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Development of a quantitative prediction model for peripheral blood stem cell collection yield in the plerixafor era

  • Author Footnotes
    ⁎ These authors contributed equally to this work.
    Akira Ishii
    Footnotes
    ⁎ These authors contributed equally to this work.
    Affiliations
    Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • Author Footnotes
    ⁎ These authors contributed equally to this work.
    Tomoyasu Jo
    Footnotes
    ⁎ These authors contributed equally to this work.
    Affiliations
    Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Department of Clinical Laboratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Center for Research and Application of Cellular Therapy, Kyoto University Hospital, Kyoto, Japan
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  • Yasuyuki Arai
    Correspondence
    Correspondence: Yasuyuki Arai, MD, PhD, Center for Research and Application of Cellular Therapy, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
    Affiliations
    Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Department of Clinical Laboratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Center for Research and Application of Cellular Therapy, Kyoto University Hospital, Kyoto, Japan
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  • Shinichiro Oshima
    Affiliations
    Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • Junya Kanda
    Affiliations
    Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • Toshio Kitawaki
    Affiliations
    Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • Keiko Matsui
    Affiliations
    Center for Research and Application of Cellular Therapy, Kyoto University Hospital, Kyoto, Japan
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  • Norimi Niwa
    Affiliations
    Center for Research and Application of Cellular Therapy, Kyoto University Hospital, Kyoto, Japan
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  • Yoko Nakagawa
    Affiliations
    Center for Research and Application of Cellular Therapy, Kyoto University Hospital, Kyoto, Japan
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  • Akifumi Takaori-Kondo
    Affiliations
    Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Center for Research and Application of Cellular Therapy, Kyoto University Hospital, Kyoto, Japan
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  • Miki Nagao
    Affiliations
    Department of Clinical Laboratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Center for Research and Application of Cellular Therapy, Kyoto University Hospital, Kyoto, Japan
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  • Author Footnotes
    ⁎ These authors contributed equally to this work.
Open AccessPublished:October 12, 2021DOI:https://doi.org/10.1016/j.jcyt.2021.09.004

      Abstract

      Background aims

      Predicting autologous peripheral blood stem cell (PBSC) collection yield before leukapheresis is important for optimizing PBSC mobilization and autologous stem cell transplantation (ASCT) for treating hematological malignancies. Although guidelines for plerixafor usage based on peripheral blood CD34+ (PB-CD34+) cell count are available, their predictive performance in the real world remains unclear.

      Methods

      This study retrospectively analyzed 55 mobilization procedures for patients with non-Hodgkin lymphoma or multiple myeloma and developed a novel quantitative prediction model for CD34+ cell collection yield that incorporated four clinical parameters available the day before leukapheresis; namely, PB-CD34+ cell count the day before apheresis (day −1 PB-CD34+), number of prior chemotherapy regimens, disease status at apheresis and mobilization protocol.

      Results

      The effects of PB-CD34+ cell counts on CD34+ cell collection yield varied widely per patient characteristics, and plerixafor usage was recommended in patients with poorly controlled disease or those with a history of heavy pre-treatments even with abundant day −1 PB-CD34+ cell count. This model suggested a more proactive use of plerixafor than that recommended by the guidelines for patients with poor pre-collection condition or those with a higher target number of CD34+ cells. Further, the authors analyzed the clinical outcomes of ASCT and found that plerixafor use for stem cell mobilization did not affect short- or long-term outcomes after ASCT.

      Conclusions

      Although external validations are necessary, the results can be beneficial for establishing more effective and safer mobilization strategies.

