk for premature atherosclerosis and cardiovascular disease. The addition of CNS radiation to TBI results in further decrements in arterial function.

Full Donor Myeloid Engraftment with Minimal Toxicity in Dyskeratosis Congenita Patients Undergoing Allogeneic Bone Marrow Transplantation without Radiation or Alkylating Agents

Dyskeratosis congenita (DC) is an inherited bone marrow failure (BMF) syndrome caused by defects in telomere biology genes. BMF occurs in approximately 80% of patients by 30 years of age and, in addition to pulmonary failure and malignancies, remains a major contributor to mortality. Hematopoietic cell transplantation (HCT) cures BMF in DC patients but is associated with a high incidence of graft failure and transplant-related mortality. Radiation and/or alkylating agents (e.g. cyclophosphamide, busulfan, melphalan) used in conditioning may have a role in the poor outcomes in DC patients following HCT. Recently, reduced-intensity conditioning approaches have improved short-term outcomes, but concerns remain about the long-term effects of DNA damaging agents in these regimens, given the multisystem disease and lifelong predisposition to malignancy conferred by telomere dysfunction.Radiation and alkylating agents are mainstays of allogeneic HCT preparative regimens: their highly effective myeloablative and immunosuppressive properties provide a niche for donor hematopoietic progenitors and decrease graft rejection. Based on a rationale that presumes (1) niche availability in DC patients with BMF, and (2) an intrinsic replicative defect in DC hematopoietic cells, we hypothesized that engraftment would be feasible in DC patients using a regimen of immunosuppressive therapy alone.Here, we report that in a single-institution prospective study, 4 consecutive patients with DC have undergone successful HCT using a radiation- and alkylator-free preparative regimen. Patients received alemtuzumab and fludarabine, followed by bone marrow transplantation (BMT) from unrelated donors. Cyclosporine A and mycophenolate mofetil were used for graft versus host disease (GVHD) prophylaxis. The primary outcome measures were neutrophil engraftment at day +30 and overall survival at day +100. Secondary outcome measures included acute toxicities and rates of graft failure, infections, and GVHD.The first two patients were 18 month-old twins with TINF2 mutations and transfusion-dependent BMF who received a BMT from a fully HLA-matched unrelated donor. The third patient was an 18 year-old female with CTC1 mutations and transfusion-dependent BMF, who underwent a B-mismatched unrelated donor BMT. The fourth patient, a 22 year-old male with clinical DC and short telomeres, had significant pulmonary disease (diffusing capacity of lung for carbon monoxide 28% of predicted) and BMF, and underwent a fully HLA-matched unrelated donor BMT.All 4 patients engrafted neutrophils by day +30, and are alive and well with follow-up ranging from 6 months (1 patient) to 2 years (3 patients). Platelet transfusion-independence occured between day +4 to +18, and red cell transfusion-independence occured between day 0 to +90. No patients required transfusions thereafter. All patients showed full donor myeloid chimerism by day +60. 3 of 4 patients showed full donor lymphoid chimerism by year 2; the fourth patient has high and increasing mixed donor lymphoid chimerism (60%) at day +180. There were no significant, unexpected toxicities, bacterial or fungal bloodstream or tissue infections. All patients were monitored weekly by serum PCR for CMV, EBV, adenovirus and HHV6 until day +100; only one patient showed CMV reactivation which was controlled with pre-emptive ganciclovir therapy. There was no acute GVHD. Only one patient developed chronic GVHD with limited skin involvement controlled with topical steroids.These results provide promising early data for engraftment and a favorable short-term toxicity profile using a radiation- and alkylator-free conditioning regimen in HCT for BMF due to DC. This approach could spare DC patients the acceleration of non-hematologic complications and malignancies, which has been attributed to HCT, and improve long-term survival. The limited toxicity of the alemtuzumab/fludarabine regimen may also allow patients with severe disease-related co-morbidities such as pulmonary dysfunction to safely undergo HCT. To our knowledge, this is the first prospective HCT study to achieve full donor myeloid engraftment in a series of patients following conditioning without radiation or alkylating agents. DisclosuresOff Label Use: alemtuzumab - conditioning for bone marrow transplantation fludarabine - conditioning for bone marrow transplantation cyclosporine A - graft versus host disease prophylaxis in bone marrow transplantation mycophenolate mofetil - graft versus host disease prophylaxis in bone marrow transplantation.

