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A fludarabine-based conditioning regimen for severe aplastic anemia

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A fludarabine-based conditioning regimen for severe aplastic anemia
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  Bone Marrow Transplantation (2001) 27 , 125–128 ©  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt A fludarabine-based conditioning regimen for severe aplastic anemia KW Chan 1 , CK Li 2 , LL Worth 1 , KW Chik  2 , S Jeha 1 , MK Shing 2 and PM Yuen 2 1  Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; and   2  Department of Pediatrics,Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China Summary:Graft rejection is a common problem after alternativedonor transplantation for patients with refractory sev-ere aplastic anemia (SAA). Intensification of the con-ditioning regimen, with the inclusion of irradiation, hasoften been advocated to combat this problem. With thisapproach engraftment rate improved, but the incidenceof transplant-related complications is also increased,resulting in little change in the overall outcome. Weinvestigated the use of the combination of fludarabine,cyclophosphamide and anti-thymocyte globulin as theconditioning regimen in five multiply-transfused SAApatients. Three patients received an HLA one-antigendisparate related donor transplant, while two patientswere given marrow from matched, unrelated donors.The regimen was well tolerated, with only grade I tox-icity encountered. With a median follow-up of 9 months,all patients are alive with complete donor chimerism.We conclude that fludarabine may be used in place of irradiation to augment the conditioning regimen of cyclophosphamide and anti-thymocyte globulin foralternative donor transplantation in children with SAA.  Bone Marrow Transplantation  (2001)  27,  125–128. Keywords:  severe aplastic anemia; fludarabine; alterna-tive donors; allogeneic stem cell transplantationAllogeneic hematopoietic stem cell transplantation (HSCT)is a curative treatment for children with severe aplastic ane-mia (SAA). Unfortunately the majority of patients lack anHLA-identical sibling donor. Transplantation using a mis-matched related or unrelated donor is associated with a highincidence of rejection in this population of previously heav-ily transfused patients. 1–4 To overcome this obstacle, anincrease in intensity of immunosuppression in alternativedonor transplants was thought to be necessary. A numberof authors reported the inclusion of irradiation in the con-ditioning regimen. 5–7 While the rate of engraftmentappeared to have increased, improvement in transplant out-come has been less impressive. 1–4,8,9 In addition, the short-and long-term side-effects of irradiation are of concern,especially in the pediatric age group. Recently, fludarabinewas reported to facilitate allogeneic marrow engraftmentwith tolerable side-effects. Most of the data, however, Correspondence: Dr KW Chan, Division of Pediatrics, MD Anderson Can-cer Center, 1515, Holcombe Blvd, Box 87, Houston, TX, USAReceived 11 July 2000; accepted 12 October 2000 involved patients with underlying malignancies. 10,11 Weapplied a fludarabine-based, chemotherapy-only regimenin five refractory SAA patients receiving HSCT fromalternative donors and report our results here. Patients and methods Patients From September 1999 to February 2000, five children withSAA received fludarabine, CY and ATG as conditioningbefore allogeneic HSCT. All patients had previously failedimmunosuppressive therapy and did not have an HLA-matched sibling donor. Median interval from diagnosis toHSCT was 36 months (range 8 to 57 months) and all weretransfusion-dependent at the time of transplant. In allpatients, Fanconi anemia was excluded by diepoxybutanetesting of peripheral blood lymphocytes for increased chro-mosome breakage. Patient 4 was suspected to have Dia-mond–Shwachmann syndrome based on short stature andfibrosis of the pancreas seen on MRI scan. Other patientcharacteristics are listed in Table 1. All patients had normalorgan functions, absence of active infections or concomi-tant life-threatening illness. The selection of donors wasbased on HLA serologic typing performed for class I andII antigens and molecular typing by sequence specificoligonucleotide probes for the DRB1 loci. Preparative regimen Informed consent was obtained from the parents. Patients1 to 3 received fludarabine 30 mg/m 2 i.v. on days  − 8,  − 7, − 6, -5 and  − 4; CY 60 mg/kg i.v. on days  − 3,  − 2, and ATG(ATGAM, Upjohn, Kalamazoo, MI, USA), 30 mg/kg i.v.on days  − 3,  − 2 and  − 1. Patients 4 and 5 received CY50 mg/kg i.v. on days  − 9,  − 8,  − 7,  − 6; and fludarabine30 mg/m 2 i.v. on days  − 5,  − 4,  − 3,  − 2. ATG at a dose of 30 mg/kg i.v. was given to patient 4 on days  − 4,  − 3 and − 2; and at 20 mg/kg i.v. on day  − 3,  − 1 and  + 1 for patient5. Both fludarabine and CY were given i.v. daily as a 2-hinfusion. Mesna was administered for uroprotection beforethe first dose of CY to 24 h after the last dose of CY.Unmanipulated HSC was infused on day 0. GVHD prophylaxis and treatment  Patients 1 to 3 received CsA 3 mg/kg/day i.v. by continuousinfusion from day  − 1. They also received methylpredniso-lone 0.5 mg/kg/day i.v. from day 7 to 14, 1.0 mg/kg/day  Fludarabine-based conditioning for SAA  KW Chan  et al  126 Bone Marrow Transplantation Table 1  Patient characteristics and engraftment data Patient Sex/Age Prior therapy Transfusion Time to Donor HLA TNC ANC Last platelets Last RBC Survival No. (years) (No. units) HSCT relationship mismatch  × 10 8   /kg   500 transfusion transfusion (days)/PS (months) 1 F/11.5 CSA 46 36 Mother 1 B-locus 4.9 d14 d13 d16 255 +  /100%2 F/7.5 ATG  +  MP   100 42 Brother 1 A-locus 13.5 d13 d11 d13 298 +  /100% +  CSA  ×  23 F/0.7 EPO  +  G-CSF 30 8 Mother 1 DR- 40.8 d14 d47 d45 222 +  /80%locus4 F/6 ATG  +  MP   100 48 MUD 0 3.78 d20 d51 d21 303 +  /70% +  CSA  ×  2;SCF; G-CSF +  EPO5 F10 ATG  +  MP  +  32 37 MUD 0 6.12 d11 d10 d-3 150 +  /100%CsA  ×  2MP  =  methylprednisolone; HSCT  =  hematopoietic stem cell transplant; EPO  =  erythropoietin; TNC  =  total nucleated cells; SCF  =  stem cell factor;PS  =  Lansky performance score. from day 15 to 28, and 0.5 mg/kg/day day 29 to 42, fol-lowed by tapering over 2 to 3 weeks. Patients 4 and 5received tacrolimus 0.03 mg/kg/day i.v. by continuousinfusion from day  − 2. They also received MTX 5 mg/m 2 i.v. on days 1, 3, 6, and 11. Following engraftment, whenthe patient was able to eat, CsA or tacrolimus was con-verted to oral administration to day 180 and tapered there-after. Supportive care All blood products were irradiated and filtered. Red bloodcell and platelet transfusions were given to maintain a hem-oglobin of   80 g/l and platelet count  20  ×  10 9  /l. Patients4 and 5 received filgrastim 5  g/kg/day s.c. from day 1after marrow infusion. It was continued until the neutrophilcount exceeded 1.5  ×  10 9  /l for 3 days. Infection prophylaxisduring the peritransplant period consisted of acyclovir5 mg/kg i.v. every 8 h. All patients received broad-spec-trum antibiotics for neutropenic fever and hyperaliment-ation when needed. Intravenous immunoglobulin prophy-laxis was given until day 100. When engraftment occurredthe patient received twice-weekly trimethoprim-sulfame-thoxazole or weekly dapsone orally, and CMV-seropositivepatients received prophylactic ganciclovir to day 100.  Assessment of engraftment and response Myeloid engraftment was defined as the first of 3 consecu-tive days with an absolute neutrophil count   0.5  ×  10 9  /l,and platelet recovery was defined as the day the plateletcount was  20  ×  10 9  /l with no platelet transfusions the fol-lowing week. Bone marrow aspirates were examined formorphology and cellularity at 1, 3 and 6 months after trans-plant. Hematopoietic chimerism was evaluated by conven-tional cytogenetics and FISH for sex-mismatched patient–donor pairs, and by DNA restriction fragment length poly-morphism for sex-matched pairs. Regimen-related toxicitywas graded according to the Bearman criteria. 12 Results  Engraftment and outcome A median of 6.12  ×  10 8 nucleated cells/kg body weight wasinfused. All patients showed complete hematological recon-stitution of donor srcin. Median time to ANC  0.5  ×  10 9  /lwas 14 days (range 0–18); the median time to attain a plate-let count of    20  ×  10 9  /l was 17 days (range 14–52). Allpatients have become transfusion-independent. Repeatedchimerism analysis of peripheral blood and bone marrowrevealed 100% donor hematopoiesis in all patients. On 1July 2000 all patients are alive 150 to 303 days (median255 days) after transplant. Toxicity The preparative regimen was well tolerated. There wasminimal oral mucositis or enteritis (grade I). No patientrequired intravenous narcotics for pain control. Patient 5maintained an ANC   0.5  ×  10 9  /l throughout, and did notrequire hyperalimentation during hospitalization. No renalor hepatic toxicity was detected. All patients developedfever that responded to appropriate antibiotic therapy.Patient 4 developed decreased consciousness level, irregu-lar respiration and seizures the day after marrow infusion.The clinical picture was compatible with tacrolimus neuro-toxicity and this was confirmed by an elevated blood tacrol-imus level and abnormalities of the occipital region on aMRI of the brain. Her symptoms resolved quickly aftertransient withholding of the medication. This patientdeveloped idiopathic diffuse alveolar hemorrhage on day + 25 during the phase of acute GVHD, but recovered afterventilatory support. GVHD Acute GVHD was diagnosed in all but patient 5. Patients1 and 2 had grade II, steroid-responsive disease. ChronicGVHD, limited to the skin, developed subsequently.  Fludarabine-based conditioning for SAA  KW Chan  et al  127 Patients 3 and 4 had grade III visceral and skin GVHD thatrequired ATG, IL2-R antagonist and TNF antibody therapy.Both have ongoing extensive chronic GVHD requiringcontinual immunosuppressive treatment. Discussion The prognosis for patients with refractory SAA is poor.While allogeneic HSCT using alternative donors can becurative, the results have been improving, but slowly. Forexample, the EBMT registry reported a 5-year survival of 84 HLA mismatched family donor transplants of only15%. 2 A recent report from the National Marrow DonorProgram on 141 patients showed a median 36-month sur-vival of 36%. 3 The poor outcome of these transplants ismultifactorial. Patients are often multiply-transfused, withresultant allosensitization to minor histocompatibility anti-gens. Profound neutropenia of long duration also leads torepeated infections and poor general condition. A higherincidence of severe acute GVHD was seen. 3,4 Morbidityand mortality of BMT were high. 1,4 The incidence of graftfailure in this population ranged from 10 to 71%. 13 Intensi-fication of the preparative regimen by the addition of irradiation, either as limited field or total body irradiationto CY, has been advocated to minimize graft rejection. 5–7 The outcome of irradiation-based, alternative donor BMThas been variable. 4,8,9 Recent reports of unrelated donorBMT have been somewhat better. Using T cell depletionand an intensive, TBI-based conditioning regimen, Marg-olis  et al 14 showed an overall survival of 54%. Similarly,a preliminary report showed eight of 12 patients were alivewith a conditioning regimen of 200 cGy of TBI and CY. 15 Patients who had received irradiation had a higher inci-dence of GVHD and interstitial pneumonitis. 8,9 The inci-dence of second malignancies has been high, up to 22% at8 years, even in patients who received a limited field of irradiation. 16 In addition, the long-term effects of irradiationon physical growth, fertility and hormone production areof concern. Avoidance of radiation in the preparativeregimen is clearly desirable.The experience of chemotherapy-only conditioning regi-mens in alternative donor transplants for SAA is limited.Deeg  et al 17 reported poor graft function in three of fourunrelated donor BMT recipients after conditioning withcyclophosphamide plus ATG. On the contrary, Abella  et al 18 observed engraftment in 13 of 14 patients, but the totaldose of ATG used in the combination was much higher.Purine-analogs, in particular fludarabine, possess power-ful immunosuppressive activities with mild systemic tox-icity. Fludarabine-based preparative regimens were suf-ficient to engraft patients with hematologic malignancies,using either matched sibling or alternative donors. 10,11 Therefore fludarabine would be an attractive agent to beincorporated into a conditioning regimen for HSCT of SAApatients. However the ability of these patients to reject atransplant remains a concern. First, their immune systemmay be more intact than that of leukemia or lymphomapatients who have had prior anti-cancer therapy. Further-more, frequent transfusion of blood products in SAApatients could have enhanced the allogeneic resistance to Bone Marrow Transplantation alternative donor grafts. The number of prior transfusionsand the interval between diagnosis and transplantation haveboth been shown to adversely affect post-transplant sur-vival. 3,4,8 All our patients were heavily transfused prior toHSCT. It is therefore reassuring that all our patientsengrafted despite the unfavorable prognostic factors.Considering the general condition of our patients and thechronicity of their marrow aplasia, the combination of flu-darabine, cyclophosphamide and ATG was well tolerated.No significant bowel, renal or liver toxicity was encoun-tered. This experience is in keeping with reports of mildmorbidity in unfit lymphoma patients transplanted afterfludarabine and cyclophosphamide. 19 Preliminary results of alternative donor HSCT in two aplastic anemia patientsreported by Bacigalupo  et al 20 also confirmed the lack of significant regimen-related toxicity of this combination.The results from this series must be considered prelimi-nary due to the small number of patients treated. The dur-ation of follow-up is still fairly short, although all but thelast patient have sustained donor engraftment for over 6months and are off GVHD prophylaxis. A lower graft rejec-tion rate in recent years in HLA-identical sibling transplantswas attributed to the more potent GVHD prophylaxis (withCsA or tacrolimus and MTX) employed. 4,8 It may havecontributed to the higher engraftment rate in our patients.However, such an effect has not been documented in mis-matched related donor transplant recipients. 21 In summary, this fludarabine-based conditioning regimenwas sufficiently immunosuppressive to allow engraftmentwith unmanipulated HSC grafts from alternative donors,and did not cause significant regimen-related toxicity. How-ever, the risk of GVHD remained significant, and the ulti-mate success of this regimen depends on findings ways of decreasing the incidence of this complication. References 1 Wagner JL, Deeg HJ, Seidel K  et al . Bone marrow transplan-tation for severe aplastic anemia from genotypically HLA-nonidentical relatives: an update of the Seattle experience. Transplantation  1996;  61 : 54–61.2 Bacigalupo A, Schrezenmeier H, Hows J  et al . Treatment of acquired severe aplastic anemia for the EBMT Working Partyon SAA.  Int J Pediatr Hematol Oncol  1997;  4 : 267–274.3 Deeg HJ, Seidel K, Casper J  et al . Marrow transplantationfrom unrelated donors for patients with severe aplastic anemiawho have failed immunosuppressive therapy.  Biol Blood Mar-row Transplant   1999;  5 : 243–252.4 Bacigalupo A, Bland R, Oneto R  et al . Treatment of acquiredsevere aplastic anemia: bone marrow transplantation comparedwith immunosuppressive therapy - the European Group forBlood and Marrow Transplantation experience.  