The timing of plerixafor addition to G-Csf and chemotherapy affects immunological recovery after autologous stem cell transplant in multiple myeloma

Abstract

Plerixafor inhibits CXCR4, thus inducing the mobilization of hematopoietic stem/progenitor cells in lymphoma and multiple myeloma (MM) patients eligible for autologous stem cell transplantation (ASCT). However, the kinetics of plerixafor-induced mobilization of lymphocyte subsets is poorly known. Here, we evaluated the graft content, the engraftment, and the immunological reconstitution of MM patients receiving plerixafor. Thirty-seven patients undergoing one or tandem ASCT were enrolled. After mobilization with cyclophosphamide plus G-CSF, plerixafor was added at hematological recovery regardless of CD34+ cell count. We evaluated the number of CD34+, CD34+/CD38, CD3+, CD4+, CD8+, CD19+, CD56+/CD3, CD4+/CD25+/FOXP3+, and CD138+/CD38+ cells on each apheresis. Hematological and immunological recovery were determined at 30 days, 3, 6, 9, and 12 months after ASCT. Overall, 34/37 patients mobilized a median of 10.1 × 106 CD34+ cells/Kg (IQ 7.7–13.4). Patients with <20/µL CD34+ cells at plerixafor administration (18/33) had a significantly higher CD34+ cell fold increase, but not a higher absolute number, than 16/33 patients with ≥20/µL CD34+ cells. A similar CD34+ and immune graft composition was reported. A higher number of CD3+ and CD8+ cells/µL was observed at 3 months after first ASCT (p < 0.05) in the group with ≥20 CD34+ cells/µL. Thus, in MM patients, the timing of plerixafor administration influences immunological recovery.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40000 transplants annually. Bone Marrow Transplant. 2016;51:786–92.

  2. 2.

    Palumbo A, Cavallo F, Gay F, Raimondo Di, D BY F, Petrucci MT. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371:895–905.

  3. 3.

    Bensinger W, Appelbaum F, Rowley S, Storb R, Sanders J, Lilleby K, et al. Factors that influence collection and engraftment of autologous peripheral-blood stem cells. J Clin Oncol. 1995;13:2547–55.

  4. 4.

    Allan DS, Keeney M, Howson-Jan K, Popma J, Weir K, Bhatia M, et al. Number of viable CD34+ cells reinfused predicts engraftment in autologous hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;29:967.

  5. 5.

    D’addio A, Curti A, Worel N, Douglas K, Motta MR, Rizzi S. The addition of plerixafor is safe and allows adequate PBSC collection in multiple myeloma and lymphoma patients poor mobilizers after chemotherapy and G-CSF. Bone marrow Transplant. 2011;46:356–63.

  6. 6.

    Olivieri A, Marchetti M, Lemoli R, Tarella C, Iacone A, Lanza F. Proposed definition of “poor mobilizer” in lymphoma and multiple myeloma: an analytic hierarchy process by ad hoc working group Gruppo ItalianoTrapianto di Midollo Osseo. Bone marrow Transplant. 2012;47:342–51.

  7. 7.

    Pusic I, Jiang SY, Landua S, Uy GL, Rettig MP, Cashen AF, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008;14:1045–56.

  8. 8.

    Musto P, Simeon V, Grossi A, Gay F, Bringhen S, Larocca A, et al. Predicting poor peripheral blood stem cell collection in patients with multiple myeloma receiving pre-transplant induction therapy with novel agents and mobilized with cyclophosphamide plus granulocyte-colony stimulating factor: results from a Gruppo Italiano Malattie EMatologiche dell’Adulto Multiple Myeloma Working Party study. Stem Cell Res Ther. 2015;6:64.

  9. 9.

    Steinberg M, Silva M. Plerixafor: a chemokine receptor-4 antagonist for mobilization of hematopoietic stem cells for transplantation after high-dose chemotherapy for non-Hodgkin’s lymphoma or multiple myeloma. Clin Ther. 2010;32:821–43.

  10. 10.

    DiPersio JF, Stadtmauer EA, Nademanee A, Micallef INM, Stiff PJ, Kaufman JL, 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;113:5720–6.

  11. 11.

    DiPersio JF, Micallef IN, Stiff PJ, Bolwell BJ, Maziarz RT, Jacobsen E, et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27:4767–73.

  12. 12.

    Dugan MJ, Maziarz RT, Bensinger WI, Nademanee A, Liesveld J, Badel K, et al. Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin’s lymphoma undergoing stem cell mobilization. Bone Marrow Transplant. 2010;45:39–47.

  13. 13.

    Jantunen E, Penttilä K, Pyörälä M, Mahlamäki E, Kuittinen T, Nousiainen T. Addition of plerixafor to a chemotherapy plus G-CSF mobilization in hard-to-mobilize patients. Bone Marrow Transplant. 2011;46:308–9.

  14. 14.

    Attolico I, Pavone V, Ostuni A, Rossini B, Musso M, Crescimanno A, et al. Plerixafor added to chemotherapy plus G-CSF is safe and allows adequate PBSC collection in predicted poor mobilizer patients with multiple myeloma or lymphoma. Biol Blood Marrow Transplant. 2012;18:241–9.

