Cord-Blood Transplantation Using Non-myeloablative Regimens
Abstract & Commentary
By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: Plerixafor is a novel inhibitor of stromal cell-derived factor (SDF-1) that promotes efficient hematopoietic cell mobilization. Dipersio et al randomized multiple myeloma patients scheduled for autologous transplant to hematopoietic cell mobilization using G-CSF at 10 mcg/kg/day with or without plerixafor a 240 mcg/kg/day starting on day 4. Collection was initiated on day 5. Among the 302 subjects, the target of 6 x 10(6) CD34 cells/kg in 2 apheresis days or less was reached in 71.6% receiving plerixafor/G-CSF compared to 34.4% receiving G-CSF alone (p <0.001). Neutrophil and platelet engraftment after transplant was equivalent in both arms. At one-year follow-up, survival was 95% and 96%, respectively, for plerixafor/G-CSF and placebo/G-CSR arms. Plerixafor enables rapid and improved hematopoietic cell mobilization, compared to G-CSF alone, in multiple myeloma.
Source: DiPersio J, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009;113:5720-5726.
High-dose chemotherapy, followed by autologous hematopoietic cell transplantation (autoHCT), to rescue patients from marrow aplasia has been shown to be an effective strategy for multiple myeloma (MM) and lymphoma relapse.1-4 An adequate number of hematopoietic cells, typically enumerated by CD34+ cells/kg, are required for engraftment. In addition, tandem autoHCT may be used for MM,5 demanding an even larger number of CD34 cells. The vast majority of autologous cells are collected through peripheral blood cell progenitor cell (PBPC) mobilization, either with G-CSF alone or chemotherapy with G-CSF. This approach leads to poor mobilization in around 20% of myeloma patients.6,7
Plerixafor reversibly inhibits stromal cell-derived factor-1 alpha (SDF-1) binding to the CXCR4 receptor, promoting efficient PBPC mobilization. Synergy exists between plerixafor and G-CSF, and this combination can be effective after mobilization failure following G-CSF or chemotherapy + G-CSF. DiPersio et al compared G-CSF alone against G-CSF with plerixafor among MM patients planned for autoHCT.
In this study, 302 MM patients aged 18-78 were randomized to plerixafor or placebo. G-CSF was administered at 10 mcg/kg SC daily, with plerixafor at 0.24 mg/kg or placebo SC on day 4. Collection began on day 5, and continued for four days or until 6 x 10(6) CD34 cells/kg were collected. The primary endpoint of 6 x 10(6) CD34 cells/kg in two or fewer days of collection was achieved in 106/148 (71.6%) in the plerixafor + G-CSF arm compared to 53/154 (34.4%) (p < 0.001) using G-CSF alone. Ninety-five percent of plerixafor-treated patients reached at least 2 x 10(6) CD34 cells/kg, compared to 88.3% without the drug (p < 0.001). The day 5 peripheral blood CD34 cells/uL, a measure of circulating stem cells before collection, was a median of 109.0 cells/uL with plerixafor, compared to 33.0 cells/uL without (p < 0.001).
In the plerixafor group, 95.9% underwent autoHCT, compared to 88.3% in the placebo group. The median CD34 cells/kg transplanted was 5.84 x 10(6) cells/kg, compared to 4.41 x 10(6) cells/kg for placebo. Among transplanted patients, neutrophil engraftment occurred in 99.3% of plerixafor-treated patients, compared to 100% in placebo, with a median time to engraftment of 11 days for both. The median time to platelet engraftment was 18 days for each group. At one-year follow-up, 95% of plerixafor- and 96% of placebo-treated patients were alive. During the mobilization phase, 65% of plerixafor + G-CS- and 44% of placebo/G-CSF-treated patients experienced adverse events. Diarrhea, nausea, and injection site erythema were more common in the plerixafor cohort.
