Mixed T Cell Chimerism After Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using an Alemtuzumab-Containing Regimen Is Shaped by Persistence of Recipient CD8 T Cells

Grimaldi, Francesco; Potter, Victoria; Perez-Abellan, Pilar; Veluchamy, John P.; Atif, Muhammad; Grain, Rosemary; Sen, Monica; Best, Steven; Lea, Nicholas; Rice, Carmel; Pagliuca, Antonio; Mufti, Ghulam J.; Marsh, Judith; Barber, Linda D.

doi:10.1016/j.bbmt.2016.11.003

Cited by 32 publications

(42 citation statements)

References 22 publications

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“…Many protocols with lymphodepletion using late dosing have remarkably low rates of GVHD with curative levels of MC. Persistence of recipient CD8 + effector T cells may result in T‐cell MC; a state of MC has been proposed to be protective against GVHD, notably chronic GVHD . Higher cell doses can be given with late alemtuzumab to promote myeloid engraftment without increasing chronic GVHD risk in some non‐malignant disorders in children and adults …”

Section: Timing Of Administration Of Alemtuzumabmentioning

confidence: 99%

“…Day 30 ALC and T‐cell recovery (CD4 + and CD8 + ) at Day 100 is more robust when Day 0 alemtuzumab levels are <0.57 μg/mL . T‐cell profiles post‐HCT are profoundly affected by alemtuzumab, with CD4 + being relatively more depleted with an inversion of the normal CD4:CD8 ratio and abnormal T‐cell subset composition . CD4 + and CD8 + T‐cell chimerism were differentially affected as a result, with the former being more commonly of donor origin at 1 year post‐HCT.…”

Section: Immune Reconstitutionmentioning

confidence: 99%

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Principles of alemtuzumab immunoablation in hematopoietic cell transplantation for non‐malignant diseases in children: A review

Guilcher

Shah

Shenoy

2018

Pediatric Transplantation

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Alemtuzumab is a humanized mAb targeted to CD52. Alemtuzumab is highly immunosuppressive with the ability to deplete T and B cells (in addition to other immune cell lines). A growing understanding of the PKs, dosing, and timing of administration of alemtuzumab has allowed for the study of its use as a conditioning agent for allogeneic HCT. The highly immunosuppressive properties of the drug are particularly appealing in the setting of non-malignant HCT, where GVHD provides no clinical benefit and relapse of malignancy is not applicable. In addition, the degree of immune suppression achieved with alemtuzumab has allowed for a reduction in the intensity of myeloablative cytotoxic agents included in some HCT conditioning regimens, allowing for fewer acute and late toxicities. This review paper will provide a comprehensive summary of the mechanism of action, PKs, dosing, and timing of alemtuzumab, a brief description of its use in various allogeneic HCT protocols for non-malignant conditions and a summary of the data regarding its use for GVHD therapy. The goal of this review was to provide an understanding as to how alemtuzumab might be safely incorporated into HCT conditioning regimens for children with non-malignant disease, allowing for expanded access to curative HCT therapy.

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Section: Timing Of Administration Of Alemtuzumabmentioning

confidence: 99%

Section: Immune Reconstitutionmentioning

confidence: 99%

Principles of alemtuzumab immunoablation in hematopoietic cell transplantation for non‐malignant diseases in children: A review

Guilcher

Shah

Shenoy

2018

Pediatric Transplantation

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“…However, subsequent studies in older transplant recipients (age > 30) did not show a survival benefit when compared to IST [36]. To reduce toxicity in older patients, newer regimens have incorporated fludarabine with lower-dose cyclophosphamide and with ATG (FCA) or alemtuzumab (FCC), with improved OS [37–39]. A CIBMTR analysis of 833 AA bone marrow transplants evaluated the role of ATG source on transplant outcomes, and demonstrated that rabbit ATG (Thymoglobulin, Sanofi, France) results in lower rates of acute and chronic GVHD for MSD transplants, improves survival, and lowers rates of acute GVHD for MUD transplants [40].…”

Section: Transplant-based Therapies For Saa/vsaamentioning

confidence: 99%

Diagnosis and Treatment of Aplastic Anemia

Peslak

Olson

Babushok

2017

Curr. Treat. Options in Oncol.

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Opinion Statement Acquired aplastic anemia (AA) is a rare, life-threatening bone marrow failure (BMF) disorder that affects patients of all ages and is caused by lymphocyte destruction of early hematopoietic cells. Diagnosis of AA requires a comprehensive approach with prompt evaluation for inherited and secondary causes of bone marrow aplasia, while providing aggressive supportive care. The choice of frontline therapy is determined by a number of factors including AA severity, age of the patient, donor availability, and access to optimal therapies. For newly diagnosed severe aplastic anemia, bone marrow transplant should be pursued in all pediatric patients and in younger adult patients when a matched sibling donor is available. Frontline therapy in older adult patients and in all patients lacking a matched sibling donor involves immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine A. Recent improvements in upfront therapy include encouraging results with upfront closely matched unrelated donor transplants in younger patients and the emerging benefits of eltrombopag combined with initial IST, with randomized studies underway. In the refractory setting, several therapeutic options exist, with improving outcomes of matched unrelated donor and haploidentical bone marrow transplantation as well as the addition of eltrombopag to the non-transplant AA armamentarium. With the recent appreciation of frequent clonal hematopoiesis in AA patients and with the growing use of next-generation sequencing in the clinic, utmost caution should be exercised in interpreting the significance of somatic mutations in AA. Future longitudinal studies of large numbers of patients are needed to determine the prognostic significance of somatic mutations and to guide optimal surveillance and treatment approaches to prevent long term clonal complications.

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“…This is common after transplant and can be converted to full donor chimerism by the use of early donor lymphocyte infusion . The use of either Thymoglobuline ® , Grafalon ® or Campath ® is largely center and country determined because all 3 have been shown to be effective in GVHD prevention but recently the use of alemtuzumab has been more and more extended, especially for non‐malignant diseases …”

Section: Introductionmentioning

confidence: 99%

“…9,17,18 The use of either Thymoglobuline ® , Grafalon ® or Campath ® is largely center and country determined because all 3 have been shown to be effective in GVHD prevention but recently the use of alemtuzumab has been more and more extended, especially for non-malignant diseases. [19][20][21] Given the lack of randomized trials that compare RIC regimen with alemtuzumab vs ATG, we pooled the data of consecutive patients transplanted in 3 centers (2 in France and 1 in London) to specifically analyze the outcome in the unrelated setting for myeloid malignancies.…”

mentioning

confidence: 99%

Alemtuzumab vs anti‐thymocyte globulin in patients transplanted from an unrelated donor after a reduced intensity conditioning

Robin

Raj

Chevret

et al. 2018

European J of Haematology

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Mixed T Cell Chimerism After Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using an Alemtuzumab-Containing Regimen Is Shaped by Persistence of Recipient CD8 T Cells

Abstract: HighlightsClinical outcomes are excellent using an alemtuzumab-containing hematopoietic stem cell transplantation regimen for aplastic anemia.Outcomes are excellent despite prolonged abnormality of the T cell profile.Recipient-derived CD8 T cells shape persistent mixed chimerism.

Cited by 32 publications

References 22 publications

Principles of alemtuzumab immunoablation in hematopoietic cell transplantation for non‐malignant diseases in children: A review

Principles of alemtuzumab immunoablation in hematopoietic cell transplantation for non‐malignant diseases in children: A review

Diagnosis and Treatment of Aplastic Anemia

Alemtuzumab vs anti‐thymocyte globulin in patients transplanted from an unrelated donor after a reduced intensity conditioning

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