Publications by authors named "Scott T Avecilla"

30 Publications

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Universal Engraftment after Allogeneic Hematopoietic Cell Transplantation Using Cryopreserved CD34-Selected Grafts.

Transplant Cell Ther 2021 May 13. Epub 2021 May 13.

Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.

As a result of the COVID-19 pandemic, most centers performing allogeneic hematopoietic cell transplantation (allo-HCT) have switched to the use of cryopreserved grafts. Previous investigators have suggested that cryopreserved allografts may heighten risk of nonengraftment. To date, no study has investigated the effect of cryopreservation of CD34-selected hematopoietic progenitor cells (CD34 HPCs) used as the sole graft source. In this study, we sought to evaluate outcomes after unrelated donor or matched sibling allo-HCT with cryopreserved CD34 HPCs. This was a single-center analysis of adult patients with hematologic malignancies who underwent allo-HCT with cryopreserved CD34-selected allo-HCT grafts between January 2010 and June 2017. All patients received ablative conditioning and antirejection prophylaxis with rabbit antithymocyte globulin. G-CSF-mobilized leukapheresis products underwent CD34 selection using the CliniMACS Reagent System. Cells were then cryopreserved in DMSO (final concentration 7.5%) to -90 °C using a controlled-rate freezing system before being transferred to vapor-phase liquid nitrogen storage. In internal validation, this method has shown 92% mean CD34 cell viability and 99.7% mean CD34 cell recovery. Engraftment was defined as the first of 3 consecutive days of an absolute neutrophil count of ≥0.5. Platelet recovery was recorded as the first of 7 consecutive days with a platelet count ≥20 K/μL without transfusion. Kaplan-Meier methodology was used to estimate overall survival (OS) and relapse-free survival (RFS), and cumulative incidence functions were used to estimate rates of relapse, nonrelapse mortality (NRM), and acute graft-versus-host disease (GVHD). A total of 64 patients received a cryopreserved CD34-selected graft. The median CD34 cell count before cryopreservation was 6.6 × 10/kg (range, 1.4 to 16.1 × 10/kg), and the median CD3 cell count was 2.0 × 10/kg (range, 0 to 21.1 × 10/kg). All patients were engrafted, at a median of 11 days post-HCT (range, 8 to 14 days). One patient had poor graft function in the setting of cytomegalovirus viremia, necessitating a CD34-selected boost on day +57. The median time to platelet recovery was 16 days (range, 13 to 99 days). The estimated 2-year OS was 70% (95% confidence interval [CI], 58% to 83%) with cryopreserved grafts versus 62% (95% CI, 57% to 67%) with fresh grafts (hazard ratio [HR], 0.86; 95% CI, 0.54 to 1.35; P = .5). The estimated 2-year RFS in the 2 groups was 59% (95% CI, 48% to 74%) versus 56% (95% CI, 51% to 61%; HR, 1.01; 95% CI, 0.68 to 1.51; P > .9). The cumulative incidence of relapse at 2 years was 29% (95% CI, 17% to 41%) versus 23% (95% CI, 19% to 27%; P = .16), and the cumulative incidence of NRM at 2 years was 17% (95% CI, 9% to 28%) versus 23% (95% CI, 19% to 28%; P = .24). The cumulative incidence of grade II-IV acute GVHD by day +100 was 16% with cryopreserved grafts (95% CI, 8% to 26%) and 16% (95% CI, 13% to 20%; P = .97) with fresh grafts. Moderate to severe chronic GVHD by day +365 occurred in only 1 recipient of a cryopreserved graft (2%). Our data show that in patients with hematologic malignancies who received cryopreserved allogeneic CD34 HPCs, engraftment, GVHD, and survival outcomes were consistent with those seen in recipients of fresh allogeneic CD34 HPC grafts at our center. Our laboratory validation and clinical experience demonstrate the safety of our cryopreservation procedure for CD34-selected allografts.
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http://dx.doi.org/10.1016/j.jtct.2021.04.026DOI Listing
May 2021

A simplified CD34+ based preharvest prediction tool for HPC(A) collection.

Transfusion 2021 May 11;61(5):1525-1532. Epub 2021 Mar 11.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: Hematopoietic stem cell transplantation is an important treatment that is dependent on the collection of sufficient CD34+ hematopoietic progenitor cells. The peripheral blood CD34 count (PB CD34+ counts) measured by flow cytometry can be used in predicting CD34+ stem cell yields hours before the completion of collection. Previously described formulas to predict the yield have used many different variables. As such, there is currently no consensus on an industry-standard algorithm or formula.

Study Design And Methods: Retrospective reviews of same-day PB CD34+ counts and the ensuing absolute CD34+ yields of mobilized donors (allogeneic and autologous) were used to develop and validate a formula using regression analysis to predict the CD34+ stem cell yield. A metric of prediction correlation, using root mean square error (RMSE), was used to assess the robustness of our prediction formula in addition to comparisons with two other published formulas, as well as subset analysis.

Results: A formula in the form of y = mx with r = 0.95 and 95% confidence intervals was generated and validated. The ratio of actual to predicted yield demonstrated a high correlation coefficient (r = 0.96) with linear regression and overall RMSE of 228.4, which was lower than the two prior studies (calculated RMSE = 330.8 and 405.2). Subset analyses indicated male patients, lymphoma patients, and patients >60 years of age demonstrated lower RMSEs.

