Prior Bone Marrow Transplantation Research Articles

Therapeutic Plasma Exchange for the Treatment of Thrombotic Microangiopathy without Severe ADAMTS13 Deficiency: A Propensity Score-Matched Study

▪Introduction: Thrombotic microangiopathies (TMA) are a group of uncommon disorders characterized clinically by the presence of thrombocytopenia and microangiopathic hemolytic anemia (MAHA). Therapeutic plasma exchange (TPE) is a proven treatment for cases of autoimmune thrombotic thrombocytopenic purpura (TTP) characterized by an ADAMTS13 activity level of ≤10%, but the efficacy of TPE in TMA with an ADAMTS13 activity level of >10% remains controversial.Methods: We conducted a retrospective cohort study of 186 adult patients included in the Harvard TMA Research Collaborative registry who presented with MAHA and thrombocytopenia concerning for TTP but an ADAMTS13 activity level of >10%. A propensity score (PS) logistic regression model was constructed based on 11 clinically relevant confounding variables: age; sex; ethnicity; Charlson Comorbidity Index (CCI); history of prior solid organ or bone marrow transplant; the presence of neurologic symptoms; the presence of sepsis, shock, or multiorgan failure (MOF); platelet count; creatinine; LDH; and INR. Matching was performed using a 1:1 nearest neighbor method without replacement within a set caliper distance. Standardized differences were used to assess the quality of matching and ensure balance of baseline characteristics. The primary outcome was 90-day survival. Secondary outcomes included in-hospital mortality, percent of patients experiencing platelet count recovery, time to platelet count recovery, and hospital length of stay (LOS).Results: Prior to matching, patients treated with TPE (N=71) had a lower acuity of illness compared to untreated patients (N=115) as reflected by a lower mean CCI (2.3 vs. 3.4, P = 0.003), lower mean INR (1.1 vs. 1.3, P = 0.02), and lower incidence of sepsis, shock or MOF (23% vs. 36%, P = 0.06). Consistent with this confounding, TPE in the pre-matched cohort appeared to be associated with reduced mortality at 90 days (HR 0.51, P = 0.01). The PS match was performed to address these imbalances and resulted in 59 TPE-treated patients paired to 59 untreated controls. After matching, baseline characteristics of the treated and untreated groups were well balanced, with a standardized difference of ≤11% in all PS variables (see Figure).In contrast to the unmatched cohort, Cox regression analysis stratified by matched pairs showed no significant difference in the primary outcome of 90-day survival between the treated and untreated groups (HR 0.88, 95% CI 0.44-1.8, P = 0.72) (see Table). We performed subgroup analyses by age, diagnostic category, and ADAMTS13 activity level and again did not observe any benefit to TPE. With regard to secondary outcomes, in-hospital mortality (OR 0.77, P = 0.53), percent of patients with platelet count recovery (OR 1.6, P = 0.21), median time to platelet count recovery (6 vs. 6 days, P = 0.99), and median hospital LOS (14 vs. 18 days, P = 0.93) did not differ significantly between the two groups.Conclusions: In the absence of a randomized controlled trial, PS matching represents a rigorous statistical approach to study the effect of treatment while adjusting for differences in baseline characteristics across groups of patients. Here we have used PS matching to assess the efficacy of TPE in the management of TMA associated with an ADAMTS13 activity level of >10%. Our data indicate that there is no benefit from TPE for this diverse group of TMA patients without severe ADAMTS13 deficiency. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Phase 3 Study to Evaluate the Efficacy and Safety of Dinaciclib Compared to Ofatumumab in Patients with Refractory Chronic Lymphocytic Leukemia

Abstract Introduction: Abnormalities of cell cycle regulation have an important role in the pathogenesis of cancers. Cyclin dependent kinase (CDK) inhibitors have shown potent activity in patients with chronic lymphocytic leukemia (CLL) and other cancers. Dinaciclib (MK-7965/SCH 727965) is a novel, selective inhibitor of CDK1, CDK2, CDK5, and CDK9. Prior studies show that dinaciclib has anti-leukemic activity against CLL. The present study compared the efficacy and safety of dinaciclib with ofatumumab in patients with refractory CLL. Methods: This Phase 3 randomized, open-label, active-controlled, balanced, multi-site, group sequential confirmatory trial evaluated the progression-free survival (PFS; primary objective), overall response rate and overall survival (secondary objectives), and safety of dinaciclib vs. ofatumumab in patients with refractory CLL. Patients with a confirmed diagnosis of CLL (based on 2008 International Workshop on CLL criteria) and fludarabine or chemoimmunotherapy refractory disease were enrolled if they had no central nervous system involvement, prior allogenic bone marrow transplant or uncontrolled autoimmune anemia or thrombocytopenia. Patients previously treated with dinaciclib, ofatumumab, or other CDK inhibitors were excluded. In Cycle 1, dinaciclib was administered intravenously (IV) over 2 hours at doses of 7 mg/m2 on Day 1, 10 mg/m2 on Day 8 and 14 mg/m2 on Day 15. In Cycle 2 and thereafter, dinaciclib was dosed at 14 mg/m2 on Days 1, 8, and 15 of each 28-day cycle for a total of 12 cycles. Ofatumumab was administered IV once-weekly for 8 weeks starting in Cycle 1 on Day 1, followed by 9 monthly doses as follows: 300 mg in Cycle 1 on Day 1; 2000 mg in Cycle 1 on Days 8, 15, and 22, Cycle 2 Days 1, 8, 15, and 22, and 5 weeks later on Day 1 of Cycles 4-12. Efficacy results are from the intent to treat (ITT) population, and safety results are from the all-subjects-as-treated population. Results: In total, 44 patients were randomized (ITT) and 42 were treated (20 dinaciclib and 22 ofatumumab) due to early study termination not attributed to safety. At study entry, the median age was 62 years (range, 43-77), 32/42 (76.2%) patients were male, 26/42 (62.0%) were RAI stage III-IV, 24/42 (57.1%) had bulky disease, 40/42 (95.2%) were ECOG ≤ 1, the median number of prior therapies was 3 (range, 1-20), and 39/42 (92.9%) patients received prior fludarabine. Deletion 17p (del 17p) was present in 17/42 (38.6%) patients, 7 dinaciclib and 10 ofatumumab. Median follow-up (range) was 16.7 (0.4-26.1) months. In the dinaciclib and ofatumumab groups, respectively, 11 (55.0%) and 17 (70.8%) patients had PFS events, and median (95% CI) PFS was 59.7 (45.0, 92.1) and 25.7 (9.3, 40.7) weeks. Overall response (all partial responses) was recorded for 8 (40.0%) dinaciclib and 2 (8.3%) ofatumumab patients. Stable disease was achieved by 7 (35.0%) dinaciclib and 11 (45.8%) ofatumumab patients. Median survival (95% CI) was 21.2 (16.6, NR) months with dinaciclib and 16.7 (2.3, 20.2) months with ofatumumab; 6 (30.0%) and 11 (45.8%) patients have died in each group, respectively. There were 2 treatment-related deaths in the dinaciclib arm (pneumonia and febrile neutropenia) and none in the ofatumumab arm. Median survival (95% CI) in the del 17p population was 21.2 (1.4, 21.2) months with dinaciclib and 5.4 (0.4, NR) months with ofatumumab. Overall, 17 (85.0%) dinaciclib and 13 (59.0%) ofatumumab patients had a grade 3-5 adverse event (AE). The most common grade ≥ 3 AEs with dinaciclib and ofatumumab, respectively, were neutropenia, 7 (35.0%) vs. 2 (9.1%); thrombocytopenia, 4 (20.0%) vs. 2 (9.1%); decreased neutrophil count, 4 (20.0%) vs. 1 (4.5%); pneumonia, 1 (5.0%) vs. 3 (13.6%); sepsis, 1 (5.0%) vs. 3 (13.6%); and febrile neutropenia, 2 (10.0%) vs. 1 (4.5%). One dinaciclib patient developed tumor lysis syndrome that was deemed not treatment-related. Ten (50.0%) dinaciclib and 13 (54.2%) ofatumumab patients discontinued from the study for the following reasons: AE, 3 (15.0%) vs. 1 (4.2%); disease progression, 4 (20.0%) vs. 4 (16.7%); death, 1 (5.0%) vs. 5 (20.8%); and other/unknown, 2 (10.0%) vs. 4 (16.7%). Conclusion: The limited data from this study demonstrate potential anti-cancer activity and tolerability of dinaciclib compared with ofatumumab in patients with refractory CLL. Based on these results and given the distinct mechanism of action, combinations of dinaciclib with other novel therapies should be explored. Disclosures Ghia: Janssen: Consultancy; Acerta Pharma BV: Research Funding; Adaptive: Consultancy; Pharmacyclics: Consultancy; Roche: Consultancy, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding. Pathiraja:Merck & Co., Inc.: Employment, Other: stock/stock options. Derosier:Merck & Co., Inc.: Employment, Other: stock/stock options. Small:Merck & Co., Inc.: Employment, Other: stock/stock options.