Quantitative Significance of Minimal Residual Disease Before Myeloablative Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in First and Second Complete Remission

AbstractAbstract ▪655▪This icon denotes a clinically relevant abstract Background:Minimal residual disease (MRD), detectable by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT), is associated with increased relapse and lower disease-free survival (DFS) and overall survival (OS) in acute myeloid leukemia (AML) in first complete remission (CR1). As the relationship between MRD and outcome is less studied for patients in second CR (CR2), we assessed whether this association is similar to that seen in CR1 patients, and examined the impact of MRD levels on outcome. Patients and Methods:We studied 253 consecutive patients (median age: 43.1 [range: 0.6–72.6] years) receiving myeloablative HCT for AML in first (n=183) or second (n=70) CR or CR with incomplete blood count recovery (CRi) between May 2006 and November 2011. Pre-HCT bone marrow aspirates were obtained in all patients and analyzed by routine karyotyping and ten-color MFC. MRD was identified as a cell population showing deviation from normal antigen expression patterns as compared with normal or regenerating marrow. Any level of residual disease was considered MRDpos. Data are current as of August 6, 2012. Results:Before HCT, 85.7% of patients met morphological criteria for CR, whereas 14.3% had CRi. Thirty-six (19.7%) patients in CR1 and 18 (25.7%) patients in CR2 had MRD (MRDpos) as determined by MFC, with median of 0.29% (range: 0.007–7.8%) and 0.41% (0.05–3.5%) abnormal blasts for MRDpos CR1 and CR2 patients. Among CR1 patients, the 3-year estimates of OS where 73% (64–80%) and 27% (10–47%) for MRDneg and MRDpos patients, respectively; among CR2 patients, 3-year OS was estimated to be 71% (55–82%) and 47% (23–69%), respectively (Figure 1). Three-year estimates of relapse among CR1 patients were 21% (14–28%) and 59% (41–73%), respectively, and 20% (9–32%) and 68% (37–86%), respectively, among CR2 patients. This relatively similar outcome for CR1 and CR2 patients may be at least partly accounted for by more favorable cytogenetic risk profile of the leukemias in patients transplanted in CR2 (favorable-risk: 22.9% vs. 3.3%; adverse-risk leukemias: 11.4% vs. 26.2%; secondary AML: 8.6% vs. 34.4%). The risk of death for patients who were MRDpos was 3.27-times that among patients who were MRDneg (95% CI, 2.11–5.05; p<0.0001), and the risk of relapse was also increased (hazard ratio [HR]=5.46 [3.39–8.81], p<0.0001). The association of MRD with outcome among patients in CR1 is similar to that among patients in CR2 (p=0.46, p=0.48 tests of interaction for mortality, relapse). If MRD was modeled as a continuous linear variable, both the risk of death and the risk of relapse increased as MRD increased (p=0.001, p<0.0001). Categorizing MRD levels as 0 (n=199), 0.1% or less (n=14), >0.1–1% (n=24), and >1% (n=16), the risk of death increased with each increasing level of MRD relative to the MRDneg group (Figure 2), but the magnitude was fairly similar across all MRDpos groups (HR=2.69, HR=2.96, HR=4.41), and the lowest level of MRD (0.1% or less) was not statistically significantly different from the highest level of MRD (>1%, p=0.30). Similarly, the risks of death in the three MRDpos groups relative to the MRDneg group were HR=5.24, HR=4.32, and HR=8.67, and the difference between the groups with the lowest and highest levels of MRD were not statistically significant (p=0.28). Adjustment for cytogenetic risk, CR duration, pre-HCT karyotype, pre-HCT blood count recovery, and the HCT preparative regimen led to the same qualitative results. Conclusion:The negative impact of MRD on outcome among AML patients in CR2 is similar to the negative impact seen in patients in CR1. Our data indicate that outcomes of MRDneg AML patients are excellent after myeloablative HCT in either CR1 or CR2. Even patients with minute amounts of MRD (0.1% or less) have significantly worse outcomes than MRDneg patients. Patients with higher levels of MRD (>1%) had worse outcome than those with minute amounts, but the limited number of MRDpos patients limit the power to detect statistically significant differences between these groups. The poor outcome of MRDpos patients provides the rationale for studies investigating whether cure rates could be improved by MRD-directed therapy before, during, or after HCT. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Hematopoietic Bone Marrow Transplantation (BMT) for Patients with High-Risk Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), or Myelodysplastic Syndrome (MDS) Using HLA-Haploidentical Related Donors: A Trial Using Radiolabeled Anti-CD45 Antibody Combined with Immunosuppression Before and After BMT

