ABSTRACT Autologous peripheral blood stem cell transplantation should be considered first-line therapy in young patients with POEMS. The best protocol to collect peripheral blood stem cells remains to be defined, because of the disease rarity and the heterogeneity of published case series. We collected clinical and laboratory data from 25 patients undergoing mobilization, of whom 11 were mobilized using cyclophosphamide (CY) followed by granulocyte colony-stimulating factor (G-CSF) and 14 patients using G-CSF. The incidence of poor mobilization was low and not statistically different between the 2 groups. Both schemes (CY plus G-CSF versus G-CSF alone) were able to harvest a sufficient CD34+ cell dose

Andrea Bacigalupo

Andrea Nozza

Federica Sorà

Francesco Autore

Gina Zini

Idanna Innocenti

Luca Castagna

Luca Laurenti

Nicola Piccirillo

Patrizia Chiusolo

Rossana Putzulu

Simona Sica

Stefania Bramanti

English

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ARTICLE IN PRESSBiol Blood Marrow Transplant 000 (2019) 13Biology of Blood andMarrow Transplantationjournal homepage: www.bbmt.orgBrief articlePeripheral Blood Hemopoietic Stem Cell Mobilization Regimens inPOEMS Syndrome: A Retrospective Study at 2 Hematologic ItalianCentersFrancesco Autore1,*, Nicola Piccirillo1,2, Andrea Nozza3, Idanna Innocenti1, Rossana Putzulu1,Patrizia Chiusolo1,2, Federica Sora1,2, Gina Zini1,2, Andrea Bacigalupo1,2, Luca Castagna3,Simona Sica1,2, Stefania Bramanti3, Luca Laurenti1,21 Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy2 Istituto di Ematologia, Universita Cattolica del Sacro Cuore, Rome, Italy3Humanitas Cancer Center, Rozzano, Milan, ItalyArticle history:Received 3 May 2019Accepted 12 August 2019Financial disclosure: See Acknowled* Correspondence and reprint reqlogia, Dipartimento Diagnostica peEmatologia, Fondazione Policlinico UA. Gemelli 8, 00168 Rome, Italy.E-mail address: francesco_autorehttps://doi.org/10.1016/j.bbmt.2019.1083-8791/© 2019 American SocietyPublished by Elsevier Inc.A B S T R A C TAutologous peripheral blood stem cell transplantation should be considered first-line therapy in young patientswith POEMS. The best protocol to collect peripheral blood stem cells remains to be defined, because of the diseaserarity and the heterogeneity of published case series. We collected clinical and laboratory data from 25 patientsundergoing mobilization, of whom 11 were mobilized using cyclophosphamide (CY) followed by granulocyte col-ony-stimulating factor (G-CSF) and 14 patients using G-CSF. The incidence of poor mobilization was low and notstatistically different between the 2 groups. Both schemes (CY plus G-CSF versus G-CSF alone) were able to harvesta sufficient CD34+ cell dose.© 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.Keywords:POEMS syndromeMobilizing regimenPeripheral blood hemopoieticstem cellCyclophosphamideG-CSFgments on page 2.uests: Francesco Autore, MD, UOC Emato-r Immagini, Radioterapia Oncologica edniversitario A. Gemelli IRCCS, Roma, Largo@yahoo.it (F. Autore).08.011for Transplantation and Cellular Therapy.INTRODUCTIONPOEMS syndrome is a rare paraneoplastic condition associ-ated with an underlying plasmacellular dyscrasia. POEMS isthe acronym referring to the main features of this syndrome:polyradicoloneuropathy, organomegaly, endocrinopathy,monoclonal plasma cell disorder, and skin changes [1-3]. Theuse of alkylating agents and autologous peripheral blood stemcell transplantation (aPBSCT) seems to be the best strategy ineligible patients [4-8]. At present, aPBSCT should be consid-ered first-line therapy in young patients with POEMS syn-drome, eligible for high-dose melphalan (HD-Mel), in theabsence of organ dysfunction. The optimal protocol forhematopoietic stem cell (HSC) mobilization in patients withPOEMS remains to be defined, due to small numbers ofpatients and heterogeneity of published case series. However,there is evidence that cyclophosphamide (CY) plus granulocytecolony-stimulating factor (G-CSF) mobilizes more CD34+ cellsand reduces the incidence of engraftment syndrome inpatients with POEMS, although it may potentially increase therisk of the procedure, without a significant reduction of tumormass [9,10].METHODSIn this undefined scenario, Fondazione Policlinico Universitario AgostinoGemelli IRCCS (FPG) and Humanitas Research Hospital (HRH) retrospectivelycollected over the years patients with POEMS syndrome mobilized with dif-ferent regimens and compared the outcome of these regimens. We are nowreporting the results of this study, aimed at