Phase 1 Study of CB-839, a First-in-Class, Orally Administered Small Molecule Inhibitor of Glutaminase in Patients with Relapsed/Refractory Leukemia

Background: Malignant cells alter metabolism in order to enable their highly anabolic state. In addition to a massive increase in glycolysis, neoplastic cells frequently depend on glutamine to feed the TCA cycle and provide key building blocks for cell growth and proliferation. CB-839 is a first-in-class potent and selective inhibitor of the glutaminase (GLS), the first step in glutamine metabolism, and has broad in vitro and in vivo anti-tumor activity in solid and heme malignancies. Acute myeloid leukemia (AML) cells are particularly dependent on glutamine, and treatment of AML cell lines and primary AML cells with CB-839 results in growth arrest and/or cell death (Padre et al., ASH, 2014 and Jacque et al., Blood, 2015). CB-839 causes a decrease in glutamate and glutamate-derived metabolites, such as TCA cycle intermediates and glutathione, crippling the proliferative capacity of these cells and in some cases inducing apoptosis.Methods: CX-839-003 is an ongoing Phase 1 (Ph1) trial of CB-839 in patients with relapsed/refractory hematologic malignancies. This study includes a dose escalation cohort to identify a recommended Phase 2 dose (RP2D), followed by expansion cohorts of patients (pts) with relapsed/refractory AML (IDH wt and mutant), acute lymphocytic leukemia, and IDH-mutant myelodysplastic syndrome (MDS). Pharmacokinetics (PK) is being monitored on Days 1 and 15.Results: Safety data are available for a total of 20 patients (18 AML, 1 ALL, and 1 mixed-lineage leukemia) that have enrolled across the dose escalation and expansion cohorts. These patients have received a median of 3 prior lines of systemic induction therapy, with 5 pts (25%) having received prior allogeneic bone marrow transplantation. Patients' median age was 75 (range 35 to 84). Dose levels from 100-1000 mg TID were explored during the dose escalation. CB-839 has been well tolerated to date, with no DLTs occurring on study. One patient discontinued due to an adverse event (AE) of elevated transaminases, and 5 pts (25%) had G3/4 AEs considered possibly related to study drug. Across three Ph1 studies for CB-839 in solid tumors and heme malignancies, reversible asymptomatic elevations in transaminases have been the primary G3 AE. Although initially CB-839 was given three times daily (TID) without food, the drug is now being given twice daily (BID) with meals based on PK and safety data generated across these 3 studies. Liver abnormalities occurred primarily on the TID schedule in 6/59 (10.2%) pts, but in only one of 60 pts (1.7%) receiving the BID regimen. Pts are currently being enrolled in expansion cohorts at the RP2D, 600 mg BID. Inhibition of GLS activity was evaluated across all 3 Ph1 studies and established clear exposure-dependent inhibition of the target in peripheral blood 4 hr after the first dose of CB-839, with >90% inhibition being maintained for most patients at the RP2D. Preliminary evidence of clinical activity has been noted, including reductions in blast counts in the bone marrow and/or periphery in 2 pts, one of whom achieved a CRi and remains on study for more than one year. 5 (31%) of 16 evaluable pts have remained on study for at least 4 cycles (range 4-17). Additional data from >8 additional patients have recently started on the "BID with meals" regimen will be presented. Correlative studies on clinical samples will also be presented.Conclusions: CB-839 has been well tolerated at and above doses that produced robust inhibition of GLS in blood platelets and in tumors. Dosing BID with food has mitigated the frequency and severity of LFT elevations, which has been the primary safety signal to date. Reductions in marrow and peripheral blast counts in a heavily pretreated acute leukemia population, with a significant number of patients tolerating therapy and remaining on study for a prolonged period, provide the rationale for continued evaluation of CB-839 as a single agent, and in combination with azacitidine, in AML patients. DisclosuresWang:Immunogen: Research Funding. Orford:Calithera Biosciences: Employment, Equity Ownership. Bennett:Calithera Biosciences: Employment, Equity Ownership. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Efficient Trafficking of Chimeric Antigen Receptor (CAR)-Modified T Cells to CSF and Induction of Durable CNS Remissions in Children with CNS/Combined Relapsed/Refractory ALL