      Key Words

      Introduction

      Autologous stem cell transplantation (ASCT) following high-dose chemotherapy is widely used for the treatment of patients with hematological malignancies, including those with refractory or relapsed non-Hodgkin lymphoma (NHL) and transplant-eligible multiple myeloma (MM) [
      • Copelan E.A.
      Hematopoietic stem-cell transplantation.
      ]. The optimization of peripheral blood stem cell (PBSC) mobilization regimens as well as conditioning regimens prior to transplantation plays an important role in improving engraftment and the overall outcome after ASCT.
      There are two conventional regimens for PBSC mobilization: granulocyte colony-stimulating factor (G-CSF) in combination with chemotherapy and G-CSF alone [
      • Giralt S.
      • Costa L.
      • Schriber J.
      • Dipersio J.
      • Maziarz R.
      • McCarty J.
      • Shaughnessy P.
      • Snyder E.
      • Bensinger W.
      • Copelan E.
      • Hosing C.
      • Negrin R.
      • Petersen F.B.
      • Rondelli D.
      • Soiffer R.
      • Leather H.
      • Pazzalia A.
      • Devine S.
      Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations.
      ]. The combination of chemotherapy and G-CSF can provide higher CD34+ hematopoietic stem cell (HSC) yields; however, the restricted PBSC mobilization window periods, which are often unpredictable beforehand, can be a burden for both patients and apheresis centers with respect to scheduling. Moreover, the incidence and severity of adverse effects with chemotherapy plus G-CSF are increased compared with G-CSF alone [
      • Pusic I.
      • Jiang S.Y.
      • Landua S.
      • Uy G.L.
      • Rettig M.P.
      • Cashen A.F.
      • Westervelt P.
      • Vij R.
      • Abboud C.N.
      • Stockerl-Goldstein K.E.
      • Sempek D.S.
      • Smith A.L.
      • DiPersio J.F.
      Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation.
      ,
      • Gertz M.A.
      • Kumar S.K.
      • Lacy M.Q.
      • Dispenzieri A.
      • Hayman S.R.
      • Buadi F.K.
      • Dingli D.
      • Gastineau D.A.
      • Winters J.L.
      • Litzow M.R.
      Comparison of high-dose CY and growth factor with growth factor alone for mobilization of stem cells for transplantation in patients with multiple myeloma.
      ]. By contrast, the regimen of G-CSF alone can be beneficial with regard to predictable apheresis scheduling (usually 4–5 days after G-CSF initiation) and the rare occurrence of adverse events; however, the existence of poor mobilizers is a serious problem, particularly for patients with a history of heavy pre-treatment [
      • Giralt S.
      • Costa L.
      • Schriber J.
      • Dipersio J.
      • Maziarz R.
      • McCarty J.
      • Shaughnessy P.
      • Snyder E.
      • Bensinger W.
      • Copelan E.
      • Hosing C.
      • Negrin R.
      • Petersen F.B.
      • Rondelli D.
      • Soiffer R.
      • Leather H.
      • Pazzalia A.
      • Devine S.
      Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations.
      ].
      Plerixafor, a chemokine receptor antagonist, disrupts the interaction between stromal-derived factor 1α and C-X-C chemokine receptor type 4 in the bone marrow niche, thereby facilitating the HSC mobilization effect of G-CSF [
      • Jantunen E.
      Novel strategies for blood stem cell mobilization: special focus on plerixafor.
      ]. Therefore, the regimen of plerixafor plus G-CSF can significantly expand the mobilization of CD34+ HSCs and may be particularly beneficial for patients at high risk of poor mobilization [
      • D'Addio A.
      • Curti A.
      • Worel N.
      • Douglas K.
      • Motta M.R.
      • Rizzi S.
      • Dan E.
      • Taioli S.
      • Giudice V.
      • Agis H.
      • Kopetzky G.
      • Soutar R.
      • Casadei B.
      • Baccarani M.
      • Lemoli R.M.
      The addition of plerixafor is safe and allows adequate PBSC collection in multiple myeloma and lymphoma patients poor mobilizers after chemotherapy and G-CSF.
      ,
      • Lanza F.
      • Lemoli R.M.
      • Olivieri A.
      • Laszlo D.
      • Martino M.
      • Specchia G.
      • Pavone V.
      • Imola M.
      • Pasini A.
      • Milone G.
      • Scortechini I.
      • Todisco E.
      • Guggiari E.
      • Cascavilla N.
      • Martinelli G.
      • Rambaldi A.
      • Bosi A.
      Factors affecting successful mobilization with plerixafor: an Italian prospective survey in 215 patients with multiple myeloma and lymphoma.
      ], thereby enabling nearly all patients to successfully yield a sufficient number of HSCs.
      This situation has raised the clinical question of whether plerixafor is indispensable to every patient for HSC mobilization. The current guidelines of the American Society for Blood and Marrow Transplantation (ASBMT) and the position statement of the European Society for Blood and Marrow Transplantation (EBMT) propose the use of plerixafor in a pre-emptive manner based on the peripheral blood CD34+ (PB-CD34+) cell count or as salvage therapy in the case of low apheresis yield [
      • Giralt S.
      • Costa L.
      • Schriber J.
      • Dipersio J.
      • Maziarz R.
      • McCarty J.
      • Shaughnessy P.
      • Snyder E.
      • Bensinger W.
      • Copelan E.
      • Hosing C.
      • Negrin R.
      • Petersen F.B.
      • Rondelli D.
      • Soiffer R.
      • Leather H.
      • Pazzalia A.
      • Devine S.
      Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations.
      ,
      • Mohty M.
      • Hubel K.
      • Kroger N.
      • Aljurf M.
      • Apperley J.
      • Basak G.W.
      • Bazarbachi A.
      • Douglas K.
      • Gabriel I.
      • Garderet L.
      • Geraldes C.
      • Jaksic O.
      • Kattan M.W.
      • Koristek Z.
      • Lanza F.
      • Lemoli R.M.
      • Mendeleeva L.
      • Mikala G.
      • Mikhailova N.
      • Nagler A.
      • Schouten H.C.
      • Selleslag D.
      • Suciu S.
      • Sureda A.
      • Worel N.
      • Wuchter P.
      • Chabannon C.
      • Duarte R.F.
      Autologous haematopoietic stem cell mobilisation in multiple myeloma and lymphoma patients: a position statement from the European Group for Blood and Marrow Transplantation.
      ]. However, the predictive performance of the guidelines and position statement has not been fully evaluated in the real world. Furthermore, the effects of several factors other than PB-CD34+, which have been reported to affect CD34+ cell yield [
      • Lanza F.
      • Lemoli R.M.
      • Olivieri A.
      • Laszlo D.
      • Martino M.
      • Specchia G.
      • Pavone V.
      • Imola M.
      • Pasini A.
      • Milone G.
      • Scortechini I.
      • Todisco E.
      • Guggiari E.
      • Cascavilla N.
      • Martinelli G.
      • Rambaldi A.
      • Bosi A.
      Factors affecting successful mobilization with plerixafor: an Italian prospective survey in 215 patients with multiple myeloma and lymphoma.
      ,
      • Kumar S.
      • Dispenzieri A.
      • Lacy M.Q.
      • Hayman S.R.
      • Buadi F.K.
      • Gastineau D.A.
      • Litzow M.R.
      • Fonseca R.
      • Roy V.
      • Rajkumar S.V.
      • Gertz M.A.
      Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma.
      ,
      • Mendrone Jr., A.
      • Arrais C.A.
      • Saboya R.
      • Chamone Dde A.
      • Dulley F.L.
      Factors affecting hematopoietic progenitor cell mobilization: an analysis of 307 patients.
      ], have not been assessed quantitatively in previous studies. Therefore, developing a precise predictive model for HSC yield with PB-CD34+ and other factors is necessary to answer the aforementioned clinical question.
      The effects of mobilization agents on ASCT outcomes need to be determined, particularly with respect to the short- and long-term safety of plerixafor, because stem cells mobilized with plerixafor differ from those mobilized by G-CSF alone [
      • Giralt S.
      • Costa L.
      • Schriber J.
      • Dipersio J.
      • Maziarz R.
      • McCarty J.
      • Shaughnessy P.
      • Snyder E.
      • Bensinger W.
      • Copelan E.
      • Hosing C.
      • Negrin R.
      • Petersen F.B.
      • Rondelli D.
      • Soiffer R.
      • Leather H.
      • Pazzalia A.
      • Devine S.
      Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations.
      ,
      • Larochelle A.
      • Krouse A.
      • Metzger M.
      • Orlic D.
      • Donahue R.E.
      • Fricker S.
      • Bridger G.
      • Dunbar C.E.
      • Hematti P.
      AMD3100 mobilizes hematopoietic stem cells with long-term repopulating capacity in nonhuman primates.
      ,
      • Gazitt Y.
      • Freytes C.O.
      • Akay C.
      • Badel K.
      • Calandra G.
      Improved mobilization of peripheral blood CD34+ cells and dendritic cells by AMD3100 plus granulocyte-colony-stimulating factor in non-Hodgkin's lymphoma patients.
      ,
      • Devine S.M.
      • Vij R.
      • Rettig M.
      • Todt L.
      • McGlauchlen K.
      • Fisher N.
      • Devine H.
      • Link D.C.
      • Calandra G.
      • Bridger G.
      • Westervelt P.
      • Dipersio J.F.
      Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction.
      ,
      • Varmavuo V.
      • Mantymaa P.
      • Kuittinen T.
      • Nousiainen T.
      • Jantunen E.
      Blood graft lymphocyte subsets after plerixafor injection in non-Hodgkin's lymphoma patients mobilizing poorly with chemotherapy plus granulocyte-colony-stimulating factor.
      ,
      • Worel N.
      • Frank N.
      • Frech C.
      • Fritsch G.
      Influence of plerixafor on the mobilization of CD34+ cell subpopulations and lymphocyte subtypes.
      ,
      • Worel N.
      • Fritsch G.
      • Agis H.
      • Bohm A.
      • Engelich G.
      • Leitner G.C.
      • Geissler K.
      • Gleixner K.
      • Kalhs P.
      • Buxhofer-Ausch V.
      • Keil F.
      • Kopetzky G.
      • Mayr V.
      • Rabitsch W.
      • Reisner R.
      • Rosskopf K.
      • Ruckser R.
      • Zoghlami C.
      • Zojer N.
      • Greinix H.T.
      Plerixafor as preemptive strategy results in high success rates in autologous stem cell mobilization failure.
      ]. Although an increasing number of patients have undergone PBSC mobilization with plerixafor, few studies have studied its effects on outcomes after ASCT.
      The authors therefore performed a retrospective cohort study to evaluate the following: (i) the impacts of pre-collection patient factors on CD34+ collection yield, thereby developing a novel quantitative estimation model with a high predictive performance, and (ii) the effects of plerixafor use on clinical outcomes after ASCT. The authors believe that the present study findings will help develop an integrated approach as well as safe PBSC mobilization and subsequent ASCT for the treatment of NHL and MM.

