Bone Marrow Transplantation Conditioning Research Articles

Thrombopoietin mimetic therapy alleviates radiation-induced bone marrow vascular injury in a bone marrow transplant mouse model.

There is a need for therapies that can mitigate bone marrow dysfunction and organ toxicity that occur following myeloablative injury and reduced intensity conditioning regimens used in patients undergoing bone marrow transplantation (BMT). The pathogenesis of adverse effects from BMT conditioning has been linked to injury to the vascular endothelium, bone marrow (BM), and other organs. To evaluate the impact of the thrombopoietin mimetic drug JNJ-26366821 (TPOm) on BM vascular recovery in mice undergoing myeloablative radiation conditioning followed by BMT. TPOm (doses: 0 µg, 300 µg, 1000 µg per Kg body weight) was administered on Days 0 and 7 after BMT, in mice receiving a total body irradiation (TBI) conditioning regimen (5.5 Gy x 2) before congenic BMT. BM donner cell engraftment was analyzed using flow cytometry on Days 7, 14, and 30 post-BMT. The morphological and biophysical properties of the BM vasculature were evaluated by intravital multiphoton microscopy (MPM) and immunofluorescence confocal imaging. Herein, morphological properties involve microvascular density (MVD), vessel diameter, and vascular area, while biophysical properties include transfer rate (Ktrans) of contrast within the BM vascular niche, as well as the fractional volume (vec ) of extracellular extravascular tissue (EES). No significant difference in donor chimerism was observed at days 7, 14, and 30 post-BMT, between TPOm and PBS-treated mice. TPOm intervention improved BM vasculature regeneration in transplanted mice. The MVD, Ktrans, and BM vasculature as well as vascular endothelial growth factor receptor-2 (VEGFR2) in the BM, showed a dose dependent improvement in mice treated with TPOm. On day 14 post-BMT, the group receiving 1000 µg/Kg TPOm showed significant shifts (p-value < 0.05) in MVD, Ktrans, and VEGFR2 expression from their corresponding control types (TPOm dose 0 µg) towards levels comparable to healthy controls. TPOm intervention augments BM vascular structure and function, which may be important for hematopoietic recovery and bone marrow function in radiation conditioned hematopoietic stem cell transplant patients, in addition to enhancing platelet recovery.

Allogeneic Transplantation for High Risk Patients with Chronic Granulomatous Disease (CGD)

CGD is an immunodeficiency characterized by infections and inflammation, particularly inflammatory bowel disease (IBD) and lung inflammation, resulting from mutations in genes encoding any one of 5 subunits of the phagocyte NADPH oxidase impairing production of microbicidal oxidants. Bone marrow transplantation (BMT) has been shown to be curative of both the predilection for CGD-specific fungal and bacterial infections, and CGD related IBD, and is being offered more frequently to patients with appropriate donors, particularly in younger children with matched related donors. However, older adult patients with CGD, especially those with fungal infection not responding to conventional therapy, those with very severe IBD, and particularly those with inflammatory lung disease characterized by significant hypoxia are often considered ineligible for transplant by many US BMT centers. Furthermore, graft versus host disease (GvHD) and graft rejection following BMT of CGD patients going into the transplant with significant inflammation disease has been a significant problem. We report here the results to date of our ongoing protocol using Campath (1mg/kg divided over 4d), Busulfan (5mg/kg divided over 2d) and TBI (300cGy) combined with post-transplant cyclophosphamide (100mg/kg divided over 2d) and sirolimus for patients with CGD, with outcomes that appear to address these issues. Patients with C-reactive protein >100 were excluded from the standard criteria protocol because this had been shown to be a high mortality risk. However 6 patients whose CRP exceeded this exclusion criteria received exceptions to be treated 'off protocol' because of infections not responding to conventional therapy. Results: Number of patients to date: 30 plus 6 of whom were exceptions treated off protocol, and 1 retransplant; Follow up: 6 months to 5 years Donor types: 34 MUD, 3 MSD Patient Characteristics: Age: Mean 30/Range 6 to 57, Gender: 5F, 33M CGD type: GP91 (29, incl.1 lyonized female carrier), P47 (6), P67 (1), P22 (1) Transplant indications (some had more than one): Hypoxic inflammatory pulmonary disease (7), Colitis (11), Active infection (predominantly fungal) despite prolonged conventional therapy (14). See table Summary: Low dose Busulfan with TBI plus Campath and post-transplant cytoxan followed by sirolimus for BMT of CGD patients with CRP <100 at transplant is well tolerated, and results in improved engraftment rates with minimal GvHD. Patients with severe infections, hypoxic inflammatory lung disease, severe colitis and older age, but who have CRP<100 tolerate this conditioning regimen and benefit from the transplant with resolution of their underlying infection and/or non-infectious lung disease and/or severe IBD, even in patients who would not be considered eligible for transplant at other centers. This NIH non-myeloablative /immune suppressive BMT conditioning regimen not only significantly reduces incidence of graft failure and severe GVHD, but expands the group of CGD patients eligible for transplant to older patients and those with ongoing infection, hypoxic inflammatory lung disease, and/or severe IBD. These patients can be transplanted successfully and achieve cure of infection and/or significant improvement in their inflammatory pulmonary disease and IBD if a matched donor is available with this NIH CGD BMT conditioning regimen. Our studies confirm that patients with CRP>100 at transplant should not be transplanted and going forward are excluded without exception from this protocol. Also of note is that transplanted CGD patients have a high rate of fever, diarrhea and newly elevated CRP, but without hypoxia or hypotension, appearing to be a form of 'engraftment syndrome' that occurs starting at 10-12 days post transplant and resolving about the time that ANC >200-300. In 10 patients this was sufficiently severe to warrant treatment with tocilizumab 4mg/kg, which in all cases promptly resolved the fever. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I Dose Escalation Trial of 3-Day Total Marrow and Lymphoid Irradiation for Leukemia as Part of Myeloablative Conditioning in Unrelated Bone Marrow Transplantation