Conclusion: We have demonstrated a simple yet robust formula that can be used prospectively to accurately predict the CD34+ stem cell yield in both autologous and allogeneic donors, which also accounts for recipient weight.
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http://dx.doi.org/10.1111/trf.16356DOI Listing
May 2021

High progression-free survival after intermediate intensity double unit cord blood transplantation in adults.

Blood Adv 2020 12;4(23):6064-6076

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Cord blood transplantation (CBT) after high intensity or nonmyeloablative conditioning has limitations. We investigated cyclosporine-A/mycophenolate mofetil-based intermediate intensity (cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 10 mg/kg, total body irradiation 400 cGy) unmanipulated double-unit CBT (dCBT) with prioritization of unit quality and CD34+ cell dose in graft selection. Ninety adults (median age, 47 years [range, 21-63]; median hematopoietic cell transplantation comorbidity index, 2 [range, 0-8]; 61 [68%] acute leukemia) received double-unit grafts (median CD34+ cell dose, 1.3 × 105/kg per unit [range, 0.2-8.3]; median donor-recipient human leukocyte antigen (HLA) match, 5/8 [range 3-7/8]). The cumulative incidences of sustained CB engraftment, day 180 grade III-IV acute, and 3-year chronic graft-versus-host disease were 99%, 24%, and 7%, respectively. Three-year transplant-related mortality (TRM) and relapse incidences were 15% and 9%, respectively. Three-year overall survival (OS) is 82%, and progression-free survival (PFS) is 76%. Younger age and higher engrafting unit CD34+ cell dose both improved TRM and OS, although neither impacted PFS. Engrafting unit-recipient HLA match was not associated with any outcome with a 3-year PFS of 79% in 39 patients engrafting with 3-4/8 HLA-matched units. In 52 remission acute leukemia patients, there was no association between minimal residual disease (MRD) and 3-year PFS: MRD negative of 88% vs MRD positive of 77% (P = .375). Intermediate intensity dCBT is associated with high PFS. Use of highly HLA mismatched and unmanipulated grafts permits wide application of this therapy, and the low relapse rates support robust graft-versus-leukemia effects even in patients with MRD.
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http://dx.doi.org/10.1182/bloodadvances.2020003371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724901PMC
December 2020

Guidelines for Cord Blood Unit Thaw and Infusion.

Biol Blood Marrow Transplant 2020 10 27;26(10):1780-1783. Epub 2020 Jun 27.

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1016/j.bbmt.2020.06.018DOI Listing
October 2020

Engraftment kinetics after transplantation of double unit cord blood grafts combined with haplo-identical CD34+ cells without antithymocyte globulin.

Leukemia 2021 03 18;35(3):850-862. Epub 2020 Jun 18.

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Double unit cord blood (dCB) transplantation (dCBT) is associated with high engraftment rates but delayed myeloid recovery. We investigated adding haplo-identical CD34+ cells to dCB grafts to facilitate early haplo-identical donor-derived neutrophil recovery (optimal bridging) prior to CB engraftment. Seventy-eight adults underwent myeloablation with cyclosporine-A/mycophenolate mofetil immunoprophylaxis (no antithymocyte globulin, ATG). CB units (median CD34+ dose 1.1 × 10/kg/unit) had a median 5/8 unit-recipient human leukocyte antigen (HLA)-match. Haplo-identical grafts had a median CD34+ dose of 5.2 × 10/kg. Of 77 evaluable patients, 75 had sustained CB engraftment that was mediated by a dominant unit and heralded by dominant unit-derived T cells. Optimal haplo-identical donor-derived myeloid bridging was observed in 34/77 (44%) patients (median recovery 12 days). Other engrafting patients had transient bridging with second nadir preceding CB engraftment (20/77 (26%), median first recovery 12 and second 26.5 days) or no bridge (21/77 (27%), median recovery 25 days). The 2 (3%) remaining patients had graft failure. Higher haplo-CD34+ dose and better dominant unit-haplo-CD34+ HLA-match significantly improved the likelihood of optimal bridging. Optimally bridged patients were discharged earlier (median 28 versus 36 days). ATG-free haplo-dCBT can speed neutrophil recovery but successful bridging is not guaranteed due to rapid haplo-identical graft rejection.
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http://dx.doi.org/10.1038/s41375-020-0922-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746597PMC
March 2021

Management of thymoma-associated pure red cell aplasia: A novel use of blood substitute HBOC-201 in a Jehovah's Witness.

Clin Case Rep 2020 Feb 26;8(2):289-292. Epub 2019 Dec 26.

Department of Medicine Memorial Sloan Kettering Cancer Center New York New York.

Pure red cell aplasia (PRCA) is a rare paraneoplastic syndrome occasionally associated with thymomas. Here, we report on the first ever use of a bovine hemoglobin-based oxygen carrier, HBOC-201 (HbO2 Therapeutics LLC; Hemopure, Waltham, MA) for the supportive management of pure red cell aplasia in a Jehovah Witness patient.
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http://dx.doi.org/10.1002/ccr3.2626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044386PMC
February 2020

A novel method for the laboratory workup of anaphylactic transfusion reactions in haptoglobin-deficient patients.

Transfusion 2020 04 23;60(4):682-687. Epub 2020 Jan 23.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Patients with congenital haptoglobin deficiency can develop anti-haptoglobin antibodies after exposure to blood products, and they can suffer from life-threatening anaphylactic transfusion reactions. Here, we present a case of a 57-year-old Chinese male with myelodysplastic syndrome who manifested an anaphylactic transfusion reaction during the transfusion of platelets. The only abnormality detected during his reaction laboratory workup was an undetectable haptoglobin level in the absence of evidence of hemolysis.

