scholarly journals Tomotherapy Applied Total Lymphoid Irradiation and Allogeneic Hematopoietic Cell Transplantation Generates Mixed Chimerism in the Rhesus Macaque Model

2021 ◽  
Author(s):  
Lisa Forrest ◽  
John Fechner ◽  
Jennifer Post ◽  
Nathaniel Van Asselt ◽  
Kevin Kvasnica ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Hematopoietic Cell Transplantation ◽  
Rhesus Macaques ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Mixed Chimerism ◽  
Total Lymphoid Irradiation ◽  
Group Of Seven ◽  
Macaque Model ◽  
Total Body

Development of a new methodology to induce immunological chimerism after allogeneic hematopoietic cell (HC) transplantation in a rhesus macaque model is described. The chimeric state was achieved using a non-myeloablative, helical tomotherapy-based total lymphoid irradiation (TomoTLI) conditioning regimen followed by donor HC infusions between 1-haplotype matched donor/recipient pairs. The technique was tested as a feasibility study in an experimental group of seven rhesus macaques that received the novel TomoTLI tolerance protocol and HC allo-transplants. Two tomotherapy protocols were compared: TomoTLI (n = 5) and TomoTLI/total-body irradiation (TBI) (n = 2). Five of seven animals developed mixed chimerism. Three of five animals given the TomoTLI protocol generated transient mixed chimerism with no graft-versus-host disease (GVHD) with survival of 33, 152 and >180 days. However, the inclusion of belatacept in addition to a single fraction of TBI resulted in total chimerism and fatal GVHD in both animals, indicating an unacceptable conditioning regimen.

scholarly journals Experiences of allogeneic hematopoietic cell transplantation following non-myeloablative conditioning regimen in severely comorbid patients with myelofibrosis: case series with a patient presenting with extensive extramedullary hematopoiesis

2020 ◽  
Vol 11 ◽  
pp. 204062072093203 ◽  
Author(s):  
Jae-Ho Yoon ◽  
Sung-Soo Park ◽  
Gi June Min ◽  
Silvia Park ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Extramedullary Hematopoiesis ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Mixed Chimerism ◽  
Molecular Response ◽  
Donor Chimerism

We have performed allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced intensity conditioning regimen for curative management of advanced myelofibrosis (MF). However, allo-HCT is rarely considered for elderly or patients with severe comorbidities due to high transplantation-related mortality. In those patients, an alemtuzumab-based non-myeloablative (NMA) conditioning regimen followed by stem cell transplantation could be a possible treatment that has been tried in sickle cell anemia showing stable mixed chimerism and improvement of the disease. However, it is uncertain whether this regimen can provide durable donor-dominant chimerism also in patients with MF. We planned a two-stage allo-HCT in four patients – initially aimed at mixed chimerism with NMA conditioning and then reinforced with additional stem cell infusion if graft failure occurred. In one case with extensive extramedullary hematopoiesis, causing blindness and paraplegia, we achieved stable complete donor-chimerism and complete molecular response with disappearance of bone marrow fibrosis after allo-HCT. Although this NMA regimen failed to achieve durable donor-chimerism, additional stem cell infusion showed a possible role for stable long-term chimerism with good clinical outcomes. Although it leaves room for further improvement, allo-HCT using an NMA conditioning regimen may be worth consideration for advanced MF patients with severe comorbidity, otherwise no appropriate treatment option is available.

Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3390-3400 ◽  
Author(s):  
Peter A. McSweeney ◽  
Dietger Niederwieser ◽  
Judith A. Shizuru ◽  
Brenda M. Sandmaier ◽  
Arthur J. Molina ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Rejection ◽  
Hematopoietic Cell Transplantation ◽  
Hematologic Malignancies ◽  
Outpatient Setting ◽  
Hematopoietic Cell ◽  
Mixed Chimerism ◽  
High Dose ◽  
Antitumor Effects ◽  
Total Body

Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies.

