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Correlation of CD34+ cell dose with engraftment kinetics

CD34 is the most frequently currently used marker for estimation of engraftment success and suitability of the graft in hematology-oncology. Remarkably, almost everyone in the clinic associates this marker with hematopoietic stem cell (HSC) activity and function. Indeed, there is an HSC population within CD34+ cells, but a very tiny one. Recently, Weissman group has shown [1] that most cells in CD34+ total are progenitors (>90% for adult bone marrow and >99% for cord blood). So, I think the clinical role of progenitor cells in hematopoietic graft currently remains underappreciated.

Engraftment kinetics of hematopoietic graft depends on number and quality of both – HSC and progenitor cells. The first month after transplant we want to see rapid neurtophil and platelet engraftment which keeps myeloablative patient alive. This short-term engraftment occurs due to progenitors, but does not reflects stem cell function. Long-term engraftment occurs later and characterizes HSC number and function.

I’d like to point out that for blood lineage recovery the correct term is “repopulation” or “peripheral blood chimerism”. HSC engraftment followed by the homing and lodging into the bone marrow niche occurs quite rapidly (probably in hours) after transplantation. The time point when short-term engraftment (repopulation) switches to long-term depends upon patient conditions, pre-transplant conditioning and quality of hematopoietic graft.

Because CD34+ contain both – stem and progenitor cells, their number should directly correlate with short- and long-term repopulation (engraftment) kinetics. It is exactly what we can see in myeloablative patients with hematological malignancies – more CD34+ – better neutrophil and platelet recovery in short-term [2]. Not all groups note this correlation, but most. For example, in recent study no correlation was found [3] between CD34+ count, colony-forming units and short-term engraftment in an allogeneic group of patients.

Again, CD34+ progenitor cell number and function (not HSC) underlie correlation with rapid neutrophils and platelet recovery. Indeed, CD34+/CD38- cell population enriched for HSC did not predict early repopulation [4], unlike CD34+ total count. The same results was seen by other group [5]. Such clinical long-term outcome parameters as overall survival, 5-years survival and transplant-related mortality also was found directly correlated with CD34+ cell dose [6]. What puzzles me is that we still don’t know whether long-term outcome depends upon HSC or progenitor cell (within CD34+) engraftment and function. If we can see very good and rapid recovery of neutrophils and platelets in the first weeks, effects of progenitor cell function, we expect to see very good clinical outcome in the long-term, because the patient will overcome the critical period and survive.

Total nucleated cell number, but not CD34+ count is the best predictor in cord blood (CB) transplantation clinic for malignant diseases (EuroCord data 2010, unpublished). Interestingly, even though an average CB sample can provide the dosage only below 1 million per kg, in pediatrics, 0.1-0.3 millions per kg of CD34+ CB cells is enough for sufficient blood lineage recovery [7]. That’s means the vast progenitor pool (characterizing CB) can play significant role in HSC long-term engraftment kinetics and outcome.

The current clinical practice in hematology-oncology allows us to set up a threshold of CD34+ cell dose in hematopoietic graft for successful engraftment, which is 2-7 millions per kg of body weight. CD34+ dose below the lower border of the threshold (2 millions/kg) is associated with negative clinical results and very bad outcome. Interestingly, some groups showed that a very high dose of CD34+ (>8-10 millions per kg) was associated with increased rate of chronic GVHD [8] and relapse [9].

The link between CD34+ cell dose and engraftment is less clear in patients with reduced-intensity conditioning [10], which don’t need as many progenitors as myeloablated patients for rapid hematopoietic recovery. For example, no correlation was found [10] between CD34+ cell dose and rate of acute GVHD, non-relapse mortality, relapse rate and overall survival. Also, there was no direct correlation observed [11] between CD34+ dose and outcome in patients with non-malignant hematological disease.

All of these data made me think that we need a little number of HSC for good long-term engraftment and outcome. One of the reasons that possibility of engraftment is probably limited by bone marrow niches capacity and we can easily saturate them by infusion of one dose of hematopoietic graft. Another reason is that a good number of progenitor cells can protect patients from conditioning-associated complications, keeping them alive in the short-term and making a foundation for good clinical long-term outcome.

I’m curious to a see a study assessing the influence of labeled CD34+ dose on long-term multilineage repopulation (blood chimerism). As soon as we can detect donor CD34+ cell contribution in hematopoietic lineages a few months or years after transplant, we can assess HSC function. It will be interesting to compare malignant versus non-malignant diseases and different conditioning regimens. If you know any of studies like that, let me know.