Commentary
Based on a proven survival benefit, autoHCT remains a frequently used procedure for MM.1 AutoHCT requires collection and cryopreservation of an adequate number of hematopoietic CD34 cells/kg, typically through mobilizing peripheral blood progenitor cells (PBPC). G-CSF alone or chemotherapy plus G-CSF results in poor mobilization in around 20% of patients, which can cause prolonged cytopenias after transplant or even preclude autoHCT for extremely poor mobilization.6,7
In this randomized, controlled trial, the addition of plerixafor, a novel mobilization agent, to G-CSF enabled superior PBPC mobilization and collection. Specifically, 72% in the plerixafor plus G-CSF arm reached the target of 6 x 10(6) CD34 cells/kg in two or fewer days of apheresis, compared to only 34% in the G-CSF-only arm (p < 0.001). As expected, plerixafor led to a considerably higher number of CD34 cells in the peripheral blood prior to collection. A major secondary benefit to plerixafor was fewer days of stem cell apheresis.
The high failure rate in the G-CSF arm alone related to the stringent predefined endpoint of 6.0 x 10(6) CD34 cells/kg in two days of apheresis. Although this allows enough stem cells for two transplants with few apheresis sessions, a single autoHCT has become a more common approach. A much more lenient and practical threshold of 2 x 10(6) CD34 cells/kg in four or fewer apheresis days was met in 95% receiving plerixafor + G-CSF, compared to 88% receiving G-CSF alone. These data are more aligned with published mobilization failure rates.
Now that plerixafor (Mozobil, Genzyme) is approved for autologous PBPC collection for non-Hodgkin lymphoma and MM, the question emerges whether this has become the new mobilization standard. Alternative mobilization options exist that also may enhance collection yields relative to G-CSF alone. The standard alternatives of higher doses of G-CSF, GM-CSF, adding chemotherapy, large-volume apheresis, and/or bone marrow harvest do not appear to dramatically improve mobilization and/or have considerable toxicity.8-10 The mobilization results with plerixafor and G-CSF were excellent, well tolerated, and allowed rapid procurement of PBPC generally within one week.
One must note several limitations. Although only a small number of subjects mobilized poorly in the plerixafor + G-CSF arm, outside of the patient selection in a clinical trial, one can expect mobilization failure to be much higher. Further, patients with poor disease response could potentially benefit from debulking chemotherapy or other agents used together with PBPC collection (i.e., chemotherapy mobilization). Studies of alternative strategies of plerixafor and G-CSF + chemotherapy or other novel agents are now underway. One might anticipate plerixafor would also add to mobilization success with these treatment strategies as well. Finally, although survival appeared no different in progression-free or overall survival at one year, longer-term follow-up at three and five years will be needed to evaluate the impact of plerixafor and tumor cell contamination in the graft, as plerixafor may mobilize tumors cells in leukemia patients.
In summary, the combination of plerixafor and G-CSF is superior to G-CSF alone in hematopoietic cell mobilization for MM. Although long-term follow-up will be required, these data affirm plerixafor plus G-CSF is a reasonable mobilization regimen for autologous stem cell collection.
References:
1. Attal M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91-97.
2. Child JA, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-1883.
3. Schmitz N, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet. 2002;359:2065-2071.
4. Philip T, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995;333:1540-1545.
5. Attal M, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495-2502.
6. Pusic I, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008;14:1045-1056.
7. Demirer T, et al: Factors influencing collection of peripheral blood stem cells in patients with multiple myeloma. Bone Marrow Transplant. 1996;17:937-941.
8. Desikan KR, et al. Comparable engraftment kinetics following peripheral-blood stem-cell infusion mobilized with granulocyte colony-stimulating factor with or without cyclophosphamide in multiple myeloma. J Clin Oncol. 1998;16:1547-1553.
9. Weaver CH, et al. Mobilization and harvesting of peripheral blood stem cells: randomized evaluations of different doses of filgrastim. Br J Haematol. 1998;100: 338-347.
10. Desikan KR, et al. Collection of more hematopoietic progenitor cells with large volume leukapheresis in patients with multiple myeloma. Leuk Lymphoma. 1998;28:501-508.
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