Anti-CD45 Radioimmunotherapy Facilitates Donor Engraftment and Prolongs Survival in the Absence of TBI Prior to Haploidentical Bone Marrow Transplantation in a Disseminated Murine Leukemia Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4101-4101
Author(s):  
Johnnie J. Orozco ◽  
Aimee Kenoyer ◽  
Ethan R. Balkin ◽  
Donald K. Hamlin ◽  
D Scott Wilbur ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Flow Cytometric Analysis ◽  
Hematologic Malignancies ◽  
Leukemic Cells ◽  
Mixed Chimerism ◽  
Cd8 Cells ◽  
Flow Cytometric ◽  
Total Body

Abstract Abstract 4101 Background: Despite the curative promise of hematopoietic cell transplantation (HCT), many patients with hematologic malignancies relapse and others may not proceed to HCT due to the unavailability of a matched donor. Toxicities remain high with HCT, due in part to the administration of non-specific therapies such as total body irradiation (TBI) as part of preparative regimens. We aim to overcome these limitations by replacing TBI with anti-CD45 radioimmunotherapy (RIT) for haploidentical HCT to deliver radiation directly to leukemic cells while sparing normal organs and minimizing non-specific toxicities. Methods: We established an initial TBI HCT regimen in B6SJLF1/J mice (H-2Db haplotype) conditioned with fludarabine (FLU, days -6 to -2), followed by TBI (250, 500, 750 cGy; day -1). The mice then received 15 million donor (CB6F1/J, H-2Dd) BM cells (day 0), followed by cyclophosphamide (CY) for graft-versus-host disease (GvHD) prophylaxis (day +2). Subsequent RIT HCT studies involved B6SJLF1/J mice conditioned with and without fludarabine (FLU) and escalating doses (200–400 μCi) of 90Y-anti-CD45 Ab (30F11) RIT without TBI, followed by infusion of haploidentical BM cells from CB6F1/J mice and a single dose of cyclophosphamide (CY) 2 days after HCT. Chimerism studies were performed using flow cytometric analysis to assay for engraftment of donor CD8+ cells. Therapeutic studies were performed in B6SJLF1/J mice given 105 syngeneic leukemia cells via tail vein (day -5), followed by 200 or 400 μCi 90Y-30F11 (day -3), and 1.5 × 107 BM donor cells (day 0) and two doses of CY (days -2 and +2) without FLU. Results: Using this model we have demonstrated that mixed chimerism was established in mice transplanted with TBI or escalating doses (200–400 μCi) of 90Y-30F11 RIT followed by injection of haploidentical BM donor rescue cells. TBI-based HCT showed that chimerism as determined by flow cytometric analysis for donor CD8+ cells was TBI dose-dependent; mice receiving ≥500 cGy were fully chimeric 4 weeks post-HCT, and persisted ≥12 months. RIT-based HCT also revealed mice with mixed chimerism, with up to 89% of donor CD8+ cells 1 month after HCT. Elimination of FLU from the conditioning regimen did not significantly decrease chimerism, as mice transplanted without FLU showed up to 70% donor CD8+ cells 1 month after HCT. Subsequent RIT experiments in B6SJLF1/J mice harboring AML were treated with escalating doses of 90Y-30F11 prior to HCT without FLU. Mice treated with anti-CD45 RIT using 200 μCi and 400 μCi of 90Y-30F11 had a median overall survival (OS) of 73 (p<0.001) and 107.5 (p=0.0015) days, respectively, compared to untreated leukemic control mice which had a median OS of 34 days after HCT (p values by Log rank (Mantel-Cox) testing)(Figure). Two mice in the 400 μCi-90Y-30F11 group were euthanized on day 3 for excessive weight loss, without gross histology abnormality in kidneys or liver. Conclusion: These studies suggest that anti-CD45 RIT in the absence of TBI and FLU prior to haploidentical HCT can lead to establishment of mixed chimerism. Moreover, this anti-CD45 RIT in combination with haploidentical HCT can lead to improvement in survival for mice with AML. These results suggest that clinical studies with anti-CD45 RIT in lieu of TBI and FLU in a haploidentical HCT regimen should be considered for further investigation. Disclosures: No relevant conflicts of interest to declare.

Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients

Blood ◽  
2004 ◽  
Vol 103 (1) ◽  
pp. 78-84 ◽  
Author(s):  
William J. Hogan ◽  
Michael Maris ◽  
Barry Storer ◽  
Brenda M. Sandmaier ◽  
David G. Maloney ◽  
...  
Keyword(s):  
Liver Injury ◽  
Cell Transplantation ◽  
Hepatic Injury ◽  
Hematopoietic Cell Transplantation ◽  
Serum Bilirubin ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Graft Versus Host ◽  
Total Body

Abstract Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 μM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P = .04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P = .07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 μM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 μM (4-6.9 mg/dL; 20%), 119.7 to 169.29 μM (7.0-9.9 mg/dL; 17%), and 171.0 μM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival.

scholarly journals Total Body Irradiation for Hematopoietic Stem Cell Transplantation: What Can We Agree on?