Abstract 4164Patients with advanced leukemia or high-risk MDS undergoing conventional hematopoietic cell transplantation (HCT) have a significant risk of both relapse and non-relapse mortality. We previously conducted a series of studies in patients with high-risk AML, ALL or MDS using radiolabeled anti-CD45 antibody as part of an allogeneic HCT preparative regimen employing HLA-matched donors. This approach has made it possible to deliver high doses of radiation relatively specifically to sites of disease while sparing normal organs. This advance may also allow us to maximize the anti-tumor effect and minimize toxicity of a preparative regimen. We have now extended this therapeutic strategy to patients without HLA-matched donors, often patients of mixed ethnicity or belonging to ethnic minority groups. We and others have utilized a combination of immunosuppressive agents, including cyclophosphamide (CY) administered before and after HCT with non-T-cell depleted bone marrow (BM) from HLA-haploidentical donors, to facilitate engraftment and delete highly alloreactive T-cell clones presumably involved in graft-versus-host disease (GvHD). We report a Phase I/II study using 131I-BC8 antibody at escalating doses in combination with a less toxic reduced-intensity conditioning regimen in the setting of haploidentical BMT.This dose escalation study was designed to determine the maximum tolerated dose of 131I-anti-CD45 (BC8) antibody that can be combined with fludarabine (FLU) and 2Gy total body irradiation (TBI) in addition to pre-and post-BMT CY. Ten patients over 18 years of age with advanced AML, ALL or high-risk MDS (>5% blasts) have been treated with a median of 508 mCi (range: 300–818) of 131I delivering a median of 7.9 Gy (range: 1.8–42) to the BM, a median of 74.6 Gy (range: 45.6–178.8) to the spleen, and a median of 15.8 Gy (range: 12.2–22.1) to the liver (does-limiting organ). Patients then received FLU (30 mg/m2 daily for 5 days), 2 Gy TBI, CY (14.5 mg/kg daily for 2 days), and HLA-haploidentical BM grafts, with GvHD prophylaxis consisting of post-transplant CY, tacrolimus and mycophenolate mofetil. The median age of patients was 47.2 years (range: 31–64). Six patients had AML: one patient was in second complete remission, 2 patients had MDS that progressed to AML, 2 had primary refractory disease, and 1 patient had relapsed after previous HCT. One patient had high-risk MDS, one patient had ALL in second remission with minimal residual disease (MRD) and two patients had CML presenting in blast crisis (one in myeloid blast phase and one in lymphoid blast phase). All AML patients had intermediate or high-risk disease by cytogenetic and molecular criteria. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a complete remission in all 10 patients, and 8 had 100% donor CD3+ and CD33+ cell engraftment by day 28 post-transplant. The remaining 2 patients were not tested on day 28, however they achieved 100% donor CD3+ and CD33+ by day 56 chimerism evaluation. The absolute neutrophil count surpassed 500/μL at a median of 14 days (range: 12–16) after BMT, and platelets became self-sustained at ≥ 20,000/μL at a median of 22 days (range: 12–35) after BMT. Four patients are surviving relapse-free for a median of 2.8 years (range: 1.6–4.2) after BMT. Five patients experienced disease relapse at 1.8 to 10.7 months after transplant. The overall day-100 non-relapse mortality was 10%, with one death attributed to sepsis in the setting of steroid-refractory GvHD. This study demonstrates that, in addition to a reduced intensity transplant regimen, 131I labeled anti-CD45 antibody can deliver an average of 14.2 Gy of targeted radiotherapy to BM, and an average of 89.2 Gy to the spleen, without a marked increase in 100-day mortality. The maximum tolerated dose of absorbed radiation has not been estimated, and we continue to escalate the radiation dose, with the most recently enrolled patient receiving 24Gy to the liver. This study shows that anti-CD45 radioimmunotherapy yields encouraging results with haploidentical BMT for patients who lack an HLA-matched donor. Disclosures:No relevant conflicts of interest to declare.

