Chemotherapy and donor peripheral blood progenitor cells for acute leukemia in early relapse after allogeneic bone marrow transplantation

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1 Bone Mrrow Trnsplnttion, (1999) 23, Stockton Press All rights reserved /99 $ Chemotherpy nd donor peripherl blood progenitor cells for cute leukemi in erly relpse fter llogeneic bone mrrow trnsplnttion EP Alessndrino 1, P Bernsconi 1, D Clder 1, A Colombo 1, L Mlcovti 1, G Mrtinelli 1, M Bonfichi 1, G Pgnucco 1, L Slvneschi 2 nd C Bernsconi 1 1 Istituto di Emtologi, Università di Pvi nd 2 Servizio di Immunoemtologi e Trsfusione, IRCCS Policlinico S Mtteo, Pvi, Itly Summry: Ten ptients with cute leukemi (AL) in erly relpse fter llo-bmt were treted with modified MEC (mitoxntrone, etoposide nd Ar-C) regimen followed by donor PBPC collected fter mobiliztion with G- CSF. Seven ptients chieved CR or hd norml hemopoietic reconstitution: two hd n erly relpse t dys +53 nd +48, two ptients died from cute GVHD t dys +31 nd +96, one died of interstitil pneumoni t dy +55, nd two ptients experienced long-term survivl. One ptient with refrctory disese nd nodl involvement who did not respond to the first BMT hd overt expnsion of the leukemi t dy +36; one ptient with Ph+ ALL nd one with ANLL evolving from MDS, both with skin involvement, hd blst cells in peripherl blood t dy +27 nd +26, respectively. Trnsient cytopeni occurred in ll ptients; norml grnulocyte nd pltelet count ws chieved within 3 weeks in ll ptients but one; cute GVHD occurred in six ptients, nd four hd chronic GVHD. This pproch is fesible in ptients in erly relpse fter llo-bmt. It ssists prompt re-estblishment of norml donor hemtopoiesis voiding the prolonged cytopeni observed fter donor lymphocyte infusion in AL ptients relpsed fter llo-bmt. Keywords: PBPC; grft-versus-leukemi; relpse fter llo-bmt; llogeneic bone mrrow trnsplnttion; cute leukemi Relpse fter llogeneic bone mrrow trnsplnttion (llo- BMT) is n dverse event occurring in 21 36% of ptients with cute leukemi (AL). 1 Higher relpse rtes of up to 70% hve been observed in ptients with dvnced disese or in those receiving T-depleted grft. 2 Response to conventionl chemotherpy is poor 1 nd second BMT is successful only in ptients with lte relpse. 3 5 Some uthors hve proposed new strtegies imed t stimulting donor hemtopoiesis 6 or t potentiting the grft-versus-leukemi Correspondence: Dr EP Alessndrino, Centro Trpinti di Midollo Osseo, Istituto di Emtologi, IRCCS Policlinico S Mtteo, Pvi, Itly Received 1 July 1998; ccepted 22 October 1998 (GVL) effect by infusion of donor immunocompetent cells 7,8 or by using humn recombinnt interleukin-2 in vivo. 9 We report 10 cses of AL in relpse fter llo-bmt treted by stndrd chemotherpy followed by the infusion of donor peripherl blood progenitor cells (PBPC) collected by leukpheresis fter mobiliztion with G-CSF. One cse of ANLL hs been previously reported. 10 Methods Ptient chrcteristics nd BMT procedures Ten ptients with AL underwent n llo-bmt from n HLA-identicl sibling. Nine received bone mrrow cells while one ptient hd PBPC trnsplnt. Seven ptients hd ANLL, three with previous history of myelodysplstic syndrome (MDS); in ll cses but one, vrious cytogenetic bnormlities were found. Three ptients hd cute lymphocytic leukemi (ALL), two with t(9;22) trnsloction. The medin ge ws 32 yers (rnge 19 48); six were femle, four mle. Two ptients received their trnsplnt in first or second complete remission (CR); the reminder were in prtil remission (PR) (one ptient), hd resistnt disese (RD) (one ptient), were in first or second relpse (five ptients) or hd ctive untreted disese (one ptient). Conditioning consisted of TBI nd cyclophosphmide in four ptients, busulfn nd cyclophosphmide in two ptients, while four ptients received busulfn, etoposide nd cyclophosphmide. Grft-versus-host disese (GVHD) prophylxis ws cyclosporin A (CsA), methotrexte (MTX) nd methylprednisolone (MP) in six ptients while the reminder received CsA with low dose of MP. Ptient chrcteristics nd sttus of disese t trnsplnt re summrized in Tble 1. Relpse ws defined s the presence of more thn 5% of leukemic cells in bone mrrow smples. One ptient with ANLL fter MDS relpsed on dy +104 nd seven ptients relpsed between dys +120 nd One ptient with extensive chronic GVHD hd relpse on dy from BMT (he did not undergo second trnsplnt due to poor performnce sttus). One ptient with resistnt disese filed to rech remission fter trnsplnt: he entered the study t dy +40 from BMT. In three cses bone mrrow relpse ws

2 608 Tble 1 Chrcteristics of ptients nd sttus of the disese t trnsplnt Ptient Age/Sex Dignosis Kryotype Sttus Conditioning Response GVHD GVHD cgvhd Remission of regimen prophylxis grde durtion disese (dys) TM b 42/M ANLL 47XY, inv(16), II REL BU-VP-CY CR CsA-MTX-MP 0 no /48XY, inv(16) SF 38/M ANLL 46XY/46XY, II CR BU-VP-CY CR CsA-MP I yes 280 t(9;11) DO 32/F ANLL 46XX, t(9;11), RD TBI-CY NR CsA-MP 0 no not del(7) reched DS 24/F ANLL not vilble I REL BU-VP-CY CR CsA-MTX-MP I no 153 AO 25/F ANLL-MDS 46XX, 7, AD BU-VP-CY CR CsA-MTX-MP 0 no ring, t(3;21) DM 29/M ANLL-MDS 46XY, inv(3), PR BU-CY CR CsA-MP I yes 1550 del(12), del(6) MG 19/M ALL 46XY/46Y, II REL TBI-CY CR CsA-MP II yes 165 7, +mr GG 30/F ALL 46XX/46XX, I REL TBI-CY CR CsA-MTX-MP 0 yes 325 t(9;22) FM 33/F ALL 46XX, del(17), I REL TBI-CY CR CsA-MTX-MP 0 no 158 t(9;22) RS 48/F ANLL-MDS 45XX, 7 I CR BU-CY CR CsA-MTX-MP 0 yes 318 REL = relpse; AD = ctive disese; RD = resistent disese; PR = prtil remission; BU-VP-CY = busulfn (16 mg/kg of body weight), etoposide (30 mg/kg) nd cyclophosphmide (120 mg/kg in continuous infusion); TBI-CY = totl body irrdition (1200 cgy in 6 frctions over 3 dys) nd cyclophosphmide (120 mg/kg); BU-CY = busulfn (16 mg/kg) nd cyclophosphmide (120 mg/kg). This ptient received llogeneic PBPC trnsplnt. b ssocited with skin or nodl involvement. Grde I cute GVHD occurred in three cses; only one ptient who received n llogeneic PBPC trnsplnt hd grde II cute GVHD followed by limited erly chronic GVHD. Tretment of relpse Ptients gve their informed consent, previously pproved by the institutionl review bord. Nine ptients received three-drug regimen consisting of mitoxntrone 8 mg/m 2 /dy for 5 dys intrvenously, etoposide 60 mg/m 2 /dy intrvenous 1 h infusion for 5 dys nd Ar-C 1 g/m 2 /dy intrvenous infusion over 6 h for 5 dys. Two dys lter ptients received the donor PBPC infusion. One ptient hd etoposide 80 mg/m 2 /dy nd mitoxntrone 8 mg/m 2 /dy for 5 dys. 11 All ptients received t lest /kg mononucler cells nd minimum of /kg CD34 + cells. Only one ptient received G-CSF t dose of 5 g/kg/dy i.v. fter infusion until the WBC count reched /l. GVHD ws scored ccording to stndrd criteri. 