Study Design And Methods: Surface plasmon resonance (SPR) was explored as a method to be able to detect the presence of anti-haptoglobin antibodies in serum. First, haptoglobin was immobilized to the surface of an SPR sensor chip. The patient's serum sample was injected, and the binding response was monitored in real time. Serum samples from five healthy volunteers were used as negative controls. Binding specificity was assessed in competition experiments using soluble haptoglobin. Anti-IgG, -IgA, -IgM, -IgD and -IgE antibodies were used to identify the antibody isotype.

Results: An IgG anti-haptoglobin antibody was detected in the patient's serum with SPR.

Conclusion: SPR provided a rapid, readily available method for the detection of an IgG anti-haptoglobin antibody in an anhaptoglobinemic individual. This confirmed the underlying etiology of the anaphylactic nonhemolytic transfusion reaction and justified the necessity of stringently washed cellular products for all future transfusions and strong caution for future use of plasma-containing products.
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http://dx.doi.org/10.1111/trf.15657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204907PMC
April 2020

Method comparison study of peripheral blood CD34+ count performed on an Abbott CELL-DYN Sapphire hematology analyzer versus flow cytometry reference procedure (modified ISHAGE).

Adv Cell Gene Ther 2018 Sep 13;1(2). Epub 2018 Aug 13.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Introduction: CD34+ cell enumeration is a critical parameter used to determine the timing of apheresis collections of hematopoietic progenitor cell products (HPC(A)). Automated hematology analyzers equipped with flow cytometry capabilities may be a solution to the problem of limited access to standard flow cytometry testing.

Methods: We compared CD34+ cell enumeration using a reference flow cytometry procedure employing modified International Society of Hematotherapy and Graft Engineering (ISHAGE) analysis with a hematology analyzer /flow cytometer hybrid (CELL DYN (CD)Sapphire) using a sequential gating analysis designed to emulate the ISHAGE gating strategy.

Results: CD34+ cell values obtained from the ISHAGE and CD Sapphire analysis were plotted and compared in a linear regression analysis which showed a high degree of correlation (R=0.96). No statistically significant (p=0.53) differences in CD34+ cell enumeration values were observed between the flow cytometer and automated hematology analyzer using manual analysis schema.

Conclusions: We have demonstrated that an automated hematology analyzer equipped with a flow module can provide CD34+ cell enumeration results in the peripheral blood for clinical decision algorithms without the need for a dedicated flow cytometry laboratory.
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http://dx.doi.org/10.1002/acg2.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411087PMC
September 2018

Standard Antithymocyte Globulin Dosing Results in Poorer Outcomes in Overexposed Patients after Ex Vivo CD34 Selected Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 08 1;25(8):1526-1535. Epub 2019 Mar 1.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.

Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG.
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http://dx.doi.org/10.1016/j.bbmt.2019.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302932PMC
August 2019

Evaluation of peripheral blood mononuclear cell collection by leukapheresis.

Transfusion 2019 05 12;59(5):1765-1772. Epub 2019 Feb 12.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Adoptive immunotherapy using engineered lymphocytes has shown promising results in treating cancers even in patients who have failed other treatments. As the first essential step, the number of peripheral mononuclear cell (MNC) collection procedures is rapidly increasing. In this retrospective study, we reviewed the collection results to determine factors that affect MNC collection.

Study Design And Methods: We reviewed 184 collections that were performed on 169 adult allogenic donors and patients with acute lymphoid leukemia, chronic lymphoid leukemia, lymphoma, multiple myeloma, or solid-organ tumors. All the leukapheresis procedures were performed after a complete cell count with differential was obtained. Total blood volume (TBV) was defined as processed blood volume divided by patient blood volume.

Results: There was a significant association between the precollection MNC count (pre-MNC) and the MNC yields normalized by TBV (r = 0.926; p < 0.001) and a regression formula was created to predict MNC yields. Multiple regression analyses showed that pre-MNC, TBV, and precollection hemoglobin were strongly associated with MNC yield (R = 0.866; F (3180) = 388.472; p < 0.001), and pre-MNC had the greatest influence on MNC yield (β = 0.960; p < 0.001) followed by TBV (β = 0.302; p < 0.001), and Hgb (β = 0.136; p < 0.001).

Conclusion: Our results suggest that the optimal time for MNC collection can be determined based on pre-MNC and that processing volume should be determined based on collection goal and pre-MNC to optimize and personalize the harvesting procedure.
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http://dx.doi.org/10.1111/trf.15186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416722PMC
May 2019

Immune Cytopenias after Ex Vivo CD34+-Selected Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 06 6;25(6):1136-1141. Epub 2019 Jan 6.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.

