Intra-bone cord blood transplantation – the new clinical route to enhance engraftment

by Alexey Bersenev on September 19, 2008 · 2 comments

in clinical trials and cases

I have been waiting for the results of the first trial for about the last 5 years. Finally it’s here – Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study.

The authors proposed intra-bone route of hematopoietic stem cell (HSC) transplantation as the way to increase engraftment and bring stem cells directly to the niche. This is a modern look at this approach.

Poor engraftment and low number of HSC in the graft are central problems in bone marrow transplantation (BMT) clinic. In particular, cord blood, which is supposedly one of the best alternatives to bone marrow for transplant has a limited number of HSCs in one sample and delayed engraftment. Basically we can solve these problems in a few ways, i listed below:
1. HSC expansion ex vivo;
2. double unit cord blood transplantation (mix of 2 or more samples);
3. new conditioning treatment by making more niche available in bone marrow;
4. new routes to transplantation of HSC.

All of them, excluding the second, are in clinical trials right now and now we have the first report, showing how approach #4 works for leukemic patients.

Interestingly, that intra-bone route for bone marrow transplantation (BMT) was described many years ago together with intravenous and intramuscular. In 1940 Morrison performed intrasternal transfusion of human bone marrow (JAMA 1940;115:1708).

The original studies of human bone marrow transplantation were carried out by direct infusion into bone marrow spaces. However, this approach was abandoned as there was no advantage in speed or rate of engraftment over intravenous infusion. Since these early days of transplantation, there have been sporadic attempts to evaluate intra-osseous infusion of stem cells, but no advantage over intravenous infusion was ever found. The reason for this is thought to be that direct infusion of stem cells into the marrow cavity is in fact identical to intra-arterial or intra-venous infusion, and most stem cells enter the general circulation before homing into marrow spaces throughout the body.

Later, intra-bone BMT technique was significantly modified in experimental settings by Ikehara group. Experimental work that was done with some modifications of this technique by a few groups in the last decade brought some important conclusions:
intra-bone BMT allows:
– better and rapid HSC egraftment;
– none, or very low rate of graft-versus-host disease (GVHD) and graft failure;
– rapid repopulation with full lymphocytic recovery.

Now, the Italian group, recently published in Lancet Oncology, demonstrated for the first time that intra-bone cord blood transplantation in leukemia clinical settings is safe, feasible and has potential efficacy.

(Schematic of intra-bone delivery used in Frassoni study)

I’d like to refer you to John Wagner’s commentary to the paper and look at the table, which compared data of the Italian group with previously reported cord blood transplantation trials for treatment of acute leukemia by intravenous delivery.

Intrabone injection is a potential solution to the cell dose limitation of cord–blood transplantation, which currently prevents its near universal use. However, randomised trials or single-arm clinical trials aimed at replicating the fi ndings reported by Frassoni and colleagues are now needed before this approach can be generally adopted.

*************
Lancet Oncology2008;9:831

Will Intra-osseous Injection of Umbilical Cord Blood Reduce Graft Failures?

{ 2 comments… read them below or add one }

JWS September 19, 2008 at 5:13 pm

Good diagram – didn’t know where people actually inject. I was hoping something very high engraftment rate though – why is it still not even close to 100% success rate after cells are directly injected into niche?

Reply

Alex September 21, 2008 at 5:35 pm

engraftment in both ways of delivery (iv or intra-bone) should be very high, because of body irradiation or myeloablative regimen of chemotherapy. The targeting difference is “time of engraftment” or how soon we can see donor’s cells in bloodstream. So compare with iv route, intra-bone seem like give a little bit faster engraftment for neutrophils (23 days median) and platelets (36 days median).

Even you can accept that you deliver HSC directly to the niche, you really don’t know is this true or not, because you can’t measure (visualize) it so far. Even so, a lot of donor’s cells injected into the bone goes directly to the bloodstream and travel around the body because bone cavity is highly vascularized.

Reply

Cancel reply

Leave a Comment

Previous post:

Next post: