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.
Oxygen Carriers
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.
Be well,
Chaya
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13 comments on "Coming Up The Learning Curve"
Follow-up comment rss or Leave a TrackbackWonderful news!So happy for you all!
Liz
May our “Bravos and Clapping” be heard where you are. Keep the good news coming!
An after post thought/query. Chaya, you did an interesting article on T-regulatory cells and how they keep a check on the powerful killer instincts of the T cells. As Harvey’s cord blood builds up the cell lines do the Tregs co-develop with the T cells and are Tregs considered as a control mechanism for the balancing act you have articulated above?
WWW
Sounds like “Harvey” is doing great. Congratulations! My wife is back in the clink (albeit 70 miles south of you) for treatment of GvHD. She just passed the 2 year mark on her transplant which illustrates the cure is a long process. The good news is that there is absolutely no CLL present and her blood counts are perfect in all respects. The GvHD she faces only presents as a painful skin rash and shows no other organ involvement. The treatment is a series of full-body moist dressings. A steroid cream is applied and then the moist dressing. They alternate between moisturizer and steroid cream for the first 24 hours and then go to a 3-a-day schedule. After only 18 hours there is already a nice improvement. They will change her immune suppression from Cyclosporine to CelCept. They feel this will improve her situation.
We learned yesterday from Drs. Zent and Hogan that they are seeing an average of 3 years of immune suppression for patients who have undergone a mini allo transplant. I informed Dr. Zent of “Harvey’s” progress. He said a lot of his patients were keeping him up to date.
Of course “Harvey” will likely not face many GvHD issues. This is one of the many nice things about the cord blood transplants and something that really wasn’t available to us only 2 short years ago! I personally think those who are diagnosed with CLL today will face a greatly improved set of choices when the time comes to make major treatment decisions. In the case of my wife she had approximately 7 years between diagnosis and transplant. CLL treatments seven years from today will likely be a much different animal. Better results, less toxicity, lower mortality rates, and more complete cures are certain to be the norm.
Bruce:
Thanks for the update on your wife’s GVHD status. You are right, getting a stem cell transplant is not a quickie project, it takes long term commitment to getting healthy.
To answer Wayne’s question: as Bruce mentioned above, GVHD is considered to be less of an issue with cord blood, which is why it is acceptable to transplant patients in significantly less well matched HLA situations. For example Harvey’s cords were both 4 out of 6 HLA match, a far cry from the 10 out of 10 (or higher) matching mandated for adult donor transplants.
There are many theories as to why GVHD is less of a problem with cord blood. One of the more well accepted theories is that cord blood has higher percentage of T-regs (compared to effector T-cells) than adult stem cell collections. The higher proportion of T-regs is necessary in order for the fetus and mother to co-exist for the nine months of the pregnancy. The higher proportion of T-regs means early onset of acute GVHD is significantly modulated in cord blood transplants.
Tomorrow I will be publishing a full length article on the subject of GVHD, which will address this and many other issues related to the subject.
Bruce, best wishes to your wife. She is in good hands. Clive Zent is one of my favorite CLL experts, and I was very impressed by Dr. Hogan when I met him at Mayo several years back.
Chaya
excellent summary; glad to hear that Harvey is doing so well (and, hopefully, Serena as well!).
One thing that everyone should understand is that transfused RBCs and platelets never work as well as those manufactured endogenously…largely due to “storage” related degradation. A rough rule of thumb is a 10% or greater degradation in numbers (and, likely, greater degradation of O2 carrying capacity) right off the bat with ongoing degradation. That’s why transfusions are only (albeit important) stop-gap measures.
You are right, home made red blood cells are a whole lot better than transfused ones, even if every effort is made to use irradiated and leukocyte reduced blood products. Not to mention risk of iron overload problems in patients who get too many red blood cell transfusions.
Getting GCSF (neutrophil growth factor) shots each day until the ANC is respectable seems to be a good idea to me. But I am just as happy that the protocol does not use erythropoietin drugs (such as Aranesp, Procrit) to goose red blood cell production. There has been a flood of bad news about using epo drugs in cancer patients and we have been reviewing this on http://clltopics.org for several years now. Using red blood cell transfusions as a stop gap measure and waiting for local production of RBC seems to be a safer way to go.
Chaya
Chaya,
I have followed your diary entries with considerable self-interest. I am in “recovery” at the present time from CLL. With a rituximab/Solu-Medrol infusion I have rolled the WBC back into the normal range with healthy ANC and rapidly improving RBC and hemoglobin. However, I am not willing to wait for a resurgence of CLL again, and your diary has been most helpful in understanding the statistics behind cord blood cell transplantation. I like the odds that you quote from MDA, one of the two places I have visited. I am currently on loan to Seattle Cancer Care Alliance for the remaining infusions and follow-up with Dr. D.M. However, given Hutch/SCCA’s current view of transplantations, I will be turning to MDA and DR. K for advice. I watched my mother die because she was afraid of undergoing a heart operation that could have prolonged her life by 10 years or more 40 years ago. I have no intention of waiting until I am a “basket case” for an attempt at a stem transplant. Keep up the great work; you and Harvey are a great inspiration that has given me the courage to think proactively about stem transplant. Harvey, keep getting better; you deserve it because of your courage and internal strength.
Barry
Chaya
I check your notes of progress on Harvey daily. You and Harvey are in my thoughts and prayers. I am so thrilled with his progress.
I am now on IVIG again. Because of your gentle coaching and pushing and my acting up or out (which ever it is.) I get it!!
Blessings,
Rita
I am very happy to see such good progression. I wish nothing but good days for Harvey!
Bravo! Both of your are a continuing source of inspiration. Mind (and spirt) over matter. Of course such feats are possible!
Question: Can you make a few comments about those non-nucleated red blood cells in Harvey’s transplant?
Thanks,
Chip and Vera
Chaya,
Glad to read the good news. And thanks again for the helpful updates
My transplant is now 2 months away. The pre transplant work up deserves some comment. It can be daunting. City of Hope wants me to have CT scans, bone marrow biopsy, 24 urine collection, blood and stool tests, arterial blood gases, pulmonary function tests, chest x-ray. echocardiogram, cardiac stress test and various consults with the dietary staff and the surgical staff (about a Hickman) as a starter.
But compared to the transplant itself, the prep will be a cakewalk.
Be well. Stay strong
Brian (another doc with CLL)
Chaya,
I can’t thank you enough for your [internet] presence, approach and info. It’s been enormously helpful for me in just ‘living with’ my wife’s cll. You and Harvey are truly extraordinary.
Bill M.