      Methods

      Study cohort and inclusion criteria

      This study enrolled adult patients with NHL or MM who underwent PBSC collection and transplantation at Kyoto University Hospital from January 2013 to July 2020. Patients with data on PB-CD34+ cell counts a day before apheresis (day −1 PB-CD34+) were included to analyze parameters affecting stem cell mobilization. Moreover, those who subsequently underwent ASCT were subject to outcome analyses. This study was approved by the institutional review board of Kyoto University and was conducted according to the principles of the Declaration of Helsinki.

      Definition of disease status

      Disease status at leukapheresis and transplantation was assessed using the Revised Response Criteria for Malignant Lymphoma [
      • Cheson B.D.
      • Pfistner B.
      • Juweid M.E.
      • Gascoyne R.D.
      • Specht L.
      • Horning S.J.
      • Coiffier B.
      • Fisher R.I.
      • Hagenbeek A.
      • Zucca E.
      • Rosen S.T.
      • Stroobants S.
      • Lister T.A.
      • Hoppe R.T.
      • Dreyling M.
      • Tobinai K.
      • Vose J.M.
      • Connors J.M.
      • Federico M.
      • Diehl V.
      L. International Harmonization Project on, Revised response criteria for malignant lymphoma.
      ] and International Myeloma Working Group Uniform Response Criteria [
      • Kumar S.
      • Paiva B.
      • Anderson K.C.
      • Durie B.
      • Landgren O.
      • Moreau P.
      • Munshi N.
      • Lonial S.
      • Blade J.
      • Mateos M.V.
      • Dimopoulos M.
      • Kastritis E.
      • Boccadoro M.
      • Orlowski R.
      • Goldschmidt H.
      • Spencer A.
      • Hou J.
      • Chng W.J.
      • Usmani S.Z.
      • Zamagni E.
      • Shimizu K.
      • Jagannath S.
      • Johnsen H.E.
      • Terpos E.
      • Reiman A.
      • Kyle R.A.
      • Sonneveld P.
      • Richardson P.G.
      • McCarthy P.
      • Ludwig H.
      • Chen W.
      • Cavo M.
      • Harousseau J.L.
      • Lentzsch S.
      • Hillengass J.
      • Palumbo A.
      • Orfao A.
      • Rajkumar S.V.
      • Miguel J.S.
      • Avet-Loiseau H.
      International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.
      ]. The disease status was then categorized as follows: complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). CR included CR and unconfirmed CR in NHL as well as CR and stringent CR in MM, whereas PR included PR in NHL as well as PR, very good PR and near CR in MM. The definitions of SD and PD were based on the aforementioned criteria for NHL and MM.

      Standardized procedures for stem cell mobilization

      Before the approval of plerixafor in Japan in 2016 [
      • Matsue K.
      • Kumagai K.
      • Sugiura I.
      • Ishikawa T.
      • Igarashi T.
      • Sato T.
      • Uchiyama M.
      • Miyamoto T.
      • Ono T.
      • Ueda Y.
      • Kiguchi T.
      • Sunaga Y.
      • Sasaki T.
      • Suzuki K.
      Plerixafor for mobilization and collection of haematopoietic stem cells for autologous transplantation in Japanese patients with non-Hodgkin lymphoma: a randomized phase 2 study.
      ], stem cell mobilization was performed almost exclusively during bone marrow recovery following chemotherapy with G-CSF boost (defined as the CG protocol). After plerixafor approval, stem cell mobilization was performed with either G-CSF alone or plerixafor plus G-CSF without any preceding chemotherapy (defined as the G or PG protocol). For G-CSF administration, either lenograstim or filgrastim was administered at a dose of 10 μg/kg for lenograstim or 400 μg/m2 for filgrastim when used alone or in combination with plerixafor and 5 μg/kg for lenograstim or 400 μg/m2 for filgrastim when administered after chemotherapy as per the guidelines for the appropriate use of G-CSF in Japan [
      • Usui N.
      [Appropriate use of granulocyte-colony stimulating factor in treating hematologic malignancies].
      ]. Plerixafor was administered at a dose of 240 μg/kg, and its prescription was determined by the physicians in charge based on the position statement of EBMT [
      • Mohty M.
      • Hubel K.
      • Kroger N.
      • Aljurf M.
      • Apperley J.
      • Basak G.W.
      • Bazarbachi A.
      • Douglas K.
      • Gabriel I.
      • Garderet L.
      • Geraldes C.
      • Jaksic O.
      • Kattan M.W.
      • Koristek Z.
      • Lanza F.
      • Lemoli R.M.
      • Mendeleeva L.
      • Mikala G.
      • Mikhailova N.
      • Nagler A.
      • Schouten H.C.
      • Selleslag D.
      • Suciu S.
      • Sureda A.
      • Worel N.
      • Wuchter P.
      • Chabannon C.
      • Duarte R.F.
      Autologous haematopoietic stem cell mobilisation in multiple myeloma and lymphoma patients: a position statement from the European Group for Blood and Marrow Transplantation.
      ]. For example, plerixafor administration was actively considered in cases with a day −1 PB-CD34+ cell count of <10/μL but not in cases with a day −1 PB-CD34+ cell count of >20/μL, and a dynamic approach based on patient characteristics was suggested in those with a day −1 PB-CD34+ cell count of 10–20/μL. Plerixafor was also given at the physicians’ discretion despite high CD34 values.

