What is Autologous Heamatopeitic Stem Cell Therapy

There is a lot of interest in AHSCT because  of the panorama programme this week but what is it. You will have heard of it on the TV programme but you will not have been told what it involves. 

The problem is this means many different things and many ways to do this are used, which makes it difficult when you are trying to assess risk verses benefit. 

There are two main types (a) myoablative and (b) non-myoablative.
The aim of the (a) myoablative is to replace your immune system whereas (b) is to re-boot your immune system and so is the ultimate immunomodulator

Autologous Blood Stem Cells
First of all the infusions are with your own cells (autologous) because if they were from someone else when they arrive they would reject your organs and cause graft-verses host disease.

Autologous HSCT requires the extraction of haematopoietic stem cells (HSC) from you and storage of the harvested cells in a freezer. The person with MS is then treated with high-dose chemotherapy at the cost of partial or complete bone marrow ablation during myoablative treatment (destruction of patient's bone marrow's ability to grow new blood cells). The pwMS own stored stem cells are then transfused into his/her bloodstream, where they replace destroyed tissue and resume the pwMS normal blood cell production. Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment since the recovery of immune function is rapid. Also, the incidence of pwMS experiencing rejection (graft-versus-host disease) is very rare due to the donor and recipient being the same individual. 

Haematopoietic progenitor cell antigen CD34 is a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of stem cells to bone marrow extracellular matrix or directly to stromal cells.Cells expressing CD34 (CD34+ cell) are normally found in the umbilical cord and bone marrow as hematopoietic cells

These stem cells do not turn back the MS clock to make new nerves and myelin. These are the stem cells and their job is to regrow white blood cells and they are not the type of stem cells that are going to make new nerves or new myelin. Therefore you cannot expect the treatment to replace lost function. One hopes that it stops any more attacks by the immune system and stabilises the disability or if the treatment is occurring during disease activity, it stops that activity so that the bodies own repair mechanisms are allowed to work and the inflammation is removed such that there is improvement. Please note this is not really repair of established disability it is driving the inflammatory response into remission

Lower dose cyclophosphamide  and filgratim is used to get the stem cells out of the bone marrow and into the blood. These are  frozen down and then you get the immune abalation.

Filgrastim is a granulocyte colony-stimulating factor (G-CSF) analog used to stimulate the proliferation and differentiation of granulocytes. In somes cases granulocyte-macrophage colony-stimulating factor (GM-CSF), also called sargramostim and molgramostim.GM-CSF stimulates stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Monocytes exit the circulation and migrate into tissue, whereupon they mature into macrophages and dendritic cells.
Then comes the therapy this is the immune depletion. One approach is myoablation and this may use a combination of drugs and may use BEAM (Carmustine, Cytarabine, Etoposide, Melphalan) chemotherapy protocol which is administered over a period of six days often with the addition of anti-thymocyte globulin (T Cell depletion) for a couple of days as supplementary rather than essential lymphoablation.

Carmustine (bis-chloroethylnitrosoureaBCNUBiCNU) is a medication used mainly for chemotherapy and sometimes for immunosuppression before transplant. It is a nitrogen mustard β-chloro-nitrosourea compound used as an alkylating agent. As a dialkylating agent, BCNU is able to form interstrand crosslinks in DNA, which prevents DNA replication and DNA transcription so it kills dividing cells.

Cytarabine or cytosine arabinoside (Cytosar-U or Depocyt) is a chemotherapy agent used mainly in the treatment of cancers of white blood cells. It kills cells by interfering with DNA synthesis.It is called cytosine arabinoside because it combines a cytosine base with an arabinose sugar. Cytosine normally combines with a different sugar, deoxyribose, to form deoxycytidine, a component of DNA. Cytosine arabinoside is similar enough to human cytosine deoxyribose (deoxycytidine) to be incorporated into human DNA, but different enough that it kills the cell. 
Etoposide or VP-16 (trade name Etopophos) is a cytotoxic anticancer drug which belongs to the topoisomerase inhibitor drug class.:

Melphalan is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents.
This chemical alteration inhibits DNA synthesis and RNA synthesis, functions necessary for cells to survive. These changes cause cytotoxicity in both dividing and non-dividing cells
This destroys the immune system and if you do not get stem cells to replace your immune system you cannot fight infection and there is a risk of a lethal infection.

However the non-myoablative therapy does not eliminate your immune system and this is what is being proposed as a treatment.

The  treatmement is not the stem cells the treatment are the immune depleting agents.

This treatment uses a combination of drugs one used is alemtuzumab (T and B cell depleting), others use rituximab (B cell depleting), others use anti-thymocyte antibody ( T cell depleting). They are often used in combination with high dose cyclosphosphamide.Cyclophosphamide  is an alkylating agent of the nitrogen mustard type. An alkylating agent adds an alkyl group to DNA. It attaches the alkyl group to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring. This interferes with DNA replication

Adverse drug reactions from cyclophosphamide include chemotherapy-induced nausea and vomiting, stomach ache, haemorrhagic cystitis, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair (in the BBC programe people lot their hair), changes in color and texture of the hair.

