Comparison of autologous peripheral blood stem cell dosing by ideal vs actual body weight

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1 Bone Mrrow Trnsplnttion, (1999) 23, Stockton Press All rights reserved /99 $ Comprison of utologous peripherl blood stem cell dosing by idel vs ctul body weight JM Wples 1, JS Moreb 1, M Sugrue 1, G Belnger 1, P Kubilis 2, JW Lynch 1, V Gin 1, F Weeks 1 nd J Wingrd 1 1 Deprtment of Medicine, nd 2 Deprtment of Biosttistics, University of Florid, Ginesville, FL, USA Summry: In this retrospective study, we evluted the predictbility of PBSC dose for hemtopoietic engrftment compring tht clculted by idel body weight (IBW) vs nother clculted by ctul body weight (ABW) for ech ptient. Sixty-three consecutive ptients treted similrly using one trnsplnt protocol were nlyzed. While ll ptients hd dt vilble on CFU-GM nd nucleted cells (NC), dt on CD34 + enumertion ws present only in 34 ptients. We found tht 49% of the ptients were greter thn 25% over their IBW. In ddition, lest-squres liner regression ws used to ssess the strength of the liner reltionship between the inverse of cell dose/kg of ABW or IBW nd time to AGC or pltelet engrftment nd showed no difference in r 2 vlues for pltelet engrftment, while using dose/kg of IBW gretly improved the bility of NC (r 2 improved from 0.19 for ABW to 0.35 for IBW) nd CFU-GM (r 2 improved from 0.35 for ABW to 0.53 for IBW) to predict time to AGC engrftment, but did not chnge the CD34 r 2. Hzrd rtios were estimted using Cox proportionl hzrds regression nd in ll instnces were found greter thn 1.0 indicting tht the probbility of engrftment incresed s cell dose/kg ABW or IBW incresed. Finlly, our dt showed tht 10 ptients (16%) could hve hd one less pheresis procedure performed to obtin their set trget stem cell dose clculted per kg IBW rther thn ABW. In conclusion, PBSC dose per kg IBW is s good or better predictor of engrftment of AGC nd my led to cost svings in certin subset of ptients. Keywords: utologous stem cell trnsplnttion; cell dose; ctul body weight; idel body weight High-dose chemotherpy (HDC) with peripherl blood stem cell (PBSC) rescue is n cceptble form of therpy for high-risk nd metsttic brest cncer, relpsed nd refrctory Hodgkin s or non-hodgkin s lymphom, multiple myelom, nd other mlignncies. Utiliztion of HDC with PBSC support hs lrgely replced bone mrrow s the source of utologous hemtopoietic stem cells. 1 6 PBSC Correspondence: Dr J Moreb, Division of Hemtology/Oncology, PO Box , Ginesville, FL , USA Received 31 July 1998; ccepted 2 December 1998 products minimize the chief side-effects of HDC by fst reconstitution of hemtopoiesis. In erly studies, the PBSC product ws evluted prospectively by totl number of nucleted or mononucler cells nd retrospectively by CFU-GM per kilogrm of ctul body weight, the vlue of which is known to correlte with dys to engrftment of pltelets (PLT) nd bsolute grnulocyte counts (AGC) Presently, the stem cell product is chrcterized in most lbortories by the number of CD34 +, CFU-GM, nd totl mononucler cells per kilogrm ptient ctul body weight (ABW). 1, The number of CD34 + cells correltes well with CFU-GM content nd serves s better predictor of engrftment thn totl mononucler cells per kilogrm of ABW. 21, 22 Recent evidence suggests tht mrkers of primitive hemtopoietic progenitors such s CD34 + /CD33 nd CD34 + /CD38 s well s others my continue to improve the evlution of the stem cell product nd its predictive 23, 24 vlue of rpid nd sustined hemtopoietic recovery. The min impct for this nd other improvements in the collection of PBSC will be to reduce ptient morbidity by ensuring rpid engrftment, prticulrly of pltelets, nd reduce costs by preventing unnecessry pheresis procedures. Recent reports hve indicted tht the use of greter thn CD34 + cells/kg of ABW will result in significntly shorter time to pltelet engrftment, 2 thus reducing the number of pltelet trnsfusions nd the relted morbidity. However, in order to chieve such cell dose, more pheresis procedures will be required which in turn increse the cost of peripherl blood stem cell trnsplnttion. 