      Leukapheresis and CD34+ cell measurement

      PBSCs were collected using the Spectra Optia (Terumo BCT, Tokyo, Japan) and mononuclear cell collection program with a ratio of anticoagulant (acid citrate dextrose solution A) to blood of 1:12 and maximum blood volume processed (BVP) of 0.3 L/kg body weight, which are within the range recommended by ASBMT [
      • Giralt S.
      • Costa L.
      • Schriber J.
      • Dipersio J.
      • Maziarz R.
      • McCarty J.
      • Shaughnessy P.
      • Snyder E.
      • Bensinger W.
      • Copelan E.
      • Hosing C.
      • Negrin R.
      • Petersen F.B.
      • Rondelli D.
      • Soiffer R.
      • Leather H.
      • Pazzalia A.
      • Devine S.
      Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations.
      ]. Routine analyses of the peripheral blood or apheresis product samples included complete blood count, CD34+ cell count, viability tests and product volume measurement. CD34+ cells were measured using flow cytometry with single-platform assays on a FACSCanto II (BD Biosciences, Heidelberg, Germany) [
      • Keeney M.
      • Chin-Yee I.
      • Weir K.
      • Popma J.
      • Nayar R.
      • Sutherland D.R.
      Single platform flow cytometric absolute CD34+ cell counts based on the ISHAGE guidelines.
      ]. Poor mobilization was defined as the failure to collect a minimum of 2.0 × 106 CD34+ cells/kg body weight after completing all apheresis sessions. To adjust variations in BVP among the patients, the authors compared the total CD34+ cell yield collected on the first day of apheresis per 10 L BVP.

      Standardized procedures of ASCT and definition of outcomes

      Patients received high-dose chemotherapy, including ranimustine, etoposide, cytarabine and melphalan [
      • Sugimoto M.
      • Ito S.
      • Mashima K.
      • Umino K.
      • Minakata D.
      • Nakano H.
      • Yamasaki R.
      • Kawasaki Y.
      • Ashizawa M.
      • Yamamoto C.
      • Fujiwara S.
      • Okazuka K.
      • Hatano K.
      • Sato K.
      • Oh I.
      • Ohmine K.
      • Suzuki T.
      • Muroi K.
      • Kako S.
      • Kanda Y.
      Retrospective evaluation of the MEAM regimen as a conditioning regimen before autologous peripheral blood stem cell transplantation for lymphoma in two centers with different dosing schedules of melphalan.
      ], and high-dose thiotepa plus busulfan [
      • Wada F.
      • Nishikori M.
      • Hishizawa M.
      • Watanabe M.
      • Aiba A.
      • Kitano T.
      • Shimazu Y.
      • Shindo T.
      • Kondo T.
      • Takaori-Kondo A.
      Secondary failure of platelet recovery in patients treated with high-dose thiotepa and busulfan followed by autologous stem cell transplantation.
      ] in NHL and high-dose melphalan [
      • Child J.A.
      • Morgan G.J.
      • Davies F.E.
      • Owen R.G.
      • Bell S.E.
      • Hawkins K.
      • Brown J.
      • Drayson M.T.
      • Selby P.J.
      Medical Research Council Adult Leukaemia Working, High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.
      ] in MM followed by autologous CD34+ cell transplantation on day 0. After transplantation, neutrophil engraftment was defined as the first of 3 consecutive days with an absolute neutrophil count of ≥0.5 × 109/L without growth factor support, platelet engraftment was defined as the first of 3 consecutive days with a platelet count of ≥20 × 109/L or 50 × 109/L without transfusion and erythrocyte engraftment was defined as the first of 3 consecutive days with a reticulocyte count ≥1%. Non-infectious fever was defined as an axillary body temperature of ≥37.5 °C with onset between day 0 and day 30 after transplantation, during which complete infectious workups should be negative.

      Statistical analyses

      For baseline patient characteristics, categorical variables were assessed using Fisher exact test, whereas continuous variables were compared using two-tailed unpaired Student's t-test or one-way analysis of variance with Tukey post-hoc test. The predictive factors of stem cell collection were analyzed using Pearson correlation and univariate regression models. In multivariate analyses for the prediction factors of stem cell collection, all variables with P < 0.1 in univariate analyses and known poor collection risk factors were included and a multiple regression model using a backward stepwise elimination method (significance level = 0.05) was performed. In the regression analyses, all continuous variables were log-transformed to normalize the skewed distribution. The cumulative curves of engraftments or non-infectious fever were described using the Gray method [
      • Gooley T.A.
      • Leisenring W.
      • Crowley J.
      • Storer B.E.
      Estimation of failure probabilities in the presence of competing risks: new representations of old estimators.
      ], considering death or death and evident infection as competing risks. The survival curves were calculated using the Kaplan–Meier method, and the impacts of plerixafor use on the outcomes of ASCT were analyzed using the Fine and Gray test [
      • Fine J.P.
      • Gray R.J.
      A Proportional Hazards Model for the Subdistribution of a Competing Risk.
      ] or log-rank test. P < 0.05 was considered statistically significant. All statistical analyses were performed using Stata 16 software (StataCorp LLC, College Station, TX, USA).

      Results

      Patient characteristics with regard to CD34+ cell mobilization

      Patient clinical characteristics for CD34+ cell mobilization and collection are presented in Table 1. The authors included 55 patients with a median age of 57 years (range, 26–70) at apheresis. The underlying diseases included NHL (N = 37, 67.3%) and MM (N = 18, 32.7%), and CR was achieved at mobilization attempt in 19 (34.5%) patients. For the chemotherapy regimens before mobilization, nine (16.4%) patients were heavily treated with ≥3 regimens and 12 (21.8%) patients were administered treatments comprising lenalidomide. For the mobilization protocol, 11 (20.0%), nine (16.4%) and 35 (63.6%) patients underwent stem cell mobilization in the chemotherapy plus G-CSF (CG), G-CSF only (G) and plerixafor plus G-CSF (PG) groups, respectively. The baseline patient characteristics were similar, with the exception of the history of lenalidomide administration, which was observed in only the PG group.
      Table 1Patient characteristics for CD34+ cell harvest according to mobilization strategy.
      TotalCGGPG
      N = 55N = 11N = 9N = 35P value
      Basal demographics
      Age at apheresis, years (range)57 (26–70)62 (27–66)53 (33–69)57 (26–70)0.58
      Male, n (%)31 (56.4)5 (45.5)5 (55.6)21 (60.0)0.79
      Body weight, kg (range)61.1 (33.0–96.3)55.1 (39–67.5)60.8 (49.8–75.1)64.0 (33.0–96.3)0.16
      Disease0.06
      NHL, n (%)37 (67.3)7 (63.6)9 (100.0)21 (60.0)
      MM, n (%)18 (32.7)4 (36.4)0 (0.0)14 (40.0)
      Disease status at apheresis0.59
      CR, n (%)19 (34.5)3 (27.3)2 (22.2)14 (40.0)
      PR, n (%)34 (61.8)7 (63.6)7 (77.8)20 (57.1)
      SD/PD, n (%)2 (3.6)1 (9.1)0 (0.0)1 (2.9)
      Number of prior chemotherapy regimens0.83
      1, n (%)19 (34.5)3 (27.3)4 (44.4)12 (34.3)
      2, n (%)27 (49.1)5 (45.5)4 (44.4)18 (51.4)
      ≥3, n (%)9 (16.4)3 (27.3)1 (11.1)5 (14.3)
      Use of myelotoxic agents
      Lenalidomide, n (%)12 (21.8)0 (0.0)0 (0.0)12 (34.3)0.01
      P < 0.05.
      Radiation, n (%)11 (20.0)3 (27.3)1 (11.1)7 (20.0)0.79
      CBC day −1
      WBCs, 109/L (range)34.3 (0.3–68.9)1.2 (0.3–15.8)34.3 (14.6–49.2)42.2 (1.3–68.9)< 0.01
      P < 0.05.
      Neutrophils, 109/L (range)26.6 (0.1–60.0)0.3 (0.1–13.9)26.8 (11.8–45.3)34.4 (0.6–60.0)< 0.01
      P < 0.05.
      Monocytes, 109/L (range)2.0 (0.0–8.6)0.2 (0.0–1.1)2.5 (0.5–5.7)2.6 (0.3–8.6)< 0.01
      P < 0.05.
      Metamyelocytes, 109/L (range)0.0 (0.0–1.8)0.0 (0.0–0.1)0.0 (0.0–1.8)0.0 (0.0–1.1)0.11
      Myelocytes, 109/L (range)0.0 (0.0–3.4)0.0 (0.0–0.3)0.4 (0.0–3.4)0.0 (0.0–3.1)0.07
      Hemoglobin, g/dL (range)10.8 (7.0–14.1)9.5 (7.0–10.7)11.2 (8.7–14.1)11.5 (7.3–14.1)0.01
      P < 0.05.
      Platelets, 104/μL (range)17.0 (2.4–56.2)4.4 (2.7–13.4)22.6 (6.8–56.2)18.1 (2.4–49.0)< 0.01
      P < 0.05.
      Mobilization outcome
      Day −1 PB-CD34+, /μL (range)6.0 (0.0–244.0)4.0 (0.0–244.0)45.7 (15.2–109.8)5.0 (0.7–170.0)0.04
      P < 0.05.
      Day 0 PB-CD34+, /μL (range)40.3 (4.2–236.0)12.0 (5.0–64.0)54.9 (51.5–117.3)54.5 (4.2–236.0)0.07
      Number of aphereses0.18
      1, n (%)42 (76.4)6 (54.5)8 (88.9)28 (80.0)
      2, n (%)12 (21.8)4 (36.4)1 (11.1)7 (20.0)
      3, n (%)1 (1.8)1 (9.1)0 (0.0)0 (0.0)
      CD34+ cell yield, first day, 106/kg (range)4.2 (0.3–29.5)1.5 (0.3–29.5)6.2 (1.1–13.4)3.8 (0.8–13.1)0.36
      CD34+ cell yield, total, 106/kg (range)4.6 (0.3–29.5)4.2 (0.3–29.5)6.2 (3.0–13.4)4.5 (1.7–13.1)0.20
      CD34+ cell yield <2.0 × 106/kg, first day (range)14 (25.5%)6 (54.5%)1 (11.1%)7 (20.0%)0.05
      CD34+ cell yield <2.0 × 106/kg, total (range)4 (7.3%)3 (27.3%)0 (0.0%)1 (2.9%)0.04
      P < 0.05.
      Blood volume processed, first day, L (range)10.0 (4.8–14.5)10.0 (10.0–10.4)10.0 (8.7–10.3)10.0 (4.8–14.5)0.92
      Total CD34+ cell yield/10 L BVP, first day, 1082.5 (0.1–19.9)0.9 (0.1–19.9)3.6 (0.8–6.8)2.4 (0.5–13.2)0.83
      CBC, complete blood count; WBCs, white blood cells.
      a P < 0.05.
      During the mobilization protocol, complete blood cell counts, including white blood cell counts, hemoglobin levels and platelet counts on day −1, were lower in the patients of the CG group than in the patients of other mobilization groups. Although day −1 PB-CD34+ cell count was significantly higher in the patients of the G group than in the patients of the CG or PG group, PB-CD34+ cell count on the first day of apheresis (day 0) was comparable between those in the G and PG groups (Table 1).
      With respect to harvest yields, the median number of CD34+ cells collected on the first day of leukapheresis was 4.2 × 106 cells/kg (range, 0.3–29.5), with a median value of 10.0 L (range, 4.8–14.5) BVP. Forty-two (76.4%) patients underwent 1-day apheresis to obtain a sufficient number of CD34+ cells, whereas the other patients required two or three apheresis sessions. The median number of CD34+ cells collected in total leukaphereses was 4.6 × 106 cells/kg (range, 0.3–29.5), and poor mobilization was present in four (7.3%) patients (Table 1).

