MOBILIZATION FAILURE IN HEMATOPOIETIC STEM CELL TRANSPLANTATION Siret Ratip Department of Haematology, Acıbadem University School of Medicine, İstanbuy, Turkey G-CSF–based mobilization regimens have a plantations, G-CSF is given at 10 μg/kg per day 5%-30% failure rate among healthy donors and subcutaneously with apheresis beginning on the patients, but the rate can be up to 60% in high- fifth day until the yield target is reached. There is risk patients such as those exposed to fludarabine. no evidence that twice daily administration gives a Poor mobilization has significant consequences for higher yield than once-daily (4). the patient with potential loss of the transplant as a treatment option. Repeated attempts at mobiliza- Combining G-CSF with chemotherapy for tion increase resource use, morbidity, and patient/ mobilization donor inconvenience. Therefore, there is much Combining G-CSF with chemotherapy achieves interest in the prevention and salvage of mobiliza- both mobilization and antitumor activity and has tion failure with novel strategies. been shown to result in a higher CD34+ cell yield than G-CSF alone (5). Regimens such as cyclo- The role of CD34+ cell dose in phosphamide, doxorubicin, vincristine, and pred- haematopoeitic stem cell transplantation nisone/dexamethasone, high-dose cytarabine, and Benefits of rapid recovery in HSCT are reduced cisplatin or cyclophosphamide 1-5 g/m2 have been hospitalization, blood product usage, and infec- used with G-CSF which is commenced 1-3 days tions. Minimum threshold of CD34+ cell dose for following cyclophosphamide. Apheresis is usually autologous transplantation is currently 2 × 106 started when leukocyte count reaches > 2 × 109/L. CD34+ cells/kg body weight (BW) (1). Many cen- Benefit of higher mobilization yield with high- ters use a minimum of 3 × 106 CD34+ cells/kg BW er doses of chemotherapy needs to be balanced for myeloablative and nonmyeloablative allogeneic against more red cell and platelet transfusions, and matched unrelated transplantations. Further- and, frequently, hospitalization for febrile neu- more, > 5 × 106 CD34+ cells/kg BW is associated tropenia, and it is more justified when significant with even lower resource use and faster and more antitumor effects exist (6). A prospective study that complete platelet engraftment and better survival compared 5 versus 10 μg/kg per day after stan- in allogeneic transplantations (2). It is probable dard chemotherapy was inconclusive (7). G-CSF 5 that higher cell doses (eg, ≥ 5 × 106 CD34+ cells/ μg/kg per day is used in most units for combined kg BW) may be similarly beneficial in mismatched G-CSF/chemotherapy mobilization. transplantations. In haplotype mismatched trans- plantations doses of ≥ 10 × 106 CD34+ cells/kg BW Pegylated G-CSF in mobilization are often used (3). The pegylated long acting form of G-CSF (peg- filgrastim) showed similar kinetics of mobilization Current stem cell mobilization regimens as filgrastim. A study in healthy donors report- ed suboptimal mobilization with a dose of 6 mg GCSF-based mobilization regimens but satisfactory yield with 12 mg (8). Such dose G-CSF with or without myelosuppressive che- dependence was not seen when pegfilgrastim was motherapy has been the most commonly used used with cyclophosphamide. Pegfilgrastim has the mobilization protocol since the 1990s. When used advantages of an earlier start of apheresis, reduc- alone, in both autologous and allogeneic trans- tion in the number of apheresis procedures and a 106 XXXIX. Ulusal Hematoloji Kongresi reduced number of injections in comparison with (1) insufficient number of HSCs because of HSC unconjugated G-CSF (9) but it is more costly. intrinsic factors Lenograstim compared with Filgrastim in (2) insufficient HSC number because of low stem cell mobilisation number or defective niches Lenograstim is a glycosylated form of G-CSF, (3) inadequate number or response of effector/ whereas filgrastim is nonglycosylated. Several pro- supporter cells such as BM macrophages or β-ad- spective studies have shown higher mobilization renergic nerves. yield with lenograstim. In contrast to healthy The following major criteria are proposed by the donors CD34+ cell yield appears similar in patients Italian GITMO working group as the definition of receiving either lenograstim or filgrastim after che- a poor mobilizer: (1) after adequate mobilization motherapy (10). (G-CSF 10 μg/kg if used alone or ≥5 μg/kg after chemotherapy) circulating CD34(+) cell peak is Stem cell factor in mobilization <20/μL up to 6 days after mobilization with G-CSF Stem Cell Factor (SCF (Ancestim)) exists as or up to 20 days after chemotherapy and G-CSF or a soluble form as well as a surface molecule on (2) they yielded <2.0 × 10(6) CD34(+) cells per kg in BM stromal cells. It binds to c-kit on HSCs and ≤3 apheresis (15). modulates proliferation and adhesion. As a single agent SCF has limited efficacy in HSC mobilization; Effects of underlying disease on mobilization of stem cells however, synergy between SCF and G-CSF exists. SCF