12 No GVHD prophylxis ws given. Acute GVHD ws treted with intrvenous CsA nd MP. CsA ws given t dose of 3 mg/kg/dy over 12 h, intrvenously, mintined t 1 mg/kg/dy in responsive ptients. MP ws dministered t dose of 5 mg/kg/dy for 4 dys; the dose ws then lowered to 2.5 mg/kg/dy for 4 dys nd fterwrds tpered to rech minimum dose of 0.2 mg/kg/dy. PBPC mobiliztion nd collection Donor chrcteristics re shown in Tble 2. The medin ge ws 30 yers (rnge 24 47). Three were femle nd seven mle. Five were sex mismtched with their recipients. Mobiliztion ws with G-CSF nd its potentil risks were explined in detil; written informed consent ws obtined from the donors ccording to the institutionl guidelines. Donors were treted with dily subcutneous injection of 5 g of G-CSF per kilogrm body weight for 5 or 6 consecutive dys. Leukpheresis ws strted on dy 5 or 6 of G-CSF dministrtion using the Cobe spectr pheresis system (Cobe Lbortories, Lkewood, CO, USA). Nine or 10 l of blood were processed using cubitl veins in ll cses. Progenitor cells were infused without further mnipultion. Cytogenetic nlysis nd fluorescence in situ hybridiztion Seril cytogenetic studies were performed on mrrow spirtes before tretment, nd therefter ccording to stndrd techniques. Twenty-five metphses were nlyzed if possible nd reported ccording to stndrd nomenclture. 13 Ptients receiving PBPC from sex-mismtched donors were ssessed t different time points for hemtopoietic chimerism using conventionl cytogenetic tests or fluorescence in situ hybridiztion for sex chromosomes (X-Y FISH) (Tble 3). In situ hybridiztion ws performed on bone mrrow cells lredy prepred for cytogenetic studies. Dul-colour FISH ws crried out before therpy, t the time of engrftment nd every time ptients underwent bone mrrow spirtion. In order to determine the confidence limits, sensitivity nd specificity of the technique, we followed the pproch of Dewld et l. 14 In our experience the norml rnge for XX cells in mles ws fixed t up to % nd tht for XY cells in femles ws fixed

3 Tble 2 PBPC collection by recombinnt humn G-CSF (5 g/kg s.c. for 5 or 6 dys) in helthy donors 609 Donor Age/Sex No. MNC CD34 + CFU-GM CD3 + leukphereses 10 8 /kg 10 6 /kg 10 4 /kg 10 6 /kg Donor for TM b 34/F Donor for SF 30/M Donor for DO 30/M Donor for DS 27/F Donor for AO 24/M Donor for DM 31/M Donor for MG 29/M Donor for GG 28/M Donor for FM 30/M Donor for RS 47/F The reported vlues of MNC CD34 + nd CD3 + cells, CFU-GM refer to recipient s body weight. b Tble 3 Evlution of BM morphology nd chimerism by X-Y FISH Ptient % BM blsts % Host cells % BM blsts % Host cells % BM blsts % Host cells pre-pbct pre-pbct dys dys dys dys TM,b SF 20 NE 5 NE 5 NE DO NE 90 DS 100 NE 5 NE 100 NE AO DM 100 NE 5 NE 5 NE MG 90 NE 5 NE GG c 1.8 c FM RS 50 NE 5 NE 5 NE These ptients received PBPC from sex mismtched donors. b c This ptient relpsed on dy +53; the nlysis ws performed t dy +41. NE = not evluted. t up to %. The men percentge of host nd recipient cells ws lwys corrected for the cut-offs reported bove. Hybridiztion signls were counted in 1000 inter-phse cells with fluorescence microscope equipped with dul-pss filter. Assessment of response Effect of chemotherpy nd donor PBPC infusion ws ssessed by evlution of blood nd bone mrrow morphology. Complete hemtologicl response ws defined s grnulocyte count bove /l in peripherl blood with norml bone mrrow showing less thn 5% of blst cells for t lest 4 weeks. Miniml residul disese ws detected by clonl nd host specific mrkers using cytogenetic nlysis nd/or in situ hybridiztion. Bone mrrow ws spirted 1, 3, 6 months fter therpy or more frequently if cliniclly indicted. Results Seven ptients chieved CR or hd norml hemopoietic reconstitution: two of them experienced erly relpse discovered t dys +53 nd +48, two died of cute GVHD t dy +31 nd t dy +96, one ptient died of interstitil pneumoni t dy +55, the remining two ptients experienced long-term survivl. One ptient with refrctory disese nd nodl involvement who did not