▪BackgroundRelapsed/refractory pediatric acute lymphoblastic leukemia (ALL) poses a substantial therapeutic challenge. This is especially true in children with multiple central nervous system (CNS)/combined relapses that have been through radiation and bone marrow transplant (BMT) with no curative options left. We previously reported complete remissions (CR) and prolonged persistence of engineered T cells in children with ALL treated with CTL019 (CD19 CAR T cells). We now report on outcomes of 12 children with prior CNS relapse, isolated or combined with bone marrow (BM) relapse, treated with CTL019.ObjectivesEstablish the safety and efficacy of CTL019 for children with a history of CNS relapse of CD19+ ALL. In all patients, establish the frequency and magnitude of CTL019 trafficking to CNS.DesignWe identified ALL pts who had an isolated CNS or combined BM/CNS relapse as their indication for CTL019 therapy. CNS relapse was defined as CNS3 by lumbar puncture (≥ 5 WBC/uL with blasts present on cytospin), or brain/ocular involvement by imaging. Treatment for the CNS relapse prior to CTL019 was determined by the local treating physician. All pts had to be CNS1 (no blasts) or CNS2 (<5 WBC/uL with blasts on cytospin) at the time of infusion and all pts with ocular involvement had to undergo focal radiation with evidence of response. Post-infusion, pts had diagnostic lumbar punctures (LP) done at D28, and months 3, 6, 9, and 12. Pts received no CNS directed therapy post-infusion other than CTL019.ResultsOf 53 pts with CD19+ ALL infused with CTL019, 12 had a CNS3 status 1-12 months prior to infusion (median 4 months). Seven had an isolated CNS relapse and 5 were combined BM/CNS. Three pts with CNS involvement by LP also had ocular involvement and 2 had parenchymal changes on brain MRI. All 12 pts had prior CNS directed radiation and 11/12 had undergone a prior BMT. Patients ranged from a 2nd to a 6th relapse pre-CTL019: one 1st, six 2nd, three 3rd and 2 with 4+ CNS relapses. One day prior to infusion, 4 pts (2 with prior CNS, 2 with no prior CNS ALL) had blasts detected in the CSF (CNS2a). All pts were CNS1 on day 28 post infusion, and none have recurred in the CNS.47 pts (89%) had at least 1 CSF sample evaluated by PCR. 46/47 (98%) of the initial (D28) CSF samples showed high levels of gene marking indicating CTL019 cells, ranging from 1530 to 252,356 copies/ug genomic DNA. Persistence in the CSF was similar to that seen in peripheral blood and bone marrow. Of the 46 pts with CTL019 cells in the CSF, 42 (91%) had cells detected by PCR at their most recent CSF sampling. This included all patients (9/9 pts; 2177 to 15,727 copies by PCR) whose final CSF sample was obtained per protocol at month 12. 8/9 of these pts remain in remission.Encephalopathy, a known side effect of CTL019 therapy, was not increased in pts with a prior CNS relapse. Grade 2-3 encephalopathy was observed in 3/12 (25%) of pts with prior CNS relapse and 12/41 (29%) of non-CNS pts. Grade 2-4 seizure occurred in 4 pts (1 with history of CNS relapse as well as prior seizure).Eight of the 12 CNS pts (67%) remain in a continual CR 3 - 22 months post infusion (median 8 months). Four pts had recurrent BM disease and were CNS negative at subsequent relapse. The patient with the 6th CNS relapse of Ph+ ALL remains in a CR 22 months post infusion. To date none of the 53 pts, regardless of site of prior relapse, has had a subsequent CNS relapse.ConclusionSingle agent CTL019 immunotherapy can induce potent and durable responses in pts with CNS involvement of their relapsed/refractory ALL. Neurotoxicity does not appear to be enhanced in CNS pts, who tolerated therapy equally well. Due to this promising data, a cohort designed for patients who are CNS3 at time of infusion is now enrolling to further assess safety and efficacy in this setting. The unexpected trafficking and durable persistence of CAR T cells to CSF after intravenous infusion may enable treatment of other CNS malignancies. DisclosuresRheingold:Endo: Other: Husband's employer, has equity interest; Novartis: Consultancy. Off Label Use: CTL019 is not yet FDA approved for therapy for ALL. Maude:Novartis: Consultancy, Research Funding. Aplenc:Sigma Tau: Consultancy. Lacey:Novartis: Research Funding. Levine:Novartis: Patents & Royalties, Research Funding. Melenhorst:Novartis: Research Funding. Shaw:Novartis: Research Funding. Teachey:Novartis: Research Funding. June:University of Pennsylvania: Patents & Royalties: financial interests due to intellectual property and patents in the field of cell and gene therapy. Conflicts of interest are managed in accordance with University of Pennsylvania policy and oversight; Novartis: Research Funding. Grupp:Novartis: Consultancy, Research Funding.

In vivo administration of granulocyte colony‐stimulating factor restores long‐term depression in hippocampal slices prepared from transgenic APP/PS1 mice

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine that also possesses neurotrophic and antiapoptotic properties. G-CSF has been reported to decrease amyloid burden significantly, promote hippocampal neurogenesis, and improve spatial learning in a mouse model of Alzheimer's disease. To understand better the effects of G-CSF on hippocampal-dependent learning, the present study focused on electrophysiological correlates of neuroplasticity, long-term potentiation (LTP), and long-term depression (LTD). Two cohorts of transgenic APP/PS1 mice, with or without prior bone marrow transplantation from Tg GFP mice, were treated in vivo for 2 weeks with G-CSF or vehicle. After completion of the treatments, hippocampal slices were prepared for electrophysiological studies of LTP and LTD. LTP was induced and maintained in both G-CSF-treated and vehicle-treated groups of Tg APP/PS1. In contrast, LTD could not be induced in vehicle-treated Tg APP/PS1 mice, but G-CSF treatment restored LTD. The LTP and LTD results obtained from the cohort of bone marrow-grafted Tg APP/PS1 mice did not differ from those from nongrafted Tg APP/PS1 mice. The mechanism by which G-CSF restores LTD is not known, but it is possible that its capacity to reduce amyloid plaques results in increased soluble oligomers of amyloid-β (A-β), which in turn may facilitate LTD. This mechanism would be consistent with the recent report that soluble A-β oligomers promote LTD in hippocampal slices.

