Poor mobilization status: a lingering legacy for allograft recipients

Abstract

Poor mobilization of autologous peripheral blood stem cells (HPC-A) in patients requiring high dose chemotherapy represents an ongoing clinical challenge. A key diffi culty in interpreting the literature in this area is that there is no uniform defi nition of poor mobilization. A mobilization “ failure ” at one institution may represent “ suboptimal mobilization ” at another, and thresholds for defi ning a peripheral blood CD34 count as suffi cient to commence collection vary dramatically between institutions. Th e 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]. Th e mechanism of the suboptimal outcome in patients with a history of poor HPC-A is likely to be complex. Th is 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 signifi cance 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 identifi ed 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, ” defi ned as a CD34 cell count 20 10 9 /L on the fi rst day of apheresis, the group of “ poor mobilizers, ” who failed to achieve this threshold, had an increased non-relapse mortality. Th is diff erence 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 defi ned as poor mobilizers, ultimately succeeded in the collection of 2 10 6 /kg CD34 cells, showed a slower neutrophil engraftment. Th is fi nding may refl ect 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 signifi cantly worse in the poor mobilizer group. Th is fi nding 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, posttransplant 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