      Predictive performance of PB-CD34+ cell count for CD34+ cell yield on the first day of apheresis

      As the next step, the authors analyzed the correlation between day −1 PB-CD34+ cell count and total CD34+ cell yields on the first day of apheresis (per 10 L BVP) to evaluate the predictive performance of the PB-CD34+-based approach that is recommended in the current EBMT position statement. Thus, day −1 PB-CD34+ cell count correlated significantly with CD34+ cell collection yield on the first day of apheresis in the entire cohort (Figure 1A) and in each mobilization group (Figure 1B). However, the coefficient of determination (R2) was remarkably low, particularly in the CG (0.45) and PG (0.43) groups; this indicated that CD34+ cell collection yield cannot be predicted by day −1 PB-CD34+ cell count alone. Moreover, the simplified model of prediction for the success of apheresis using day −1 PB-CD34+ cell count data was suboptimal (see supplementary Tables 1–4). Sufficient CD34+ cell yield was successfully obtained on the first day of apheresis in all patients with a day −1 PB-CD34+ cell count of ≥20/μL. However, among patients with a day −1 PB-CD34+ cell count of <20/μL, 66% achieved the target yield, whereas the other 34% failed, irrespective of plerixafor use; the difference was not predicted using day −1 PB-CD34+ cell count (see supplementary Table 4). These analyses indicated that prediction models solely dependent on PB-CD34+ cell count can be applicable only in limited clinical situations.
      Fig 1
      Fig. 1Correlation between CD34+ cell collection yield and PB-CD34+. (A) Correlation between total CD34+ cell yield on first day of apheresis/10 L BVP and peripheral blood CD34+ cell counts on day −1 PB-CD34+ in total patients and (B) in each mobilization group. Axes are displayed in logarithmic scales, and black dots indicate patients in whom CD34+ cell collection yield was <2.0 × 106/kg on the first day of apheresis. * indicates P < 0.05.

      Univariate and multivariate analyses of predictive factors for CD34+ cell yield

      Day −1 PB-CD34+ cell count alone was insufficient to predict the harvest yield; thus, the authors investigated other factors that potentially affect CD34+ cell collection yield (Table 2, Figure 2A,B; also see supplementary Figure 1A,B). In the univariate analyses, lower body weight, less controlled disease status (SD or PD), larger number of prior chemotherapy regimens (≥3), use of CG mobilization protocol and lower peripheral blood white blood cell, myelocyte and platelet counts on day −1 as well as lower day −1 PB-CD34+ cells were significantly associated with poorer CD34+ collection yield (Table 2, Figure 2A,B). In the multivariate regression analyses, poorly controlled disease status (SD or PD, P = 0.01), larger number of prior chemotherapy regimens (≥3, P = 0.01), mobilization protocols without plerixafor (G group, P = 0.01, CG group, P = 0.03) and lower day −1 PB-CD34+ cell count (P < 0.01) were significantly associated with lower CD34+ cell collection yield (Table 2).
      Table 2Univariate and multivariate analyses of parameters for CD34+ cell yield in first apheresis.
      UnivariateMultivariate
      Coefficient95% CIP valueCoefficient95% CIP value
      Basal demographics
      Age at apheresis, years–0.902–2.197–0.3920.17
      Sex, female versus male
      Binary variable.
      0.7040.401–1.2360.22
      Body weight, kg1.5300.139–2.9210.03
      P < 0.05.
      Disease, MM versus NHL
      Binary variable.
      1.6300.904–2.9370.10
      Disease status, SD/PD versus CR/PR
      Binary variable.
      0.1410.034–0.5780.01
      P < 0.05.
      0.2430.089–0.6650.01
      P < 0.05.
      Number of prior chemotherapy regimens, ≥3 versus ≤2
      Binary variable.
      0.2470.127–0.478< 0.01
      P < 0.05.
      0.4800.286–0.8040.01
      P < 0.05.
      Lenalidomide, yes versus no
      Binary variable.
      0.8560.432–1.6990.65
      Radiation, yes versus no
      Binary variable.
      0.9590.472–1.9480.91
      Harvest regimen
      Binary variable.
      G versus PG1.4730.702–3.0910.300.4810.278–0.8330.01
      P < 0.05.
      CG versus PG0.4620.233–0.9160.03
      P < 0.05.
      0.6000.384–0.9390.03
      P < 0.05.
      CBC day –1
      WBCs, 109/L0.1930.013–0.3720.04
      P < 0.05.
      Neutrophils, 109/L0.115–0.024–0.2550.10
      Monocytes, 109/L0.1460.080–0.3710.20
      Metamyelocytes, 109/L0.109–0.152–0.3690.41
      Myelocytes, 109/L0.3160.097–0.5340.01
      P < 0.05.
      Hemoglobin, g/dL1.424–0.100–2.9480.07
      Platelets, 104/μL0.7220.317–1.1280.01
      P < 0.05.
      PB-CD34+, /μL0.4630.302–0.625< 0.01
      P < 0.05.
      0.5250.376–0.674< 0.01
      P < 0.05.
      CBC, complete blood count; CI, confidence interval; WBCs, white blood cells.
      a P < 0.05.
      b Binary variable.
      Fig 2
      Fig. 2Factors affecting CD34+ cell collection yield. (A) Comparison of total CD34+ cell yield on the first day of apheresis/10 L BVP with respect to indicated categorical variables. (B) Correlation between total CD34+ cell yield on the first day of apheresis/10 L BVP and indicated continuous variables. Axes are displayed in logarithmic scales, and black dots indicate patients in whom CD34+ cell collection yield was <2.0 × 106/kg on the first day of apheresis. * indicates P < 0.05. WBC, white blood cell.
      The multivariate model estimated that poor disease control at mobilization and ≥3 chemotherapy lines before mobilization reduced CD34+ cell collection yield on the first day of apheresis by 24% and 48%, respectively. By contrast, plerixafor use in combination with G-CSF increased CD34+ cell collection yields by 208% compared with G-CSF alone (Table 2).

      Development of a prediction model for CD34+ collection with various patient conditions