A First-In-Man Phase 1 Study Of CUDC-907, a First-In-Class Chemically-Designed Dual Inhibitor Of PI3K and HDAC In Patients With Refractory Or Relapsed Lymphoma and Multiple Myeloma

BackgroundPI3K and HDAC inhibitors have demonstrated single agent clinical activity in patients (pts) with a variety of B-cell malignancies, including lymphoma and multiple myeloma (MM). Preclinical experiments indicated synergistic effects between HDAC and PI3K pathway inhibitors. CUDC-907 is a chemically-designed small molecule that combines the active hydroxamate moiety of HDAC inhibitors with a PI3K inhibitor morpholinopyrimidine pharmacophore. CUDC-907 potently inhibits class I PI3K (alpha, beta, and delta) as well as HDACs class I and II enzymes. Preclinical experiments demonstrated that CUDC-907 inhibits the PI3K-AKT-mTOR pathway and compensatory MEK/ERK and STAT3 signaling pathways. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells, including human B-cell tumor xenograft models. Here we present the preliminary results of a First-In-Human Phase 1 study of CUDC-907. MethodsThis is a Phase 1 study using a standard 3+3 dose escalation design. CUDC-907 was orally administered to pts with lymphoma and MM. Patients were eligible if they had relapsed or refractory disease after at least 2 prior regimens and adequate bone marrow and organ functions. The starting dose was 30mg given continuously once daily in 21-day cycles without rest, with planned escalations until the maximum tolerated dose was reached. In the absence of dose limiting toxicities (DLTs), pts were allowed to continue treatment until disease progression. DLTs were defined so as to include ≥ Grade 3 adverse events (AE) or any Grade AE resulting in dose delay ≥7 days. Tumor response was assessed every 2 cycles using standard criteria appropriate for the disease type. Blood samples for pharmacokinetic (PK) and pharmacodynamic analyses were collected during Cycle 1. ResultsAt the time of this abstract, 6 pts were treated on study: 3 each at 30 and 60 mg/day dose. The median age was 70 years (range 61-77) and 2 pts had MM, 3 Non-Hodgkin's lymphoma and 1 Hodgkin's lymphoma. The median number of prior regimens was 3 (range 2-8) and 3 pts had prior bone marrow transplant. The most common treatment-related AEs were diarrhea (6 pts, Grade 1-3) and thrombocytopenia (5 pts, Grade 1-4). The severity and time to onset of these events appear to be dose-related. In general, thrombocytopenia recovered quickly by withholding treatment and diarrhea was well controlled with loperamide co-administration. However, 1 pt at the 60 mg/day dose level with a history of diabetes and poor co-medication compliance (i.e., loperamide and insulin) developed multiple DLTs including diarrhea (Grade 3), thrombocytopenia (Grade 4) and hyperglycemia (Grade 4). Of the 6 pts, 2 remain on treatment at ≥ 5 cycles with stable disease. CUDC-907 was rapidly transformed to 2 metabolites, M1 and M2, with M2 retaining potent PI3K inhibition activity. While CUDC-907 had low plasma exposure and a short half-life, M2 levels increased during the 24 hour PK sampling period. ConclusionTo address AEs and further dose escalate, with consideration of the PK profile of the parent and M2 metabolite, the protocol was modified to include 2 additional dosing schedules: 2x/week and 3x/week administration. In addition, the 30mg continuous daily dose cohort was expanded to further assess the tolerability of this schedule. Updated results from pts treated with the 3 schedules will be presented. Disclosures:Younes:Gilead: Honoraria; Seattle Genetics: Honoraria; Millenium: Honoraria; Celgene: Honoraria; Johnson & Johnson: Honoraria; Pharmacyclics: Honoraria. Fattaey:Curis, Inc.: Employment. Lai:Curis, Inc.: Employment. Laliberte:Curis, Inc.: Employment. Voi:Curis, Inc.: Employment.

Immunocompromised Status in Patients With Necrotizing Soft-Tissue Infection

There is a scarcity of research on immunocompromised patients with necrotizing soft-tissue infection (NSTI). To evaluate the effect of immunocompromised status in patients with NSTI. Single-institution retrospective cohort study at a tertiary academic teaching hospital affiliated with a major cancer center. Patients with NSTI. Treatment at Brigham and Women's Hospital and Dana-Farber Cancer Institute between November 25, 1995, and April 25, 2011. Necrotizing soft-tissue infection-associated in-hospital mortality. Two hundred one patients were diagnosed as having NSTI. Forty-six were immunocompromised (as defined by corticosteroid use, active malignancy, receipt of chemotherapy or radiation therapy, diagnosis of human immunodeficiency virus or AIDS, or prior solid organ or bone marrow transplantation with receipt of chronic immunosuppression). At presentation, immunocompromised patients had lower systolic blood pressure (105 vs 112 mm Hg, P = .02), glucose level (124 vs 134 mg/dL, P = .03), and white blood cell count (6600/μL vs 17 200/μL, P < .001) compared with immunocompetent patients. Immunocompromised patients were less likely to have been transferred from another institution (26.1% vs 52.9%, P = .001), admitted to a surgical service (45.7% vs 83.2%, P < .001), or undergone surgical debridement on admission (4.3% vs 61.3%, P = .001). Time to diagnosis and time to first surgical procedure were delayed in immunocompromised patients (P < .001 and P = .001, respectively). Immunocompromised patients had higher NSTI-associated in-hospital mortality (39.1% vs 19.4%, P = .01). AND RELEVANCE Immunocompromised status in patients with NSTI in this study is associated with delays in diagnosis and surgical treatment and with higher NSTI-associated in-hospital mortality. At presentation, immunocompromised patients may fail to exhibit typical clinical and laboratory signs of NSTI. Physicians caring for similar patient populations should maintain a heightened level of suspicion for NSTI and consider early surgical evaluation and treatment.