2 Although improvements to dte hve incresed our bility to predict erly hemtopoietic engrftment, to our knowledge no one hs evluted the influence of body weight on PBSC enumertion nd engrftment. It ws suggested by some studies 25, 26 but not others 13, 27, 28 tht obese individuls hve greter PBSC yields. The explntion for such vribility remins poorly understood nd it could be relted to different rtes of metbolism of growth fctors or n rtifct of the cell dose clcultion in obese ptients. In the United Sttes, it is common knowledge tht pproximtely 40% of the popultion is overweight nd therefore the difference in PBSC dose when clculted by idel body weight (IBW) vs ABW my be significnt. Perhps clcultion of the stem cell dose per IBW my yield more precise predictor of erly engrftment thn ABW. If the bility of the PBSC product to reconstitute hemtopoiesis is function of intrmedullry bone mrrow volume nd bone mrrow volume is not function of ptient s pnnus,

2 868 we predict IBW might be more precise vrible to use in the clcultion. However, if totl blood volume is n importnt vrible in the PBSC product bility to generte hemtopoietic recovery, then ABW my be better mesure to use in PBSC dose clcultion. In survey for the purpose of this study, we found tht nine of 10 mjor bone mrrow trnsplnt centers use ctul body weight for the clcultion of the PBSC dose. Therefore, in this study, we hve evluted the predictbility of PBSC dose for hemtopoietic engrftment compring tht clculted by IBW vs nother clculted by ABW for ech ptient. We report tht cell dose per kg IBW is s good or better predictor of engrftment of AGC nd PLT thn tht PBSC dose clculted per kg ABW nd my led to cost svings in certin subset of ptients. Mterils nd methods Sixty-three consecutive ptients with stge II IV brest cncer, relpsed or refrctory Hodgkin s or non-hodgkin s lymphom were treted with HDC nd PBSC support between 1993 nd The HDC protocols used were pproved by the Institutionl Review Bord nd ptients gve written informed consent. Although 51 other ptients were trnsplnted between 1996 nd the time this mnuscript ws prepred, the tretment of these ptients ws not similr in terms of trget cell for hrvest, use of different growth fctors or different strting dy post-trnsplnt, use of selected CD34 + cells for trnsplnttion, nd use of different conditioning regimens. Becuse of these resons, we were left with the 63 ptients s the lrgest group of ptients treted similrly to be used for the current nlysis. Ptient chrcteristics re shown in Tble 1. All ptients with mesurble disese were responsive to chemotherpy t the time of HDC. Prmeters obtined for retrospective review included: ptient ABW nd IBW t the time of HDC, dys to engrftment of bsolute grnulocyte count (the first of 3 consecutive dys with AGC 500/ l), pltelet count (PLT l), nucleted cell (NC) dose, CFU-GM dose, nd CD34 + cell dose (vilble in only 34 ptients). IBW ws clculted by stndrd formul using gender nd height: for mles, 50 kg + (2.3 Y) nd for femles 45.5 kg + (2.3 Y) where Y indictes ptient s height in inches bove 5 feet. 29 Tble 1 Ptient chrcteristics (n = 63) Age (yers) Medin 43 Rnge Sex Mle 8 (12.7) Femle 55 (87.3) Disese Brest cncer 44 (69.81) Non-Hodgkin s lymphom 9 (14.3) Hodgkin s lymphom 10 (15.9) Vlues in brckets represent percentge of totl number of ptients. PBSC collection nd cryopreservtion PBSCs were mobilized fter chemotherpy with G-CSF t 5 g/kg/dy or with G-CSF lone t 10 g/kg/dy. Different regimens of chemotherpy used for mobiliztion included doxorubicin or CAF for brest cncer nd cytoxn with VP-16 or DHAP for ptients with lymphom. Leukpheresis begn on dy 5 if PBSC were mobilized with G-CSF lone nd dys with rising ( / l) white blood count if chemotherpy nd