Immune-mediated cytopenias (ICs), such as immune thrombocytopenia and immune hemolytic anemia, are among the adverse events after allogeneic hematopoietic cell transplantation (allo-HCT). Previous reports suggest that in vivo T cell depletion may increase the incidence of IC after allo-HCT. We evaluated whether a strategy that reduces functional donor T cells via ex vivo CD34-selection associates with the development of IC in a cohort of 408 patients who underwent allo-HCT for hematologic malignancy. The cumulative incidence of IC at 6, 12, and 36 months after the 30-day landmark post-HCT was 3.4%, 4.9%, and 5.8%, respectively. Among 23 patients who developed IC, 7 died of relapse-related mortality and 4 of nonrelapse mortality. A median 2 types of treatment (range, 1 to 5) was required to resolve IC, and there was considerable heterogeneity in the therapies used. In univariable analyses, a hematologic malignancy Disease Risk Index (DRI) score of 3 was significantly associated with an increased risk of IC compared with a DRI of 1 or 2 (hazard ratio [HR], 4.12; P = .003), and IC (HR, 2.4; P = .03) was associated with increased risk of relapse. In a multivariable analysis that included DRI, IC remained significantly associated with increased risk of relapse (HR, 2.4; P = .03). Our findings show that IC events occur with relatively similar frequency in patients after ex vivo CD34-selected allo-HCT compared with unmodified allo-HCT, suggesting that reduced donor T cell immunity is not causative of IC. Moreover, we noted a possible link between its development and/or treatment and increased risk of relapse.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559823PMC
June 2019

Investigational use of PEGylated carboxyhemoglobin bovine in a Jehovah's Witness with hemorrhagic shock.

Transfusion 2018 10 11;58(10):2297-2300. Epub 2018 Sep 11.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Jehovah's Witnesses pose a clinical challenge in the setting of critical anemia. Most do not accept transfusions, but some accept hemoglobin-based oxygen carriers on a compassionate-use basis. PEGylated carboxyhemoglobin bovine (PCHB) is an acellular dual-action carbon monoxide (CO)-releasing and oxygen transfer agent currently being investigated in Phase II clinical trials.

Case Report: We present the case of a 42-year-old Jehovah's Witness with an acute upper gastrointestinal bleed and hemorrhagic shock who required emergent PCHB for stabilization during lifesaving interventions. After PCHB infusion, the patient's shock and encephalopathy improved with decreased vasopressor requirement. Through gastroenterology and interventional radiology procedures, the patient's bleeding stabilized. While receiving five additional doses of PCHB and other supportive therapies (iron, folate, vitamin B12, darbepoetin alfa), the patient was extubated and weaned off vasopressors.

Conclusions: PCHB was used to stabilize (bridge) a critically ill anemic patient for lifesaving interventions without adverse effects. Additional studies are warranted to explore the drug's safety profile and efficacy in patients declining blood products.
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http://dx.doi.org/10.1111/trf.14799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011806PMC
October 2018

Impact of Toxicity on Survival for Older Adult Patients after CD34 Selected Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2018 01 22;24(1):142-149. Epub 2017 Sep 22.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.

Ex vivo CD34 selection before allogeneic hematopoietic stem cell transplantation (allo-HCT) reduces graft-versus-host disease without increasing relapse but usually requires myeloablative conditioning. We aimed to identify toxicity patterns in older patients and the association with overall survival (OS) and nonrelapse mortality (NRM). We conducted a retrospective analysis of 200 patients who underwent CD34 selection allo-HCT using the ClinicMACS® system between 2006 and 2012. All grade 3 to 5 toxicities by CTCAE v4.0 were collected. Eighty patients aged ≥ 60 years with a median age of 64 (range, 60 to 73) were compared with 120 patients aged < 60 years. Median follow-up in survivors was 48.2 months. OS and NRM were similar between ages ≥ 60 and <60, with 1-year OS 70% versus 78% (P = .07) and 1-year NRM 23% versus 13% (P = .38), respectively. In patients aged ≥ 60 the most common toxicities by day 100 were metabolic, with a cumulative incidence of 88% (95% CI, 78% to 93%), infectious 84% (95% CI, 73% to 90%), hematologic 80% (95% CI, 69% to 87%), oral/gastrointestinal (GI) 48% (95% CI, 36% to 58%), cardiovascular (CV) 35% (95% CI, 25% to 46%), and hepatic 25% (95% CI, 16% to 35%). Patients aged ≥ 60 had a higher risk of neurologic (HR, 2.63 [95% CI, 1.45 to 4.78]; P = .001) and CV (HR, 1.65 [95% CI, 1.04 to 2.63]; P = .03) toxicities but a lower risk of oral/GI (HR, .58 [95% CI, .41 to .83]; P = .003) compared with those aged < 60. CV, hepatic, neurologic, pulmonary, and renal toxicities remained independent risk factors for the risk of death and NRM in separate multivariate models adjusting for age and hematopoietic cell transplantation-specific comorbidity index. Overall, the toxicity of a more intense regimen is potentially balanced by the absence of toxicity related to methotrexate and calcineurin inhibitors in older patients. Prospective study of toxicities after allo-HCT in older patients is essential.
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http://dx.doi.org/10.1016/j.bbmt.2017.08.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731766PMC
January 2018

Effects of Late Toxicities on Outcomes in Long-Term Survivors of Ex-Vivo CD34-Selected Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2018 01 1;24(1):133-141. Epub 2017 Sep 1.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.