chieve ny response to first BMT hd overt expnsion of the leukemic clone t dy +36; one ptient with Ph+ ALL nd one with ANLL from MDS, both with skin involvement, hd blst cells in the peripherl blood t dys +27 nd +26, respectively. Trnsient cytopeni occurred in ll ptients, followed by complete hemtologicl reconstitution in responding ptients (Tble 4). A norml grnulocyte nd pltelet count ws chieved within 3 weeks in ll the ptients but one; ll hd mild mucositis, nd fever occurred in six out 10 ptients. GVHD nd tretment-relted mortlity Six out of 10 ptients developed grde II or more cute GVHD; they were treted with systemic MP nd CsA; two died of cute GVHD t dys +31 nd +96, one died of interstitil pneumoni t dy +55, while the other three ptients developed lichenoid chnges of the orl mucos nd other signs of extensive chronic GVHD. Two with ANLL re live nd well t dys +650 nd +900; the third, with Ph+ ALL, died of leukemi 170 dys fter relpse.

4 610 Tble 4 Outcome of ptients in relpse fter llo-bmt nd treted with MEC nd PBPC infusion Ptient Sites of Chemotherpy Tke PMN PMN PLT PLT GVHD cgvhd Response Outcome relpse grde (dys) 10 9 /l 10 9 /l 10 9 /l 10 9 /l TM BM MX-VP-Ar-C II yes CR (+650) live in CR SF BM MX-VP-Ar C IV yes CR (+900) live in CR DO BM, LN MX-VP-Ar C NE no NR (86) died of refrctory disese DS BM MX-VP-Ar C yes CR (93) died of relpse occurred t dy +48 AO BM, skin MX-VP-Ar C NE no NR (66) died of refrctory disese DM BM, skin MX-VP III no CR (96) died of MOF MG BM MX-VP-Ar C IV no CR (31) died of GVHD GG BM MX-VP-Ar C II yes CR (223) died of relpse occurred t dy +53 FM BM MX-VP-Ar C NE no NR (105) died of refrctory disese RS BM MX-VP-Ar C IV no CR (55) died of interstitil pneumoni LN = lymph nodes; MOF = multi-orgn filure. One ptient hd de novo erly chronic GVHD; he relpsed t dy +48 nd died t dy +93. Chimerism Dt on chimerism by X-Y FISH were vilble in only five sex-mismtched couples; they re summrized in Tble 3. Dt collected t the time of the hemopoietic recovery showed the persistence of host cells in ll cses evluted. A very low number of host cells ws detected t dy +15 in one long-term survivor where we were ble to demonstrte complete chimerism 1 yer fter trnsplnt; in the other long-term survivor who received this trnsplnt from sexmtched donor, conventionl cytogenetic nlysis filed to demonstrte the specific kryotypic bnormlities discovered t dignosis. At first evlution, the percentge of host cells ws prticulrly high in two ptients who hd only trnsient response to the tretment. In nother ptient with ALL, we noticed progressive increse in host cells from dy +30 onwrds: he relpsed t dy +53. Discussion Aggressive chemotherpy, second BMT nd donor leukocyte infusion (DLI) re vrious options for leukemic relpse fter llogeneic trnsplnttion. Thirty per cent of ptients my chieve remission fter chemotherpy; however, ptients who relpse erly re lucky to gin meningful remission. 1 A second llogeneic BMT is recommended only in lte relpses: ptients relpsing within the first yer of BMT experience the worst outcome. 3,4 Encourging results hve been obtined with DLI; the procedure my promote expnsion of donor hemtopoiesis by GVL effect imed t destroying the leukemic clone. The probbility of response is high in chronic grnulocytic leukemi (CGL) while in AL the results re poor. 15,17 Acute GVHD nd pncytopeni re the mjor cuses of morbility nd mortlity: 15,16 GVHD hs been reported to be s high s 80%, 16 while pncytopeni occurs in 12 25% of ptients. 