With this treatment the immune system reboots as occrs with alemtuzumab and cladribine. However you do not need stem cells for treatment and the immune system will regenerate with time.

However in non-myoablative HSCT, CD34+ stem cells are transplanted to more rapidly repopulate the body with Neutrophils, which are our first line defense against infection. These are further stimulated with Filgrastim (G-CSF) or GM-CSF. Neutrophil granulocytes are the most abundant (40% to 75%) type of white blood cells in most mammals. They form an essential part of the innate immune system. This repopulation takes about 20 days and this is when you are most at risk from infection. T cells and B cells will take longer to regenerate.

So the idea that this is a stem cell therapy is rather misleading , it is just a very aggressive form of immunosuppression. 

Is this the most aggressive immunosuppression, the answer is no because myoablative is more aggressive and you need to re vaccinate yourself when you repopulate you immune system. 

However, which combination is optimum and do you need to deplete your innate (neutrophils and monocytes) system. Dogma would say no...unless you are certain type of mouse EAEer where there is a view that neutrophils are the important cell type. 

Therefore are you simply inducing side effects and not really targeting any thing extra. Although using stem cells may help in the re-booting process but this is not their function and the immune cells causing MS may not all be destroyed and relapses can occur.

The people doing the HSCT trials state a 1% mortality rate on their websites, but the trials indicate this risk may well be much lower  

I would say yes there is something different and that is because cyclosphosphamide and the phosphorylated form of cyclosphosphamide enters the brain, unlike current DMT. However could this be achieved by drugs that are less toxic than cyclophosphamide.

What are the problems with the trials.

When the trials were started in 2006 the landscape was very different, there were few treatments available and most of them were not very effective, natalizumab had been shown to be risky.

Alemtuzumab (and Ocreluzimab and Movectro) were not around

The trials are unblinded and the investigators are openly saying that the treatment works. The lack of blinding in the Alemtuzumab was critisized by the FDA, but there is no randomisation, no blinding and the investigators are helping to create the placebo effect. 

The HSCT treatment uses multiple drugs to deplete the immune system so you can imagine that two is better than one. One can argue that there is an 80% reduction in disease activity shows that this is the most effective. I can agree with this, but this group is a selected group of active pwMS.

 Some may have  failed with a "big gun drug" and get the treatment option on a compassionate basis but in the trials Alemtuzumab is an exclusion criteria. 

However people may say there is no evidence that it is really any better than other effective treatments.  This I suspect will be argued by opponents of HSCT and this argument cannot be countered because this has not been tested. 

It would need a head to head trial of AHSCT verses Alemtuzumab (currently) or ocrelizumab (in the future). 

If it takes until 2020-2022 to finish the trials and go to the regulators, the landscape may be different as some treatments may be out of patent and the cost constrainst will work against the cost-effectiveness. Will it get third line approval, as it is used now, or will it get first line  useage

HSCT induces secondary Autoimmunity
People may also say that I don't want the autoimmunity associated with Alemtuzumab, but this is occurring in HSCT also.

This includes ITP. People treated with Alemtuzumab are screened every month to detect this for up to 4 years after their treatment. Is this occurring following HSCT? Certainly the people doing health tourism are not getting follow-up treatment from their treating physician. Therefore ensure that you are followed up properly to mitigate this risk

In the Burt et al study in 2015

"Immune-mediated thrombocytopenia (ITP) developed in 3 of 22 (14%; 95% CI, 3%-35%) patients treated with alemtuzumab compared with 4 of 129 (3.1%; 95% CI, 0.9%-7.8%) patients treated with antithymocyte globulin (P = .07). Drug-free remission of ITP occurred in all cases after transient treatment with corticosteroids and intravenous immunoglobulin or rituximab.


Hypothyroidism was present in 9 patients (6.2%; 95% CI, 2.9%-11.4%) before receiving HSCT. After transplant, 7 additional patients developed hypothyroidism or hyperthyroidism. For patients with normal thyroid function before HSCT, thyroid dysfunction developed post-transplant in 2 of 20 treated with alemtuzumab (9%; 95% CI, 1%-32%) and 5 of 122 treated with anti-thymocyte globulin (4.0%; 95% CI, 1.3%-9.3%) (P = .26). The incidence rate of posttransplant immune dysfunction (ITP, hypothyroidism, or hyperthyroidism) was 22.7% (95% CI, 7.8%-45.4%) in 5 of 22 patients receiving alemtuzumab compared with 6.9% (95% CI, 3.2%-12.7%) in 9 of 129 patients receiving anti-thymocyte globulin (P = .03).

So are the risks any different.

Labels: