Poor mobilization status: a lingering legacy for allograft recipients

Poor mobilization of autologous peripheral blood stem cells (HPC-A) in patients requiring high dose chemotherapy represents an ongoing clinical challenge. A key difficulty in interpreting the literature in this area is that there is no uniform definition of poor mobilization. A mobilization “failure” at one institution may represent “suboptimal mobilization” at another, and thresholds for defining a peripheral blood CD34+ count as sufficient to commence collection vary dramatically between institutions.

The most common reason for a failure to mobilize and collect HPC-A is prior exposure to cytotoxic chemotherapy, in particular protracted courses of alkylators and purine analogs [1–3]. More recently lenalidomide exposure has also been implicated in impairment of HPC-A [4]. A recognition and avoidance of these risk factors and the well-timed use of novel mobilization therapies such as plerixafor have seen a lower incidence and greater ability to salvage those patients demonstrating HPC-A mobilization [5,6].

Where repeated attempts at salvage mobilization have been required to obtain a transplantable dose of cells, there are concerns that this subset of hard-to-mobilize patients have an adverse disease-free and overall survival following autologous transplant [7]. The mechanism of the suboptimal outcome in patients with a history of poor HPC-A is likely to be complex. This group of patients is enriched for patients with refractory disease, who are likely to have residual tumor involvement within the marrow resulting in cell contamination of the graft (the significance of which remains uncertain [8]), and bone marrow microenvironmental damage as a result of multiple lines of prior therapy and multiple mobilization attempts. As a result of these factors and despite the application of granulocyte-colony stimulating factor (G-CSF) and/or plerixafor there is a small group of patients who ultimately cannot achieve an adequate collection for safe autologous transplant.

In this edition of Leukemia and Lymphoma, Crocchiolo and co-authors explore whether a history of poor mobilization continues to impart a similar adverse outcome in a cohort of patients with multiple myeloma or lymphoma despite receiving a normal stem cell donation from an allogeneic donor following reduced intensity conditioning [9]. In a retrospective analysis they identified two cohorts of patients who had previously attempted autologous stem cell mobilization but for various reasons proceeded to allogeneic transplant. Compared to the cohort of prior “good mobilizers,” defined as a CD34+ cell count > 20 × 10⁹/L on the first day of apheresis, the group of “poor mobilizers,” who failed to achieve this threshold, had an increased non-relapse mortality. This difference was not due to impaired myeloid engraftment, as post-allogeneic transplant recovery of neutrophils and platelets was similar in the two cohorts. Somewhat paradoxically, assessment of a sub-cohort who, despite being defined as poor mobilizers, ultimately succeeded in the collection of > 2 × 10⁶/kg CD34+ cells, showed a slower neutrophil engraftment. This finding may reflect a group enriched for patients in whom the disease risk resulted in an imperative to move to transplant, which in turn led to more collection days and/or more repeated mobilization attempts, and who were likely to be more heavily pretreated, with a resultant impairment of the bone marrow microenvironment and delayed allogeneic stem cell engraftment.

Overall the poor mobilizer cohort had similar rates of relapse and graft-versus-host disease to those of the good mobilizers. Despite this, the non-relapse mortality and overall survival were significantly worse in the poor mobilizer group. This finding was independent of the patient/donor gender matching or number of prior autografts. No clear pattern emerged in the cause of death in these patients.

In the allograft setting, where the engrafting cells are presumably healthy, the putative “lesion” in graft dysfunction is likely to be the marrow microenvironment. Whilst platelet and neutrophil engraftment were not clearly impaired in this study, immune reconstitution was not measured.

Recovery of lymphocyte subsets, and perhaps just as importantly lymphocyte function, may lag substantially in poor mobilizer patients. Where it has been studied, post-transplant lymphocyte recovery is directly correlated with post-transplant outcome in the autograft and allograft setting [10–12]. Impaired lymphocyte recovery in the poor mobilizer group could translate to increased susceptibility to opportunistic viral and fungal infections in the post- transplant period. The lymphocyte content of the graft, whether it be autologous or allogeneic, may be significantly impacted by the mobilization regimen utilized. The use of plerixafor has been shown to mobilize grafts with a higher CD4+, CD8+and natural killer (NK) cell content. In the type of patients described by Crocchiolo et al., who likely have an impairment of the bone marrow microenvironment, the poor outcome post-allograft might have been mitigated by using plerixafor-mobilized cells from healthy donors.

Although this article raises some interesting insights in a unique group of patients, further prospective data are clearly required to address this often-neglected aspect of engraftment post-transplant.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.