Semin Hema-tol  2000;  37 : 69–80.5 Gaziev D, Giardini C, Galimberti M  et al . Bone marrow trans-plantation for transfused patients with severe aplastic anemiausing cyclophosphamide and total lymphoid irradiation asconditioning therapy: long-term follow-up from a singlecenter.  Bone Marrow Transplant   1999;  24 : 253–257.6 Kojima S, Inaba J, Kondo M  et al . Unrelated donor marrowtransplantation for severe acquired aplastic anemia usingcyclophosphamide, antithymocyte globulin, and total bodyirradiation.  Blood   1995;  85 : 291–292.  Fludarabine-based conditioning for SAA  KW Chan  et al  128 Bone Marrow Transplantation 7 Deeg HJ, Schoch G, Ramsay N  et al . Marrow transplantationfrom unrelated donors for patients with aplastic anemia whofailed immunosuppressive therapy.  Blood   1997;  90 : 397a(Abstr. 1763).8 Champlin RE, Horowitz MM, van Bekkum DW  et al . Graftfailure following bone marrow transplantation for severe apl-astic anemia: risk factors and treatment results.  Blood   1989; 73 : 606–613.9 Gluckman E, Horowitz MM, Champlin RE  et al . Bone mar-row transplantation for severe aplastic anemia. Influence of conditioning regimen and graft-versus-host disease prophy-laxis regimens on outcome.  Blood   1992;  79 : 269–275.10 Giralt S, Estey E, Albitar M  et al . Engraftment of allogeneichematopoietic progenitor cells with purine analog-containingchemotherapy: harnessing graft-versus-leukemia without mye-loablative therapy.  Blood   1997;  89 : 4331–4336.11 Slavin S, Nagler A, Naparstek E  et al . Non-myeloablativestem cell transplantation and cell therapy as an alternative toconventional bone marrow transplantation with lethal cytored-uction for the treatment of malignant and nonmalignant hema-tological diseases.  Blood   1998;  91 : 756–763.12 Bearman SI, Appelbaum FR, Buckner CD  et al . Regimen-related toxicity in patients undergoing bone marrow transplan-tation.  J Clin Oncol  1998;  6 : 1562–1568.13 Margolis DA, Casper JT. Alternative-donor hematopoieticstem-cell transplantation for severe aplastic anemia.  Semin Hematol  2000;  37 : 43–55.14 Margolis D, Camitta B, Pietryga D  et al . Unrelated donor bonemarrow transplantation to treat severe aplastic anemia in chil-dren and young adults.  Br J Haematol  1996;  94 : 65–72.15 Deeg HJ, Amylon M, Harris R  et al . Marrow transplantationfrom unrelated donors for patients with aplastic anemia(AA) – optimization of a conditioning regimen.  Blood   1999; 94 : 713a.16 Socie G, Henry-Amar M, Cosset JM  et al . Increased incidenceof solid malignant tumors after bone marrow transplantationfor severe aplastic anemia.  Blood   1991;  78 : 277–279.17 Deeg HJ, Anasetti C, Petersdorf E  et al . Cyclophosphamideplus ATG is insufficient for sustained hematopoietic reconsti-tution in patients with severe aplastic anemia transplanted withmarrow from HLA-A, B, DRB matched unrelated donors.  Blood   1994;  83 : 3417–3418.18 Abella E, Karanes C, Klein J  et al . Superior results followingmatched unrelated donor bone marrow transplants in severeaplastic anemia patients using a non-TBI containing prepara-tive regimen.  Proc IBMTR/ASBMT Meet   1999; 44 (Abstr. O1).19 Khouri IF, Keating M, Korbling M  et al . Transplant-lite:induction of graft-versus-malignancy using fludarabine-basednonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment of lymphoid malignancies.  J Clin Oncol  1998;  16 : 2817–2824.20 Bacigalupo A, Van Lint MT, Lamparelli T  et al . Alternatedonor transplants for aplastic anemia: unmanipulated bonemarrow following conditioning with fludarabine, cyclophos-phamide and anti-thymocyte globulin.  Bone Marrow Trans- plant   1999;  23  (Suppl. 3): S70 (Abstr. 226).21 Stucki A, Leisenring W, Sandmaier BM  et al . Decreasedrejection and improved survival of first and second marrowtransplants for severe aplastic anemia (a 26-year retrospectiveanalysis).  Blood   1998;  92 : 2742–2749.
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