<h3>Purpose/Objective(s)</h3> Increasing the total body irradiation (TBI) dose during allogeneic hematopoietic stem cell transplantation (HSCT) has the potential to decrease relapse rates. However, higher doses of TBI increase toxicity and long-term morbidity. Total marrow and lymphoid irradiation (TMLI) allow for increased treatment intensity while avoiding dose escalation for at-risk organs. TMLI is expected to improve long-term survival outcomes of HSCT for hematologic malignancies. This prospective phase I trial aimed to determine the recommended dose of 3-day TMLI for a myeloablative conditioning regimen, by increasing the dose per fraction. <h3>Materials/Methods</h3> The eligibility criteria for this study were as follows, 1) diagnosed with hematologic malignancy, 2) planned HSCT with a myeloablative regimen, 3) with clinical remission status at pre-transplantation, and 4) with no evidence of extramedullary disease. The primary endpoint of this single-institution dose escalation study was the recommended TMLI dose, based on the frequency of dose-limiting toxicity (DLT) within 100 days after HSCT; a 3 + 3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (14/16/18 Gy in 6 fractions over 3 days) were set, and the treatment protocol began at 14 Gy. DLTs were defined as grade 3 or 4 non-hematological toxicities including those of cardiac, bladder, renal, pulmonary, hepatic, and central nervous system tissues, oral mucositis, gastrointestinal toxicities according to Bearman's criteria, and other grade 3 or higher non-hematological toxicities according to the Common Terminology Criteria for Adverse Events version 4.0. Grade 4 neutropenia (as per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) associated with fever or infection lasting beyond 3 weeks, or grade 4 neutropenia persisting for at least 28 days were also considered DLTs. <h3>Results</h3> The median follow-up period after HSCT was 453 (range, 131–915) days. Three patients were enrolled for each dose level. None of the patients exhibited DLT within 100 days of HSCT. Three patients experienced relapse, and no non-relapse mortality was documented during the observation period. One patient died 306 days after HSCT due to disease relapse. <h3>Conclusion</h3> The recommended dose of 3-day TMLI for a myeloablative conditioning regimen was 18 Gy in 6 fractions. The efficacy of this regimen is currently being planned in a phase II study.

Surge in Procalcitonin Levels Post ATG During Stem Cell Transplantation for Aplastic Anemia: A Diagnostic Dilemma with Sepsis?

Allogenic Stem Cell Transplantation (AlloSCT) has paved way for curative therapy in numerous hematologic diseases such as Aplastic Anemia. Anti-Thymocyte Globulin (ATG), a polyclonal T-cell antibody is an integral part of the numerous conditioning regimens. Its purpose is the T-cell depletion of the recipient, which is of utmost importance for the prevention of graft rejection and successful engraftment. Febrile responses after ATG administration pose a diagnostic dilemma in these patients who are frequently neutropenic [1]. During the conditioning phase before AlloSCT, patients undergo substantial immunosuppression and immune-alteration under the effect of pharmacotherapy and total body irradiation. Conditioning with ATG can be associated with febrile episodes, circulatory instability and/or respiratory insufficiency. The severity of this reaction especially in a neutropenic patient can closely resemble sepsis. Since blood cultures can take a few days in reporting, biochemical markers of inflammation, such as C-Reactive Protein (CRP) and Procalcitonin (PCT) levels have a diagnostic value. In contrast to CRP, Procalcitonin is a sensitive and specific marker for systemic bacterial infection and fungal sepsis [2,3]. We observed a surge in procalcitonin levels after ATG administration in a patient suffering from severe aplastic anemia undergoing conditioning for allogenic bone marrow transplantation from a matched sibling donor. The patient weighing 72 kilograms, received rabbit ATG as GVHD prophylaxis at the rate 1.5mg/kg (5 vials of 25mg each) on Day - 3 of conditioning and developed high grade fever with chills, reaching a peak temperature of 103.6 degrees Fahrenheit. Microbiological cultures and procalcitonin levels were sent to rule out sepsis as part of the protocol. First line intravenous antibiotics were started and antipyretics were administered. Fever settled on its own once the ATG therapy was completed. On day -2 and -1, the same dose of ATG was given and the patient did not develop any febrile episodes. The median PCT elevation on day 1 after ATG infusion was 87.68mcg/L, nearly 70 times the baseline level. Patient was clinically stable with no features of sepsis. There was a steady decline in PCT levels over the next 4 days, 58.54, 24.79, 4.38 and 1.13 (mcg/L) respectively. No derangements in liver function tests or renal function tests were observed. Subsequently, the microbiological cultures were sterile ruling out sepsis. Several previous reports suggested limited diagnostic value of PCT and CRP in the presence of anti-T-lymphocyte antibodies. Dornbusch et al. compared 15 consecutive febrile episodes after T cell antibody infusion without clinical signs of infection with nine episodes of Gram-negative sepsis. After T-cell antibody infusion PCT and CRP serum levels increased to a similar extent as in Gramnegative sepsis. They concluded that during T-cell antibody treatment neither PCT nor CRP are adequate for differentiating between fever due to infection or to unspecific cytokine release. The median PCT elevation on day1 after T-cell antibody infusion was nearly 40 times the baseline [4]. In our patient, the levels reached 70 times the baseline value probably related to higher ATG dose according to the weight of the patient. Brodska et al., prospectively evaluated the validity of CRP and PCT to diagnose infection in patients receiving ATG prior to hematopoietic stem cell transplantation. They assessed renal and liver functions and their relationship to PCT and CRP changes. They found no interrelationship between PCT levels and BL markers of renal or liver functions (P &gt; 0.05 for all comparisons) [5]. Similarly in our patient, no derangements in LFT or RFTs were seen. To conclude, febrile episodes during treatment with ATG are associated with markedly elevated levels of PCT directly proportional to the dose of ATG given. This causes a diagnostic dilemma with sepsis and early use of antimicrobials, which may be kept in reserve during actual crisis in the post-transplant period. In such a scenario, detailed clinical assessment of patient’s condition and careful interpretation of biochemical and microbiological investigations is of utmost importance for judicious use of antimicrobials in this era of emerging antibiotic resistance.