Survival of pig-to-rhesus corneal xenografts prolonged by prior donor bone marrow transplantation

The aim of the present study was to explore the survival of pig-rhesus corneal xenografts following donor bone marrow transplantation(BMT). Wuzhishan pigs were used as donors and rhesus monkeys as recipients for corneal xenotransplantation. Twelve rhesus monkeys were divided into two groups. Group1 received intravenous injection of cyclophosphamide (CP) followed by pig bone marrow cell transplantation, while group2 was used as a control and only received intravenous CP injection. All xenografts were evaluated using a slit-lamp microscope. The immunological status of the recipients following transplantation, including the formation of chimerism, mixed lymphocyte reaction (MLR) and immunoglobulin and complement in the serum, was analyzed. Two rhesus monkeys in each group were sacrificed for corneal histopathology examination. The mean survival time was 36.0±4.7days in group1 and 17.7±3.2days in group2. The mean chimerism percentage in group1 at week1 was 5.20±1.02%, but decreased with time and was <1% after week3. MLR demonstrated that immune reactivity to donor spleen cells in group1 was decreased following surgery. Immunoglobulin and complement levels in the serum revealed a decreasing trend. Histopathological examination demonstrated that the corneal xenografts in group1 had minimal inflammatory cell infiltration and no eosinophil infiltration. Survival of corneal xenografts may be prolonged by prior BMT, suggesting that immune reactivity to donors is suppressed, and is highly dependent on chimerism formation.

Phase I Trial of Combination Therapy with 90y Ibritumomab Tiuxetan and Gemcitabine in Patients with Non-Hodgkin's Lymphoma, Final Report.

AbstractAbstract 2753Y90-ibritumomab tiuxetan radioimmuotherapy (Y90-RIT) is an effective therapy against CD20+ lymphomas approved for use in patients (pts) with relapsed/refractory low grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL), as well as consolidation of first remission low grade NHL. Gemcitabine (Gem) also is active against NHL and is a potent radiation sensitizer. We conducted a phase I trial to assess the safety of concomitant administration of Y90-RIT and G in patients with NHL. Eligible pts had any histologic subtype of recurrent CD20+ NHL (not candidates for potentially curative options) and met standard Y90-RIT criteria: platelets 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to <25% of bone marrow and no prior bone marrow or stem cell transplant. Initially, nine pts in three cohorts were treated with 250 mg/m2 of Gem IV on days 1 and 8 of the Y90-RIT treatment program (rituximab + 111In-ibritumomab day 1 and rituximab + Y90 ibritumomab day 8), with Y90-RIT at 0.2, 0.3 or 0.4 mCi/kg respectively. We confirmed that a standard Y90-RIT dose of 0.4 mg/kg can be safely administered with Gem at 250 mg/m2. In subsequent cohorts, escalating doses of Gem were used according to a Bayesian based system. Response evaluation was by CT scan criteria (IWG JCO 1999). Between 2004–2012, twenty pts were treated (10 follicular (FL), 3 marginal zone (MZL), 7 diffuse large B-cell (DLBCL) lymphomas). Median age is 71.5 (range 55–82). The median number of prior treatments is 3 (range 1–6). Gem doses ranged from 250 mg/m2 to the maximum planned dose of 800 mg/m2 on days 1 and 8. One DLT occurred (thrombocytopenia) and MTD was not reached. Treatment-related toxicities consisted of grades 3 (N=11) and 4 (N = 2) neutropenia, grade 3 (N=11) leukopenia, grades 3 (N=14) and 4 (N=8) thrombocytopenia. One grade 3 infection occurred, unrelated to study drugs. All pts recovered counts to ≤ grade 1 by week 12. The only grade 3 non-hematologic toxicity was elevated bilirubin in 1 and increased GGT in 2 pts. Best responses seen include: 3 CR/CRu, 7 PR, 4 SD, 4 PD and 2 patients still in follow up. Median PFS for all patients is 192 days. Median PFS for all non-DLBCL histologies (10 FL and 3 MALT) is 202 days and for DLBCL is 77 days. Conclusion:Standard dose Y90-RIT combined with gemcitabine days 1 and 8 is safe and well-tolerated at doses up to 800 mg/m2 in pts with relapsed/refractory NHL. Further investigation with the established doses in non-DLBCL histologies is warranted. Disclosures:Borghaei:Biogen-IDEC: Research Funding. Off Label Use: 90Y Ibritumomab Tiuxetan in relapsed DLBCL. Schilder:Biogen-IDEC: Research Funding. Smith:Biogen-IDEC: Research Funding.

Evaluation of circulating concentrations of CXCL1 (Gro-α), CXCL10 (IP-10) and CXCL12 (SDF-1) in ALL patients prior and post bone marrow transplantation

The immune system plays an important role in the development of leukemia. CXC chemokines, as the molecular members of this system, are involved in the immune responses. Therefore, this study was designed to examine and compare the levels of CXCL1 (Gro-α), CXCL10 (IP-10) and CXCL12 (SDF-1) in ALL patients prior to and post bone marrow transplantation (BMT).In this experimental study, samples were obtained from ALL patients and controls, and subjected to ELISA for detection of chemokines. Demographic data were also collected by a questionnaire. Data were analyzed using SPSS software.Our results showed that the serum levels of CXCL1 (Gro-α), CXCL10 (IP-10) and CXCL12 (SDF-1) were significantly increased in ALL patients compared to the controls. We also showed that the CXCL10 (IP-10) level was increased after BMT in ALL patients, while CXCL1 (Gro-α) and CXCL12 (SDF-1) were inversely decreased.Our results allow for the conclusion that CXCL1 (Gro-α), CXCL10 (IP-10) and CXCL12 (SDF-1) are important for the pathogenesis of ALL. Notably, these chemokines might be used as pivotal biological markers in the diagnosis of leukemia. Recombinant CXCL1 (Gro-α), CXCL10 (IP-10) and CXCL12 (SDF-1) may be applied as a therapeutic approach in the treatment of leukemia patients.