G-CSF were utilized. Approximtely 50% nd 90% of ptients obtined the desired PBSC product with one or two pheresis procedures, respectively. The PBSC trget ws CD34 + /kg or NC/kg of ABW. Leukpheresis ws performed using either COBE-BCT Spectr (Lkewood, CO, USA) or Bxter Fenwl CS3000 plus (Deerfield, IL, USA) ccording to the protocols for mononucler hrvesting s recommended by the mnufcturers. Venous ccess ws ccomplished by dilysis ctheter inserted in the internl jugulr vein such tht high flow rtes were obtined. Volumes processed rnged from 16 to 20 liters. PBSC were stored overnight nd frozen the following dy using finl concentrtion of 10% DMSO cryoprotective solution in controlled rte freezer ccording to stndrd protocol. Conditioning regimen All ptients were treted in-house with the STAMP V conditioning regimen which include cyclophosphmide, thiotep nd crbopltinum given by continuous infusion for 96 h. All ptients received G-CSF t 5 g/kg/dy from dy +1, defined s the dy fter the PBSC infusion, nd continued until engrftment of AGC 1500/ l for 3 consecutive dys. No other growth fctors were utilized. Engrftment ws defined s the first dy of AGC 500/ l following the ndir. Time to PLT recovery ws defined s the number of dys to rech n unsupported pltelet count of greter thn / l from dy of PBSC infusion. Evlution of the PBSC grft Ech PBSC product ws ssessed for nucleted cell content (NC), nd colony-forming units (CFU-GM). NC counts were performed on the products upon initil dilution nd following the processing procedure. Counts were performed using the Sysmex F-800 (Bxter) employing Quicklyse (TOA Medicl Electronics, Kobe, Jpn) to lyse red blood cells s recommended by the mnufcturer. Clonogenic ssys were performed on ll PBSC products fter thwing. A totl of 10 5 NC per 1 ml liquots of methylcellulose with PHA-LCM (Stem Cell Technologies, Vncouver, BC, Cnd), were seeded in 35 mm Petri dishes nd incubted for dys t 37 C in fully humidified tmosphere contining 5% CO 2. Aggregtes of 50 cells were scored for CFU-GM, CFU-GEMM or BFU- E. Totl CFU-GM dose ws clculted ccording to NC counts. CD34 + enumertion ws performed on the lst 34 ptients only, using flow cytometry on fresh smples obtined from ech pheresis product. A set of three monoclonl ntibodies for CD34, CD14 nd CD45 (Becton

3 Dickinson, Sn Jose, CA, USA) ws used with the pproprite controls. Red cells were lysed with luminum chloride solution before nlysis. The percentge of CD34 + cells of totl vible (propidium iodide excluded) nucleted cells ws determined fter exclusion of CD14 + nd CD45 cells. A totl of cells ws nlyzed in ech smple. Totl CD34 cell dose ws clculted ccording to the nucleted cell counts. Sttisticl methods Ptients were divided into low, intermedite nd high cell dose groups for ech of the three prmeters used (NC, CFU-GM, CD34 + ), both clculted ccording to ABW or IBW. The AGC nd PLT engrftment time rnk sums were then compred mong these groups using the Wilcoxon rnk sum test. Nonprmetric Low-ESS smoothing nd 1/x liner regression (ie liner regression) using the inverse of the predictor vrible were used to ssess NC, CFU-GM, nd CD34 (scled by either ABW or IBW) s predictors of time to engrftment of AGC nd PLT. The r 2 ws used to indicte the strength of the liner ssocition between the inverse of cell dose per kg ABW or IBW nd dy of engrftment. Cell dose nd engrftment dy 95% predictive intervls (PIs) t dy 10 were estimted from corresponding liner regression lines. Finlly, Cox proportionl hzrds regression ws used to ssess the influence of cell dose scled by ABW or IBW on the probbility of engrftment. Results Study popultion nd ptient exclusion Initil liner regression model fitting indicted one ptient to be highly influentil with regrd to NC nd CD34 + prmeter estimtes. Upon review of this ptient s stem cell product, lthough the initil PBSC hrvest counts were high, the vibility t the time of thwing nd reinfusion ws mrkedly reduced (12%) well out of the norml rnge (medin of 76% on 30 consecutive PBSC smples other thn those included in this study, rnge of 45 92%). The low PBSC vibility ppers to hve prolonged this ptient s engrftment significntly beyond wht would be predicted by the NC nd CD34 + regression models with this ptient excluded. This ptient ws therefore excluded from ny further nlyses. One other ptient ws excluded becuse of lck of informtion on his height needed for the clcultion of IBW. Seven other ptients were missing the exct time to engrftment of PLT or both PLT nd AGC, nd were excluded where pproprite. Weight nlysis Our nlysis of IBW shows tht 49% of the ptients were greter thn 25% over their IBW. The medin ctul weight for ll ptients ws 73 kg (rnge kg), nd the medin IBW ws 56.1 kg (rnge kg). Stem cell dose in reltionship to engrftment The trget for collection ws the totl number of NC in the first 29 ptients nd the number of CD34 + cells/kg in the lst 34 ptients. Dt on the CFU-GM nd NC dose re vilble on ll ptients. A correltion between ech of these prmeters nd the medin time to engrftment of AGC nd PLT is shown in Tbles 2, 3 nd 4. Tble 2 shows correltion of the NC with engrftment. Ptients were divided into three stem cell doses s shown in Tble 2. Four ptients in group 1 were plced in group 2 when the stem cell dose ws clculted by IBW. In ddition, 11 ptients in group 2 were ultimtely plced in group 3 when their stem cell dose ws clculted by IBW. As shown in Tble 2, engrftment of AGC nd PLT in ptients who chnged groups when the stem cell dose ws clculted by IBW tended to be very similr to those ptients whose cell group did not chnge using ABW or IBW. Tble 3 shows correltion of CFU-GM content with engrftment. Agin, ptients were divided into three groups ccording to CFU- GM dose. Similrly seven nd three ptients were dvnced from groups I nd II (respectively) to the next cell dose group, when their cell dose ws clculted per IBW. Tble 4 shows correltion of CD34 + cell content with engrftment. Ptients were divided into three groups bsed on CD34 + cell dose. Two ptients in group 1 by ABW chnged to Group 2 when clculted by IBW nd six ptients in group 2 by ABW chnged to group 3 when clculted by IBW. Ptients who chnged groups when clculted by IBW hd similr engrftment chrcteristics to those ptients where cell dose did not chnge with IBW or ABW. IBW vs ABW effects on engrftment Lest-squres liner regression ws used to ssess the strength of the liner reltionship between the inverse of cell dose/kg of ABW or IBW nd time to AGC or PLT engrftment in the 63 study ptients. Using dose/kg of IBW gretly improved the bility of NC nd CFU-GM to predict time to AGC engrftment reltive to dose/kg of ABW, see Tble 5. The NC r 2 improved from 0.19 for ABW to 0.35 for IBW while the CFU-GM r 2 improved from 0.35 for ABW to 0.53 IBW. Using dose/ibw did not significntly chnge the CD34 r 2 for predicting time to AGC. Similr nlysis ws performed for PLT engrftment, but no difference in r 2 vlues ws detected for ny of the reltionships exmined (dt not shown). An ttempt to nlyze the whole group of trnsplnted ptients (n = 14), s mentioned in Mterils nd methods, the r 2 vlues obtined were consistently less thn 0.1 indicting the gret heterogeneity in this ptient popultion. However, when the reltionship between the cell dose/kg of ABW or IBW nd time to AGC nd PLT engrftment ws ssessed s described bove, the r 2 vlues showed improvement in fvor of IBW. For exmple, the CD34 r 2 (n = 86) for AGC engrftment improved from for ABW to for IBW. There ws greter improvement seen in the r 2 for NC nd CFU-GM dose clculted by IBW. Hzrd rtios were estimted using Cox proportionl 869

