Alemtuzumab based reduced intensity transplantation for pediatric severe aplastic anemia

Ngwube, Alexander; Hayashi, Robert J.; Murray, Lisa; Loechelt, Brett; Dalal, Jignesh; Jaroscak, Jennifer Joi; Shenoy, Shalini

doi:10.1002/pbc.25458

Cited by 10 publications

(8 citation statements)

References 43 publications

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“…An ALC of 1 × 10 9 /L and CD4 + T‐cell count of 0.2 × 10 9 /L were achieved typically by 5 and 9 months post‐HCT, respectively. Reports from Shenoy and collaborators described pediatric and young adult cohorts with non‐malignant diseases who received alemtuzumab days −21 to −19 at a total dose of either 48 or 33 mg (<10 kg and >10 kg, respectively), also in combination with fludarabine and melphalan using a variety of stem cell source . B cells and CD4 + T cells recovered to 50% of pre‐HCT levels at 3 months and normalized by 6‐9 months.…”

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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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: 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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“…Limitations of our case series include its retrospective, single‐institution design and heterogeneity of both inherited and acquired BMFS diagnoses which limits comparisons to single diagnosis studies, including studies of RIC for pediatric patients with SAA, 6 DBA, 7 and PNH with SAA 8 . However, the heterogeneity of diagnoses—including a cohort of four unrelated patients with CAMT—also makes our excellent outcomes broadly generalizable to pediatric patients with BMFS (with the exclusion of patients with marrow failure due to Fanconi anemia, dyskeratosis congenita, or Shwachman‐Diamond syndrome—all notably absent from our case series).…”

Section: Discussionmentioning

confidence: 99%

Irradiation‐free RIC HSCT has a tolerable safety profile and is effective therapy for pediatric bone marrow failure syndromes

Wang

Anderson

Gloude

et al. 2020

Pediatric Transplantation

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For patients with bone marrow failure syndromes (BMFS) who may tolerate gradual donor engraftment and achieve adequate disease control with stable mixed chimerism, RIC regimens may be preferable to myeloablative regimens. We performed a retrospective analysis of outcomes for patients who underwent HSCT at our institution between 2009 and 2017 for BMFS using an irradiation‐free RIC regimen. Fourteen pediatric patients with BMFS received fludarabine (30 mg/m2 IV daily × 3), thiotepa (5 mg/kg IV every 12 hours × 2), and melphalan (70 mg/m2 IV daily × 2) prior to HSCT. Our cohort included the following diagnoses: SAA (n = 7), CAMT (n = 4), SCN (n = 1), DBA (n = 1), and non‐Fanconi congenital BMF (n = 1). Seven patients underwent a MSD transplant; seven underwent an unrelated donor transplant. All patients are alive with median follow‐up of 1112 days (range 455‐2549 days). The median time to neutrophil engraftment was 16 days (range 10‐26 days). All were transfusion independent by day + 100. The highest grade of aGVHD was grade 2; 8 (57%) did not develop aGVHD. Four (28.5%) developed extensive cGVHD, 4 (28.5%) developed limited cGVHD, and 6 (43%) did not develop cGVHD. No patients developed SOS. None died from GVHD or infectious complications. HSCT with RIC with fludarabine, thiotepa, and melphalan for BMFS was effective with a tolerable safety profile. Probability of OS at 100 days and 1 year was 100%.

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“…Infectious complications included adenoviremia (2.3%), EBV viremia (22.7%), and CMV viremia (22.7%) ( 35 ). Our group published a report of 17 patients undergoing HCT with alemtuzumab, fludarabine and melphalan conditioning ( 36 ). While NK cells recovered early, T cell (both CD4 and CD8) and B cell recovery was markedly delayed with all populations normalizing by 1 year after HCT ( 36 ).…”

Section: Disease-specific Outcomesmentioning

confidence: 99%

“…Our group published a report of 17 patients undergoing HCT with alemtuzumab, fludarabine and melphalan conditioning ( 36 ). While NK cells recovered early, T cell (both CD4 and CD8) and B cell recovery was markedly delayed with all populations normalizing by 1 year after HCT ( 36 ). Consistent with these kinetics, infection rates were higher in the first 6 months post HCT ( 36 ).…”

Section: Disease-specific Outcomesmentioning

confidence: 99%

Immune Reconstitution in Pediatric Patients Following Hematopoietic Cell Transplant for Non-malignant Disorders

Bhatt

Bednarski

2020

Front. Immunol.

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Allogeneic hematopoietic cell transplant (HCT) is curative for pediatric patients with non-malignant hematopoietic disorders, including hemoglobinopathies, bone marrow failure syndromes, and primary immunodeficiencies. Early establishment of donorderived innate and adaptive immunity following HCT is associated with improved overall survival, lower risk of infections and decreased incidence of graft failure. Immune reconstitution (IR) is impacted by numerous clinical variables including primary disease, donor characteristics, conditioning regimen, and graft versus host disease (GVHD). Recent advancements in HCT have been directed at reducing toxicity of conditioning therapy, expanding donor availability through use of alternative donor sources, and addressing morbidity from GVHD with novel graft manipulation. These novel transplant approaches impact the kinetics of immune recovery, which influence post-transplant outcomes. Here we review immune reconstitution in pediatric patients undergoing HCT for non-malignant disorders. We explore the transplant-associated factors that influence immunologic recovery and the disease-specific associations between IR and transplant outcomes.

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Alemtuzumab based reduced intensity transplantation for pediatric severe aplastic anemia

Abstract: HCT using this RIC approach was well tolerated and successful in achieving donor engraftment and early immune reconstitution with good quality of life free of immune suppression. Children with SAA can be successfully transplanted using alemtuzumab based conditioning.

Cited by 10 publications

References 43 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

Irradiation‐free RIC HSCT has a tolerable safety profile and is effective therapy for pediatric bone marrow failure syndromes

Immune Reconstitution in Pediatric Patients Following Hematopoietic Cell Transplant for Non-malignant Disorders

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