1024PD - Surveillance of Adolescents and Young Adult Patients with Fanconi Anemia (FA): Awareness of Diagnosing Solid Tumors at a Young Age

ABSTRACT Disclosure All authors have declared no conflicts of interest. A great proportion of FA patients reaches adulthood and become at risk for developing secondary malignancies. In 2009, the High Risk and Cancer Prevention Unit (HRCPU) at Hospital Vall d'Hebron started a follow-up program for adolescents and adult patients with FA. The goal was to advocate for prevention measures to reduce cancer risk, and coordinate a multidisciplinary surveillance for different neoplasms. During annual HRCPU visits, FA patients undergo a complete anamnesis and receive health education. The surveillance program includes: hematological follow up with hemograms and bone marrow aspiration; examination for head and neck lesions by an otolaryngologist; detailed examination of the oral cavity by a maxillofacial specialist; semestral gynecologic examinations for women with annual cervical cytology testing and breast examination. Finally, HPV vaccination is encouraged. Since 2009, 14 FA patients have been enrolled in our follow-up program. Overall, 50% were women, and median age was 22 years (14-32). Their mean age at diagnosis of FA was 6.5 years, 57% belonged to FANCA group and 57% underwent a bone marrow transplantation (BMT). Follow up has ranged from 1 month to 3 years, 70% of patients have adhered properly with the program and 83% of women have received HPV vaccination. So far, 4 patients (29%) have been diagnosed with a malignant tumor and another two with a premalignant lesion. Premalignant lesions were found in the oral cavity (hyperplasia with mild dysplasia of the tongue) and gynecological (squamous intraepithelial lesion of the cervix CIN1). From those diagnosed with cancer, two of them had head and neck tumors. One was a lingual squamous cell carcinoma pT2N1M0 diagnosed at 24 years which recurred at 4 years and the patient died at age 30. The patient had received a BMT at age 8. The other one was a squamous cell carcinoma of the epiglottis pT4N1M0 diagnosed at 32 years in a patient with mosaicism. The third and fourth patients have developed several basal cell carcinomas in the jaw and back since age 21 and both had undergone BMT at 7 and 8 years. Head and neck tumors are frequent neoplasms in young adults with FA, regardless prior BMT. We need to reinforce surveillance and prevention strategies to reduce the risk of malignancies in these locations.

Enzyme replacement therapy improves joint motion and outcome of the 12‐min walk test in a mucopolysaccharidosis type VI patient previously treated with bone marrow transplantation

Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome, OMIM #253200) is a rare disorder involving multiple organs and manifested particularly by severe skeletal abnormalities. Bone marrow transplantation (BMT) improves cardiopulmonary function and facial features, but has limited success in ameliorating skeletal abnormalities and short stature. Here, we report the outcome of enzyme replacement therapy (ERT) with recombinant human arylsulfatase-B (ASB, Naglazyme, BioMarin, Novato, CA) in an MPS VI patient who received BMT 10 years prior to ERT induction. Administration of weekly Naglazyme for 18 months was effective in improving range of motion in several joints [shoulders (improvement of flexion (Right/Left): 40°/55°; improvement of extension 30°/40°; improvement of abduction 10°/10°), elbows (improvement of flexion 25°/25°; improvement of extension 10°/15°), hips (improvement of flexion 25°/10°), and knees (improvement of flexion 45°/40°; improvement of extension 50°/60°)]. Improvement in the outcome of the 12-min walk test (70% increase) and 3-min stair-climbing test (29% increase) was also noted after ERT. Because ERT improved clinical features in an MPS VI patient who had undergone prior BMT, the role of ERT post successful BMT in MPS VI needs further investigation.

Final Results From a Phase II Trial of Triapine® Plus Fludarabine for Adults with Aggressive Myeloproliferative Disorders

Abstract 1755▪▪This icon denotes a clinically relevant abstractPatients with aggressive myeloproliferative neoplasms (MPN) including MPN in accelerating phase, advanced stage chronic myelomonocytic leukemia (CMML), chronic myelogenous leukemia (CML) in accelerated phase or blast crisis, and other MPN transformed into acute myelogenous leukemia (sAML) have dire outcomes with conventional therapies including bone marrow transplant (BMT). One approach for malignant cell control is the ribonucleotide reductase (RR) inhibitor hydroxyurea (Hu). Triapine® is a novel RR inhibitor that binds to the M2 subunit of RR with 100 – 1000 fold greater potency than Hu and selectively depletes intracellular dATP. On this basis, we previously designed a phase I trial of Triapine® (Tri) and fludarabine (Flu) for patients with refractory acute leukemia and aggressive MPN. The overall response rate (ORR) was 21%, with the majority of responses occurring in patients with MPN including patients with sAML out of MPN. We have now completed a phase II trial of this novel combination in 37 patients (19 male, 18 female) where median age was 64 (35–75) and 9/37 (24%) were over 70 years old. Diagnoses included CMML (8), accelerating MPN (3), sAML out of CMML (7) or MPN (15), and imatinib resistant CML in blast crisis (4). The duration of underlying CMML or MPN ranged from 1 month to 19 years. Twenty three (59%) had previous exposure to Hu and 15 (41%) had received 1–3 prior induction regimens including full multi-drug AML induction regimens. Seven patients had prior allogeneic BMT. Poor risk cytogenetics were present in 16 cases (43%). Four patients had splenectomy (3) or splenic radiation (1) prior to enrollment.Triapine® was administered at 105 mg/m2 followed at 4 hours by fludarabine, 30 mg/m2 daily × 5 days. A total of 99 cycles (median 2.5 per patient, range 1–6) were administered, with > 4 cycles given to 9 patients. Four patients died of multi-organ failure after less than 4 weeks of treatment; three of these four presented with hyperleukocytosis (50 – 260K/mm3) and leukostasis. Drug-related toxicities included grade 3 acidosis (13/99 cycles), hypoxemia without dyspnea (6/99), and transient methemoglobinemia. In patients receiving > 4 cycles, chemotherapy was delivered every 33 days (range 20 – 61). Nine patients (24%) achieved complete remission lasting between 2 – 26 months (mean = 8 months, median = 5 months), and an additional three patients (8%) achieved partial remission, giving an ORR of 32%. An additional 8 patients (21%) had hematological improvement on trial. Three patients underwent BMT in CR and one received splenectomy after cytoreduction.We calculated hazard ratios evaluating multiple host and disease clinical and molecular features. Positive trends were observed for achieving CR, male sex, MPN or CMML diagnosis, JAK2 mutation. Negative trends were observed for CML-BC diagnosis, age over 60, prior splenectomy. Patients with JAK2 mutations received significantly more cycles of therapy compared to wild type (WT) individuals (3.6 vs. 2.1, p=0.02). The proportion of individuals alive at 6 months with JAK2 mutation vs. WT was 0.71 vs. 0.45. To determine if JAK2 mutations bore a relationship to in vitro drug sensitivity, we performed drug sensitivity assays of HEL cells that contain the JAK2 mutation, compared to controls. There were no differences in individual component sensitivities, testing for combination synergy is in progress. The hazard ratios for patients with WBC >50,000 and proliferative disease were no different, arguing against cell cycle effects as the sole mechanism of cytotoxicity of the combination. Finally, SNP-A genomic analysis of amplification, deletion, and uniparental disomy identified acquired molecular abnormalities in the majority of the cases tested, but no specific loci correlated with either positive or negative response.In summary, the novel combination of Triapine® plus fludarabine, modeled for biochemical synergy, demonstrates clinical responses in poor prognosis aggressive MPDs, including those transformed to AML. JAK2 mutational status may select for responders. Selected patients may benefit from this therapy as a bridge to bone marrow transplant or splenectomy. Our final report solidifies our preliminary results (McDevitt et al., 2008, ASH) and suggests that additional studies looking at this type of combination in addition to molecularly targeted JAK2 inhibitors may improve CR rate and duration. Disclosures:Off Label Use: Off label use of fludarabine for aggressive myeloid malignancies in combinations will be discussed.

