How to make hematopoietic stem cell transplantation less toxic

by Alexey Bersenev on September 18, 2009 · 0 comments

in clinical trials and cases

Clinical hematopoietic stem cell (HSC) transplantation is associated with high toxicity due to the so-called “conditioning regimen”, which is aimed at depleting host immune and hematopoietic cells in order to achieve significant engraftment of donor cells. The standard conditioning includes chemotherapy and total body irradiation (TBI). Furthermore, after engraftment, donor cells can provoke severe alloimmune reaction against residual host cells – graft-versus-host-disease (GVHD), associated with high mortality.

This outcome generates much risk of morbidity and mortality for the recipient. Therefore risk of transplantation is weighed against risk of disease in decision algorithms. The difficulty is that although HSCT might be the most secure way to be alive in three decades, it is also the most likely way of being dead in 3 months.

There are many ongoing clinical trials, aimed to reduce intensity (which is equal to reduced toxicity) of conditioning and in the same time retain optimal engraftment of donor’s HSC. One of the most promising approaches is depletion of recipient’s bone marrow cells by antibodies against surface antigens. I wrote about one experimental study, showed the proof-of-principal of “making more bone marrow niches available for donor’s HSC”.

Now we have the first clinical report about the possibility of minimization of conditioning regimen toxicity by antibody-based clearance of host immune and hematopoietic cells.

In the protocol, published in the Lancet journal, TBI and standard chemotherapeutic doses were replaced by monoclonal antibodies – CD45 and CD52, in 16 high-risk children with primary immunodeficiency. High risk mean that these children are not going to survive without bone marrow transplant, but they are so weak that will not able to resist toxic conditioning treatment. This approach called “minimal-intensity conditioning” (MIC). Anti-CD45 antibody was used for myelosupression, anti-CD52 – for immunosupression.

Our study provides a novel approach for allogeneic stem-cell transplantation and represents a shift from the paradigm that intensive chemotherapy or radiotherapy, or both, with a stem-cell agent is needed to secure engraftment of donor haemopoietic stem cells. This novel conditioning regimen enables successful transplantation in patients who would not previously be eligible for stem-cell transplantation with presently available regimens, and might thus extend the benefits of such transplantation to virtually all those with primary immunodeficiency.

2 important conclusions were made by the authors: first – the engraftment level achieved in the study is similar to those children which underwent reduced-intensity conditioning; the second – relatively low and comparable (to conventional and reduced-intensity conditioning regimens) level of GVHD as complication of MIC was observed.

This trial is remarkable! It’s a proof-of-principal study showed that monoclonal antibody can be used for depletion host marrow hematopoietic cells, reduce toxicity and pretransplant comorbidity in non-malignant disease. It brings us a hope to treat more patients with non-malignant disorders, such as immunodeficiency, metabolic defects and maybe autoimmune diseases.

You can see the evolution of conditioning regimens in scheme below:

Lancet 2009;374;912
Citation from: Lancet 2009;374;856

Connotea tag: clinical trial

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