2021 ◽  
Vol 28 (1) ◽  
pp. 903-917
Author(s):  
Mitchell Sabloff ◽  
Steven Tisseverasinghe ◽  
Mustafa Ege Babadagli ◽  
Rajiv Samant
Keyword(s):  
Cell Transplantation ◽  
Total Body Irradiation ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Late Toxicity ◽  
Hepatic Function ◽  
Vascular Supply ◽  
Entire Body ◽  
Hematopoietic Stem ◽  
Total Body

Total body irradiation (TBI), used as part of the conditioning regimen prior to allogeneic and autologous hematopoietic cell transplantation, is the delivery of a relatively homogeneous dose of radiation to the entire body. TBI has a dual role, being cytotoxic and immunosuppressive. This allows it to eliminate disease and create “space” in the marrow while also impairing the immune system from rejecting the foreign donor cells being transplanted. Advantages that TBI may have over chemotherapy alone are that it may achieve greater tumour cytotoxicity and better tissue penetration than chemotherapy as its delivery is independent of vascular supply and physiologic barriers such as renal and hepatic function. Therefore, the so-called “sanctuary” sites such as the central nervous system (CNS), testes, and orbits or other sites with limited blood supply are not off-limits to radiation. Nevertheless, TBI is hampered by challenging logistics of administration, coordination between hematology and radiation oncology departments, increased rates of acute treatment-related morbidity and mortality along with late toxicity to other tissues. Newer technologies and a better understanding of the biology and physics of TBI has allowed the field to develop novel delivery systems which may help to deliver radiation more safely while maintaining its efficacy. However, continued research and collaboration are needed to determine the best approaches for the use of TBI in the future.

Improved outcomes with maintenance therapy after salvage autologous hematopoietic cell transplantation (AHCT) in multiple myeloma: A CIBMTR study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8022-8022
Author(s):  
Oren Pasvolsky ◽  
Raphael Fraser ◽  
Noel Estrada-Merly ◽  
Moshe Yeshurun ◽  
Uri Rozovski ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Improved Outcomes ◽  
Autologous Hematopoietic Cell Transplantation ◽  
Maintenance Group

8022 Background: Maintenance therapy in multiple myeloma (MM) after first autologous hematopoietic cell transplantation (AHCT1) is considered standard of care. Data regarding maintenance therapy after a salvage AHCT (AHCT2) in the setting of relapsed MM are scarce. Therefore, we used data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to examine the use of maintenance therapy after AHCT2 in MM patients and its effect on post-transplant patient outcomes. Methods: We included US adult MM patients who underwent AHCT2 after melphalan conditioning regimen from 2010-2018, and excluded patients who underwent tandem transplants. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Cox proportional hazards models were developed to study the main effect (maintenance use) with other covariates of interest including age, sex, race, performance status, HCT-comorbidity index, MM subtype, stage, creatinine, cytogenetic, conditioning melphalan dose, disease status at transplant, and time from AHCT1 to AHCT2. Results: Of 522 patients, 342 received maintenance therapy and 180 did not after AHCT2. Baseline characteristics were similar between the two groups. Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Common maintenance regimens included immunomodulatory drugs (IMID)-lenalidomide (N = 145, 42%) or pomalidomide (N = 46, 13%) and proteasome inhibitor, bortezomib (N = 45, 13%). Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, p < 0.001, REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)%, p 0.003, PFS 27.8% (22.4-33.5) vs. 9.8% (5.5-15.2), p < 0.001, and OS 54% (47.5-60.5) vs 30.9% (23.2-39.2) p < 0.001, respectively. IMID-containing maintenance regimens were associated with an improved 5-year PFS and OS compared to other maintenance regimens. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis, including NRM: hazard ratio (HR) 0.19 (0.08-0.44), p 0.0001, REL: HR 0.58 (0.47-0.72), p < 0.0001, PFS HR 0.52 (0.43-0.64), p < 0.0001, and OS HR 0.46 (0.36-0.60), p < 0.0001. We conducted additional analyses to investigate a possible selection bias in the maintenance group including landmark analysis at 100-days and 6-months post-AHCT2 as well as a subgroup analysis of patients who received melphalan 200mg/m2 as conditioning for AHCT2 (as a surrogate for fitness)- all these analyses also showed improved outcomes in the maintenance group. Second cancers were reported in 17 (5%) patients in the maintenance group and 6 (3%) patients and no-maintenance group (p 0.39). Conclusions: Maintenance therapy after AHCT2 is associated with superior outcomes in MM patients.

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