Replacement of Liver Parenchyma in Analbuminemic Rats with Allogenic Hepatocytes is Facilitated by Intrabone Marrow-Bone Marrow Transplantation

Although hepatocyte transplantation (HCTx) is expected to become a useful therapy for human liver diseases, allogenic hepatocytes still tend to be rejected within a short period due to host immunosurveillance. In the present study, we investigated the effect of prior bone marrow transplantation (BMTx) for the engraftment of allogenic hepatocytes using the analbuminemic rat transplantation model. The hepatocytes of Lewis (LEW) rats were not accepted in the liver of retrorsine (RS)/partial hepatectomy (PH)-treated analbuminemic F344 (F344-alb) rats, which express the disparate major histocompatibility complex (MHC) against that of LEW rats. Prior BMTx with the LEW bone marrow cells (BMCs) after sublethal irradiation achieved acceptance and repopulation of LEW hepatocytes in the liver of the RS/PH-treated F344-alb rats, associated with elevation of serum albumin. The replacement of hepatic parenchyma with albumin positive (Alb(+)) donor hepatocytes and elevation of serum albumin levels were dependent on the bone marrow reconstitution by donor BMCs, which was more efficiently achieved by intrabone marrow (IBM)-BMTx than by intravenous (IV)-BMTx. Our results demonstrate that efficient bone marrow reconstitution by IBM-BMTx enables the replacement of the hepatic parenchyma with allogenic hepatocytes in RS/PH-treated analbuminemic rats without immunosuppressants.

Irradiated haploidentical donor leukocyte infusions as an adoptive immunotherapy strategy to induce host-versus-tumor effects

Previous research has shown that irradiated splenocytes preserve the antitumor effect and induce relatively weaker graft-versus-host disease in parent C57BL/6~CB6F1 transplantation. The present study was designed to investigate the antitumor effect of 5-Gy-irradiated haploidentical donor leukocyte infusions (DLI) without prior bone marrow transplantation and the possibly involved mechanism in (H-2d/k)~(H-2b/d) infusion model systems. Hepa 1-6 tumor-bearing mice were used to evaluate the antitumor effect and the possible mechanism of irradiated haploidentical DLI treatment. Changes in tumor volume, lymphocyte proliferation and cytotoxicity, IFN-gamma and IL-2 secretion and donor cell survival in vivo were analyzed. After irradiated haploidentical DLI treatment of the poorly immunogeneic Hepa 1-6 tumor mouse model, the donor cells were rejected and disappeared within 4 days. Surprisingly, an antitumor response was still observed. The infusion treatment effectively inhibited tumor growth and prolonged the survival of recipients, and this effect could be enhanced by combined treatment with cyclophosphamide and impaired by deleting donor-derived T cells. Moreover, the infusion treatment increased the levels of type 1 cytokines including IFN-gamma and IL-2, and enhanced the proliferation of lymphocyte subsets, particularly CD8 + T and NK cells. Specifically, multiple infusions proved to enhance the antitumor effect without inducing graft-versus-host disease. As an adoptive therapy, irradiated haploidentical DLI without bone marrow transplantation might be a promising and safe treatment for cancer.

Preliminary evaluation of radioimmunotherapy with Tenarad, a I-131 labeled antibody fragment targeting the extra-domain A1 of tenascin-C, in patients with refractory Hodgkin lymphoma.

8063 Background: The extra-domain A1 (ED-A1) of tenascin-C is a highly expressed component of the tumor extracellular matrix and constitutes a valuable target for radionuclide therapy. Tenarad is a human antibody which is capable of recognizing ED-A1, has been labeled with I-131 and is expressed as small immunoprotein (SIP) for improving its biodistribution properties. Previous phase I/II studies with a similar compound (131I-L19SIP) have shown efficacy in a variety of cancer types. In this ongoing phase I/II trial, Tenarad is administered to patients with progressive Hodgkin lymphoma refractory to conventional treatment. Methods: Eight patients (4 M, 4 F, 19-41 yo) have been enrolled between April and December 2010. All patients had undergone at least three lines of chemotherapy; seven pts had prior external beam radiation therapy and six had prior autologous bone marrow or stem cell transplantation. All patients presented with nodal disease and some had involvement of the bone (n=3), lung (n=2) or liver...

Abstract 1477: Tumor cell-leukocyte fusion in human cancer: A melanoma brain metastasis with a donor-patient hybrid genome following allogeneic BMT

Abstract Tumor cell fusion with motile bone marrow-derived cells (BMDCs) has long been proposed as a mechanism for metastasis, but while such fusion has been demonstrated in animal models little is known of this in human cancer. Here we report the first genetic evidence for BMDC-tumor fusion and genomic hybridization in a human melanoma brain metastasis from a patient with a prior allogeneic bone marrow transplant (male-male, sibling). STR analyses of DNA from melanoma cells throughout the tumor revealed the presence of both donor and patient alleles, with common aberrant allelic patterns at multiple chromosomal loci indicating a clonal origin of the tumor. Methods. All procedures were in accordance with HIPAA regulations and approved by the Yale HIC. Donor and patient DNAs were obtained from frozen lymphocytes and from a patient buccal swab. Formalin-fixed, paraffin-embedded tumor specimens were stained by immuniohistochemistry with common leucocyte antigen (CLA) in order to avoid leucocytes during microdissection of tumor cells. LCA-negative tumor cells were isolated with an Arturus XT laser dissection microscope system. DNA was extracted and analyzed for donor and patient alleles using forensic STR analyses at 13 chromosomal loci and amelogenin for the X and Y. Tissue sections were analyzed from 14 areas throughout the tumor. Results. DNA from donor and patient lymphocytes showed balanced diploidy at all loci and the allelic patterns were consistent with the sibling relationship. On the other hand, DNA from tumor cells contained a mixture of donor and host alleles at some loci, only donor or patient alleles at others, and numerous allelic imbalances throughout–particularly for the X and Y (X:Y = 2.8:1) that pointed to a probable tumor genotype of XXXY. With few exceptions, aberrant genetic profiles seen in one tumor section were seen in all, demonstrating a clonal origin of the tumor. Conclusions. The results provide the first genetic proof of leucocyte-tumor fusion and genomic hybridization in human cancer and indicate that the tumor was generated from a single fusion event. While this report concerns only one case, we demonstrate that forensic genetic analyses of tumors arising as secondary malignancies represents a fruitful area for research in tumor cell fusion in human cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1477. doi:10.1158/1538-7445.AM2011-1477