      Based on the multivariate model shown in Table 2, the total CD34+ cell yield on the first day of apheresis per 10 L BVP was predicted using the following equation (see supplementary Figure 2): estimated CD34+ cell collection yield on the first day of apheresis/10 L BVP (108) = 1.062 × (day −1 PB-CD34+ cell count [/μL])0.525 (if disease status in SD or PD × 0.243) (if number of chemotherapy regimens ≥3 × 0.480) (if G group × 0.481, if CG group × 0.600).
      The estimated CD34+ cell collection yield significantly correlated with the actual CD34+ cell collection yield in the entire cohort (Figure 3A) and in each mobilization group (Figure 3B); the coefficient of determination (R2) was remarkably improved compared with the model using PB-CD34+ cell count alone (Figure 1). As per this new model, poor mobilization was predicted with an accuracy of 85.7% (Table 3).
      Fig 3
      Fig. 3Development of a prediction model for CD34+ cell collection yield based on patient conditions. Correlation between actual CD34+ cell yield on the first day of apheresis/10 L BVP and predicted CD34+ cell yield/10 L BVP using the mathematical formula of estimated CD34+ cell collection yield on the first day of apheresis/10 L BVP (108) = 1.062 × (day −1 PB-CD34+ cell count [/μL])0.525 (if disease status in SD or PD × 0.243) (if number of chemotherapy regimens ≥3 × 0.480) (if G group × 0.481, if CG group × 0.600) in (A) total patients and (B) each mobilization group. Axes are displayed in logarithmic scales, and black dots indicate patients in whom CD34+ cell collection yield was <2.0 × 106/kg on the first day of apheresis. (C) Predictive heatmap for CD34+ cell yield (showing an example where BVP is 10 L and the patient's body weight is 60 kg). The number in each cell indicates the predicted CD34+ cell yield on the first day of apheresis (106/kg) under the designated condition (1–4) and mobilizing protocol (G or PG). Shading indicates that the predicted CD34+ cell collection yield is <2.0 × 106/kg or 5.0 × 106/kg.* indicates P < 0.05.
      Table 3Predictive value of estimation for CD34+ cell yield.
      Estimated yield , 106/kg/10 L BVP (%)
      <2≥2Total
      Actual yield, 106/kg/10 L BVP (%)<212 (85.7)3 (7.3)15 (27.3)
      ≥22 (14.3)38 (92.7)40 (72.7)
      Total14 (100.0)41 (100.0)55 (100.0)
      P < 0.01 based on Fisher exact test.
      This model can also be applied to determine the need for plerixafor based on both pre-collection parameters and target CD34+ cell number for collection (Figure 3C). For example, in a patient weighing 60 kg and a day −1 PB-CD34+ cell count of 10/μL whose disease was well controlled with a limited number of prior chemotherapy regimens (condition 1), 2.85 × 106/kg CD34+ cells were collected on the first day of apheresis with a BVP of 10 L when mobilized with G-CSF alone, whereas 5.93 × 106/kg CD34+ cells were collected with plerixafor plus G-CSF. By contrast, even with 20/μL PB-CD34+, plerixafor was required in patients with a history of heavy chemotherapy regimens (condition 2) or those with poorly controlled disease (condition 3) to obtain >2.0 × 106/kg CD34+ cells on the first day of apheresis. It is noteworthy to mention that the effects of PB-CD34+ cell count differed widely based on patient characteristics.

      Effects of plerixafor use on engraftment and short- and long-term outcomes after ASCT

      The authors’ model suggests that pre-emptive plerixafor use is beneficial in a wider range of patients than that indicated in the position statement from EBMT. However, the influence of plerixafor on post-ASCT outcomes, including engraftment and short- and long-term complications, has not been systematically analyzed. Therefore, among all patients who underwent PBSC collection, the authors analyzed 72 patients who subsequently underwent ASCT and compared patient outcomes after ASCT, including hematopoietic recovery, engraftment syndrome, disease relapse and survival between groups treated with and without plerixafor for mobilization. Patient characteristics are shown in supplementary Table 5. No significant differences were observed in the basic characteristics of patients, including transplanted CD34+ cell number, between groups. Thus, the time course and cumulative incidence of engraftment for all lineages were similar between the groups treated with and without plerixafor (PG versus G or CG) (Figure 4A,B; also see supplementary Figure 3A,B). The cumulative incidence and duration of non-infectious fever were comparable between the groups (Figure 4C,D).
      Fig 4
      Fig. 4Effects of plerixafor use on clinical outcomes of ASCT. Engraftment of (A) neutrophils and (B) platelets following ASCT. (C) Cumulative incidence and (D) duration of non-infectious fever following ASCT. (E) OS and (F) PFS after ASCT. OS, overall survival; PFS, progression-free survival.
      With regard to long-term outcomes, the 2-year overall survival after ASCT in patients treated with plerixafor appeared slightly worse compared with those treated without plerixafor (70.1% versus 86.5%); however, the difference was not significant (P = 0.11) (Figure 4E). The incidence of progression-free survival, relapse-free survival and relapse was similar between subjects treated with and without plerixafor; no significant difference was detected (Figure 4F; also see supplementary Figure 3C,D).