531 - BMT CTN 1803: Haploidentical Natural Killer Cells (K-NK002) to Prevent Post-Transplant Relapse in AML and MDS (NK-REALM)

Background and Rationale: Relapse remains the leading cause of treatment failure for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic bone marrow transplantation (BMT). Although the risk depends on parameters such as age and conditioning intensity, relapse is experienced by 30-50% of patients after conventional BMT in high-risk AML/MDS. Initial safety and post-BMT relapse risk reduction results were reported from a phase I study of haploidentical (haplo) donor-derived natural killer (NK) cells expanded ex vivo on feeder cells expressing IL-21 and 4-1BBL (FC21-NK) in conjunction with haploBMT. Of 13 patients with high-risk myeloid malignancies treated with FC21-NK cells, no infusion reactions or dose-limiting toxicities occurred and only 1 patient, treated at the lowest dose of 1×105 cells/kg, relapsed (Ciurea, Blood, 2017). This experience supports investigation of K-NK002, a product derived from haploidentical donor NK cells and expanded ex vivo in a feeder cell-free system using plasma membrane (PM21) particles bearing membrane-bound IL-21 and 4-1BBL. We used contemporary data from the Center for International Blood and Marrow Transplant Research registry to determine baseline relapse rates that informed the statistical design. K-NK002 will be given in the peri-transplant period to test the hypothesis that haploidentical NK cells can mediate an effective anti-leukemia response. Trial Design and Methods: BMT CTN 1803 is a phase II, single-arm, open-label, multicenter trial designed to investigate the safety and efficacy of K-NK002 for the treatment of patients with high-risk AML or MDS undergoing haploBMT (NCT04395092). An initial 6 patient safety run-in phase will precede enrollment into the full study of approximately 60 patients. Major inclusion criteria of patients and donors are listed in Table 1. Production of the haploidentical donor NK-cells is completed prior to the planned haploBMT. BMT conditioning will consist of 140 mg/m2 (100 mg/m2 for patients ≥60 years old) melphalan on Day -7; 40 mg/m2 fludarabine on Days -7, -6, -5, and -4; and 2 Gy of total body irradiation on Day -3. Donor bone marrow will be harvested and given on Day 0. Three doses of K-NK002 (1×108 NK cells/kg) will be administered IV on Days -2, +7, and +28, relative to the haploBMT. Graft-versus-host disease (GVHD) prophylaxis consists of post-transplantation cyclophosphamide with tacrolimus and mycophenolate mofetil. The primary endpoint is cumulative incidence of relapse at 1 year post haploBMT in patients receiving at least 1 infusion of K-NK002. Secondary endpoints are safety and tolerability of K-NK002; overall survival; non-relapse mortality; relapse-free survival; GVHD-free survival; cumulative incidence of acute GVHD and chronic GVHD; hematologic recovery; donor-cell engraftment; primary and secondary graft failure; overall incidence of toxicity; and cumulative incidence of infections including cytomegalovirus re-activation and symptomatic BK virus hemorrhagic cystitis. Exploratory endpoints are systemic immunosuppression-free survival; immune reconstitution at Days 28, 100, and 365 post haploBMT; proportion of patients with detectable minimal residual disease at Days 28 and 100 post haploBMT; feasibility of administering the planned K-NK002 doses; and impact of NK-cell alloreactivity on relapse and survival. Download : Download high-res image (319KB) Download : Download full-size image Disclosures Bejanyan: Kiadis Pharma: Membership on an entity’s Board of Directors or advisory committees. Devine: Magenta Therapeutics: Consultancy. Luznik: WindMil Therapeutics: Patents & Royalties: Patent holder; Genentech: Research Funding; Merck: Research Funding, Speakers Bureau; AbbVie: Consultancy. Sandler: Kiadis Pharma: Current Employment. Krakow: HighPass Bio: Research Funding. Fitzgerald: Kiadis Pharma: Current Employment. Tracey: Kiadis Pharma: Current Employment. Champlin: DKMS America: Membership on an entity’s Board of Directors or advisory committees; Takeda: Patents & Royalties; Actinium: Consultancy; Johnson and Johnson: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; Genzyme: Speakers Bureau.

Body Irradiation Using Tomotherapy Helical &amp; Direct Technique Using Radixact for Young and Paediatric Patients

Background: We have treated 14 patients of total body irradiation (TBI) in Helical Tomotherapy, out of which 9 are males and 5 are females, age is 5 years to 33 years with acute lymphoblastic leukemia (ALL) remission or acute myeloic leukemia (AML). Total Body Irradiation is an important procedure in the conditioning for Bone Marrow and stem cell transplantation. We present here our treatment technique, treatment planning, delivery and dose verification. Standard Total prescribed dose of target volume 12 Gy in 6 fractions twice daily over 3 days to the whole body with Simultaneous Integrated Boost of 14 Gy/6# to brain. Dose volume constraint for the planning treatment volume (PTV) 95% of prescribed dose is getting by 95% of the volume. Material and Methods: We immobilized the whole body of the patients from Vac-loc and thermoplastic mask for head. We take two computerized tomography (CT) scan for treatment Planning. Result: Average dose D95 to the planning treatment volume was 11.7 Gy corresponding to a mean coverage of the planning treatment volume of 95%. Average dose (D-mean) for the lungs was not exceeding 9 Gy. Conclusions: Total Body Irradiation using helical Tomotherapy is achievable and well tolerated. Each dose distribution is homogeneous and reduce dose to at risk organ.

Prevention and treatment of radiation-induced lung injury.

Radiation-induced lung injury (RILI) is a common complication in cancer patients receiving local thoracic radiation and bone marrow transplantation conditioning. It is divided into early-stage radiation pneumonitis and advanced radiation fibrosis of thelung. This severely hampers the quality of life and survival of cancer patients. Meanwhile, RILI is a major factor limiting radiation doses in clinical practice, which affects the local control of cancer. Unfortunately, the mechanism of RILI is still not well defined, and there are no treatment options available for these patients. In this reviewwe summarizethe methods and agents used for the treatment and prevention of RILI, with theaim of increasingunderstanding ofRILI.