17 In our study, ptients with erly relpse fter trnsplnttion received chemotherpy t stndrd doses followed by donor PBPC. We modified the MEC chemotherpy regimen reportedly effective in refrctory AL. 18 Our intention ws to use combined pproch imed t controlling the tumor burden by chemotherpy, while PBPC were given to reinforce donor hemtopoiesis nd to induce GVL. Use of chemotherpy nd PBPC in combintion could provide fster response thn DLI lone recently reported to result in medin time to remission of 34 dys (rnge dys) in AL nd 85 dys (rnge ) in CGL. 17 We observed only trnsient cytopeni relted to the use of chemotherpy followed by rpid reconstitution of donor hemopoiesis (medin time: 15 dys rnging from 12 to 26 dys) (Tble 4). In recent study Glss et l 19 reported comprble results in six ptients with cute leukemi in relpse fter llo-bmt, treted by chemotherpy nd PBPC infusion (three cses) or PBPC lone. They ll chieved short CR with medin durtion of 24 weeks. PBPC mobilized by hemopoietic growth fctors re incresingly employed in llogeneic BMT We gve 10 helthy donors 5 g/kg of G-CSF subcutneously s mobilizing gent; one or two leukphereses provided n dequte yield of progenitor cells, with high number of CD3 + cells. The high concentrtion of T cells in PBPC collections cused some concern with regrd to the risk of severe GVHD, but severl reports suggest tht, in llogeneic PBPC trnsplnttion, incidence of cute GVHD is not incresed Mechnisms to ccount for the unexpected low incidence of cute GVHD re being explored: 26 in mice, G-CSF ws found to switch donor T cells towrd type 2 T-helper response with decrese of IL-2 nd IFN- nd reduction in cute GVHD. 27 Although recent experimentl dt show n improved GVL effect in murine model receiving PBPC trnsplnttion, 28 it is still uncler if this G-CSF-induced immunologicl pttern my hve n impct on the humn GVL potentil. In the present study six out of 10 ptients developed cute GVHD nd three hd chronic GVHD. The incidence of cute GVHD ws high, probbly due to the lck of ny

5 GVHD prophylxis following PBPC infusion; ttempts to reduce GVHD without losing the GVL effect re worthwhile. The reltionship between GVHD nd GVL hs been demonstrted by Weiden et l, 29 however, the precise interction is still uncler. A study by Sullivn et l 30 filed to prove ny modifictions in relpse rte in AL ptients specificlly treted with DLI; recently some dt in ANLL ptients treted by T cell-depleted llogrft support the hypothesis tht lmost complete elimintion of cute nd chronic GVHD my not compromise the ntileukemic effect. 31,32 In our study, the long-term survivors experienced cute nd chronic GVHD. The only long-term responders hd ANLL, while ptients with ALL died erly in relpse; these dt seem to confirm the observtion of others who hve filed to demonstrte n dequte GVL effect in ALL. 2,15 Tretment with stndrd chemotherpy nd PBPC infusion is fesible in AL ptients in relpse fter llo- BMT; it fvors prompt re-estblishment of norml donor hemtopoiesis, voiding the prolonged cytopeni observed fter tretment with DLI. 15,17 On the bsis of our dt, this pproch does not seem dvisble in ptients with primry resistnt disese who never reched stble complete chimerism fter the first trnsplnt or in those with extrmedullry relpse. Further ttempts to improve the efficcy of this procedure should include mild immunosuppression fter trnsplnt to decrese the incidence of cute GVHD. References 1 Mortimer J, Blinder MA, Schulmn S et l. Relpse of cute leukemi fter mrrow trnsplnttion: nturl history nd results of subsequent therpy. J Clin Oncol 1989; 7: Mrmont AM, Horowitz MM, Gle RP et l. 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