identifying, if possible, the bestCD34+ cell mobilization strategy.We collected clinical and laboratory data of patients with POEMS syn-drome undergoing HSC mobilization for aPBSCT from 2003 to 2018 at FPGand HRH. The minimum dose for transplant was defined as 2£ 106/kg CD34+cells.We compared 2 HSC mobilization regimens: CY 4 g/m2 followed by G-CSF5 mg/kg, or G-CSF 10 mg/kg/d alone for 5 consecutive days. The COBE Spectracontinuous flow cell separator (Terumo BCT, Shinagawa, Tokyo) was used forleukocytapheresis, and citrate dextrose solution was used as anticoagulant.Patients were defined as poor mobilizers if they were not able to mobilize atleast 20 CD34+ cells/mL or obtain a minimum threshold of 2£ 106/kg CD34+cells within a single mobilization. The conditioning regimen before aPBSCTconsisted of melphalan 200 mg/m2 for all patients.Data, collected by medical records and laboratory tests, were organizedto perform a statistical analysis using GraphPad Prism (GraphPad Software,San Diego, CA). Mann-Whitney U test was used to analyze continuous factors,and chi-square test was chosen for the analysis of the categorical factors. Theresults of hematopoietic recovery were analyzed according to the Kaplan-Meier method. Statistical significance was defined as P< .05.Table 1Peripheral Blood Stem Cell Collection Characteristics According to Mobilization ScheduleCharacteristic Total (n = 25) Cyclophosphamide plus G-CSF (n = 11) G-CSF (n = 14) P ValueAge 54 (39-67) 55 (39-62) 54 (41-67) .9Precollection peripheral CD34+, mL 40 (12-308) 57 (12-308) 33 (14-75) .035Precollection peripheral WBCs, £109/L 29.4 (2.5-87) 8.1 (2.5-31.9) 40 (20.2-87) .0002Processed TBVs 2.85 (0.9-3.5) 2.3 (0.9-3) 3 (2.4-3.5) .0013CD34+collected cell dose, £106/kg 3.85 (0.8-15) 3.85 (1.6-15) 3.85 (0.8-7.5) .41Second procedure, n 11 4 7 .68Poor mobilizers, n 3 1 2 .69CD34+ cell dose infused, £106/kg 4.7 (2.5-8.4) 4.4 (2.986-7.5) 5 (2.5-8.4) .57Time to engraftment PMNs 0.5£ 109/L 14.5 (10-48) 14 (10-31) 19 (12-48) .12Time to engraftment PLTs 25£ 109/L 14 (10-67) 13 (10-35) 17 (11-67) .14Values are presented as median (range) unless otherwise indicated.PLTs indicates platelets.ARTICLE IN PRESS2 F. Autore et al. / Biol Blood Marrow Transplant 00 (2019) 13RESULTSOur data set consisted of 25 patients, of whom 11 weremobilized using regimen A (CY 4 g/m2 followed by G-CSF 5 mg/kg), and 14 patients were mobilized with regimen B (G-CSF 10mg/kg for 5 days). All patients received antibiotic prophylaxiswith trimethoprim/sulfamethoxazole; we registered 2 epi-sodes of fever of unknown origin in regimen A, without furthercomplications. All patients were mobilized: median preaphe-resis CD34+ cell count was 40 (12 to 308) with a median WBCcount of 29.4£ 109/L (range, 2.56 to 87). Median whole-bloodprocessed volume was 2.85 total blood volumes (TBVs) (0.9 to3.5). Median CD34+ cell/kg body weight collected per patientafter first cell collection procedure was 3.85£ 106/kg (0.8 to15). Eleven of 25 (44%) patients repeated a stem cell apheresison the following day: median preapheresis CD34+ cell countbefore the second procedure was 31 (11 to 65) with a medianWBC count of 31.4£ 109/L (range, 9 to 82). Median whole-blood processed volume was 3 TBVs (2-3.2). Median CD34+cell/kg body weight collected per patient during the secondcell collection procedure was 2.6£ 106/kg (0.4 to 6.4). Becauseof a low CD34+ cell count (<20/mL), 3 patients were treatedwith plerixafor, achieving a median preapheresis CD34+ cellcount of 28/mL, and collected a median CD34+ cell/kg of4.5£ 106/kg body weight. All patients underwent aPBSCT afterthe HD-Mel conditioning regimen and received an infusion ofa median of 4.7£ 106 (range, 2.5 to 8.4) CD34+ cell/kg bodyweight. All patients achieved a successful engraftment:median time to 500 polymorphonuclear leukocytes (PMNs)/mLwas 14 days (range, 10 to 48); median time to 1000 PMNs/mLwas 15 days (range, 10 to 54); median time to 25£ 109 plate-lets/L was 14 days (range, 10 to 67); and median time to50£ 109 platelets/L was 19.5 days (range, 13 to 84). AfteraPBSCT hospitalization, 13 patients (52%) experienced fever,and pneumonia was diagnosed in 6 patients, which wasresolved successfully with broad-spectrum antibiotics.To compare mobilization schedules, we performed a com-parison analysis between 11 patients receiving chemotherapyas a mobilizing regimen versus 14 patients receiving only G-CSF. Data analysis according to mobilization schedule arereported in Table 1.DISCUSSIONAnalyzing mobilization efficacy, chemomobilizedpatients achieved a higher preapheresis