BMT CTN 1803: Haploidentical Natural Killer Cells (K-NK002) to Prevent Post-Transplant Relapse in AML and MDS (NK-REALM)

Background and Rationale: Relapse remains the leading cause of treatment failure for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic bone marrow transplantation (BMT). Although the risk depends on parameters such as age and conditioning intensity, relapse is experienced by 30-50% of patients after conventional BMT in high-risk AML/MDS. Initial safety and post-BMT relapse risk reduction results were reported from a phase I study of haploidentical (haplo) donor-derived natural killer (NK) cells expanded ex vivo on feeder cells expressing IL-21 and 4-1BBL (FC21-NK) in conjunction with haploBMT. Of 13 patients with high-risk myeloid malignancies treated with FC21-NK cells, no infusion reactions or dose-limiting toxicities occurred and only 1 patient, treated at the lowest dose of 1×105 cells/kg, relapsed (Ciurea, Blood, 2017). This experience supports investigation of K-NK002, a product derived from haploidentical donor NK cells and expanded ex vivo in a feeder cell-free system using plasma membrane (PM21) particles bearing membrane-bound IL-21 and 4-1BBL. We used contemporary data from the Center for International Blood and Marrow Transplant Research registry to determine baseline relapse rates that informed the statistical design. K-NK002 will be given in the peri-transplant period to test the hypothesis that haploidentical NK cells can mediate an effective anti-leukemia response. Trial Design and Methods: BMT CTN 1803 is a phase II, single-arm, open-label, multicenter trial designed to investigate the safety and efficacy of K-NK002 for the treatment of patients with high-risk AML or MDS undergoing haploBMT (NCT04395092). An initial 6 patient safety run-in phase will precede enrollment into the full study of approximately 60 patients. Major inclusion criteria of patients and donors are listed in Table 1. Production of the haploidentical donor NK-cells is completed prior to the planned haploBMT. BMT conditioning will consist of 140 mg/m2 (100 mg/m2 for patients ≥60 years old) melphalan on Day -7; 40 mg/m2 fludarabine on Days -7, -6, -5, and -4; and 2 Gy of total body irradiation on Day -3. Donor bone marrow will be harvested and given on Day 0. Three doses of K-NK002 (1×108 NK cells/kg) will be administered IV on Days -2, +7, and +28, relative to the haploBMT. Graft-versus-host disease (GVHD) prophylaxis consists of post-transplantation cyclophosphamide with tacrolimus and mycophenolate mofetil. The primary endpoint is cumulative incidence of relapse at 1 year post haploBMT in patients receiving at least 1 infusion of K-NK002. Secondary endpoints are safety and tolerability of K-NK002; overall survival; non-relapse mortality; relapse-free survival; GVHD-free survival; cumulative incidence of acute GVHD and chronic GVHD; hematologic recovery; donor-cell engraftment; primary and secondary graft failure; overall incidence of toxicity; and cumulative incidence of infections including cytomegalovirus re-activation and symptomatic BK virus hemorrhagic cystitis. Exploratory endpoints are systemic immunosuppression-free survival; immune reconstitution at Days 28, 100, and 365 post haploBMT; proportion of patients with detectable minimal residual disease at Days 28 and 100 post haploBMT; feasibility of administering the planned K-NK002 doses; and impact of NK-cell alloreactivity on relapse and survival. Disclosures Bejanyan: Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees. Devine:Magenta Therapeutics: Consultancy. Luznik:WindMil Therapeutics: Patents &amp; Royalties: Patent holder; Genentech: Research Funding; Merck: Research Funding, Speakers Bureau; AbbVie: Consultancy. Sandler:Kiadis Pharma: Current Employment. Krakow:HighPass Bio: Research Funding. Fitzgerald:Kiadis Pharma: Current Employment. Tracey:Kiadis Pharma: Current Employment. Champlin:DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents &amp; Royalties; Actinium: Consultancy; Johnson and Johnson: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; Genzyme: Speakers Bureau.

Novel Approach for Bone Marrow Transplantation Conditioning in Acute Myelogenous Leukemia not Responding to the Induction Therapy Using Etoposide Carried in Lipid Core Nanoparticles: A Pilot Clinical Study

Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for acute myelogenous leukemia (AML) not responding to induction therapy. It is a therapeutic choice for the blast phase of chronic myelogenous leukemia (CML-BP) in patients failing to respond to tyrosine kinase inhibitors (TKIs). Lipid core nanoparticles (LDEs) concentrate severalfold more in blast cells than in corresponding normal cells. Incorporation of anticancer drugs to LDE formulations increases the pharmacologic action and decreases the toxicity. We tested a drug-targeting system, LDE-etoposide plus total body irradiation (TBI; 1200 cGy dose), in 13 patients with AML not responding to the induction therapy and in 2 patients with CML-BP refractory to second-generation TKIs. The mean patient age was 46.7 years (range, 22 to 66 years). The LDE-etoposide dose was escalated at 20, 30, 40, 50, and 60 mg/kg. No patients developed grade 4 or 5 toxicity; however, mucositis grade 3 occurred in 6 patients, 3 patients experienced diarrhea, and 1 patient had an elevated total bilirubin level. No deaths were related to conditioning. All patients were successfully engrafted. The median times to neutrophil and platelet engraftment were 20 ± 5 days and 16 ± 4 days, respectively. Five patients (33.4%) had acute graft-versus-host-disease (GVHD), including 4 grade I, and 1 with grade II, and 8 patients (57.1%) had moderate-to-severe chronic GVHD. This pilot study shows the potential of LDE-etoposide plus TBI as an HCT conditioning regimen in AML patients not responding to the induction and refractory therapies for CML-BP patient. These findings pave the way for subsequent larger clinical trials.

Image-guided total-body irradiation with a movable electronic portal imaging device for bone marrow transplant conditioning

IntroductionTo prevent radiation pneumonitis following total body irradiation (TBI) clinicians usually use lung shield blocks. The correct position of these shields relative to the patient's lungs is usually verified via mega-voltage imaging and computed radiographic (CR) films. In order to improve this time-consuming procedure, we developed in our department a dedicated, movable, real-time imaging system for image-guided TBI. Material & MethodsThe system consists of an electronic portal imaging device (EPID) mounted on a dedicated support whose motion along a rail can be controlled from the linac console outside the bunker room. Images are acquired online using a stand-alone console. To test the system efficacy we retrospectively analyzed data of lung blocks positioning from two groups of 10 patients imaged with EPID or CR-films, respectively. ResultsThe median number of portal images per fraction was 2 (range 1-5) and 1 (range 1-2) for the EPID and the CR-film system, respectively. The minimum time required for an EPID image acquisition, without interpretation and no need of patient position correction in the bunker, was 20seconds against 214seconds for the CR-film. Lung shielding positioning in the right-left and superior-inferior directions was improved using the EPID system (p<0.01). ConclusionsCompared to CR-films, our movable real-time imaging EPID system is a simple technical solution able to reduce the minimum imaging time for lung shielding by a factor of 10. With the increased possibility to acquire more images as compared to CR-film system the EPID system has the potential to improve patient alignment, as well as patient's comfort and overall setup time.