  15. 15.

    Hübel K, Fresen MM, Salwender H, Basara N, Beier R, Theurich S, et al. Plerixafor with and without chemotherapy in poor mobilizers: results from the German compassionate use program. Bone Marrow Transplant. 2011;46:1045–52.

  16. 16.

    Russell N, Douglas K, Ho AD, Mohty M, Carlson K, Ossenkoppele GJ, et al. Plerixafor and granulocyte colony-stimulating factor for first-line steady-state autologous peripheral blood stem cell mobilization in lymphoma and multiple myeloma: results of the prospective PREDICT trial. Haematologica. 2013;98:172–8.

  17. 17.

    Baertsch M-A, Schlenzka J, Lisenko K, Krzykalla J, Becker N, Weisel K, et al. Cyclophosphamide-based stem cell mobilization in relapsed multiple myeloma patients: a subgroup analysis from the phase III trial ReLApsE. Eur J Haematol. 2017;99:42–50.

  18. 18.

    Lefrère F, Mauge L, Réa D, Ribeil J-A, Dal Cortivo L, Brignier AC, et al. A specific time course for mobilization of peripheral blood CD34+ cells after plerixafor injection in very poor mobilizer patients: impact on the timing of the apheresis procedure. Transfusion. 2013;53:564–9.

  19. 19.

    Lanza F, Lemoli RM, Olivieri A, Laszlo D, Martino M, Specchia G, et al. Factors affecting successful mobilization with plerixafor: an Italian prospective survey in 215 patients with multiple myeloma and lymphoma. Transfusion. 2014;54:331–9.

  20. 20.

    Olivieri J, Attolico I, Nuccorini R, Pascale SP, Chiarucci M, Poiani M, et al. Predicting failure of hematopoietic stem cell mobilization before it starts: the predicted poor mobilizer (pPM) score. Bone Marrow Transplant. 2018;53:461–73.

  21. 21.

    Sorasio R, Bonferroni M, Grasso M, Strola G, Rapezzi D, Marenchino D, et al. Peripheral blood CD34+ percentage at hematological recovery after chemotherapy is a good early predictor of harvest: a single-center experience. Biol Blood Marrow Transplant. 2014;20:717–23.

  22. 22.

    Costa LJ, Nista EJ, Buadi FK, Lacy MQ, Dispenzieri A, Kramer CP, et al. Prediction of poor mobilization of autologous CD34+ cells with growth factor in multiple myeloma patients: implications for risk-stratification. Biol Blood Marrow Transplant. 2014;20:222–8.

  23. 23.

    Costa LJ, Abbas J, Hogan KR, Kramer C, McDonald K, Butcher CD. Growth factor plus preemptive (’just-in-time') plerixafor successfully mobilizes hematopoietic stem cells in multiple myeloma patients despite prior lenalidomide exposure. Bone Marrow Transplant. 2012;47:1403–8. No

  24. 24.

    Milone G, Tripepi G. Algorithms for early identification of poor mobilization and for on-demand use of plerixafor in patients mobilized by chemotherapy and granulocyte-colony stimulating factor. Leuk Lymphoma. 2014;55:725–6.

  25. 25.

    Rossi G, Skert C, Morello E, Almici C, Arcaini L, Basilico C, et al. PBSC mobilization in lymphoma patients: analysis of risk factors for collection failure and development of a predictive score based on the kinetics of circulating CD34+ cells and WBC after chemotherapy and G-CSF mobilization. Hematol Oncol. 2015;33:125–32.

  26. 26.

    Farina L, Guidetti A, Spina F, Roncari L, Longoni P, Ravagnani F, et al. Plerixafor “on demand”: results of a strategy based on peripheral blood CD34+ cells in lymphoma patients at first or subsequent mobilization with chemotherapy+G-CSF. Bone Marrow Transplant. 2014;49:453.

  27. 27.

    Kim DH, Sohn SK, Won DI, Lee NY, Suh JS, Lee KB. Rapid helper T-cell recovery above 200 × 106/l at 3 months correlates to successful transplant outcomes after allogeneic stem cell transplantation. Bone Marrow Transplant. 2006;37:1119.

  28. 28.

    A’Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med. 2001;20:859–66.

  29. 29.

    Olivieri A, Marchetti M, Lemoli R, Tarella C. Proposed definition of “poor mobilizer” in lymphoma and multiple myeloma: an analytic hierarchy process by ad hoc working group Gruppo ItalianoTrapianto di Midollo Osseo. Bone Marrow Transplant. 2012. https://www.nature.com/articles/bmt201182

  30. 30.

    Dugan MJ, Maziarz RT, Bensinger WI, Nademanee A, Liesveld J, Badel K, et al. Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin’s lymphoma undergoing stem cell mobilization. Bone Marrow Transplant. 2010;45:39.

  31. 31.

    Jantunen E, Varmavuo V. Plerixafor for mobilization of blood stem cells in autologous transplantation: an update. Expert Opin Biol Ther. 2014;14:851–61.

