Myeloablative Versus ‘Mini-Allo’ Transplants

Sometimes I think ‘medicalese’ is used deliberately by doctors to keep out the riff-raff. It reminds me of the time my husband and I spelled out words rather than use the actual words, when our daughter was a precocious 3 year old desperately trying to figure out what the adults were talking about.

When it comes to transplant related jargon, our very lives depend on getting a good understanding of the risks and rewards involved in the various protocols. I don’t know about you, but I hate being treated like a kid. Especially when my life hangs in the balance. We will make every attempt to demystify some of the most important concepts of stem cell transplants in this journal.

Back in the ‘old’ days before the invention of ‘kinder and gentler’ mini-allo transplants, the name of the game was full strength myeloablative transplants. Patients are given massive amounts of chemotherapy cocktails, as well as high dose total body radiation as part of the preconditioning regimen. The game plan with this take-no-prisoners approach is to try and kill every single cancer cell in the patient’s body, as well as nuke all remaining hematopoietic stem cells, T-cells etc. After the destruction is complete, patients are given the new stem cell graft. Without competition from the prior residents, the new stem cells quickly make a home for themselves in the bone marrow, settle down and start churning out all the various blood cell lines that are essential for survival.

This ‘Shock & Awe’ approach works well, but with certain important restrictions and drawbacks. Myeloablative preconditioning is so aggressive that only reasonably fit and sufficiently young patients can tolerate it – there are strict age and fitness restrictions on who is eligible to get a full bore myeloablative preconditioning ahead of transplant. Typically, the age limit is 50 years or younger, a cut-off point that leaves most CLL patients out in the cold.

Another problem is that even if the patients are healthy going in, a significant percentage of them suffer damage to essential organs in the process of the myeloablative therapy. Treatment related mortality (TRM) is unacceptably high unless strict guidelines are used in patient selection. The obvious advantage is that by taking this drastic approach of throwing out all of the old bums, chances are high that the new donor stem cells are quickly engrafted and can get to work, without interference from pesky remnants of the old immune system. Graft rejection is low, and engraftment is high with myeloablative procedures. Since the vast majority of cancer cells are also killed in the process of ‘Shock & Awe’ preconditioning, the new graft enjoys a bit of honeymoon period, a chance to get its bearings, before having to take on the job or eradicating the last few CLL stragglers. Put it another way, relapse risk is lower with myeloablative transplants.

‘Mini-allo’ Approach to Transplanting Older Patients

It is amazing how fast things are changing in blood stem cell transplant procedures. In just a few years, non-myeloablative (also called Reduced Intensity Conditioning or RIC, or the layperson term “mini-allo“) have come up the learning curve. For the vast majority of CLL patients, mini-allo transplant procedures have been a life saving and welcome development. Without this approach, most of our guys would be out of luck, ineligible for full myeloablative procedures on account of age or general fitness.

This is how mini-allo transplants work: first, the patient is encouraged to get into as good a remission as he can, so that the new graft coming in does not have to do heavy lifting right off the bat, in terms of cancer control. Second, relatively low key preconditioning is done to take the edge off of the patient’s existing stem cells and T-cells. This is an important step, and experts have been experimenting with various chemotherapy / radiation combinations to get it exactly right. If the patient’s own stem cells are still full of vim and vigor, they will not be happy about giving up their comfy bone marrow homes to the new comers and the fight they put up may result in graft rejection. If too many of the old T-cells are still around, these defenders of the body will see the new graft coming in as the enemy and do everything they can to kill the invaders. The technical name for this is host-versus-graft-disease. Once again, the net result of this is graft failure.

Bottom line, the major emphasis of mini-allo preconditioning is to do just enough damage to leave your old stem cells reeling, unable to fight for their old turf, easily overwhelmed / killed by the newcomers coming into the neighborhood. The other item of importance is to get rid of your old T-cell defenders – they were not doing such a hot job anyway, or they would not have allowed the cancer to establish a toehold in the first place – so that the precious new stem cells coming in are not attacked. It is fully understood that in the mini-allo approach there is no effort to eradicate every last cancer cell we can find in the body by means of preconditioning.

That is where graft-versus-leukemia (GVL, also called graft-versus-cancer, graft-versus-tumor etc) comes in. After the newly grafted stem cells settle down in their bone marrow homes, they start producing new immune system cells. Among them, newly minted defenders such as T-cells, B-cells, neutrophils, macrophages etc. Gone are the bad old days when the cancer had corrupted the very immune system cells that are supposed to hunt cancer cells. To these fresh and uncorrupted immune system cells, the cancer cells left over from the prior corrupt administration look like bizarre freaks and dangerous terrorists. Given enough time to grow strong and increase their numbers, the new immune system cells are capable of hunting down and killing each and every cancer cell in your body. The net result? Why, you are cured of cancer! How sweet is that?!

What are the special risks associated with mini-allo transplants? There is higher risk of graft failure with mini-allo transplants, if too many of the old T-cells are left behind to fight another day; or if the new graft cannot find a toehold in the marrow because the old stem cells are still hogging all the good real-estate. The second major problem to consider is relapse risk. If there is too many cancer cells still around when the new graft starts to function, it may not have enough time and resources to be able to fight the cancer cells. It is a case of out-numbered armies. If the enemy is too strong, or too numerous, the new immune system can get overwhelmed and defeated even before it can even get started.

This is why it is so important to go into transplants with as low a tumor burden as you can manage. The mini-allo preconditioning regimens will help reduce some of the tumor load, but unlike full strength myeloablative procedures, there is no concerted effort made to get rid of all of the cancer cells during preconditioning. For most late stage CLL patients getting rid of cancer cells in the circulating blood is not all that difficult. Getting rid of CLL cells hiding in the swollen lymph nodes is much harder. It has been suggested that the lymph node environment protects and nurtures CLL cells, making it hard to kill them in these locations. For most of us, the number of CLL cells in blood circulation is only the tip of the iceberg, often only 5-10% of the total count of cancer cells in the body. The vast bulk of cancer cells reside in the bone marrow, swollen lymph nodes, liver and spleen. Getting rid of these buggers where they hide, that is the name of the game.