Reduced Intensity Conditioning for Haploidentical Bone Marrow Transplantation in Patients with Symptomatic Sickle Cell Disease: BMT CTN Protocol 1507

Background: Hematopoietic cell transplantation (HCT) has curative potential in sickle cell disease (SCD). A reduced intensity haploidentical bone marrow transplant (haplo-BMT) platform piloted by investigators at Johns Hopkins, addressed key barriers in HCT for SCD, donor availability and toxicity, but had a graft rejection rate of 43%. (Blood. 2012;120(22):4285-4291). Subsequently, a Vanderbilt University Medical Center supported multi-institution learning collaborative with London, France and United States was developed in 2013 with the objective of reducing this graft rejection rate. Evolution of this haplo-BMT platform with the addition of only thiotepa, resulted in a reduction in the graft rejection rate to 7% (1 of 15), an event free survival (EFS) of 93% (14 of 15), &amp;gt; 95% stable donor engraftment at 6 months and 100% overall survival (Biol Blood Marrow Transplant. 2019 Jun;25(6):1197-1209). Based on the preliminary data from the learning collaborative, we initiated an NIH sponsored BMT CTN, dual-strata, phase II, multi-center prospective clinical trial, (clinicaltrials.gov # NCT03263559) to estimate event free survival (EFS) at 2 years in children with neurological morbidity and adults with severe SCD. Study Design and Methods: Eligibility: Patients are stratified into 2 groups: (1) children with SCD (Hb SS or Sβ+ Thalassemia) between 5.00 - 14.99 years of age with central nervous system (CNS) disease (stroke, elevated transcranial Doppler (TCD) with evidence of intracranial vasculopathy; silent cerebral infarction) and (2) adults with severe SCD (Hb SS, SC, Sβ° thalassemia, Sβ+ Thalassemia, SD, S-OArab), between 15.00 - 45.99 years of age who have had a stroke, recurrent ACS, recurrent vaso-occlusive pain episodes, chronic transfusions to prevent sickle complications and tricuspid valve regurgitant jet velocity (TRJV) ≥2.7 m/sec. Participants must have an HLA haploidentical first degree relative donor with 2, 3, or 4 (out of 8) HLA-mismatches who is willing and able to donate bone marrow. Those with an HLA-matched sibling are excluded. Primary objective is to estimate EFS at 2 years after haplo-BMT in patients with SCD enrolled in each stratum. Secondary objectives include determining the effect of haplo-BMT on clinical and laboratory manifestations of SCD by 2 years post-transplant and determining the incidence of other transplant-related outcomes. A key secondary analysis will be central adjudication of CNS progression in children and adults with evidence of previous CNS injury. Treatment Description: Preconditioning with hydroxyurea 30mg/kg daily (Day -70 to Day -10). The conditioning regimen includes: Thymoglobulin (rATG) (0.5mg/kg on Day -9, 2mg/kg on Day -8, Day -7), Thiotepa 10mg/kg on Day -7, Fludarabine (30mg/m2 on Day -6 to Day -2), Cyclophosphamide 14.5mg/kg on Day -6 and Day -5, and TBI 200cGy on Day -1. Day 0 is the day of infusion with non T-cell depleted bone marrow. Cyclophosphamide 50 mg/kg and Mesna 40mg/kg is given on Days +3 and +4, and GVHD prophylaxis (sirolimus and mycophenolate mofetil) begin on Day +5 (Figure). Study Accrual and Endpoints: The target sample size is 40 patients enrolled and treated in each stratum; if the stopping rule for graft failure is triggered within the first 12 evaluable participants in either stratum using the 200cGy dose of TBI and the DSMB and sponsor approve the pre-defined switch in conditioning regimen, then accrual for that strata will restart under the modified conditioning regimen with 400 cGy TBI. The estimated accrual period is 4 years. The rate of overall mortality by Day 180 after starting hydroxyurea therapy pre-transplant, acute grade III-IV GVHD at 100 days, and severe chronic GVHD at 18 months post-transplant will be monitored by a sequential probability ratio test (SPRT) for censored exponential data for each of these. Graft failure at 100 days post-transplant will be monitored by using a SPRT for binary data. Conclusion: This NIH sponsored BMTCTN phase II trial of HLA-haploidentical HCT is active at 30 BMT CTN sites. This study will determine if a modulated conditioning regimen has adequate donor engraftment, with acceptable risks of transplant-related morbidity and mortality to support a future comparative clinical trial in SCD. Figure Disclosures Walters: AllCells, Inc: Consultancy; TruCode: Consultancy; Editas Medicine: Consultancy. Brodsky:Achillion: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding.

Total body irradiation: Significant dose sparing of lung tissue achievable by helical tomotherapy

PurposeTotal body irradiation (TBI) is an important procedure in the conditioning for bone marrow and hematopoietic stem cell transplantation. Doses up to 12Gy are delivered in hyperfractionated regimes. TBI performed with helical Tomotherapy® (Accuray, Madison, Wisconsin, USA) is an alternative to conventional techniques to deliver dose in extended target volumes with the possibility of simultaneous dose sparing to organs at risk. In this study we focused on maximum dose reduction to the lungs in TBI using helical Tomotherapy®. Material and methodsForty treatment plans of patients who received TBI were calculated with TomoH® (Accuray, Madison, Wisconsin, USA, Version 2.0.4) with a dose of 12Gy delivered in six equal fractions (2×2Gy/day). Planning iterations necessary to accomplish ICRU 83 report should be less than 250. Treatment time should be practicable in daily routine (<60min.). Besides the usual contouring of organs at risk special contouring was required for optimization processes which focused on maximum dose sparing in the central lung tissue. Dose constraints (D2, D98, D99) were predefined for target volumes (i.e. PTV TBI D99: 90% of prescribed dose). Homogeneity index <0.15 was defined for acceptability of the treatment plan. ResultsFor all patients acceptable treatment plan fulfilling the predefined constraints were achievable. An average time of 46min is required for treatment. Thirty-four of forty patients fulfilled D2 in the PTV TBI. Four patients failed D2 due to a high BMI >28 (maximum dose 13.76Gy=114.7%). The D98 in the PTV TBI was not reached by 2/40 patients due to BMI>31 (minimum dose 11.31Gy=dose coverage of 94.2%). Also these two patients failed the homogeneity index <0.15. The mean lung dose over all patients of the right lung was 7.18Gy (range 6.4–9.5Gy). The left lung showed a median (D50) dose of 7.9Gy (range 6.7–9.3Gy). Central lung dose showed a mean dose (D50) of 5.16Gy (range 4.02–7.29Gy). The D80 of the central lung showed an average dose of 3.87Gy. ConclusionsTotal body irradiation using helical Tomotherapy® can be delivered with maximum lung tissue sparing (<6Gy) but without compromise in adjacent PTV TBI structures (i.e. ribs, heart). High conformity and homogeneity in extended radiation volumes can be reached with this technique in an acceptable planning and treatment time. Limitations may occurred in patients with high body mass index.

Eculizumab to Treat Posterior Reversible Encephalopathy Syndrome Due to Underlying Transplant-Associated Thrombotic Microangiopathy in Patients Receiving Allogeneic Hematopoietic Cell Transplant for Sickle Cell Disease

Pre-existing endothelial dysfunction and vascular injury sustained during allogeneic hematopoietic stem cell transplantation (HCT) increases risk for endothelial injury-related complications like posterior reversible encephalopathy (PRES) and transplant-associated thrombotic microangiopathy (TA-TMA) in patients with sickle cell disease (SCD). Herein, we report two SCD HCT recipients in whom PRES-related symptoms resolved only after eculizumab therapy was initiated for underlying TA-TMA. Case 1 25-year-old male with SCD developed PRES-related seizures and headaches on Day+30 following matched sibling donor bone marrow transplant (BMT) and reduced-intensity conditioning (RIC) with fludarabine/melphalan/alemtuzumab and graft-versus-host disease (GvHD) prophylaxis with tacrolimus and methotrexate (MTX). Symptoms initially resolved after discontinuing tacrolimus. However, on Day+60, he presented with hypertension (HTN), status epilepticus, and right intracranial hemorrhage. Despite adequate HTN control and maximal anti-epileptic therapy, his symptoms persisted. Two weeks later, laboratory testing confirmed TA-TMA. Both PRES and TA-TMA symptoms and signs resolved after five weeks of eculizumab therapy (Figure 1). Case 2 Eight-year-old female with SCD underwent 10/10 matched unrelated BMT following RIC with fludarabine/melphalan/thiotepa/alemtuzumab and MTX/tacrolimus/abatacept for GvHD prophylaxis. She developed altered mental status, seizures, and HTN and Day+74 MRI brain confirmed PRES. Her symptoms also persisted despite tacrolimus cessation and effective HTN control. One week later, laboratory testing confirmed TA-TMA. Complete resolution of neurological symptoms occurred after three weeks of eculizumab therapy. (Figure 2). Conclusion Our cases highlight maintaining a high level of clinical suspicion for TA-TMA in SCD patients presenting with PRES post-HCT and consideration for eculizumab therapy in such patients.

Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide.

Post-transplant cyclophosphamide (PTCy) can be used as the sole immunosuppression after myeloablative conditioning (MAC) for HLA-matched bone marrow transplantation (BMT). However, the effects of graft-versus-host disease (GVHD) with this platform are undefined. We retrospectively analyzed 298 consecutive adult patients with hematologic malignancies who engrafted after MAC HLA-matched sibling donor (MSD; n = 187) or HLA-matched unrelated donor (MUD; n = 111) T-cell-replete BMT with PTCy 50 mg/kg on days +3 and +4. After MSD and MUD BMT, 35% and 57% of patients, respectively, developed grade II acute GVHD (aGVHD) by 100 days, 11% and 14% grade III to IV aGVHD by 100 days, and 9% and 16% chronic GVHD (cGVHD) by 1 year. In landmark analyses at 100 days after HLA-matched BMT, 4-year overall survival (OS) and progression-free survival (PFS) were 57% (95% confidence interval [CI], .49 to .67) and 40% (95% CI, .31 to .51) in patients without grades II to IV aGVHD, and 68% (95% CI, .59 to .78) and 54% (95% CI, .44 to .65) in patients with grade II aGVHD. In adjusted time-dependent multivariable analyses, grade II aGVHD was associated with improved OS (hazard ratio, .58; 95% CI, .37 to .89; P = .01) and PFS (hazard ratio, .50; 95% CI, .34 to .74; P < .001) after HLA-matched BMT with PTCy. The ability of PTCy to limit grades III to IV aGVHD and cGVHD while maintaining grade II aGVHD may contribute to its effectiveness, and further attempts to reduce aGVHD may be detrimental.

Bendamustine Conditioning Alters Host Dendritic Cell Composition and Function

BackgroundA largely understudied strategy for reducing graft-versus-host disease (GvHD) is the modification of conditioning regimens. We have demonstrated that pre-transplant bendamustine (BEN) used in combination with total body irradiation (TBI) significantly reduces GvHD compared to the more commonly used cyclophosphamide (CY) + TBI. The short half-lives of BEN/CY (<4h), which are given 48h prior to transplant, indicate that these drugs do not directly affect the donor cells. Therefore, the striking improvement in GvHD by substituting CY with BEN must be due to differential effects on the host cells. Conditioned host immune cells diminish over time, but are the majority early after transplant and are able to critically interact with the infused donor cells at the earliest stages of GvHD pathogenesis.MethodsUsing an MHC-mismatched murine model of bone marrow transplantation (BMT) with C57BL/6 donors into BALB/c recipients (H2Kb into H2Kd), we evaluated the differential effects of BEN conditioning on host dendritic cells (DCs) early after transplant, as compared to CY conditioning. Transplant recipient mice were conditioned with BEN or CY on day -2 pre-BMT, and supplemented with 400cGy of total body irradiation on day -1. On days 1, 3, and 5 post-BMT, splenic pan-DCs were isolated and analyzed by flow cytometry to evaluate host (H2Kb-) DC phenotype and activation state. Further, on day 0 (without BMT), circulating leukocytes and splenic pan-DCs were isolated from conditioned mice and analyzed by flow cytometry, qPCR and allogeneic mixed leukocyte reactions.ResultsWe found that BEN-conditioned pan DCs are less stimulatory of allogeneic T-cells than CY-treated DCs. BEN conditioning significantly alters host DC composition compared to CY conditioning, resulting in a significantly higher frequency and number of host CD8α+ DCs on days 1 and 3 post-BMT. BEN-conditioned CD8α+ DCs also display a highly regulatory phenotype (CD80highCD86low) and have greater suppressive ability compared to CY-conditioned CD8α+ DCs. Analysis of host DCs on day 0 (without BMT) revealed a significantly greater percentage of BEN-conditioned DCs positively expressing the Flt3 receptor compared to CY.ConclusionsThese findings advocate a potential role of Flt3L-dependent DCs, particularly CD8α+ DCs, in the mechanism by which BEN alters GvHD pathogenesis to limit morbidity and mortality. Thus, BEN may have advantages as an alternative agent to CY for pre-transplant conditioning in allogeneic BMT. DisclosuresNo relevant conflicts of interest to declare.

