Most of us who have dealt with CLL for any length of time know all too well that most infamous acronym, W&W. Some call it “Watch & Wait”, but most of us call it Watch & Worry. Unlike most solid cancers where time is of the essence and patients need to get therapy as soon as they are diagnosed, CLL gives its victims the “luxury” of doing nothing, twiddling our fingers and toes while we wait for the disease to get ripe enough for treatment. For type A personalities like me, waiting is one of the hardest thing to do.
Well, Harvey is in a different kind of W &W now. We are watching and waiting breathlessly for the first sign of life from the two umbilical cord units infused into him on DAY ZERO. Today is Day +7. Patients are given G-CSF (Granulocyte Colony Stimulating Factor, brand name “Neupogen”) every night starting Day Zero in an effort to encourage the new immune system to start producing the life protecting white blood cells. Fortunately, no daily needle stick involved since the GCSF is injected into one of the two lines with direct access to Harvey’s blood stream. We have come to appreciate the value of a direct access catheter.
Why only Neupogen? Why not also Procrit (or some other erythropoietin growth factor) to goose up production of red blood cells? And how about platelet production? The answers are quite straightforward. Low red blood cells and low platelets can be handled easily by means of transfusions, this is not a big deal. Sure, they have to be careful to use irradiated blood products (mandated for all transplant patients, for the rest of their lives) to avoid risk of infection transmission. Since mature red blood cells and platelets do not have a nucleus inside them, there is no need to worry about DNA / HLA matching etc when receiving these products as transfusions. Neutrophils are a different story. They are part of the “nucleated cells”, along with T-cells, B-cells etc. It is not possible to give patients neutrophil transfusions, their own immune systems have to make them from scratch. Since neutrophils are the front-line shock troops that protect us from infections, lack of these precious fighters increases the risk of infections – hence the extra efforts to goose their production as soon as possible. Patients who take a long time to engraft run higher risk of mortality due to infections.
The good news about non-myeloablative (mini-allo) conditioning is that while every effort is made to kill lymphoid cells (B-cells, T-cells, NK cells etc) as well as the progenitors of these cells, it is entirely possible for a goodly number of non-lymphoid cells to survive. In plain English, while heavy duty full myeloablative transplants typically destroy red blood cells, platelets and other cell lines besides B-cells, T-cells, NK cells etc, in the kinder and gentler mini-allo transplants patients can still have pretty good red blood cell counts and platelet counts after the preconditioning.
In Harvey’s case, his RBC, hemoglobin, hematocrit and platelets did take a hit after the chemo and radiation (see the earlier “Big Guns” article for the details of the preconditioning), but they were not completely destroyed. He is still able to work out, keep the old treadmill in his hospital room from gathering dust. His hemoglobin is still hanging in there, in the vicinity of 9.5, quite a ways from the cutoff of 8.0 that triggers red blood cell transfusion in this protocol. His platelet count is around 50, once again no where close to the trigger point of 10 that mandates platelet transfusion. Bottom line, Harvey has not had any need for blood product transfusions thus far to support him through this period of W & W. Chances are that there will be a time when his old red blood cells and platelets have given up, and the new production has not yet kicked in. He will need transfusions then. But it is good that he is able to bridge much of the gap between the old and the new, and thereby reduce his dependence on transfusions.
His WBC (white blood count) did tank to a dizzying low level of 0.1 after the preconditioning, as expected and desired. After all, that is the whole point of the massive ATG (Antithymocyte globulin) therapy he had during preconditioning, a take no prisoners attitude to destroying host T-cells before the precious cord blood units make their entry. We do not want the old T-cells hanging around and perhaps killing off the new immune system before it has a chance to get established.
Now we wait for the WBC to recover from this nadir. The first members of the white blood cells to make an appearance are the neutrophils, followed later on by T-cells, B-cells etc. “Engraftment” is a very important milestone, since it is an indication that the grafted stem cells have made it safely to their new bone marrow homes and have in fact started their job of producing all the cell lines needed to keep Harvey healthy.
Time to Engraftment
Engraftment happens relatively quickly when the donor is an adult, and there are plenty of stem cells in the donated graft. Single cord blood transplants work fine as well, when the recipient of the cord blood is also a child. But when it comes to much larger adult patients getting cord blood stem cells, the smaller stem cell dose (defined as number of nucleated cells per kilogram body weight of the recipient) means significant delays in engraftment. As you can imagine, the longer the window where the patient does not have a functioning immune system, especially sufficient number of neutrophils, the higher the risk of lethal infections. That is why the double cord protocol invented at the University of Minnesota is so important. By using two well matched cord units (not only matched to the patient but also to each other), U of M has done away with some of the risk factors associated with lower cell dose and improved (shortened) time to engraftment.
Below is the graph from their recent 2007 “Blood” paper, showing how neutrophil engraftment happened in their mostly double cord transplanted patients. In this reasonably large size cohort (110 patients), neutrophil recovery happened in 92% of the patients by day 42 and a full 50% of the patients had neutrophil recovery by day 12.
As you can see below in the second graph, platelet recovery took a lot longer. As much as 6 months later, only 65% of the patients were able to maintain platelet production that kept their counts over the 50K level. I am told the patients whose platelet counts do not recover to this degree may need platelet transfusions every couple of weeks (or more frequently, depending on individual characteristics) until their immune systems learn how to do this job on their own.
Where is Harvey On This Journey?
I thought you would never ask. Below is a chart of Harvey’s WBC starting from DAY ZERO to now. As you can see, the WBC has just begun to trend up from the nadir of 0.1 He is not yet classified as “engrafted” since the definition is absolute neutrophil counts of 0.5 or higher for three days running. Right now his WBC is 0.4 and they don’t do the split between ALC (absolute lymphocyte count) and ANC (absolute neutrophil count) until the WBC is at least 0.5. So, some of the 0.4 WBC Harvey has right now are lymphocytes, and some are neutrophils. When he has 0.5 ANC for three days in a row, that is when he will be officially declared as engrafted. If the trend we see now continues without waffling around, I hope to report Harvey is officially engrafted in the next several days.
While I am delighted we are beginning to see some action and Harvey seems to be right on schedule for engraftment by about Day 12, we still have to worry about late stage graft failure. Not a very high probability occurrence, but one never knows. You can bet I will be following his daily counts like a hawk.
For now, things are looking good. He is able to eat better, the WBC is improving and he is still able to exercise without need for red blood cell transfusions. What is not to like?
We have gotten to know many of the wonderful nurses on the staff here. They are an interesting bunch, many of them are from far away places with interesting stories. Discarding the single “incident” on our traumatic DAY ZERO, Harvey and I have been delighted with the level of care he has received. Nurses make the world go round and I take my hat off to the long hours of hard work they put in without losing their sense of compassion and dedication.