Pharmacological Immunosuppression Reduces But Does Not Eliminate the Need for Total-Body Irradiation in Nonmyeloablative Conditioning Regimens for Hematopoietic Cell Transplantation

In the dog leukocyte antigen (DLA)-identical hematopoietic cell transplantation (HCT) model, stable marrow engraftment can be achieved with total-body irradiation (TBI) of 200 cGy when used in combination with postgrafting immunosuppression. The TBI dose can be reduced to 100 cGy without compromising engraftment rates if granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMC) are infused with the marrow. T cell-depleting the G-PBMC product abrogates this effect. These results were interpreted to suggest that the additional T cells provided with G-PBMC facilitated engraftment by overcoming host resistance. We therefore hypothesized that the TBI dose may be further reduced to 50 cGy by augmenting immunosupression either by (1) tolerizing or killing recipient T cells, or (2) enhancing the graft-versus-host (GVH) activity of donor T cells. To test the first hypothesis, recipient T cells were activated before HCT by repetitive donor-specific PBMC infusions followed by administration of methotrexate (MTX) (n = 5), CTLA4-Ig (n = 4), denileukin diftitox (Ontak; n = 4), CTLA4-Ig + MTX (n = 8), or 5c8 antibody (anti-CD154) + MTX (n = 3). To test the second hypothesis, recipient dendritic cells were expanded in vivo by infusion of Flt3 ligand given either pre-HCT (n = 4) or pre- and post-HCT (n = 5) to augment GVH reactions. Although all dogs showed initial allogeneic engraftment, sustained engraftment was seen in only 6of 42 dogs (14% of all dogs treated in 9 experimental groups). Hence, unless more innovative pharmacotherapy can be developed that more forcefully shifts the immunologic balance in favor of the donor, noncytotoxic immunosuppressive drug therapy as the sole component of HCT preparative regimens may not suffice to ensure sustained engraftment.

Chimerism Analysis Is Predictive of Relapse-Free Survival After Allogeneic Transplantation for MDS

