Hematopoietic stem cell transplantation is effective curative treatment in pediatric refractory/aggressive Langerhans cell histiocytosis

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with non-malignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current genotoxic conditioning regimens mediate tissue injury and potentially incite and amplify GVHD, limiting use of this potentially curative treatment beyond malignant disorders. Minimizing genotoxic conditioning while achieving alloengraftment without global immune suppression is highly desirable. Antibody-drug-conjugates (ADCs) targeting hematopoietic cells can specifically deplete host stem and immune cells and enable alloengraftment. Here we report an anti-mouse CD45-targeted-ADC (CD45-ADC) that facilitates stable murine multi-lineage donor cell engraftment. Conditioning with CD45-ADC (3mg/kg) was effective as a single agent in both congenic and minor-mismatch transplant models resulting in full donor chimerism comparable to lethal total body irradiation (TBI). In an MHC-disparate allo-HSCT model, pre-transplant CD45-ADC (3mg/kg) combined with low-dose TBI (150cGy) and a short course of costimulatory blockade with anti-CD40 ligand antibody enabled 89% of recipients to achieve stable alloengraftment (mean value: 72%). When CD45-ADC was combined with pre-transplant TBI (50cGy) and post-transplant Rapamycin, Cytoxan or a JAK inhibitor, 90-100% of recipients achieved stable chimerism (mean: 77%, 59%, 78%, respectively). At a higher dose (5mg/kg), CD45-ADC as a single agent was sufficient for rapid, high level multi-lineage chimerism sustained through the 22 weeks observation period. Therefore, CD45-ADC has potential utility to confer the benefit of fully myeloablative conditioning but with substantially reduced toxicity when given as a single agent or at lower doses in conjunction with reduced intensity conditioning.

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Autologous hematopoietic stem cell transplantation for efficient treatment of multisystem, high-risk, BRAF V600E-negative Langerhans cell histiocytosis

Journal of International Medical Research ◽

10.1177/0300060519864807 ◽

2019 ◽

Vol 47 (9) ◽

pp. 4522-4529

Author(s):

Yaozhu Pan ◽

Rui Xi ◽

Cunbang Wang ◽

Lei Fang ◽

Jiaofeng Bai ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Lymph Nodes ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Langerhans Cell Histiocytosis ◽

Braf V600e ◽

Hematopoietic Stem

Langerhans cell histiocytosis (LCH) is a disorder caused by clonal proliferation of CD1a+/CD207+ cells and characterized by varying degrees of organ involvement. Treatment of LCH is risk adapted; patients with multisystem disease and risk-organ involvement require more intensive therapy. Optimal therapies for multisystem, high-risk LCH remain uncertain. Recently, targeted therapy using inhibitors of mutated BRAF (the gene encoding serine/threonine-protein kinase B-Raf) has proven very effective in patients with multisystem refractory LCH. Herein, we report a case of LCH with involvement of the bones, liver, and lymph nodes. Using next-generation sequencing of the patient’s pathological sample, we identified a mutation in MAP2K1 in exon 3 (c.362G>C, p.Cys121Ser) and no mutation in BRAF; thus, high-risk, multisystem LCH with MAP2K1 mutation and wild-type BRAF was diagnosed. After four chemotherapy treatments (COEP regimen), the patient received autologous hematopoietic stem cell transplantation (auto-HSCT). Complete remission was confirmed by follow-up positron emission tomography–computed tomography, which showed no lesions in liver, lymph nodes, or bones compared with the pretreatment period. To date, the patient has sustained good health for 24 months. In conclusion, auto-HSCT may be an effective treatment option for high-risk, multisystem BRAF V600E-negative LCH.

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