  32. 32.

    Yuan S, Nademanee A, Krishnan A, Kogut N, Shayani S, Wang S. Second time a charm? Remobilization of peripheral blood stem cells with plerixafor in patients who previously mobilized poorly despite using plerixafor as a salvage agent. Transfusion. 2013;53:3244–50.

  33. 33.

    Sancho J-M, Duarte R, Medina L, Querol S, Marín P, Sureda A, et al. Mobilization of peripheral blood stem cells with plerixafor in poor mobilizer patients. Med Clin. 2016;147:223.e1–223.e7.

  34. 34.

    Farina L, Spina F, Guidetti A, Longoni P, Ravagnani F, Dodero A, et al. Peripheral blood CD34+ cell monitoring after cyclophosphamide and granulocyte-colony-stimulating factor: an algorithm for the pre-emptive use of plerixafor. Leuk Lymphoma. 2014;55:331–6.

  35. 35.

    Milone G, Martino M, Spadaro A, Leotta S, Di Marco A, Scalzulli P. Plerixafor on‐demand combined with chemotherapy and granulocyte colony‐stimulating factor: significant improvement in peripheral blood stem cells mobilization and harvest with no increase in costs. Br J Haematol. 2014;164:113–23.

  36. 36.

    Porrata LF, Gertz MA, Geyer SM, Litzow MR, Gastineau DA, Moore SB, et al. The dose of infused lymphocytes in the autograft directly correlates with clinical outcome after autologous peripheral blood hematopoietic stem cell transplantation in multiple myeloma. Leukemia. 2004;18:1085–92.

  37. 37.

    Porrata LF, Litzow MR, Inwards DJ, Gastineau DA, Moore SB, Pineda AA, et al. Infused peripheral blood autograft absolute lymphocyte count correlates with day 15 absolute lymphocyte count and clinical outcome after autologous peripheral hematopoietic stem cell transplantation in non-Hodgkin’s lymphoma. Bone Marrow Transplant. 2004;33:291–8.

  38. 38.

    Hiwase DK, Hiwase S, Bailey M, Bollard G, Schwarer AP. Higher infused lymphocyte dose predicts higher lymphocyte recovery, which in turn, predicts superior overall survival following autologous hematopoietic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant. 2008;14:116–24.

  39. 39.

    Atta EH, de Azevedo AM, Maiolino A, Coelho CJBP, Sarcinelli SMP de Alvarenga Máximo C, et al. High CD8+ lymphocyte dose in the autograft predicts early absolute lymphocyte count recovery after peripheral hematopoietic stem cell transplantation. Am J Hematol. 2009;84:21–8.

  40. 40.

    Arteche-López A, Kreutzman A, Alegre A, Sanz Martín P, Aguado B, González-Pardo M, et al. Multiple myeloma patients in long-term complete response after autologous stem cell transplantation express a particular immune signature with potential prognostic implication. Bone Marrow Transplant. 2017;52:832–8.

  41. 41.

    Varmavuo V, Mäntymaa P, Silvennoinen R, Nousiainen T, Kuittinen T, Jantunen E. CD34+ cell subclasses and lymphocyte subsets in blood grafts collected after various mobilization methods in myeloma patients. Transfusion. 2013;53:1024–32.

  42. 42.

    Holtan SG, Porrata LF, Micallef INM, Padley DJ, Inwards DJ, Ansell SA, et al. AMD3100 affects autograft lymphocyte collection and progression-free survival after autologous stem cell transplantation in non-Hodgkin lymphoma. Clin Lymphoma Myeloma. 2007;7:315–8.

  43. 43.

    Gaugler B, Arbez J, Legouill S, Tiberghien P, Moreau P, Derenne S, et al. Characterization of peripheral blood stem cell grafts mobilized by granulocyte colony-stimulating factor and plerixafor compared with granulocyte colony-stimulating factor alone. Cytotherapy. 2013;15:861–8.

  44. 44.

    Roug AS, Hokland LB, Segel E, Nielsen K, Toft-Petersen M, Van Kooten Niekerk PB, et al. Unraveling stem cell and progenitor subsets in autologous grafts according to methods of mobilization: implications for prediction of hematopoietic recovery. Cytotherapy. 2014;16:392–401.

  45. 45.

    Simonetta F, Chiali A, Cordier C, Urrutia A, Girault I, Bloquet S, et al. Increased CD127 expression on activated FOXP3+CD4+ regulatory T cells. Eur J Immunol. 2010;40:2528–38.

Download references

Acknowledgements

This research is supported in part by Sanofi which provided Plerixafor vials free of charge.

Author information

Correspondence to Michele Cavo.

Ethics declarations

Conflict of interest

RML received travel grants by Sanofi. All other authors declare no relevant competing financial interests in relation to the work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tolomelli, G., Mancuso, K., Tacchetti, P. et al. The timing of plerixafor addition to G-Csf and chemotherapy affects immunological recovery after autologous stem cell transplant in multiple myeloma. Bone Marrow Transplant (2019). https://doi.org/10.1038/s41409-019-0756-1

Download citation