4 870 Tble 2 Influence of nucleted cell content (NC) on AGC nd PLT engrftment time Group I Group II Group III to ABW IBW ABW IBW ABW IBW Dys to AGC 500 l n Medin (P25, P75) (13,14) (13, 20) (9, 11) (9.5, 12) (10, 11) (9, 11) Dys to PLT l n Medin b (P25, P75) (27, 42) (26, 42) (11, 28) (12, 30) (12, 17) (11, 17) Three different groups of NC dose were nlyzed. n = number of ptients; P25 = 25th percentile; P75 = 75th percentile. Significntly lower thn group I (P 0.05). b Significntly higher thn group III (P 0.05). Tble 3 Influence of CFU-GM content on AGC nd PLT engrftment time Group I Group II Group III to ABW IBW ABW IBW ABW IBW Dys to AGC 500 l n Medin (P25, P75) (10, 12) (10, 13) (9, 10) (10, 12) (9, 10) (9, 10) Dys to PLT l n Medin 20 b b (P25, P75) (13, 30) (13, 35) (11, 20.5) (11, 21) (8.5, 12.5) (9, 19) Three different groups of CFU-GM dose were nlyzed. n = number of ptients; P25 = 25th percentile; P75 = 75th percentile. Significntly lower thn group 1 (P 0.05). b Significntly higher thn group III (P 0.05). Tble 4 Influence of CD34 + cell content on AGC nd PLT engrftment time Group I Group II Group III to ABW IBW ABW IBW ABW IBW Dys to AGC 500 l n Medin 11.5 b 12.5 b 10 b 11 b (P25, P75) (11, 12.5) (12, 13) (10, 12) (10, 12) (9, 10) (9, 10) Dys to PLT l n Medin (P25, P75) (15, 23) (20, 26) (11, 13) (11, 17) (9, 15) (9, 14) Three different groups of CD34 + cell dose were nlyzed. n = number of ptients; P25 = 25th percentile; P75 = 75th percentile. Significntly lower thn group 1 (P 0.05). b Significntly higher thn group III (P 0.05).

5 Tble 5 Influence of ctul nd idel body weight cell dose scling on the ssocition between cell dose nd AGC engrftment time Cell type r 2 P vlue 10 dys Cell dose Engrftment dy 95% PI NC (A) (4.9, 15.1) NC (I) (5.5, 14.5) CFU-GM (A) (5.5, 14.5) CFU-GM (I) (6.1, 13.9) CD34 (A) (7.7, 12.3) CD34 (I) (7.7, 12.3) A = ctul body weight; I = idel body weight; PI = prediction intervl. hzrds regression. The hzrd rtio is interpretble s the fctor by which the probbility of engrftment chnges per unit increse in cell dose. Dose units for NC, CFU-GM nd CD34 + re defined here s , nd , respectively. When nlyzing the 63 study ptients, hzrd rtios, in ll instnces, were greter thn 1.0 indicting tht the probbility of engrftment incresed s cell dose per kg ABW or IBW incresed. Potentil svings using IBW In order to evlute potentil cost svings, we identified ptients tht switched to different cell dose grouping s defined in Tbles 2, 3 nd 4 when their cell dose ws clculted by IBW vs ABW. Among those ptients three, seven nd three ptients (totl of 10 ptients due to overlp) of the CD34 +, NC nd CFU-GM groups, respectively, could hve hd one less procedure to chieve the desired stem cell dose clculted per kg IBW. Other ptients who switched groups when their stem cell product ws clculted using IBW vs ABW hd only one pheresis procedure to obtin their desired stem cell dose nd therefore cost svings were not pplicble to them. Thus, 10 of the 63 ptients (16%) could hve hd one less procedure performed to obtin their trget stem cell dose, ie /kg for CD34 +, /kg for CFU-GM, or /kg for NC. Discussion Autologous blood stem cell trnsplnttion to support highdose chemotherpy is now commonplce in the tretment of lymphoms nd solid tumors including brest cncer. The dvntges of PBSC collections include the bility to ttin greter number of stem cells compred to bone mrrow hrvest, which results in shorter durtion of neutropeni nd pltelet engrftment nd therefore shortens hospitl sty nd reduces the number of red cell nd pltelet trnsfusions. 3 6 Other dvntges of PBSC include reduced tumor contmintion in PBSC products nd the bility to perform tndem trnsplnts. 