HLA Class I Alloimmunization and Platelet Transfusion Support in HLA-Identical Bone Marrow Transplant for Sickle Cell Disease: A Sickle Transplant Alliance for Research Study

Introduction: HLA alloimmunziation has been described in patients, including pediatric patients with sickle cell disease (SCD), who received only leukocyte-reduced red blood cell (RBC) transfusions. While HLA alloimmunization has significant implications in bone marrow transplant (BMT) with an HLA-disparate donor (donor-specific HLA antibodies increase the risk of graft rejection), the clinical significance of this alloimmunization in HLA-identical BMT is unclear. In particular, it is unknown whether HLA class I alloimmunization affects platelet transfusion support during BMT. Platelet transfusions are especially important in BMT for SCD because of the historic high incidence of intracranial bleeding and the subsequent adoption of a relatively high platelet transfusion threshold.Methods: We tested for HLA class I alloimmunization using pre-BMT serum or plasma from 32 pediatric patients with SCD undergoing BMT with an HLA-identical sibling donor. HLA class I alloimmunization was evaluated using the FlowPRA® (panel reactive antibody) screening test which detects IgG antibodies to the majority of HLA class I antigens. Pre-BMT, patients had received leukocyte-reduced RBC transfusions. All patients undergoing BMT received leukocyte-reduced, irradiated, apheresis platelet transfusions to maintain a platelet count greater than 50 x 109/L. The number of platelet transfusions received in the first 45 days post-BMT was compared between those with a positive PRA versus those with a negative PRA using a two-sample t-test.Results: Among the 32 patients studied, the mean age at BMT was 9.4 years (range 1-21 years). Pre-BMT, 40% had received greater than 10 RBC transfusions and 32% of the entire cohort was receiving chronic RBC transfusions. BMT conditioning regimens included: traditional myeloablative busulfan, cyclophosphamide, antithymocyte globulin (BU-CY-ATG) (n=10); dose-reduced BU-CY-ATG + fludarabine (flu) (n=16); reduced intensity conditioning (RIC) alemtuzumab, flu, melphalan +/- thiotepa (n=5); and RIC BU-flu-ATG (n=1). All patients received HLA-identical sibling donor bone marrow, with 3 patients receiving a combined bone marrow and cord blood graft. All patients engrafted with 100% survival at day +45. Six patients developed acute graft-versus-host disease (GVHD): 1 grade I, 3 grade II, 1 grade 3, 1 grade 4. No patient had an intracranial bleed or other serious bleeding.From testing of the pre-BMT sample, 11/32 (34%) of patients had a positive HLA class I antibody screen. HLA class I alloimmunized patients received significantly more platelet transfusions than non-alloimmunized patients: mean 19.2 (SD 13.9) vs. 11.2 (SD 8.0) transfusions, p=0.049 (Figure). On univariate analysis, age, sex, conditioning regimen, and GVHD were each not significantly associated with the number of platelet transfusions (p>0.1). Only two patients developed hepatic sinusoidal obstruction syndrome (one HLA alloimmunized patient, one non-alloimmunized patient). Mean day of platelet engraftment was not significantly different between alloimmunized compared to non-alloimmunized patients: day +34.6 (SD 10.6) vs. day +30.2 (SD 11.3), p=0.28. Among HLA class I alloimmunized patients, the mean positive PRA was 19.7% (range 4-55%); there was no association with this PRA value and the number of platelet transfusions (r2=0.0064, p=0.81).Conclusion: In pediatric HLA-identical sibling BMT for SCD, pre-BMT HLA class I alloimmunization (but not the absolute PRA value) appears to be associated with more platelet transfusions. It is unclear if this increased platelet transfusion requirement is due directly to HLA antibody immune-mediated clearance of transfused platelets or other inherent differences of HLA class I alloimmunized patients. [Display omitted] DisclosuresQayed:Novartis: Consultancy.

Dose calculation with MCNPX code for Total Body Irradiation technique in sitting and lying postures

Total Body Irradiation (TBI) is a radiotherapy technique used to destroy malignant cells in bone marrow transplant conditioning regimens. The aim of this work was to estimate the equivalent and effective doses in TBI computational scenarios to analyze the changes in these quantities for different sources (cobalt-60 source and 6 MV photon beam), postures of the phantom, irradiation geometries, backscatter factors, and attenuators. The simulations were performed in MCNPX code using hybrid phantoms from the University of Florida. The simulation results showed uniform equivalent doses for the phantoms in the lying posture. It is also observed that when the phantoms are closer to a wall, there is an additional dose contribution of up to 6.55% to organs near to this structure. When the lead attenuators for the lungs are not present in exposure scenarios, the equivalent dose increases by more than 20%. For the effective dose, the values are considerably higher for the left lateral projection due to the greater energy absorption by more radiosensitive organs. The results of the simulations reaffirm the data found in the literature about TBI procedures.

Total body irradiation in allogeneic bone marrow transplantation conditioning regimens: A review.

Hematologic malignancies may require, at one point during their treatment, allogeneic bone marrow transplantation. Total body irradiation combined with chemotherapy or radiomimetic used in allogeneic bone marrow transplantation is known to be very toxic. Total body irradiation (TBI) induces immunosuppression to prevent the rejection of donor marrow. TBI is also used to eradicate malignant cells and is in sanctuary organs that are not reached by chemotherapy drugs. TBI has evolved since its introduction in the late fifties, but acute and late toxicities remain. Helical tomotherapy, which is widely used for some solid tumors, is a path for the improvement of outcomes and toxicities in TBI because of its sparing capacities. In this article, we first review the practical aspects of TBI with patient positioning, radiobiological considerations and total dose and fractionation prescriptions. Second, we review the use of intensity modulated radiation therapy in bone marrow transplantation with a focus on helical tomotherapy TBI, helical tomotherapy total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) and their dosimetric and clinical outcomes. Finally, we review the perspective of dose escalation and the extension to older patients and patients with comorbidity who do not benefit from a standard bone marrow transplantation conditioning regimen.