The late adverse events in long-term survivors after myeloablative-conditioned allogeneic hematopoietic cell transplantation (HCT) with ex vivo CD34 cell selection are not well characterized. Using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0, we assessed all grade ≥3 toxicities from the start of conditioning to the date of death, relapse, or last contact in 131 patients who survived >1 year post-HCT, identifying 285 individual toxicities among 17 organ-based toxicity groups. Pretransplantation absolute lymphocyte count >.5 K/µL and serum albumin >4.0 g/dL were associated with a reduced risk of toxicities, death, and nonrelapse mortality (NRM), whereas serum ferritin >1000 ng/mL was associated with an increased risk of toxicities and NRM after 1 year. An HCT Comorbidity Index (HCT-CI) score ≥3 was associated with an increased risk of all-cause death and NRM, but was not associated with a specific increased toxicity risk after 1 year. Patients who incurred more than the median number of toxicities (n = 7) among all patients within the first year subsequently had an increased risk of hematologic, infectious, and metabolic toxicities, as well as an increased risk of NRM and inferior 4-year overall survival (OS) (67% versus 86%; P = .003) after the 1-year landmark. The development of grade II-IV acute graft-versus-host disease (GVHD) within the first year was associated with incurring >7 toxicities within the first year (P = .016), and also with an increased risk of all-cause death and NRM after 1 year. In multivariate models, cardiovascular, hematologic, hepatic, infectious, metabolic, neurologic, and pulmonary toxicities incurred after 1 year were independently associated with increased risk of death and NRM when adjusting for both HCT-CI and grade II-IV acute GVHD within the first year. One-year survivors of ex vivo CD34 selection had a favorable 4-year OS of 77%, although the development of grade ≥3 toxicities after the first year was associated with poorer outcomes, emphasizing the fundamental importance of improving survivorship efforts that may improve long-term toxicity burden and outcome.
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http://dx.doi.org/10.1016/j.bbmt.2017.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713288PMC
January 2018

The Impact of Toxicities on First-Year Outcomes after Ex Vivo CD34-Selected Allogeneic Hematopoietic Cell Transplantation in Adults with Hematologic Malignancies.

Biol Blood Marrow Transplant 2017 Nov 18;23(11):2004-2011. Epub 2017 Jul 18.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York. Electronic address:

Factors that impact first-year morbidity and mortality in adults undergoing myeloablative allogeneic hematopoietic cell transplantation with ex vivo CD34 selection have not been previously reported. We assessed all toxicities ≥ grade 3 from the start of conditioning to date of death, relapse, or last contact in 200 patients during the first year after transplantation, identifying 1885 individual toxicities among 17 organ-based toxicity groups. The most prevalent toxicities in the first year were of infectious, metabolic, hematologic, oral/gastrointestinal, hepatic, cardiac, and pulmonary etiologies. Renal complications were minimal. Grades II to IV and III and IV acute GVHD at day 100 were 11.5% and 3%, respectively. In separate multivariate models, cardiovascular, hematologic, hepatic, neurologic, pulmonary, and renal toxicities negatively impacted nonrelapse mortality (NRM) and overall survival during the first year. A higher-than-targeted busulfan level, patient cytomegalovirus seropositivity, and an Hematopoietic Cell Transplantation-Specific Comorbidity Index of ≥3 were associated with increased risk of NRM and all-cause death. Ex vivo CD34 selection had a favorable 1-year OS of 75% and NRM of 17% and a low incidence of sinusoidal obstruction syndrome. These data establish a benchmark to focus efforts in reducing toxicity burden while improving patient outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2017.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376603PMC
November 2017

Ex Vivo CD34-Selected T Cell-Depleted Peripheral Blood Stem Cell Grafts for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Leukemia and Myelodysplastic Syndrome Is Associated with Low Incidence of Acute and Chronic Graft-versus-Host Disease and High Treatment Response.

Biol Blood Marrow Transplant 2017 Mar 23;23(3):452-458. Epub 2016 Dec 23.

Adult Bone Marrow Transplant Service, Division of Hematology/Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York. Electronic address:

Ex vivo CD34-selected T cell depletion (TCD) has been developed as a strategy to reduce the incidence of graft-versus-host disease (GVHD) after allogeneic (allo) hematopoietic stem cell transplantation (HSCT). Clinical characteristics, treatment responses, and outcomes of patients developing acute (aGVHD) and chronic GVHD (cGVHD) after TCD allo-HSCT have not been well established. We evaluated 241 consecutive patients (median age, 57 years) with acute leukemia (n = 191, 79%) or myelodysplastic syndrome (MDS) (n = 50, 21%) undergoing CD34-selected TCD allo-HSCT without post-HCST immunosuppression in a single institution. Cumulative incidences of grades II-IV and III-IV aGVHD at 180 days were 16% (95% confidence interval [CI], 12 to 21) and 5% (95% CI, 3 to 9), respectively. The skin was the most frequent organ involved, followed by the gastrointestinal tract. Patients were treated with topical corticosteroids, poorly absorbed corticosteroids (budesonide), and/or systemic corticosteroids. The overall day 28 treatment response was high at 82%. The cumulative incidence of any cGVHD at 3 years was 5% (95% CI, 3 to 9), with a median time of onset of 256 days (range, 95 to 1645). The 3-year transplant-related mortality, relapse, overall survival, and disease-free survival were 24% (95% CI, 18 to 30), 22% (95% CI, 17 to 27), 57% (95% CI, 50 to 64), and 54% (95% CI, 47 to 61), respectively. The 1-year and 3-year probabilities of cGVHD-free/relapse-free survival were 65% (95% CI, 59 to 71) and 52% (95% CI, 45 to 59), respectively. Our findings support the use of ex vivo CD34-selected TCD allograft as a calcineurin inhibitor-free intervention for the prevention of GVHD in patients with acute leukemia and MDS.
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http://dx.doi.org/10.1016/j.bbmt.2016.12.633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398850PMC
March 2017

How do I perform hematopoietic progenitor cell selection?

