Baby’s First Steps
The sequence of immune reconstitution in a stem cell transplant is first the neutrophils, followed by red blood cells, then platelets. Lymphocytes (B cells and T-cells) can make their appearance any where along this time line, depending on the drugs used in the preconditioning and the post transplant immune suppressants.
Neutrophils are the first and most eagerly waited cell line, since they provide much needed immune protection to an otherwise very vulnerable patient. The standard of care at Fairview hospital is a shot of Neupogen (GCSF) each day starting Day Zero until the ANC (absolute neutrophil count) reaches and stays above 2.5K. The fact that a growth factor is used to goose neutrophil engraftment while red blood cells and platelets are allowed to take their own sweet time to make their debut speaks to the importance of neutrophils as front line defense troops.
‘Drug Pollution’ Can Discourage Any Graft
Harvey was sporting a nice WBC of around 2.5, of which 1.6K or thereabouts were neutrophils before he went into the hospital. The remainder were mostly monocytes, precursors of macrophages, another important ‘killer’ cell line. But all the intravenous and broad spectrum antibiotics cocktail he was getting did a real number on his new baby graft, suppressing its ability to make more good cells. WBC languished at 2.2 -2.5K for the 6 days he was in the clink and neutrophil counts actually went down some. Once they stopped all the intravenous drugs and Harvey came home yesterday, it has been a very different story.
The newly minted immune system “Seattle Slim” (somehow that sounds more appropriate given Harvey’s bantam weight of 62Kg, a better fit than “Minnesota Fats” for example – don’t you agree?) has really gone to town. Yesterday the WBC was up to a satisfactory 4.3K and today it has climbed all the way into the normal range of 5.5K! I guess it is hard for any immune system to do its job properly when it is being deluged with a dozen of more toxic drugs. Now that the pollution has died down a bit the new baby boy is working hard and churning out the old white blood cells.
As we all know, red blood cells are the oxygen carriers in our body. No red blood cells, no oxygen transport from the lungs to the rest of the body and we die a slow death due to internal suffocation. Anyone who has been through a rapid decline in red blood cell counts and therefore hemoglobin levels due to AIHA (autoimmune hemolytic anemia) will know exactly what I mean. The sense of profound fatigue is very real as hemoglobin levels trend below 9.0. The trigger point for red blood cell infusion at Fairview Hospital is 8.0. Harvey got red blood cell transfusions three times thus far. Each time he was really dragging his tail on the last day before the blessed transfusion and the influx of new oxygen carriers. But each time, the red blood cell counts and hemoglobin gradually lost ground over the next few days, setting him up for another transfusion within 4-5 days.
Not this time! Harvey got red blood cell transfusion on Tuesday, and the counts reflected that on Wednesday: RBC rose to 3.37, hemoglobin increased to 10.4. When we went into the outpatient clinic today and got his blood counts, we were delighted to see that one day later not only has the RBC not done its usual dive downwards, it had actually increased to 3.57 and the hemoglobin has bumped up to 11.2. Only one interpretation fits these numbers: our little baby boy has just learned to make red blood cells! Hopefully Harvey will not need any more red blood cell transfusions and has now become self sufficient on this front.
Two down, one more to go. Now all “Seattle Slim” has to do is demonstrate the ability to make platelets as well and we can cheer the triple play. Once Harvey no longer needs regular transfusions of red blood cells or platelets it becomes that much easier to get rid of the Hickman Catheter. While this device has been wonderful in getting rid of needle pricks every time they had to give him some new medication or the other, it is nevertheless a hassle taking care of it, making sure it did not get wet or contaminated in any way, covering it up with plastic wrap and tape while taking a shower etc. I don’t think Harvey will miss not having direct line access to his jugular vein.
The Tricky Business of Lymphocyte Engraftment
T-cells are extremely important in providing adequate immune protection, especially against viral invaders. So why don’t we try harder to get this cell lines going right off the bat? Why the emphasis on neutrophils and not T-cells? Good question but the answer is a little complicated.
True, T-cells are heroic killers of viruses and all manner of invaders. Along with NK cells (“Natural Killer” cells), T-cells are primarily responsible for graft-versus-leukemia effect that we hope will keep Harvey free of CLL for the rest of his life. Delay in T-cell engraftment or wimpy level of T-cell engraftment can spell trouble, in terms of viral reactivation or even outright cancer relapse.
But too rapid reconstitution of the donor T-cells can have negative consequences as well, as in over the top acute graft-versus-host-disease (GVHD). Several techniques are being looked at to control the timing of T-cell reconstitution from the new graft. Places like the NCI are experimenting with T-cell depleted grafts, adding back the T-cells at a later and more convenient time. M. D. Anderson uses low dose Campath in their preconditioning therapy. The idea is that this monoclonal will hang around in the body long enough after the transplant to keep T-cell numbers low and therefore prevent onset of GVHD too early in the game. Harvey had ATG (anti-thymocyte globulin) as part of his conditioning (you can look up earlier posts describing this), which too has a similar effect as Campath. Each of these approaches reduces the incidence of acute GVHD. The trick is to do it without risking too many infections, or too long a delay in getting GVL started.
If the careful balancing act works out just right, T-cells from the new graft are kept under control long enough for things to settle down a bit, but not so long that massive infections happen or the cancer gets out of control because of sparse GVL effect. This management of GVHD while allowing GVL to happen is an art form and every transplant center has its own approach to it. Frankly, the rest of transplant procedures are pretty much cookie-cutter business. Managing T-cell reconstitution is what sets apart the real expert centers from the also rans.
As of Day +30 Harvey goes off of MMF (mycophenolate mofetil, trade name “CellCept”), one of two immune (T-cell) suppressors he has been on since Day Zero. The second immune suppressant CSA (Cyclosporine A, trade name “Gengraf”) will continue for the next 6 months or more. Harvey’s blood levels of CSA will be monitored weekly for the near future so that the dosage can be carefully calculated to achieve the perfect balance between GVHD and GVL. Makes me dizzy just thinking about it – but then I never mastered the art of riding a bicycle either.