AbstractAbstract 1332Chimerism analysis permits evaluation of the extent of donor engraftment following allogeneic hematopoietic cell transplantation (HCT) via differentiation between donor- and recipient-derived cells. Though relapse remains a major cause of treatment failure post-HCT for hematologic malignancies, the clinical utility of chimerism analysis for the early detection of morphologic relapse varies between different diseases and remains controversial. The predictive value of chimerism analysis for relapse rates and mortality in myelodysplastic syndromes (MDS) is not well-described. We reviewed serial chimerism results for 72 consecutive patients (pts) who underwent allogeneic HCT for MDS between 1999 and 2009; 9 pts were excluded from analysis due to lack of appropriately timed chimerism studies. Donor engraftment was initially assessed 28 days post-HCT and then at 2-week intervals through day 100. Chimerism studies were performed with peripheral blood using a short tandem repeat assay by PCR-based analysis. Acute and chronic GVHD rate, relapse-free survival (RFS), and overall survival (OS) were assessed for patients with donor leukocyte chimerism and T-cell chimerism ≥95% and <95%. The median age was 51 years (range 20–70) and 52% were male. The median time from MDS diagnosis to HCT was 5.4 months; 9 pts (14%) were in complete remission at the time of HCT, 11 (18%) were in partial remission, 17 (27%) had relapsed or refractory disease, and 26 (41%) were untreated. HCT-comorbidity index was low in 25 pts (40%), intermediate in 18 (29%), and high in 20 (32%). 31 pts (49%) received sibling donor HCT and the remainder received an unrelated donor graft. 40 (63%) received bone marrow and 23 (37%) received peripheral stem cells. Myeloablative (MA) busulfan- or cyclophosphamide-based preparative regimens were used in 47 pts (75%) and a non-myeloablative (NMA) regimen with fludarabine and TBI was given to the remaining pts. 61 pts achieved ≥95% donor leukocyte chimerism at a median of 29 days and 39 evaluable pts achieved ≥95% donor T-cell chimerism at a median of 42 days. Two pts did not achieve donor leukocyte chimerism ≥95% and 9 did not achieve donor T-cell chimerism ≥95% at any timepoint. Univariable analysis of prognostic factors for relapse showed that donor leukocyte chimerism ≥95% was significantly associated with lower probability of relapse (hazard ratio [HR] 0.11, 95% confidence interval [CI] 0.02–0.51, p=.005), whereas prior exposure to radiation therapy (excluding exposure during HCT preparative regimen) was associated with increased probability of relapse (HR 3.48, 95% CI 1.14–10.60, p=.028). Multivariable analysis implicated donor leukocyte chimerism <95% as the only independent risk factor for relapse. Transplant type (MA vs NMA) and cell source did not significantly impact the likelihood of relapse. Donor leukocyte chimerism ≥95% was not associated with acute or chronic GVHD. Univariable analysis of risk factors for survival showed that donor leukocyte chimerism ≥95% was associated with improved RFS (HR 0.29, 95% CI 0.09–0.97, p=.045) but not OS, both findings of which were confirmed on multivariable analysis. Donor T-cell chimerism ≥95% was not significant in univariable analysis; however, in multivariable analysis, controlling for comorbidity scores, donor T-cell chimerism <95% was associated with lower risk of chronic GVHD (HR 0.18, 95% CI 0.04–0.88, p=.034) but did not significantly impact relapse, RFS, or OS. In conclusion, achievement of a high donor leukocyte chimerism post-HCT for MDS is associated with improved RFS. Donor T-cell chimerism, however, is not predictive of outcome and its routine use for MDS pts should be reevaluated. Pts with donor leukocyte chimerism <95% might be considered for immunologic interventions such as withdrawal of immunosuppression or donor lymphocyte infusion. Disclosures:No relevant conflicts of interest to declare.

Sequential Autologous Followed by Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT) From HLA-Matched Related or Unrelated Donors Improves Outcomes of Patients (pts) with Bulky Lymphoma or Chronic Lymphocytic Leukemia (CLL)

AbstractAbstract 2365Large lymph node size or chemo-refractoriness limited the success of nonmyeloablative allogeneic HCT in eradicating CLL or lymphoma. We explored an approach of combining the cyto-reductive effect of high dose chemo/radiation therapy and autologous HCT with the graft-versus-tumor effect of nonmyeloablative allogeneic HCT for pts with rapidly progressive/refractory CLL or lymphoma. Between 4/2000 and 3/2010, 45 pts with advanced indolent (16%) or aggressive (54%) non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL, 18%), or CLL (11%) ineligible for myeloablative allogeneic HCT due to age and/or comorbidities were treated with the sequential approach. Autologous HCT alone was thought to be insufficient for disease control. Pts received high-dose therapy and autologous HCT followed [at a median of 65 (range 39–128) days] by nonmyeloablative conditioning and related (n=28) or unrelated donors (n=17) allogeneic HCT. Median pt age was 49 (range 20–71) years and number of prior regimens was 4 (range 1–12). Thirty-four percent of pts had disease responsive to the last chemotherapy before autografting [30% partial (PR) and 4% complete remission (CR)] while 44% and 22% had refractory and progressive disease, respectively. Most pts had aggressive disease (72%). Conditioning for autografts consisted of BEAM (49%) or Cyclophosphamide/12 Gy TBI±VP16 (51%). After auto-grafting, 58% of pts had CR/PR (29%/29%), 36% had responses <PR, 3% had relapse, and 3% had refractory disease. Conditioning for allografts consisted of 2 Gy TBI alone (53%) or combined with FLU (47%), 90 mg/m2. Pts received G-CSF mobilized allogeneic peripheral blood mononuclear cells. All 45 pts had sustained donor engraftment. Incidences of grades II, III, and IV acute and of chronic GVHD were 46%, 16%, 0%, and 52% respectively. With median follow up of 51 (range 5–116) months, the overall response rate was 60% (46% CR). Eighteen pts died, 12 from progression/relapse, 3 from pulmonary complications, 1 from GVHD, 1 from sepsis, and 1 from multi-focal leuko-encephalopathy. Estimated 5-year rates of non-relapse mortality, relapse, overall, and progression-free survivals from the time of autografting were 15%, 44%, 55%, and 42% respectively. Pts with CLL or indolent NHL had rates of relapse and PFS of 11% and 68% compared to 47% and 37% for those with aggressive NHL and 69% and 31% for those with HL, respectively. No statistical significant differences in outcomes were detected for lymph node size (Figure), disease status at allografting, donor type, conditioning regimens for autografts or allografts, HCT-comorbidity index scores, or time between autologous and allogeneic grafting (Table). Sequential Auto-Allo HCT resulted in relatively low NRM with median survival not yet reached among pts with rapidly progressive lymphoma/CLL. This sequential transplant approach overcame the previously reported high relapse risk of bulky lymphadenopathy. [Display omitted] Disclosures:Off Label Use: All discussions about therapeutics used for HCT preparative regimens are off-label.

Impacts of Cytogenetic Abnormalities and Prior Alemtuzumab on Outcomes of Patients (pts) with High-Risk Chronic Lymphocytic Leukemia (CLL) Given Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT)

AbstractAbstract 2364Allogeneic HCT using nonmyeloablative regimens may provide long-term remission in high-risk relapsed CLL. Here, we investigated the impact of histology, disease status, lymph node (LN) size, genomic aberrations, donor type, and prior alemtuzumab on outcomes. Pts (n=136) were conditioned with 2Gy TBI alone (12%) or 2Gy TBI plus 90 mg/m2 fludarabine (88%). Median age was 56 (range 42–72) years and median number of prior regimens was 4. Ninety percent of pts had fludarabine-refractory CLL. Incidences of grades II, III, and IV acute GVHD were 39%, 14%, and 2% respectively, and chronic extensive GVHD was 51%. Complete (CR) and partial remissions (PR) were seen in 55% and 15% of pts, respectively. Estimated 5-years rates of non-relapse mortality (NRM), progression/relapse, OS, and progression-free survival (PFS) were 32%, 36%, 41%, and 32%, respectively. Overall, 58 pts are alive; 45 in CR, 5 in PR, 5 with stable disease, and 3 with progression (PD)/relapse. Univariate outcomes (Table 1) were not statistically significantly different between donor types for NRM (p=0.37), relapse (p=0.17), or PFS (p=0.88). Pts with CLL and SLL had comparable rates of relapse and PFS. Disease status at HCT had no impact on NRM (p=0.75), relapse (p=0.31), or PFS (p=0.27). Relapse (p=0.51) and PFS (p=0.45) were not statistically significantly different among the 6 groups of cytogenetic abnormalities (Table 1). Both alemtuzumab within 12 months before HCT (53% vs. 31%, p=0.007, Figure) and LN size ≥5 cm (59% vs. 28%, p=0.003) were associated with increased rates of relapse. In Cox regression model for outcomes, prior alemtuzumab (HR: 2.20, p=0.02) and LN size ≥5 cm (HR: 2.21, p=0.02) were independently associated with increased relapse; while donor type, cytogenetic abnormalities, and disease status were not. PFS was also worse for pts with prior alemtuzumab (HR: 1.55, p=0.09) and LN size ≥5 cm (HR: 1.64, p=0.06). In multivariate models, pts who had alemtuzumab within 3 months prior to HCT appeared to have the highest relapse risk (Table 2). Prior alemtuzumab had no impact on CD3 donor chimerism following HCT. Further studies are warranted to explore whether the negative impact of alemtuzumab on relapse was due to unrecognized high-risk disease features or hampering the quality of graft-versus-tumor effects such as by deletion of host dendritic cells (Blood. 2002; 99: 2586). Allogeneic nonmyeloablative HCT is associated with graft-versus-leukemia effects even against chemo-refractory and high cytogenetic-risk diseases. We currently are studying novel approaches to better debulk disease before HCT and/or to augment graft-versus-leukemia effects after HCT for CLL pts with large LN size.Table 1:Univariate outcomes in 136 patients with CLL receiving nonmyeloablative HCT5 year outcomes (%)FactorGroupNNRMRelPFSDonorHLA-matched related75264331HLA-matched unrelated53422434HLA-antigen mismatched8155629p-value0.370.170.88Disease status at HCTChemo-responsive55313238Chemo-refractory72324127Untested relapse9362242p-value0.750.310.27Cytogenetic abnormalitiesNormal39422534Del17p24493218Del11q19314029Tri1210204040Del13q18174340Other26214733p-value0.250.510.45Alemtuzumab within 12 months before HCTNo103343135Yes33225325p-value0.800.010.07LN size<5 cm36302839≥5 cm100335911p-value0.950.0030.01Note: p-values reflect underlying hazard ratios over all follow-up period. [Display omitted] Disclosures:Off Label Use: All discussions about therapeutics used for HCT preparative regimens are off-label.

Recent advances in novel radioimmunotherapeutic approaches for allogeneic hematopoietic cell transplantation

Allogeneic hematopoietic cell transplantation (HCT) can be a curative treatment for hematologic malignancies and over the last three decades, novel approaches have resulted in significant reductions in morbidity and mortality. Despite current advances, two major limitations remain: patients continue to die from recurrent disease, and rates of nonrelapse mortality are relatively high due to regimen-related organ toxicities. The ability to target therapy with radiolabeled antibodies provides an innovative way to increase the tumoricidal dose of radiation to tumor sites, whereas sparing normal organs, as further dose escalation of chemotherapy and radiotherapy in HCT preparative regimens is not feasible due to dose-limiting toxicities. This review discusses the most current allogeneic HCT data using radioimmunotherapy (RIT) and focuses on recent trials involving patients at the highest risk for relapse. The results from these studies have shown that standard-dose radiolabeled antibodies can be safely combined with reduced-intensity preparative regimens with encouraging results in a single institution phase II study. Optimism remains that these RIT approaches will improve the cure rates of allogeneic HCT for the thousands of patients with leukemias and lymphomas who undergo this procedure each year.

23 INVITED T regs in cancer

In the dog leukocyte antigen (DLA)-identical hematopoietic cell transplantation (HCT) model, stable marrow engraftment can be achieved with total-body irradiation (TBI) of 200 cGy when used in combination with postgrafting immunosuppression. The TBI dose can be reduced to 100 cGy without compromising engraftment rates if granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMC) are infused with the marrow. T cell-depleting the G-PBMC product abrogates this effect. These results were interpreted to suggest that the additional T cells provided with G-PBMC facilitated engraftment by overcoming host resistance. We therefore hypothesized that the TBI dose may be further reduced to 50 cGy by augmenting immunosupression either by (1) tolerizing or killing recipient T cells, or (2) enhancing the graft-versus-host (GVH) activity of donor T cells. To test the first hypothesis, recipient T cells were activated before HCT by repetitive donor-specific PBMC infusions followed by administration of methotrexate (MTX) (n = 5), CTLA4-Ig (n = 4), denileukin diftitox (Ontak; n = 4), CTLA4-Ig + MTX (n = 8), or 5c8 antibody (anti-CD154) + MTX (n = 3). To test the second hypothesis, recipient dendritic cells were expanded in vivo by infusion of Flt3 ligand given either pre-HCT (n = 4) or pre- and post-HCT (n = 5) to augment GVH reactions. Although all dogs showed initial allogeneic engraftment, sustained engraftment was seen in only 6 of 42 dogs (14% of all dogs treated in 9 experimental groups). Hence, unless more innovative pharmacotherapy can be developed that more forcefully shifts the immunologic balance in favor of the donor, noncytotoxic immunosuppressive drug therapy as the sole component of HCT preparative regimens may not suffice to ensure sustained engraftment.