Transfusion 2016 05 25;56(5):1008-12. Epub 2016 Feb 25.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Graft-versus-host disease remains the most important source of morbidity and mortality associated with allogeneic stem cell transplantation. The implementation of hematopoietic progenitor cell (HPC) selection is employed by some stem cell processing facilities to mitigate this complication. Current cell selection methods include reducing the number of unwanted T cells (negative selection) and/or enriching CD34+ hematopoietic stem/progenitors (positive selection) using immunomagnetic beads subjected to magnetic fields within columns to separate out targeted cells. Unwanted side effects of cell selection as a result of T-cell reduction are primary graft failure, increased infection rates, delayed immune reconstitution, possible disease relapse, and posttransplant lymphoproliferative disease. The Miltenyi CliniMACS cell isolation system is the only device currently approved for clinical use by the Food and Drug Administration. It uses magnetic microbeads conjugated with a high-affinity anti-CD34 monoclonal antibody capable of binding to HPCs in marrow, peripheral blood, or umbilical cord blood products. The system results in significantly improved CD34+ cell recoveries (50%-100%) and consistent 3-log CD3+ T-cell reductions compared to previous generations of CD34+ cell selection procedures. In this article, the CliniMACS procedure is described in greater detail and the authors provide useful insight into modifications of the system. Successful implementation of cell selection procedures can have a significant positive clinical effect by greatly increasing the pool of donors for recipients requiring transplants. However, before a program implements cell selection techniques, it is important to consider the time and financial resources required to properly and safely perform these procedures.
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http://dx.doi.org/10.1111/trf.13534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4934655PMC
May 2016

Can the interval between antibody identifications be increased for alloimmunized patients?

Transfusion 2016 Feb 12;56(2):334-8. Epub 2015 Oct 12.

Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital-Weill Cornell Medical College.

Background: New alloantibody formation is unpredictable in patients who have been previously alloimmunized. Pretransfusion testing is designed to detect these antibodies while antibody identification (ABI) techniques are designed to identify the specificity of the antibody. Pretransfusion testing intervals are prescribed by regulatory and accrediting agencies, intervals for ABI in alloimmunized patients are not. Our institution evaluated the safety of increasing the interval from every 72 hours to 14 days. The current 72-hour interval was chosen at our institution to align with AABB Standard 5.14.3.2, which requires a pretransfusion specimen drawn within 3 days of the scheduled transfusion for potentially immunized patients.

Study Design And Methods: Over 2 years, all ABI entries in the laboratory information system were screened. All cases of alloimmunized patients with an additional antibody specificity that developed within 14 days of a previous ABI were reviewed and confirmed by four transfusion medicine physicians.

Results: Initially, 8948 entries were screened. Thirty patients were identified to have formed 33 newly identified clinically significant alloantibodies within 14 days. After further categorization, only 13 antibodies (0.15% of all ABIs, 0.47% of alloimmunized patients examined) were deemed to be newly formed clinically significant antibodies that would have led to a change in transfusion practice.

Conclusion: Retrospective analysis of ABI results over a 2-year period revealed that 0.47% of previously alloimmunized patients that have samples for pretransfusion testing develop a new clinically significant alloantibody in 14 days or less. While there would be significant resource advantages to increasing the duration between repeat ABI, it does not outweigh the risk of a potential hemolytic transfusion reaction.
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http://dx.doi.org/10.1111/trf.13380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984843PMC
February 2016

Comparison of manual hematocrit determinations versus automated methods for hematopoietic progenitor cell apheresis products.

Transfusion 2016 Feb 23;56(2):528-32. Epub 2015 Sep 23.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Allogeneic hematopoietic stem cell donor selection is based primarily on human leukocyte antigen degree of match and it often occurs without regard to the red blood cell (RBC) compatibility between donor and recipient. When major ABO-mismatched grafts are infused, it is imperative that an accurate determination of the incompatible RBC content is made to ensure that the product is safe for infusion. RBC content determination requires the hematocrit (Hct) parameter which can be obtained via manual (directly measured) or automated (calculated) methods.

Study Design And Methods: Ninety-seven apheresis hematopoietic progenitor grafts were assessed for Hct by manual testing and by four commercially available automated hematology analyzer instruments. A clinical model was developed to assess the frequency of unnecessary RBC reductions or alteration in standard infusion practice.

Results: Significant (p < 0.001) differences were observed where the manual Hct value was markedly lower than automated Hct values. At stringent incompatible RBC threshold of 10 mL, the number of preventable RBC reduction procedures ranged from 18% to 69%.

Conclusion: Accurate determination of RBC content of hematopoietic progenitor grafts is essential for patient safety. Despite the rapidity and convenience offered by automated Hct methods, they significantly overestimate the incompatible RBC content of grafts, which may trigger unnecessary RBC reduction procedures or split infusions. In products where automated Hct methods indicate excessive amounts of incompatible RBCs are present, we advise the performance of confirmatory testing with a manual Hct method to ensure that the automated Hct value is not a false positive.
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http://dx.doi.org/10.1111/trf.13346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980147PMC
February 2016

Results of lookback for Chagas disease since the inception of donor screening at New York Blood Center.

Transfusion 2013 May 15;53(5):1083-7. Epub 2012 Aug 15.

New York Blood Center, New York, New York 10065, USA.

Background: Chagas disease is a parasitic infection by Trypanosoma cruzi, typically transmitted via infected triatomine bug fecal contamination of bite sites. Other routes of infection include congenital, oral, organ transplantation, and blood product transmission.

Study Design And Methods: From 2007 until 2011, New York Blood Center screened donations for the presence of T. cruzi antibodies using a Food and Drug Administration-approved test. Confirmatory testing was performed and recipients of units donated by confirmed-positive donors were investigated via lookback.