      Discussion

      This retrospective cohort study investigated PBSC harvest and subsequent ASCT in patients with NHL and MM in which all diagnostic and therapeutic procedures followed uniform institutional principles, and the authors obtained two major findings. First, the four parameters of disease status at apheresis, previous history of chemotherapy regimens, mobilization protocol and day −1 PB-CD34+ cell count are the predictive factors of CD34+ cell collection yields. A novel quantitative prediction model was established for accurate yield prediction to suggest the necessity of plerixafor administration based on the clinical status of each patient. Second, plerixafor use for mobilization has no harmful impacts on engraftment, non-infectious fever or survival after ASCT. The study findings suggest that a more proactive use of plerixafor than that indicated in the previous guidelines or position statement can be recommended, particularly for patients with heavy pre-treatments or those with poorly controlled disease.
      The authors initially developed a clinically applicable predictive model for the yields of CD34+ HSCs. In this model, disease control status and preceding chemotherapy lines were extracted from the wide variety of parameters before PBSC harvest. These factors were first clearly recognized as risk factors for poor mobilization [
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      ]. Heavily pre-treated patients, recognized as patients with a history of a large number of prior chemotherapy lines, often have exhausted bone marrow hematopoiesis or clinical/subclinical therapy-related myelodysplasia in addition to impaired marrow stroma to support HSCs [
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      ]; such a condition poses a high risk of failure in obtaining sufficient HSCs. The authors’ analyses indicated that disease status and significant chemotherapy history can suppress HSC yields to a quarter or half; thus, these parameters should be included in the prediction model along with mobilization protocol and day −1 PB-CD34+ cell count.
      The authors’ quantitative model not only predicts yields precisely using four parameters but also guides the need for plerixafor use based on the clinical status of and target yield in each patient. In the authors’ model, for example, plerixafor use is recommended not only for patients with a PB-CD34+ cell count of <10/μL to obtain ≥2.0 × 106/kg CD34+ cells, as suggested in the EBMT position statement, but also for patients heavily pre-treated or those with poorly controlled disease; this has not been clearly mentioned in any guidelines or previous studies. For patients with a day −1 PB-CD34+ cell count of 10−20/μL, there are no clear standards regarding plerixafor use. Furthermore, the authors’ model can be applied to situations where a larger number of CD34+ HSCs are required to perform ASCT more than once, particularly for patients with MM [
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      The present study can answer the following frequently asked clinical question: how many PB-CD34+ cells are enough to collect a sufficient number of CD34+ cells in the real world? Of note, the authors found that plerixafor use enabled us to harvest sufficient CD34+ cells in patients with a day −1 PB-CD34+ cell count as low as 1.2/μL in a single apheresis (Figure 1B) and in patients with a day −1 PB-CD34+ cell count as low as 0.7/μL in two apheresis sessions. These findings suggest that it is worth performing apheresis after plerixafor administration even if the day −1 PB-CD34+ cell count is extremely low. Moreover, the authors’ current model suggests a more expanded indication for plerixafor than that offered by the ASBMT guidelines and EBMT position statement, although the routine use of plerixafor should be avoided from a pharmacoeconomic standpoint [
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      ].
      Since the authors’ analyses suggested an expanded indication for plerixafor, the effects on post-ASCT clinical courses and outcomes were systematically analyzed. Previous studies have indicated no significant differences in the time to hematopoietic recovery or in survival between patients treated with and without plerixafor for mobilization [
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      ,
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      ]. However, plerixafor reportedly mobilizes different CD34+ cell subpopulations at different developmental stages as well as non-CD34+ cells, including CD4+ and CD8+ T cells, natural killer cells and dendritic cells [
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      ,
      • Gazitt Y.
      • Freytes C.O.
      • Akay C.
      • Badel K.
      • Calandra G.
      Improved mobilization of peripheral blood CD34+ cells and dendritic cells by AMD3100 plus granulocyte-colony-stimulating factor in non-Hodgkin's lymphoma patients.
      ,
      • Devine S.M.
      • Vij R.
      • Rettig M.
      • Todt L.
      • McGlauchlen K.
      • Fisher N.
      • Devine H.
      • Link D.C.
      • Calandra G.
      • Bridger G.
      • Westervelt P.
      • Dipersio J.F.
      Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction.
      ,
      • Varmavuo V.
      • Mantymaa P.
      • Kuittinen T.
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      • Jantunen E.
      Blood graft lymphocyte subsets after plerixafor injection in non-Hodgkin's lymphoma patients mobilizing poorly with chemotherapy plus granulocyte-colony-stimulating factor.
      ,
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      ,
      • Worel N.
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      Plerixafor as preemptive strategy results in high success rates in autologous stem cell mobilization failure.
      ]. Therefore, the use of PBSCs mobilized with plerixafor is expected to exert pro-inflammatory effects following ASCT and subsequently increase engraftment syndrome and non-relapse mortality. The results of the current study contradict this hypothesis, and the authors showed that plerixafor use did not increase the incidence or duration of non-infectious fever or alter hematopoietic recovery or survival after ASCT. These results suggest that the mobilization regimen can be determined without considering the effects on ASCT outcomes [
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      ]; however, studies with longer follow-up periods and more patients are necessary to reach a final conclusion.
      The present study systematically investigated PBSC harvest and subsequent ASCT for NHL and MM. However, some limitations exist with respect to the retrospective nature of the study and variation in the baseline characteristics of the three mobilization groups. For example, the proportion of patients with a history of lenalidomide-containing regimens was higher in the PG group than in other groups, reflecting the approval of frontline therapy with lenalidomide in Japan in 2015 [
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      ,
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      ]. In the present study, the effect of plerixafor in combination with chemotherapy plus G-CSF was not evaluated. The trend revealing that plerixafor use was associated with lower overall survival could be related to the potential selection of poor mobilizers for the plerixafor group and should be interpreted cautiously. Moreover, because of the small sample size of this study, the findings should be interpreted with caution. Given that the ethnicity of patients has been reported to be associated with CD34+ cell collection yield [
      • Vasu S.
      • Leitman S.F.
      • Tisdale J.F.
      • Hsieh M.M.
      • Childs R.W.
      • Barrett A.J.
      • Fowler D.H.
      • Bishop M.R.
      • Kang E.M.
      • Malech H.L.
      • Dunbar C.E.
      • Khuu H.M.
      • Wesley R.
      • Yau Y.Y.
      • Bolan C.D.
      Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population.
      ,
      • Hsu J.W.
      • Wingard J.R.
      • Logan B.R.
      • Chitphakdithai P.
      • Akpek G.
      • Anderlini P.
      • Artz A.S.
      • Bredeson C.
      • Goldstein S.
      • Hale G.
      • Hematti P.
      • Joshi S.
      • Kamble R.T.
      • Lazarus H.M.
      • O'Donnell P.V.
      • Pulsipher M.A.
      • Savani B.N.
      • Schears R.M.
      • Shaw B.E.
      • Confer D.L.
      Race and ethnicity influences collection of granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells from unrelated donors, a Center for International Blood and Marrow Transplant Research analysis.
      ,
      • Uzoka C.
      • Liu L.C.
      • Park Y.
      • Lin Y.
      • Patel P.
      • Campbell-Lee S.
      • Sweiss K.
      • Wang X.
      • Tepak E.
      • Peace D.
      • Saraf S.
      • Rondelli D.
      • Mahmud N.
      Race/ethnicity and underlying disease influences hematopoietic stem/progenitor cell mobilization response: A single center experience.
      ], the authors’ model, which is based on a Japanese population, should be evaluated in terms of patients of various ethnicities. To overcome these limitations, the authors’ predictive model warrants validation in a larger prospective cohort. Plerixafor use should be determined as per the drug label in a given country.

      Conclusions

      The present study provides valuable information regarding the prediction of PBSC collection yield and an important suggestion regarding the addition of plerixafor to the mobilization regimen. The use of plerixafor in stem cell collection appeared to have no negative influence on the outcomes of ASCT. Therefore, the authors’ results suggest that plerixafor is effective for a wider range of patients than that indicated by the existing guidelines and position statement. The authors believe that the study results and discussion could help establish more efficient and safer PBSC mobilization and ASCT protocols for the treatment of patients with NHL and MM.
      This work was supported in part by the Cell Science Research Foundation, Ono Medical Research Foundation, SGH Foundation, MSD Life Science Foundation, GlaxoSmithKline Research Grant, L-INSIGHT (Kyoto University), and Fujiwara Memorial Foundation (YA).

      Declaration of Competing Interest

      The authors have no commercial, proprietary or financial interest in the products or companies described in this article.

      Author Contributions

      Conception and design of the study: AI, TJ, SO, JK and YA. Acquisition of data: KM, NN and YN. Analysis and interpretation of data: AI, TJ, SO, JK, YA, TK, AT-K and MN. Drafting or revising the manuscript: AI, TJ, YA, SO, JK, TK, KM, NN, YN, AT-K, and MN. All authors have approved the final article.

      Acknowledgments

      The authors thank the clinical medical engineers and nurses of the artificial kidney unit, transplant coordinators and all clinicians at the Kyoto University Hospital as well as patients who contributed to this research.

      Appendix. Supplementary materials

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