CD34+ cell count(57 versus 33 cells/mL, P < .05). This result allowed asignificantly shorter procedure (2.3 versus 3 TBVs, P < 0.001).However, patients receiving G-CSF alone had a significantlyhigher WBC count than chemomobilized patients (40£ 109/Lversus 8.1£ 109/L, P < .05). The need for the use of plerixaforwas low (3 of 25 patients, 12%) and not statistically differentbetween the 2 mobilization schedules. No statistically signifi-cant differences were seen between the 2 groups in terms ofengraftment. The analysis on immune recovery showed a goodreconstitution of lymphocytes counts and immunoglobulinlevels within the first 30 days after aPBSCT, with no differencebetween our 2 groups of patients. These data are similar topreviously published immunologic recovery in patients withlymphoproliferative diseases [11,12].In conclusion, these results suggest that both approachesfor mobilization of peripheral blood progenitors (CY plus G-CSF versus G-CSF alone) were able to harvest a sufficientCD34+ cell dose and allow good and rapid engraftment. Despitethe small number of patients (n = 25), this remains one of thelargest published series. In the future, purging before harvestwith lenalidomide, shown to produce complete responsesdocumented by vascular endothelial growth factor valueswithout compromising the harvest, could be compared withfirst-line treatments.DECLARATION OF COMPETING INTERESTThere are no conflicts of interest to report.ACKNOWLEDGMENTSFinancial disclosure: The authors acknowledge the supportof Centro di Ricerca sulle cellule staminali emopoietiche e leterapie cellulari “Universita Cattolica Sacro Cuore, Roma.”REFERENCES1. Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL.Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinop-athy, M protein, and skin changes: the POEMS syndrome. Report on twocases and a review of the literature.Medicine. 1980;59:311–322.2. Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions andlongterm outcome. Blood. 2003;101:2496–2506.3. Dispenzieri A. POEMS syndrome: 2011 update on diagnosis, risk stratifica-tion and management. Am J Haematol. 2011;86:591–601.4. Hogan WJ, Lacy MQ, Wiseman GA, Fealey RD, Dispenzieri A, Gertz MA.Successful treatment of POEMS syndrome with autologous hematopoieticprogenitor cell transplantation. Bone Marrow Transpl. 2001;28:305–309.5. Jaccard A, Royer B, Bordessoule D, Brouet JC, Fermand JP. Highdose ther-apy and autologous blood stem cell transplantation in POEMS syndrome.Blood. 2002;99:3057–3059.ARTICLE IN PRESSF. Autore et al. / Biol Blood Marrow Transplant 00 (2019) 13 36. Dispenzieri A, MorenoAspitia A, Suarez GA, et al. Peripheral blood stemcell transplantation in 16 patients with POEMS syndrome, and a review ofthe literature. Blood. 2004;104:3400–3407.7. Laurenti L, De Matteis S, Sabatelli M, et al. Early diagnosis followedby frontline autologous peripheral blood stem cell transplantationfor patients affected by POEMS syndrome. Leuk Res. 2008;32:1309–1312.8. Autore F, Innocenti I, Luigetti M, et al. Autologous peripheral blood stemcell transplantation and the role of lenalidomide in patients affected bypoems syndrome. Hematol Oncol. 2018;36(2):392–398.9. Jimenez-Zepeda VH, Trudel S, Reece DE, Chen C, Rabea AM, Kukreti V.Cyclophosphamide and prednisone induction followed by cyclophospha-mide mobilization effectively decreases the incidence of engraftmentsyndrome in patients with POEMS syndrome who undergo stem celltransplantation. Am J Hematol. 2011;86(10):873–875.10. Ordway S, Gilbert L, Wanko S. POEMS syndrome: diagnostic delay andsuccessful treatment with lenalidomide, cyclophosphamide and predni-sone followed by autologous peripheral stem cell transplantation. BMJCase Rep. 2018;2018. bcr-2017-223168.11. Laurenti L, Sica S, Salutari P, et al. Assessment of hematological and immu-nological function during long-term follow-up after peripheral bloodstem cell transplantation. Haematologica. 1998;83(2):138–142.12. Laurenti L, Sica S, Cicconi S, Chiusolo P, Piccirillo N, Leone G. Immunologi-cal short term reconstitution after tandem unselected peripheral bloodprogenitor cell transplantation for multiple myeloma. Haematologica.2000;85(7):782–784.

Peripheral Blood Hemopoietic Stem Cell Mobilization Regimens in POEMS Syndrome: A Retrospective Study at 2 Hematologic Italian Centers.

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Peripheral Blood Hemopoietic Stem Cell Mobilization Regimens in POEMS Syndrome: A Retrospective Study at 2 Hematologic Italian Centers.

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