Results: A total of 204 donors were T. cruzi antibody positive representing 0.019% of all donors during this time period (1,066,516 unique donors screened). Of the enzyme-linked immunosorbent assay-reactive donors, 77 were confirmed positive by radioimmunoprecipitation assay (0.007%). At least 154 units from 29 of the confirmed-positive donors had been transfused to 141 recipients. At the time of lookback, 48 of the 141 recipients were alive and seven underwent T. cruzi screening. Two recipients were found to be immunofluorescence assay (IFA) positive. Both IFA-positive recipients received a leukoreduced apheresis platelet unit (two separate donations) from the same confirmed positive donor, a 72-year-old immigrant from Argentina.

Conclusions: Lookback analysis was able to identify the first two cases of probable transfusion-transmitted T. cruzi infection since implementation of the national screening program, which increases the total number of reported cases in the United States to 8.
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http://dx.doi.org/10.1111/j.1537-2995.2012.03856.xDOI Listing
May 2013

Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy.

Am J Clin Pathol 2012 Apr;137(4):572-4

Laboratory Medicine, University of Washington, Seattle, USA.

New anticoagulants, like the orally available direct thrombin inhibitor (DTI) dabigatran etexilate, have recently been introduced into the market for venous thromboembolic prophylaxis and for stroke prevention in atrial fibrillation. While dabigatran has been approved for use without the need for routine therapeutic monitoring, there are clinical scenarios in which monitoring can help guide clinical management. We report herein the application of a recently described plasma-diluted thrombin time (DTI assay) used to monitor intravenous DTI as a useful and easily implemented method to monitor oral DTIs.
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http://dx.doi.org/10.1309/AJCPAU7OQM0SRPZQDOI Listing
April 2012

Functional heterogeneity of the bone marrow vascular niche.

Ann N Y Acad Sci 2009 Sep;1176:47-54

Department of Genetic Medicine, Ansary Stem Cell Institute, Weill Cornell Medical College, New York, New York, USA.

Sinusoidal endothelial cells (SECs) comprise the platform where trafficking into and out of the BM occurs and where hematopoietic stem and progenitor cells (HSPC) harbor and receive cues for self-renewal, survival, and differentiation. Therefore, SECs are referred to as a bone marrow vascular niche (BMVN). Hematopoietic regeneration has been shown to occur only with concurrent angiogenic regeneration. However, there are still not sufficient means to identify and isolate SECs, therefore the "niche endothelial cell" remains incompletely characterized. VEGF-receptor-3 (VEGFR3) is expressed exclusively by the SECs, while Sca1 and Tie2 are only expressed on the VEGFR3(-) arteriolar endothelium. We previously demonstrated the importance of vascular recovery in hematopoietic regeneration from myelosuppression due to cytotoxic agents or whole-body irradiation. Therefore to establish the functional importance of SECs, the mechanisms underlying BMVN regeneration were examined utilizing a 5-fluorouracil (5-FU) myelosuppression model of vascular damage. Injection of antibodies against murine VEGFR-1 and -2 had no significant effect on hemangiogenic recovery. However, when soluble VEGFR-1, a decoy receptor for VEGF-A and PlGF, was injected after 5-FU, both angiogenic remodeling and regeneration of megakaryopoiesis were delayed. In conclusion, we show that the bone marrow vasculature comprises heterogeneous compartments. SECs are distinguished from arterioles by unique immunophenotypes. Regeneration of damaged SECs is the rate-limiting step in hematopoietic regeneration from myelosuppressive therapy. Novel, high-efficiency VEGF-binding drugs in combination with chemotherapeutic agents may lead to cases of prolonged cytopenia.
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http://dx.doi.org/10.1111/j.1749-6632.2009.04964.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945889PMC
September 2009

Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization.

J Clin Invest 2006 Dec;116(12):3277-91

Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.

Thrombopoietic cells may differentially promote or inhibit tissue vascularization by releasing both pro- and antiangiogenic factors. However, the molecular determinants controlling the angiogenic phenotype of thrombopoietic cells remain unknown. Here, we show that expression and release of thrombospondins (TSPs) by megakaryocytes and platelets function as a major antiangiogenic switch. TSPs inhibited thrombopoiesis, diminished bone marrow microvascular reconstruction following myelosuppression, and limited the extent of revascularization in a model of hind limb ischemia. We demonstrate that thrombopoietic recovery following myelosuppression was significantly enhanced in mice deficient in both TSP1 and TSP2 (TSP-DKO mice) in comparison with WT mice. Megakaryocyte and platelet levels in TSP-DKO mice were rapidly restored, thereby accelerating revascularization of myelosuppressed bone marrow and ischemic hind limbs. In addition, thrombopoietic cells derived from TSP-DKO mice were more effective in supporting neoangiogenesis in Matrigel plugs. The proangiogenic activity of TSP-DKO thrombopoietic cells was mediated through activation of MMP-9 and enhanced release of stromal cell-derived factor 1. Thus, TSP-deficient thrombopoietic cells function as proangiogenic agents, accelerating hemangiogenesis within the marrow and revascularization of ischemic hind limbs. As such, interference with the release of cellular stores of TSPs may be clinically effective in augmenting neoangiogenesis.
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http://dx.doi.org/10.1172/JCI29314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1679710PMC
December 2006

Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes.

Nat Med 2006 May 30;12(5):557-67. Epub 2006 Apr 30.

Department of Genetic Medicine, Division of Hematology-Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA.