at 20 μg/kg subcutaneously is started 4 days BM involvement by disease is associated with before the start of G-CSF and continued with the poor yields (16). There may be reduced HSC num- G-CSF until the end of apheresis. In failed mobiliz- bers partly related to the impairment of healthy ers SCF plus G-CSF with or without chemotherapy niches by malignant cells in the BM or direct com- enables adequate mobilization in 50% of patients petition between HSCs and malignant cells for a (11). In prior fludarabine-exposed patients SCF limited number of niches. with high-dose G-CSF resulted in a 63% success rate, almost doubling that in historical controls Effect of prior treatment on mobilization of that used G-CSF alone (12). stem cells Mobilization failure in autologous donors cor- GM-CSF in stem cell mobilization relates with the number of previous treatments GM-CSF is not more effective than G-CSF alone with chemotherapy. Most cytotoxic treatments and (13) and there is no synergy with G-CSF. Its use is molecules used in targeted therapies can have del- limited by dose-related toxicities. GM-CSF is rarely eterious effects on HSCs and the niches in which used in clinical practice. they reside. However, DNA cross-link agents such as melphalan or carmustine, and purine analogs Plerixafor in stem cell mobilization such as fludarabine are associated with a very high risk of mobilization failure. Cytotoxic drugs that do Plerixafor is a CXCR4 antagonist. It reduces the not specifically target cell progressing through the binding and chemotaxis of HSCs to the BM stro- S phase of the cell cycle (eg, anthracyclines, cis- ma. It is used at 240 μg/m2 subcutaneously the platin, fludarabine, carmustine, melphalan) could evening before the scheduled apheresis because potentially kill quiescent HSCs and niche cells, it generates peak CD34+ levels 6-9 hours after thereby reducing the HSC reserve. Fludarabine administration (14). It synergises with G-CSF and itself is toxic both to hematopoietic progenitors and chemotherapy. Plerixafor is the latest addition to to the niche. Alkylating agents such as chlorambu- the list of mobilizing agents and the first driven by cil given in a continuous manner may also be toxic understanding how mobilization occurs. on HSCs. Highly intensive, dose-dense regimens such as the hyper-CVAD (hyperfractionated cyclo- Risk factors for failure of mobilization of phosphamide, vincristine, doxorubicin, and dexa- stem cells methasone with methotrexate and cytarabine) reg- Poor mobilization may be inherent to a particu- imen are associated with a high risk of mobilization lar genetic combination specific to a person. It can failure beyond the first 2-4 cycles of therapy (17). also be acquired as a consequence of aging, prior Lenalidomide is associated with poor mobilization, treatments or disease. The possible defects could particularly after > 4 cycles of treatment. Lenalido- be at one or more of three levels: mide may suppress HSC motility similar to the way 23-26 Ekim 2013, Antalya 107 it reduces the motility of marrow endothelial cells for mobilization. For patients undergoing exten- in multiple myeloma. The antiangiogenic effect sive field radiotherapy, pre-treatment harvesting of Lenalidomide could also impair mobilization. should be considered if autologous transplantation Cyclophosphamide and GCSF based mobilization is a potential treatment option . is recommended for patients previously exposed to Lenalidomide (18). Long-term administration of Optimising apheresis for beter mobilization imatinib has been associated with reduced bone The peripheral blood CD34+ cell count is the turnover, which could affect HSC niche function best predictor of apheresis yield (24), and the use (19). Yields were improved if the patients temporar- of CD34+ cell counts to guide apheresis reduces ily withheld imatinib for 3 weeks prior to collection costs.If the circulating CD34+ cell count is ≥ 20/ (20). Prior radiotherapy to significant amounts of μL, 94% of collections performed the following day red marrow is associated with mobilization failure, would be expected to yield ≥ 2.0 × 106 CD34+ cells/ probably because of combined direct HSC toxicity, kg (24). In general terms if the CD34+ cell count is niche toxicity, and toxicity to the niche-supporting < 5/μL, the yield will be poor; therefore, apheresis cells (21). not warranted. Larger volume apheresis (process- ing ≥ 3 times the blood volume instead of 2 times) Effect of age on mobilization of stem cells results in higher HSC yields and may reduce the Poor mobilization is often noted in patients > number of sessions in some cases. 60 years of age (21). Firstly, there is an age-relat- ed “senescence” of actual HSCs because of pro- Improving stem cell collection in gressive telomere shortening. Secondly, there is a mobilization failure reduction in the HSC reserve caused by decreased Approaches to failed mobilization after conven- niche function with depletion of mesenchymal tional regimens include increased doses of G-CSF stem cells and osteoprogenitors.