33 However, hrvesting dequte numbers of CD34 + cells for utologous trnsplnttion cn be difficult in some ptients tht re, due to different resons, poor mobilizers of CD34 + cells into the peripherl blood. These ptients usully require higher numbers of leukphereses nd other mnipultions which cn esily exceed the cost of BM hrvest. Improvements in the evlution of the stem cell products hve incresed our bility to predict rpid hemtopoietic engrftment of both neutrophils nd pltelets. However, improvements in the evlution of the stem cell products hve been focused on qulittive mesurements of the trnsplnted cells, nd to our knowledge there re no dt evluting the effect of weight, idel vs ctul, on the bility of the stem cell product to predict engrftment. In mny trnsplnt centers, chemotherpy nd other drugs re clculted bsed on IBW, however, most centers use ABW in the clcultion of the stem cell dose. In this study, we evluted the precision of stem cell dose strtified for IBW vs ABW to predict engrftment of both AGC nd PLT count. We found tht clcultion of the stem cell dose per IBW ws equl to or superior in predicting hemtopoietic engrftment for both AGC nd pltelet count when compred to stem cell product clculted by ABW. Our ptient popultion mirrored the generl popultion with over 40% considered to be greter thn 25% over their IBW. Therefore, significnt percentge of our ptients will hve lrge disprities in their clculted stem cell dose when compring IBW to ABW. Since the stem cell dose reltionship to dys to engrftment hs been well estblished nd produces hyperbolic-shped curves, we cn expect tht djustments to IBW will ffect significnt portion of ptients. Incresing the cell dose bove CD34 cells/kg of body weight my shorten durtion of thrombocytopeni but does not shorten durtion of neutropeni ny further. There ppers to be ceiling on the cell dose on which further stem cell collection hs little or no benefit. 1,2,20 Furthermore, ptients who re very good mobilizers my not benefit from djusting cell dose from ABW to IBW since the desired cell dose will usully be obtined with one pheresis procedure. Similrly, when the stem cell dose is below CD34 + cells/kg, engrftment is typiclly poor nd more spordic, nd therefore, switching the clcultion from ABW to IBW my hve no benefit. However, there my be significnt cost sving nd reduction in morbidity by limiting the number of pheresis procedures necessry to obtin the desired stem cell dose for some ptients who re good mobilizers nd overweight. In our study, 48% of ptients required only one pheresis procedure to obtin the desired stem cell dose. However, s reported in Results, 16% of the ptients could hve hd one less procedure to ttin the desired stem cell product, if the cell dose ws clculted per IBW. Therefore, by simply clculting the stem cell dose by IBW, we cn mintin equl or improved precision in the bility to predict rpid hemtopoietic recovery of both AGC nd PLT s well s reduce morbidity nd cost in smll but significnt proportion of the ptients undergoing peripherl blood stem cell trnsplnttion. Owing to the retrospective nture of our study nd the reltively limited number of ptients with CD34 + dt vilble, future prospective studies my be needed in order to verify our results nd conclusions. Evluting the effects of body weight in the future my be even more significnt, minly becuse mny centers hve incresed their trget 871

6 872 stem cell dose to CD34 + cells/kg, dose tht hs been shown to be cost effective by ensuring rpid engrftment nd reducing pltelet trnsfusion costs. Our results suggest tht djusting stem cell dose in this rnge for IBW or ABW my not show sttisticl difference; however, reching this trget rnge using IBW my prevent dditionl pheresis in smll but significnt number of ptients tht re overweight nd thus reducing the cost of PBSC hrvesting, without ffecting the time to engrftment. Bsed on our results, the trget cell dose t our institution is currently CD34 + cells/kg of IBW. References 1 Wever CH, Hzelton B, Birch R et l. An nlysis of engrftment kinetics s function of the CD34 content of peripherl blood progenitor cell collections in 692 ptients fter the dministrtion of myelobltive chemotherpy. Blood 1995; 86: Glspy JA, Shpll EJ, LeMistre CF et l. Peripherl blood progenitor cell mobiliztion using stem cell fctor in combintion with filgrstim in brest cncer ptients. 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