The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4+ VEGFR1+ hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4+ VEGFR1+ hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2-/- Csf3-/-), profound impairment in neovascularization was detected in sKitL-deficient Mmp9-/- as well as thrombocytopenic Thpo-/- and TPO receptor-deficient (Mpl-/-) mice. SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo-/-, Mpl-/- and Mmp9-/- mice. Transplantation of CXCR4+ VEGFR1+ hemangiocytes into Mmp9-/- mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A-mediated mobilization of CXCR4+ VEGFR1+ cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4+ VEGFR1+ hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF-1 may be effective in restoring angiogenesis in individuals with vasculopathies.
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http://dx.doi.org/10.1038/nm1400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754288PMC
May 2006

The bone marrow vascular niche: home of HSC differentiation and mobilization.

Physiology (Bethesda) 2005 Oct;20:349-56

Weill Medical College of Cornell University, New York, New York, USA.

The bone marrow vascular niche consists of a network of thin-walled and fenestrated sinusoidal vessels whose integrity is maintained and supported by surrounding hematopoietic cells. However, this dependence is highly reciprocal in that the bone marrow vasculature provides not only a conduit for mature hematopoietic cells to the peripheral circulation but also a site where hematopoietic progenitors, especially megakaryocytes, differentiate and set the stage for full reconstitution of hematopoiesis.
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http://dx.doi.org/10.1152/physiol.00025.2005DOI Listing
October 2005

Tie2 activation contributes to hemangiogenic regeneration after myelosuppression.

Blood 2005 Jul 7;106(2):505-13. Epub 2005 Apr 7.

Department of Genetic Medicine and Division of Hematology-Oncology, Weill Medical College of Cornell University, 1300 York Ave, Room D601, New York, NY 10021, USA.

Chemotherapy- or radiation-induced myelosuppression results in apoptosis of cycling hematopoietic cells and induces regression of bone marrow (BM) sinusoidal vessels. Moreover, timely regeneration of BM neovessels is essential for reconstitution of hematopoiesis. However, the identity of angiogenic factors that support reconstitution of BM's vasculature is unknown. Here, we demonstrate that angiopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 (Tie2) signaling contributes to the assembly and remodeling of BM neovessels after myelosuppression. Using transgenic mice where the Tie2 promoter drives the reporter LacZ gene (Tie2-LacZ), we demonstrate that at steady state, there was minimal expression of Tie2 in the BM vasculature. However, after 5-fluorouracil (5-FU) treatment, there was a rapid increase in plasma vascular endothelial growth factor A (VEGF-A) levels and expansion of Tie2-positive neovessels. Inhibition of Tie2 resulted in impaired neoangiogenesis, leading to a delay in hematopoietic recovery. Conversely, angiopoietin-1 (Ang-1) stimulated hematopoiesis both in wild-type and thrombopoietin-deficient mice. In addition, Ang-1 shortened the duration of chemotherapy-induced neutropenia in wild-type mice. Exogenous VEGF-A and Ang-1 stimulated Tie2 expression in the BM vasculature. These data suggest that VEGF-A-induced up-regulation of Tie2 expression on the regenerating vasculature after BM suppression supports the assembly of sinusoidal endothelial cells, thereby promoting reconstitution of hematopoiesis. Angiopoietins may be clinically useful to accelerate hemangiogenic recovery after myelosuppression.
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http://dx.doi.org/10.1182/blood-2004-11-4269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895182PMC
July 2005

Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis.

Nat Med 2004 Jan 21;10(1):64-71. Epub 2003 Dec 21.

Department of Medicine, Division of Hematology-Oncology, Cornell University Medical College, 1300 York Avenue, New York, New York 10021, USA.

The molecular pathways involved in the differentiation of hematopoietic progenitors are unknown. Here we report that chemokine-mediated interactions of megakaryocyte progenitors with sinusoidal bone marrow endothelial cells (BMECs) promote thrombopoietin (TPO)-independent platelet production. Megakaryocyte-active cytokines, including interleukin-6 (IL-6) and IL-11, did not induce platelet production in thrombocytopenic, TPO-deficient (Thpo(-/-)) or TPO receptor-deficient (Mpl(-/-)) mice. In contrast, megakaryocyte-active chemokines, including stromal-derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Thpo(-/-) and Mpl(-/-) mice. FGF-4 and SDF-1 enhanced vascular cell adhesion molecule-1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release. Disruption of the vascular niche or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions and after myelosuppression. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.
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http://dx.doi.org/10.1038/nm973DOI Listing
January 2004

Tumor vasculature address book: identification of stage-specific tumor vessel zip codes by phage display.

Cancer Cell 2003 Nov;4(5):331-3

Department of Genetic Medicine, Division of Hematology-Oncology, Cornell University Medical College, New York, NY 10021, USA.

Using in vivo phage display technology with murine tumorigenesis models, two reports have identified peptide motifs that selectively home to distinct molecular vascular targets in a tumor type- and stage-specific manner (Hoffman et al., 2003 and Joyce et al., 2003 [this issue of Cancer Cell]). By probing the surface-protein repertoire of these unique vascular beds, a pioneering draft of a molecular roadmap to decipher the heterogeneity of the vascular system in the context of carcinogenic progression has been plotted. Analysis of these phage peptides that differentially home to dysplastic or invasive tumor vasculature will lay the foundation for identifying unique functional tumor vascular-specific motifs that could potentially be applied to targeted therapeutic and imaging modalities.
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http://dx.doi.org/10.1016/s1535-6108(03)00278-2DOI Listing
November 2003