Outcome of Pediatric Cataract Surgery in Patients Who Have Undergone Bone Marrow Transplantation

Purpose: Bone marrow transplantation (BMT) and pre-treatment conditioning increases the risk of developing pediatric cataracts. We present the outcome of cataract surgery in children who have had BMT. Methods: We conducted a retrospective chart study with 15 BMT patients (28 eyes) who underwent cataract extraction between 2002 and 2012. Outcome measures include change in best corrected visual acuity (BCVA) and complications. Results: 7 (47%) patients had acute lymphoid leukemia, 3 (20%) had acute myeloid leukemia, 2 (13%) had myelodysplastic syndrome, 1 (7%) had Fanconi anemia, 1 (7%) had juvenile myelomonocytic leukemia, and 1 (7%) had adrenoleukodystrophy. Patients received BMT at a mean age of 3.9 ± 1.6 years. 12 (80%) patients received total body irradiation (TBI) and 3 of these 12 received cranial irradiation in addition to TBI; one (7%) received only cranial irradiation. Total body irradiation included head and eye exposure. Mean age of cataract surgery was 9.1 ± 2.3 years; mean follow-up was 55.9 ± 45.1 months. All cataracts were of posterior subcapsular subtype. Mean BCVA improved from 0.7 ± 0.4 logMAR to 0.3 ± 0.5 logMAR (p

Reduction in Bone Marrow Insulin-like Growth Factor-1 Levels Enhances Long-Term Hematopoietic Stem Cell Engraftment Following Bone Marrow Transplantation

Efficient donor hematopoietic stem cell (HSC) engraftment is critical for successful bone marrow transplantation (BMT) and requires interactions between donor HSC and host-derived HSC niche elements. Due to disruption of perivascular stem cell niches induced by myeloablative BMT conditioning, initial engraftment of HSC following BMT occurs in niches located near the endosteum. We have previously shown that myeloablative BMT conditioning with total body irradiation (TBI) induces expansion of endosteal niche osteolineage cells in a time course correlating with increases in bone marrow (BM) levels of insulin-like growth factor (IGF)-1. We also have shown that inhibition of IGF-1 Receptor (IGF1R) signaling blocks osteolineage cell expansion after TBI, resulting in poor engraftment of long-term (LT)-HSC after BMT and suggesting a critical role for IGF-1/IGF1R interactions in regulating engraftment after BMT. We now present data in which we have defined the cellular sources of BM IGF-1 following TBI and have surprisingly discovered that reduction in BM IGF-1 levels promotes LT-HSC retention at baseline and donor LT-HSC engraftment following BMT.Using mice with floxed IGF-1 alleles (IGF1L/L) and with tissue-specific expression of Cre-recombinase, we generated models with deletion of IGF-1 derived from mature osteolineage cells (Col1A1CreIGF1Exc), hematopoietic cells (CD45CreIGF1Exc), or liver (AlbCreIGF1Exc). We additionally generated a conditional IGF-1 deletion model (MX1CreIGF1Exc) in which polyI:polyC (pI:pC) treatment disrupts IGF-1 production from all 3 of the above sources.By qPCR analysis, CD45CreIGF1Exc BM showed marked reduction (>95%) in BM IGF-1 mRNA at baseline and following TBI, suggesting that hematopoietic cells produce most of the locally derived IGF-1 in BM. Unexpectedly however, neither deletion of osteoblast-derived (Col1A1CreIGF1Exc) nor hematopoietic cell-derived (CD45CreIGF1Exc) IGF-1 significantly reduced BM extracellular or intracellular IGF-1 protein levels at baseline, or extracellular BM IGF-1 levels following TBI. In contrast, elimination of liver-derived IGF-1 in AlbCreIGF1Exc mice not only reduced plasma IGF-1 levels by 80%, but surprisingly reduced BM extracellular IGF-1 protein levels by ≥80% both at baseline and 48 hours post-TBI, and reduced BM intracellular IGF-1 protein levels by >80% and >60% at baseline and post-TBI, respectively. These data suggest that most IGF-1 protein in BM during BMT is derived from liver. Conditional IGF-1 deletion in MX1CreIGF1Exc mice resulted in severe reduction of both BM IGF-1 mRNA and protein levels, combining effects seen in CD45CreIGF1Exc and AlbCreIGF1Exc mice. None of these models, however, showed deficits in TBI-induced endosteal cell expansion, suggesting that other ligands or perhaps only low levels of IGF-1 are required to induce IGFR1 signaling-dependent endosteal cell expansion.Unexpectedly, reduction of BM IGF-1 in ALBCreIGF1Exc and MX1CreIGF1Exc mice caused a 3-4 fold increase (% of total BM) in BM Lin-cKit+Sca1+CD48-CD150+ or Lin-cKit+Sca1+CD34-CD135- HSC. ALBCreIGF1Exc BM displayed enhanced multi-lineage long-term repopulating capacity in competitive transplant assays, proving that these cells are functional LT-HSC. Given this baseline LT-HSC enhancement, we asked if reduction in BM IGF-1 levels impacted capacity of ALBCreIGF1Exc BM niches to engraft donor HSC after BMT. Using competitive secondary transplantation assays to assess numbers of engrafted WT GFP+ LT-HSC 3 weeks after primary BMT into ALBCreIGF1Exc or control mice, we found that reduced IGF-1 in the ALBCreIGF1Exc BM microenvironment resulted in >2.5 fold enhancement of donor LT-HSC engraftment. In an initial search of downstream mediators of this effect, we discovered that reduction of IGF-1 levels in MX1CreIGF1Exc BM results in a 2.5-fold increase in post-TBI CXCL12 mRNA expression, suggesting that reducing BM IGF-1 may enhance donor LT-HSC engraftment by promoting LT-HSC homing and maintenance within HSC niches.Taken together our data define a critical role for IGF-1/IGF1R interactions in regulating the efficiency of donor HSC engraftment following BMT. Therapeutic strategies to reduce BM IGF-1 may prove to be a valuable approach to improving engraftment following clinical BMT. DisclosuresNo relevant conflicts of interest to declare.