A deployable in vivo EPR tooth dosimeter for triage after a radiation event involving large populations

In order to meet the potential need for emergency large-scale retrospective radiation biodosimetry following an accident or attack, we have developed instrumentation and methodology for in vivo electron paramagnetic resonance spectroscopy to quantify concentrations of radiation-induced radicals within intact teeth. This technique has several very desirable characteristics for triage, including independence from confounding biologic factors, a non-invasive measurement procedure, the capability to make measurements at any time after the event, suitability for use by non-expert operators at the site of an event, and the ability to provide immediate estimates of individual doses. Throughout development there has been a particular focus on the need for a deployable system, including instrumental requirements for transport and field use, the need for high throughput, and use by minimally trained operators.Numerous measurements have been performed using this system in clinical and other non-laboratory settings, including in vivo measurements with unexposed populations as well as patients undergoing radiation therapies. The collection and analyses of sets of three serially-acquired spectra with independent placements of the resonator, in a data collection process lasting approximately five minutes, provides dose estimates with standard errors of prediction of approximately 1 Gy. As an example, measurements were performed on incisor teeth of subjects who had either received no irradiation or 2 Gy total body irradiation for prior bone marrow transplantation; this exercise provided a direct and challenging test of our capability to identify subjects who would be in need of acute medical care.

Aortic stenosis in a patient with Hurler's syndrome after bone marrow transplantation

We describe a case of severe aortic stenosis in a 16-year-old male with Hurler's syndrome who had prior bone marrow transplantation. The excised aortic valve leaflets showed characteristic pathologic findings of Hurler's syndrome. This is the first case report of aortic valve replacement in a patient with Hurler's syndrome treated with bone marrow transplantation that demonstrates progression of the aortic valve disease despite treatment.

The DNA Synthesis Inhibitor, Hydroxyurea, as a Potential Novel Therapeutic Approach for Fanconi Anemia: Further Studies in Complementation Group D1.

Abstract 4214Fanconi anemia (FA) is an inherited, cancer-prone bone marrow failure disease. FA is heterogeneous, with 13 complementation groups, but all groups have in common hypersensitivity to agents that produce DNA interstrand cross links (DISCLs), with associated increased clastogenicity, as a diagnostic hallmark. Although progress has been made in treating FA, particularly using bone marrow transplantation (BMT) to prevent bone marrow failure and leukemogenesis, BMT is not a trivial procedure, and treatment remains challenging. Head and neck cancers, which occur in high frequency in FA, are a particular problem that is not well remedied by BMT.Lymphoblastoid cells from normal subjects and from patients with FA were treated in culture with psoralen plus ultraviolet A radiation (PUVA) in a regimen shown to produce DISCLs. Following this, cells were treated with hydroxyurea, 5-fluorouracil, or high dose thymidine, in doses we have shown to produce a marked decrease in rate of DNA synthesis, for 24 hours. We have previously shown that clastogenicity and cytotoxicity, measured as trypan blue exclusion as well as colony forming ability (CFA), are markedly increased in FA cells, complementation groups A, B, C, and E, associated with deficiencies in their corresponding FA core proteins, but these increases are not observed in these FA cells subsequently treated with any of these other, DNA synthesis retarding agents, which effectively correct the FA phenotype in culture. FA A and C cells genetically corrected for the FANC A and G gene, respectively, display normal clastogenicity and cytotoxicity following PUVA, and do not show this correction following subsequent treatment with hydroxyurea, 5-fluorouracil, or high dose thymidine.We now report similar results for short term cell viability, and similar, although less marked, results for clastogenicity in FA complementation group D1 cells, associated with a deficiency in BRCA2. When all drugs were removed after these treatments and the cells cultured for 10 days without any drug in CFA assays, the FA group D1 cells resembled normals, however, and did not show this correction.We propose that the mechanism in FA A, B, C and G cells is related to a decrease in the rate of DNA synthesis, which we have shown occurs in normal but not FA cells following PUVA, and which is also produced by these other agents in the concentrations used here. The partial correction observed in FA group D1 cells may be due to this or a different mechanism. Partial or complete correction appears to apply to multiple FA complementation groups.Hydroxyurea has been used for many years as a safe and effective treatment for sickle cell anemia and other diseases. It is now proposed as a possible treatment for FA to delay or even prevent development of bone marrow failure and/or other complications, including leukemogenesis and carcinogenesis, with or without prior BMT. In some cases it may serve as a viable alternative where BMT is not fungible. Alternatively it may obviate the need for BMT altogether in responsive patients, or be effectively used in combination with other modalities. Complementation group may be important in determining which patients may be less responsive or require modified regimens. Disclosures:Off Label Use: We have obtained laboratory results which show partial or complete restoration of cytotoxicity and clastogenicity, as well as colony forming ability in the absence of drug in FA A, B, C, and G but not D1 cells, following treatment with a DNA cross-linking agent, in Fanconi anemia lymphoblastoid cells, by subsequent application of hydroxyurea, to normal levels. Hydroxyurea has been used for many years as a safe and effective treatment for sickle cell anemia. It is now proposed as a possible treatment for Fanconi anemia to delay or even prevent development of bone marrow failure and/or other complications, including leukemogenesis and carcinogenesis. It may be less effective in FA complementation group D1. Disclosures:Off Label Use: We have obtained laboratory results which show partial or complete restoration of cytotoxicity and clastogenicity, as well as colony forming ability in the absence of drug, following treatment with a DNA cross-linking agent, in Fanconi anemia lymphoblastoid cells, by subsequent application of hydroxyurea, to normal levels. Hydroxyurea has been used for many years as a safe and effective treatment for sickle cell anemia. It is now proposed as a possible treatment for Fanconi anemia to delay or even prevent development of bone marrow failure and/or other complications, including leukemogenesis and carcinogenesis..